Association of inflammatory markers with survival and durable benefit in heavily pretreated platinum- resistant ovarian cancer receiving pembrolizumab

Association of inflammatory markers with survival and durable benefit in heavily pretreated platinum- resistant ovarian cancer receiving pembrolizumab | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Association of inflammatory markers with survival and durable benefit in heavily pretreated platinum- resistant ovarian cancer receiving pembrolizumab Seongyun Lim, Yurimi Lee, Heeeun Ha, Young Eun Chung, Jun-Hyeong Seo, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8935041/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: This study aimed to evaluate the association between peripheral blood inflammatory markers and clinical outcomes in patients with platinum-resistant ovarian cancer treated with pembrolizumab monotherapy, focusing on clinical heterogeneity in later-line settings. We retrospectively analyzed 95 patients with advanced platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer treated with pembrolizumab between July 2018 and December 2023. The systemic inflammation response index (SII), neutrophil-to-lymphocyte ratio (NLR), and systemic immune-inflammation index (SIRI) were calculated from baseline blood tests. Cox regression models, adjusted for age, Eastern Cooperative Oncology Group (ECOG) performance status, therapy line, and albumin levels, were utilized to assess associations with progression-free survival and overall survival. Results: The median progression-free survival was two months, and the median overall survival was seven months. SIRI and NLR were associated with progression-free survival, while all evaluated inflammatory markers correlated with overall survival. Although the median progression-free survival was similar when stratified by the median SIRI, the survival curves diverged over time. A high SIRI was associated with poorer overall survival (hazard ratio 2.02, 95% CI 1.53–2.67). Notably, long-term survival was predominantly observed in the low SIRI group, demonstrating a 12-month overall survival rate of 49% compared to 13% in the high SIRI group. This trend persisted after adjusting for albumin levels, performance status, and programmed death-ligand 1 expression. Conclusion: Peripheral blood inflammatory markers were associated with distinct clinical courses in platinum-resistant ovarian cancer patients receiving pembrolizumab, particularly regarding long-term disease control. These findings suggest these markers may aid in interpreting later-line treatment outcomes, warranting prospective validation. Platinum-resistant ovarian cancer Systemic inflammation response index Pembrolizumab Late-line treatment Figures Figure 1 Figure 2 Figure 3 Background Epithelial ovarian cancer (EOC) exhibits the highest lethality among gynecologic malignancies. The 5-year relative survival rate is 51.6% (2015–2021), dropping significantly to 31.8% for distant-stage disease, which accounts for 55% of cases.[ 1 ] The standard primary treatment consists of cytoreductive surgery followed by platinum-based chemotherapy. Treatment outcomes have improved with the introduction of maintenance therapies, such as bevacizumab[ 2 ] (GOG218), or poly (ADP-ribose) polymerase (PARP) inhibitors (SOLO1[ 3 ], PRIMA[ 4 ], PAOLA-1[ 5 ]), tailored to BRCA mutation or homologous recombination deficiency (HRD) status. However, more than 80% of patients with advanced ovarian cancer eventually experience recurrence, with 15–30% recurring as platinum-resistant disease.[ 6 , 7 ] Even among patients with initially platinum-sensitive recurrence, resistance eventually develops through repeated relapses.[ 8 ] Platinum-Resistant Ovarian Cancer (PROC) is characterized by limited therapeutic options and a very poor prognosis. The median Overall Survival (OS) for patients with PROC is approximately 12–18 months, which is only half that of patients with platinum-sensitive disease.[ 7 ] To overcome this poor prognosis, various agents with novel mechanisms, including immune checkpoint inhibitors (ICIs) and antibody-drug conjugates (ADCs), as well as conventional cytotoxic agents, are being investigated. However, for heavily pretreated patients, additional chemotherapy often increases the treatment burden without providing a substantial survival benefit.[ 9 ] Therefore, determining whether to continue active treatment or transition to palliative care in later-line settings is a critical clinical decision for both clinicians and patients. Various factors, such as albumin and C-reactive protein (CRP), have been studied to assess patient condition.[ 10 ] Recently, peripheral blood-based inflammatory markers—such as the Systemic Inflammation Response Index (SIRI), Neutrophil-to-Lymphocyte Ratio (NLR), and Systemic Immune-Inflammation Index (SII)—have gained attention as prognostic factors in various cancers.[ 11 ] Calculated using combinations of platelets, lymphocytes, and neutrophils, elevated levels of these markers have been reported to correlate with poor survival outcomes.[ 12 ] Cytotoxic chemotherapy acts directly on tumor cells, potentially causing temporary tumor reduction even if the host’s immune competence is limited. In contrast, ICIs induce antitumor effects by enhancing T-lymphocyte activation;[ 13 ] thus, functional immune activation is a prerequisite for therapeutic efficacy. Consequently, rapid disease progression may be observed in the early stages of treatment in patients with insufficient immune functional reserve.[ 14 – 16 ] In particular, repeated cytotoxic therapies can induce lymphocyte depletion, leading to the failure of immunotherapy.[ 17 ] Therefore, ICI monotherapy in later-line settings can be considered a clinical scenario that most sensitively reveals the host’s immune functional reserve. In this context, this study aimed to evaluate the association between peripheral blood-based inflammatory markers and survival outcomes in patients with platinum-resistant ovarian cancer treated with pembrolizumab monotherapy, and to explore their potential as indicators reflecting the host’s functional immune status in later-line immunotherapy settings. Methods Study designs and patient population This retrospective observational study included patients with advanced platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who received pembrolizumab monotherapy at Samsung Medical Center from July 2018 to December 2023. Inclusion criteria were age ≥ 18 years. Patients with underlying autoimmune or hematologic diseases were excluded. Additionally, patients were excluded if inflammatory markers could not be calculated due to missing baseline blood tests, if they received combination therapy, or if they had other confirmed malignancies. Platinum resistance was defined as disease recurrence within 6 months of completing platinum-based chemotherapy. All patients met at least one of the following criteria: mismatch repair deficiency (dMMR) or PD-L1 positivity. This cohort reflects a real-world population selected for immunotherapy eligibility in clinical practice. Treatment and response assessment Pembrolizumab 200 mg was administered intravenously every 3 weeks. Radiologic assessment was performed using CT or MRI every 2–3 cycles, with serum CA-125 levels measured at the same intervals. Imaging was generally performed every 3 cycles; however, additional evaluations were conducted after 2 cycles in cases of rising CA-125 levels or changes in clinical symptoms. Tumor response was assessed according to RECIST version 1.1 based on the initial follow-up imaging, consistent with clinical decision-making regarding treatment continuation. Progression-Free Survival (PFS) was defined as the time from the initiation of pembrolizumab to radiologic disease progression or death. Patients who did not experience an event were censored at the last follow-up date. Overall Survival (OS) was defined as the time from treatment initiation to death. To account for the non-proportional hazards and long-term disease control patterns often observed with immune checkpoint inhibitors (ICIs), survival probabilities over time and mean survival times were evaluated in addition to median survival. Follow-up continued until December 2024. Data collection and definitions Clinical and pathological data were collected from electronic medical records. Collected variables included age, FIGO 2017 stage, histology, tumor grade, completeness of surgery (residual disease status), number of prior chemotherapy lines, Eastern Cooperative Oncology Group (ECOG) performance status, prior PARP inhibitor use, PD-L1 expression status, and MMR status. PD-L1 expression was evaluated using the 22C3 pharmDx assay, with positivity defined as a Combined Positive Score (CPS) ≥ 1 or a Tumor Proportion Score (TPS) ≥ 1%. MMR status was assessed by the expression of MLH1, MSH2, MSH6, and PMS2 proteins; the loss of any protein was classified as dMMR. Measurement of Inflammatory Markers Inflammatory markers were calculated using peripheral blood tests performed within 1–2 days prior to pembrolizumab administration using the following formulas: All inflammatory markers exhibited right-skewed distributions and were log-transformed for analysis. The primary analysis was based on continuous variable models; dichotomization by median values was used solely for descriptive visualization. Serum albumin (g/dL) was also collected to adjust for nutritional status and the influence of cachexia. Statistical analysis Associations between inflammatory markers and survival outcomes were evaluated using Cox proportional hazards regression. Multivariate models were adjusted for age, ECOG performance status, line of therapy, and albumin to reflect host status at baseline. Given the high correlation among inflammatory markers, each marker was analyzed in separate models. Markers showing consistent associations were selected as representative variables for further analysis. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated. The proportional hazards assumption was assessed using Schoenfeld residuals. Sensitivity analyses were performed using models further adjusted for PD-L1 expression status. PD-L1 status was categorized as negative (reference), positive, or unknown. The unknown category was retained to avoid case-wise deletion. Survival curves were estimated using the Kaplan–Meier method and compared using the log-rank test. As average hazard ratios may not fully capture the clinical course of immunotherapy, survival probabilities at specific time points (2, 3, 6, and 12 months) were presented. To quantify differences in treatment courses given the non-proportional hazards often observed with ICIs, Restricted Mean Survival Time (RMST) was calculated at 6 and 12 months. A 3-month landmark analysis was performed to minimize guarantee-time bias resulting from early events. Statistical significance was defined as a two-sided p-value < 0.05. All analyses were performed using R version 4.4.1. Results Study population and clinical efficacy Of the 121 patients treated with pembrolizumab, 95 were included in the final analysis after excluding those with platinum-sensitive disease (n = 17), those receiving combination therapy (n = 6), and those with other confirmed malignancies (n = 3) (Fig. 1 ). Baseline characteristics are summarized in Table 1 . The most common histology was serous carcinoma (76.8%), with high-grade tumors accounting for 92.6% and FIGO stage III–IV disease for 91.6%. The majority of patients (95.8%) received pembrolizumab as third-line therapy or later, with a median of 3 prior lines of systemic therapy (range 1–9). An ECOG performance status of ≥ 2 was observed in 24.2% of patients. The median follow-up duration was 54 months (range 15–77). Table 1 Baseline characteristics of patients with recurrent platinum-resistant ovarian cancer treated with pembrolizumab monotherapy Age, year Total (n = 95) Mean (SD) 56.1 (10.8) ≥ 65 years – no. (%) 18 (18.9) ECOG performance status – no. (%) 0–1 (good) 72 (75.8) ≥ 2 (poor) 23 (24.2) Histologic type – no. (%) Serous carcinoma 73 (76.8) Clear cell carcinoma 14 (14.7) Other ¶ 8 (8.5) Tumor histologic grade – no. (%) 1 or 2 (low grade) 7 (7.4) 3 (high grade) 88 (92.6) Surgical optimality – no. (%) Optimal surgery 39 (41.1) Suboptimal surgery 56 (58.9) FIGO Stage (2017) – no. (%) I-II 8 (8.4) III-IV 87 (91.6) No. of previous lines of systemic chemotherapy – no. (%) 1 4 (4.2) 2–3 45 (47.4) ≥ 4 46 (48.4) Median CA125 (IQR) – U/mL 310 (89.5–695) Median albumin (IQR) – g/dL 4.0 (3.5–4.3) PD-L1 expression – no. (%)* CPS 0 8 (11.8) CPS 1–9 35 (51.5) CPS ≥ 10 25 (36.8) PD-L1 Positive, CPS not available – no. (%)† 27 (28.4) MMR status– no. (%)* dMMR 31 (64.6) pMMR 17 (35.4) Not available 47 (49.5) BRCA 1/2 mutation – no. (%) Negative 69 (72.6) Positive 18 (18.9) Not available 8 (8.4) Previous PARP inhibitor use – no. (%) 16 (16.8) Values are presented as mean (SD), median (IQR), or number (%). ¶ Includes mucinous carcinoma, malignant Brenner tumor, or mixed histology. * Percentages were calculated based on the number of patients with available results, excluding those with unknown or missing data. † Indicates patients confirmed as PD-L1 positive, but for whom the specific Combined Positive Score (CPS) was not available. Percentages for this category are calculated relative to the total cohort (n = 95). Abbreviations: SD, standard deviation; ECOG, Eastern Cooperative Oncology Group; FIGO, International Federation of Gynecology and Obstetrics; IQR, interquartile range; PD-L1, programmed death-ligand 1; CPS, combined positive score; MMR, mismatch repair; dMMR, mismatch repair deficient; pMMR, mismatch repair proficient; BRCA, breast cancer gene; PARP, poly (ADP-ribose) polymerase. [Table 1 near here]. In the overall cohort, the median Progression-Free Survival (PFS) was 2 months, and the median Overall Survival (OS) was 7 months. The objective response rate was 8.3%, and the disease control rate was 28.5%. The median duration of response was 12 months (IQR 5.0–41.5). The 6-month and 12-month PFS rates were 10.5% and 7.4%, respectively. At the time of analysis, 79 patients (83.2%) had died. Baseline inflammatory marker profiles The median (IQR) values for inflammatory markers in the overall cohort were as follows: SII 752 (364.5–1647.7), SIRI 1.6 (0.7–3.8), and NLR 2.7 (1.6–5.7). All inflammatory markers exhibited a right-skewed distribution, which was reduced after natural log transformation (skewness: -0.76, 0.57, and 0.73, respectively) (Fig. S1 in Additional file 1). Consequently, all subsequent analyses were performed using log-transformed continuous variables. Association between inflammatory markers and survival In multivariable Cox analysis, log-SIRI was significantly associated with both PFS (HR 1.35, 95% CI 1.04–1.75, p = 0.025) and OS (HR 2.02, 95% CI 1.53–2.67, p < 0.001). Log-NLR was associated with PFS (HR 1.42, p = 0.026) and OS (HR 2.42, p < 0.001), while log-SII was associated only with OS (HR 1.53, p = 0.002) (Fig. 2 ). In the multivariable model using log-SIRI as the representative marker, the proportional hazards assumption was satisfied for the PFS model (global p = 0.107). Age (p = 0.564), ECOG ≥ 2 (p = 0.106), line of therapy (p = 0.153), and albumin (p = 0.408) did not show statistically significant associations with PFS (Table 2 ). Table 2. Multivariable Cox proportional hazards analysis of inflammatory markers and clinical factors associated with survival outcomes Variable PFS HR (95% CI) p-value OS HR (95% CI) p-value (A) Comparative Multivariable Analysis log-SIRI 1.35 (1.04–1.75) 0.025 2.02 (1.53–2.67) <0.001 log-NLR 1.42 (1.04–1.92) 0.026 2.42 (1.71–3.43) <0.001 log-SII 1.09 (0.87–1.36) 0.442 1.53 (1.17–1.99) 0.002 (B) Representative Multivariate Model (SIRI) log-SIRI 1.35 (1.04–1.75) 0.012 2.13 (1.59–2.85) <0.001 Age 0.99 (0.98–1.01) 0.565 0.98 (0.96–1.00) 0.088 Albumin 0.84 (0.56–1.27) 0.408 0.40 (0.26–0.60) <0.001 Treatment line 0.91 (0.80–1.04) 0.153 0.89 (0.77–1.01) 0.074 ECOG ≥ 2 1.61 (0.90–2.88) 0.106 1.26 (0.69–2.32) 0.458 (C) Sensitivity Analysis (PD-L1 adjusted) log-SIRI 1.37 (1.07–1.75) 0.012 2.01 (1.52–2.66) <0.001 PD-L1 Positive (vs. Negative) 0.92 (0.40–2.12) 0.848 1.84 (0.78–4.33) 0.164 (A) Comparative Multivariable Analysis: Each inflammatory marker (natural log-transformed) was analyzed in a separate multivariable model adjusted for age, serum albumin, line of chemotherapy, and ECOG performance status. (B) Representative Multivariable Model: Presents the detailed results of the model using log-SIRI as the representative inflammatory marker. (C) Sensitivity Analysis: The model was further adjusted for PD-L1 expression status (Positive vs. Negative). The unknown category was retained to avoid case-wise deletion. Abbreviations: HR, hazard ratio; CI, confidence interval; PFS, progression-free survival; OS, overall survival; SIRI, systemic inflammation response index; NLR, neutrophil-to-lymphocyte ratio; SII, systemic immune-inflammation index; ECOG, Eastern Cooperative Oncology Group; PD-L1, programmed death-ligand 1. In the OS model, a violation of the proportional hazard assumption was observed for albumin; therefore, a time-varying coefficient was applied (Table S1). Even after this adjustment, the effect of log-SIRI remained significant (HR 2.03, 95% CI 1.55–2.66). In the 3-month landmark analysis (n=19), the effect size was HR 2.11 (95% CI 0.60–7.40), although the confidence interval was wide due to the limited sample size. Sensitivity analysis and PD-L1 adjustment Sensitivity analysis further adjusting for PD-L1 expression status showed consistent associations (Table S2). Log-SIRI remained significantly associated with PFS (HR 1.37, 95% CI 1.07–1.75, p=0.012), while PD-L1 positivity was not (HR 0.92, 95% CI 0.40–2.12, p=0.848). Similarly, log-SIRI was associated with OS (HR 2.01, 95% CI 1.52–2.66, p<0.001), whereas PD-L1 positivity was not (HR 1.84, 95% CI 0.78–4.33, p=0.164). The proportional hazards assumption was generally met in the sensitivity analysis models (Global test: OS p=0.104, PFS p=0.087). Survival outcomes stratified by SIRI When stratified by the median SIRI, the median PFS was 2 months in both the low and high SIRI groups (Table 3), but survival curves diverged thereafter (Fig. 3, Fig. S2 in Additional file 1). When comparing the extreme quartiles (Q1 vs. Q4), the low SIRI group showed a significantly superior PFS compared to the high SIRI group (p < 0.001). Table 3. Survival outcomes stratified by the systemic inflammation response index (SIRI) Outcome Low SIRI (n=47) High SIRI (n=48) Progression-Free Survival (PFS) Median PFS, months (95% CI) 2 (2–3) 2 (2–2) 2-month PFS rate 38% 25% 3-month PFS rate 23% 16% 6-month PFS rate 17% 3% 12-month PFS rate 13% 3% Overall Survival (OS) Median OS, months (95% CI) 11 (7–22) 4 (4–7) 3-month OS rate 81% 63% 6-month OS rate 72% 33% 12-month OS rate 49% 13% Patients were dichotomized into Low and High SIRI groups based on the median value of the cohort (median SIRI = 1.6). Data represent median survival times and survival rates at specific time points estimated using the Kaplan-Meier method. Abbreviations: SIRI, systemic inflammation response index; PFS, progression-free survival; OS, overall survival; CI, confidence interval. Furthermore, in the median-stratified analysis, the PFS rates at specific time points diverged: 2-month PFS was 38% vs. 25%, 6-month PFS was 17% vs. 3%, and 12-month PFS was 13% vs. 3% (Low vs. High SIRI). The median OS was 11 months vs. 4 months, with 12-month survival rates of 49% vs. 13%, respectively. Restricted Mean Survival Time (RMST) analysis revealed that the mean PFS was significantly shorter in the high-SIRI group at both the 6-month (2.10 vs. 2.81 months, p=0.037) and 12-month (2.29 vs. 3.66 months, p=0.028) time points. Discussion This retrospective study evaluated the association between peripheral blood-based inflammatory markers and survival outcomes in patients with platinum-resistant ovarian cancer treated with pembrolizumab monotherapy. Focusing on the substantial heterogeneity in clinical courses among patients receiving identical treatment in later-line settings, we aimed to explore whether baseline systemic inflammatory status could be related to these differences. In this study, SIRI and NLR were associated with PFS, and all three markers (SIRI, NLR, SII) were associated with OS. These associations persisted even after adjusting for albumin and ECOG performance status, which reflect general patient condition. This suggests that, in addition to the biological characteristics of the tumor, the patient’s systemic inflammatory burden may be related to the clinical course in later-line treatment settings. Previous studies have similarly reported that elevated levels of these inflammatory markers are associated with poor prognosis in various malignancies, including ovarian, cervical, and colorectal cancers.[18-21] Although this single-arm study cannot strictly distinguish between predictive and prognostic roles, our results indicate that inflammatory markers serve as critical indicators of the host’s functional immune reserve in later-line treatment. Consistent with the KEYNOTE-100 study, which reported a modest median PFS of 2.1 months, our cohort also demonstrated a limited median PFS of 2 months.[22] However, median values often fail to capture the “delayed survival benefit” characteristic of ICIs. Although ovarian cancer is classified as a representative “cold tumor,” where the response rate to ICI monotherapy is only 8–15%, a subset of patients achieves durable survival benefits.[22-24] Consequently, there has been sustained interest in identifying information that can explain the differences in clinical courses among patients prior to treatment initiation. Our analysis revealed that survival curves between the high and low SIRI groups diverged over time, a pattern quantitatively confirmed by RMST analysis, which demonstrated a significant survival gain in the low SIRI group. It is well established that the therapeutic efficacy of pembrolizumab in various solid tumors, including ovarian cancer, is closely related to PD-L1 expression (CPS score).[22, 25, 26] In our study, the association between SIRI and survival outcomes was observed even after adjusting for PD-L1, a tumor-intrinsic marker. This suggests the possibility that SIRI representing the patient’s systemic status may be related to the clinical course independently of tumor characteristics. Therefore, peripheral blood-based markers could serve as complementary information alongside existing tumor-based data to aid in interpreting the patient’s clinical course. With the recent emergence of various therapeutic options, such as antibody-drug conjugates (MIRASOL, DESTINY-PanTumor02) and immunotherapeutic combinations (KEYNOTE-B96),[25, 27-29] the treatment landscape for platinum-resistant ovarian cancer is becoming increasingly complex. However, this later-line setting is characterized by the coexistence of limited treatment options, high symptom burden, decreased quality of life, and the financial toxicity of novel agents.[8, 30] Therefore, careful decision-making that balances the expected benefits of treatment attempts against the treatment burden is required. In this context, SIRI could be utilized as non-invasive, cost-effective adjunctive information in the clinical decision-making process. This study has limitations, including potential selection bias due to the single-center retrospective design and the lack of external validation. Additionally, blood markers can be influenced by infection, comorbidities, and medications, warranting caution in interpretation. Nevertheless, this study is significant as it provides real-world evidence in a heavily pretreated cohort, a population often underrepresented in clinical trials but frequently encountered in daily practice. Conclusions In conclusion, peripheral blood inflammatory markers, particularly SIRI, provide valuable insight into the heterogeneous clinical courses of patients with platinum-resistant ovarian cancer treated with pembrolizumab. In the context of later-line settings where therapeutic options are limited, these markers may serve as a practical reference for anticipating long-term outcomes and stratifying patient risk. Future prospective studies are needed to validate their utility in clinical practice. Abbreviations ADC: Antibody-drug conjugate BRCA: Breast cancer gene CI: Confidence interval CPS: Combined positive score dMMR: Mismatch repair deficient ECOG: Eastern Cooperative Oncology Group EOC: Epithelial ovarian cancer FIGO: International Federation of Gynecology and Obstetrics HR: Hazard ratio HRD: Homologous recombination deficiency ICI: Immune checkpoint inhibitor IQR: Interquartile range MMR: Mismatch repair NLR: Neutrophil-to-lymphocyte ratio OS: Overall survival PARP: Poly (ADP-ribose) polymerase PD-L1: Programmed death-ligand 1 PFS: Progression-free survival pMMR: Mismatch repair proficient PROC: Platinum-resistant ovarian cancer RECIST: Response Evaluation Criteria in Solid Tumors RMST: Restricted mean survival time SII: Systemic immune-inflammation index SIRI: Systemic inflammation response index TPS: Tumor proportion score Declarations Human Ethics and Consent to Participate declarations: The study was conducted in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board (IRB) of Samsung Medical Center (IRB No. 2025-05-013-001). The requirement for informed consent was waived by the IRB due to the retrospective nature of the study and the use of de-identified data. Clinical trial number : not applicable. Consent for publication : Not applicable Availability of data and materials: The datasets generated and analyzed during the current study are not publicly available due to institutional policy on patient data protection but are available from the corresponding author on reasonable request. Declaration of competing interests: The authors have no conflicts of interest to disclose. Funding sources: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Authors’ contributions: SL and YYL conceptualized the study. SL and HH were responsible for data curation. SL and YL performed the formal analysis and developed the methodology. JHS and YEC conducted the investigation. SL was responsible for the software, visualization, and validation of the data. TJK, JWL, CHC, and YYL provided the necessary resources for the study. YYL served as the project administrator and supervised the overall research. SL and YL were major contributors in writing the original draft. YYL reviewed and edited the final manuscript. All authors read and approved the final manuscript. Acknowledgements The authors thank Joo-Ok Jung of the Future Medicine Research Institute, Samsung Medical Center, for administrative support. References SEER Cancer Stat Facts: Ovarian Cancer [https://seer.cancer.gov/statfacts/html/ovary.html ] Burger RA, Brady MF, Bookman MA, Fleming GF, Monk BJ, Huang H, Mannel RS, Homesley HD, Fowler J, Greer BE, et al: Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med 2011, 365:2473–2483. DiSilvestro P, Banerjee S, Colombo N, Scambia G, Kim BG, Oaknin A, Friedlander M, Lisyanskaya A, Floquet A, Leary A, et al: Overall Survival With Maintenance Olaparib at a 7-Year Follow-Up in Patients With Newly Diagnosed Advanced Ovarian Cancer and a BRCA Mutation: The SOLO1/GOG 3004 Trial. J Clin Oncol 2023, 41:609–617. González-Martín A, Pothuri B, Vergote I, Graybill W, Lorusso D, McCormick CC, Freyer G, Backes F, Heitz F, Redondo A, et al: Progression-free survival and safety at 3.5 years of follow-up: results from the randomised phase 3 PRIMA/ENGOT-OV26/GOG-3012 trial of niraparib maintenance treatment in patients with newly diagnosed ovarian cancer. European Journal of Cancer 2023, 189:112908. Ray-Coquard I, Leary A, Pignata S, Cropet C, González-Martín A, Marth C, Nagao S, Vergote I, Colombo N, Mäenpää J, et al: Olaparib plus bevacizumab first-line maintenance in ovarian cancer: final overall survival results from the PAOLA-1/ENGOT-ov25 trial. Ann Oncol 2023, 34:681–692. St Laurent J, Liu JF: Treatment Approaches for Platinum-Resistant Ovarian Cancer. J Clin Oncol 2024, 42:127–133. Davis A, Tinker AV, Friedlander M: "Platinum resistant" ovarian cancer: what is it, who to treat and how to measure benefit? Gynecol Oncol 2014, 133:624–631. Lheureux S, Gourley C, Vergote I, Oza AM: Epithelial ovarian cancer. Lancet 2019, 393:1240–1253. Prigerson HG, Bao Y, Shah MA, Paulk ME, LeBlanc TW, Schneider BJ, Garrido MM, Reid MC, Berlin DA, Adelson KB, et al: Chemotherapy Use, Performance Status, and Quality of Life at the End of Life. JAMA Oncol 2015, 1:778–784. McMillan DC: The systemic inflammation-based Glasgow Prognostic Score: a decade of experience in patients with cancer. Cancer Treat Rev 2013, 39:534–540. Yang R, Chang Q, Meng X, Gao N, Wang W: Prognostic value of Systemic immune-inflammation index in cancer: A meta-analysis. J Cancer 2018, 9:3295–3302. Wang Y, Ni Q: Prognostic and clinicopathological significance of Systemic Immune-Inflammation Index in cancer patients receiving immune checkpoint inhibitors: a meta-analysis. Ann Med 2023, 55:808–819. Sharma P, Allison JP: The future of immune checkpoint therapy. Science 2015, 348:56–61. Mezquita L, Auclin E, Ferrara R, Charrier M, Remon J, Planchard D, Ponce S, Ares LP, Leroy L, Audigier-Valette C, et al: Association of the Lung Immune Prognostic Index With Immune Checkpoint Inhibitor Outcomes in Patients With Advanced Non-Small Cell Lung Cancer. JAMA Oncol 2018, 4:351–357. Champiat S, Dercle L, Ammari S, Massard C, Hollebecque A, Postel-Vinay S, Chaput N, Eggermont A, Marabelle A, Soria JC, Ferté C: Hyperprogressive Disease Is a New Pattern of Progression in Cancer Patients Treated by Anti-PD-1/PD-L1. Clin Cancer Res 2017, 23:1920–1928. Diakos CI, Charles KA, McMillan DC, Clarke SJ: Cancer-related inflammation and treatment effectiveness. Lancet Oncol 2014, 15:e493–503. Verma R, Foster RE, Horgan K, Mounsey K, Nixon H, Smalle N, Hughes TA, Carter CR: Lymphocyte depletion and repopulation after chemotherapy for primary breast cancer. Breast Cancer Res 2016, 18:10. Chao B, Ju X, Zhang L, Xu X, Zhao Y: A Novel Prognostic Marker Systemic Inflammation Response Index (SIRI) for Operable Cervical Cancer Patients. Front Oncol 2020, 10:766. Hayama T, Ochiai H, Ozawa T, Miyata T, Asako K, Fukushima Y, Kaneko K, Nozawa K, Fujii S, Misawa T, Fukagawa T: High systemic inflammation response index (SIRI) level as a prognostic factor for colorectal cancer patients after curative surgery: a single-center retrospective analysis. Sci Rep 2025, 15:1008. Nie D, Gong H, Mao X, Li Z: Systemic immune-inflammation index predicts prognosis in patients with epithelial ovarian cancer: A retrospective study. Gynecol Oncol 2019, 152:259–264. Mao H, Yang F: Prognostic significance of systemic immune-inflammation index in patients with ovarian cancer: a meta-analysis. Front Oncol 2023, 13:1193962. Matulonis UA, Shapira-Frommer R, Santin AD, Lisyanskaya AS, Pignata S, Vergote I, Raspagliesi F, Sonke GS, Birrer M, Provencher DM, et al: Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: results from the phase II KEYNOTE-100 study. Ann Oncol 2019, 30:1080–1087. Yoon WH, DeFazio A, Kasherman L: Immune checkpoint inhibitors in ovarian cancer: where do we go from here? Cancer Drug Resist 2023, 6:358–377. Pujade-Lauraine E, Fujiwara K, Ledermann JA, Oza AM, Kristeleit R, Ray-Coquard IL, Richardson GE, Sessa C, Yonemori K, Banerjee S, et al: Avelumab alone or in combination with chemotherapy versus chemotherapy alone in platinum-resistant or platinum-refractory ovarian cancer (JAVELIN Ovarian 200): an open-label, three-arm, randomised, phase 3 study. Lancet Oncol 2021, 22:1034–1046. Colombo N, Zsiros E, Sebastianelli A, Bidzinski M, Araneda CEG, Matanes E, Hasegawa K, Kose F, Maciel MEM, Herbertson RA, et al: LBA3 Pembrolizumab vs placebo plus weekly paclitaxel ± bevacizumab in platinum-resistant recurrent ovarian cancer: Results from the randomized double-blind phase III ENGOT-ov65/KEYNOTE-B96 study. Annals of Oncology 2025, 36:S1582. Fuchs CS, Doi T, Jang RW, Muro K, Satoh T, Machado M, Sun W, Jalal SI, Shah MA, Metges J-P, et al: Safety and Efficacy of Pembrolizumab Monotherapy in Patients With Previously Treated Advanced Gastric and Gastroesophageal Junction Cancer: Phase 2 Clinical KEYNOTE-059 Trial. JAMA Oncology 2018, 4:e180013–e180013. Moore KN, Angelergues A, Konecny GE, García Y, Banerjee S, Lorusso D, Lee J-Y, Moroney JW, Colombo N, Roszak A, et al: Mirvetuximab Soravtansine in FRα-Positive, Platinum-Resistant Ovarian Cancer. New England Journal of Medicine 2023, 389:2162–2174. Meric-Bernstam F, Makker V, Oaknin A, Oh DY, Banerjee S, González-Martín A, Jung KH, Ługowska I, Manso L, Manzano A, et al: Efficacy and Safety of Trastuzumab Deruxtecan in Patients With HER2-Expressing Solid Tumors: Primary Results From the DESTINY-PanTumor02 Phase II Trial. J Clin Oncol 2024, 42:47–58. Narayana RVL, Gupta R: Exploring the therapeutic use and outcome of antibody-drug conjugates in ovarian cancer treatment. Oncogene 2025, 44:2343–2356. Smith AJ, Sharma MH, Powell K, Doherty M, Hinkle SN, Ko EM: Financial toxicity in gynecologic oncology: a multi-practice survey. Int J Gynecol Cancer 2024, 34:919–925. Additional Declarations No competing interests reported. Supplementary Files Additionalfile1.docx File name: Additional file 1 File format: docx (Microsoft Word Document) Title of data: Supplementary tables and figures for the association of inflammatory markers with survival outcomes Description of data: This file contains supplementary tables and figures that support the primary findings of the study. Table S1. Robustness checks for the association between the Systemic Inflammation Response Index (SIRI) and overall survival using different statistical models (Primary Cox, Time-varying coefficient, and 3-month Landmark analysis). Table S2. Sensitivity analysis using a multivariable Cox proportional hazards model adjusted for PD-L1 expression status to verify the independent prognostic value of SIRI. Fig. S1. Frequency distribution histograms of peripheral blood inflammatory markers (SII, SIRI, and NLR) before and after natural log transformation, justifying the use of log-transformed variables. The left panels (blue) display the raw values, exhibiting a distinct right-skewed distribution. The right panels (red) display the values after natural logarithmic transformation, demonstrating a reduction in skewness and an approximation to a normal distribution, which justified the use of log-transformed variables in the subsequent regression analyses. Fig. S2. Full-length Kaplan-Meier survival curves (up to 80 months) for progression-free survival and overall survival, stratified by SIRI median and extreme quartiles. Survival curves are plotted over the entire follow-up period (up to 80 months) to illustrate the long-term clinical course. Survival probabilities were estimated using the Kaplan–Meier method and compared using the log-rank test. Shaded regions represent 95% confidence intervals. (A) Progression-free survival (PFS) stratified by median SIRI (B) PFS comparison between extreme quartiles (Q1 vs. Q4) (C) Overall Survival (OS) stratified by median SIRI Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8935041","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":606851840,"identity":"ddf97b54-889f-40e3-b9b8-2bc6e993032f","order_by":0,"name":"Seongyun Lim","email":"","orcid":"","institution":"Samsung Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Seongyun","middleName":"","lastName":"Lim","suffix":""},{"id":606851841,"identity":"13873249-41d1-46d8-aee7-697d4eb2bc56","order_by":1,"name":"Yurimi Lee","email":"","orcid":"","institution":"Samsung Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Yurimi","middleName":"","lastName":"Lee","suffix":""},{"id":606851844,"identity":"cd03d977-9e33-48f9-8e2d-4feae7f992d5","order_by":2,"name":"Heeeun Ha","email":"","orcid":"","institution":"Samsung Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Heeeun","middleName":"","lastName":"Ha","suffix":""},{"id":606851846,"identity":"fce83e9c-39f3-4ba3-b7e0-64b8ac99447d","order_by":3,"name":"Young Eun Chung","email":"","orcid":"","institution":"Samsung Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Young","middleName":"Eun","lastName":"Chung","suffix":""},{"id":606851849,"identity":"365634f0-e550-448d-9cc1-07f2292988b7","order_by":4,"name":"Jun-Hyeong Seo","email":"","orcid":"","institution":"Samsung Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Jun-Hyeong","middleName":"","lastName":"Seo","suffix":""},{"id":606851851,"identity":"773a70e3-7270-42a0-9f9f-73b958222ba1","order_by":5,"name":"Chel-Hun Choi","email":"","orcid":"","institution":"Samsung Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Chel-Hun","middleName":"","lastName":"Choi","suffix":""},{"id":606851853,"identity":"9b6a6cbc-d3e4-4ce7-80b2-fddb1955a858","order_by":6,"name":"Tae-Joong Kim","email":"","orcid":"","institution":"Samsung Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Tae-Joong","middleName":"","lastName":"Kim","suffix":""},{"id":606851854,"identity":"6bff1230-e4f7-497c-b8fb-d7256a062bb8","order_by":7,"name":"Jeong-Won Lee","email":"","orcid":"","institution":"Samsung Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Jeong-Won","middleName":"","lastName":"Lee","suffix":""},{"id":606851855,"identity":"3a873630-7334-40bf-aaf7-1d513e1058b3","order_by":8,"name":"Yoo-Young Lee","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9UlEQVRIiWNgGAWjYFADdiD+QJoWZgYGxhkka2HmIUahwfHmYxIf2+7YNTAzH3xs88cuWn5G7uEXDDU20Ti1nDmWJjmz7VlyAzNbsnFuW3Luhht5aRYMx9JyG3BpuZFjJs3bdjgZ6Coz6dwG5twNEjlmBowNh4nRwv/9t8Wf+tz5M4jUYge0hY2ZgQ2o8kaO8QN8WiTPHEu2nHHucAIbM5uxZG/b8dwNZ96YMSTg8Qvf8eaDNz6UHbbnZ29++OHHn+rc+e05xh8+1Njg1KJwgIFFAkgntiEJskkk4FAOAvINDMygZGKPLMhMYsIZBaNgFIyCYQ4AdEpazFXtse8AAAAASUVORK5CYII=","orcid":"","institution":"Samsung Medical Center","correspondingAuthor":true,"prefix":"","firstName":"Yoo-Young","middleName":"","lastName":"Lee","suffix":""}],"badges":[],"createdAt":"2026-02-21 17:53:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8935041/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8935041/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104878891,"identity":"6a002fb4-7841-4c22-82a0-78437093d5d9","added_by":"auto","created_at":"2026-03-18 08:59:02","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":82113,"visible":true,"origin":"","legend":"\u003cp\u003eFlow diagram of the study population selection process. Out of 121 patients with epithelial ovarian cancer treated with pembrolizumab screened for eligibility, 26 were excluded. Reasons for exclusion included platinum-sensitive disease (n=17), receipt of combination therapy (e.g., bevacizumab, lenvatinib) (n=6), and diagnosis of other primary malignancies (n=3). Ultimately, 95 patients with platinum-resistant ovarian cancer treated with pembrolizumab monotherapy were included in the final analysis.\u003c/p\u003e","description":"","filename":"figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8935041/v1/ffba6b844bfeb31b981fe925.jpg"},{"id":104878907,"identity":"7feebc95-2676-4adb-b044-7e4b24c0d273","added_by":"auto","created_at":"2026-03-18 08:59:07","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":57426,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot of multivariable Cox proportional hazards regression analysis for inflammatory markers associated with survival outcomes\u003c/p\u003e\n\u003cp\u003eThe plot displays the Hazard Ratios (HR) and 95% Confidence Intervals (CI) for Progression-Free Survival (PFS) and Overall Survival (OS) associated with log-transformed inflammatory markers. Each marker was analyzed in a separate multivariable model adjusted for age, line of treatment, serum albumin, and ECOG performance status. The vertical dashed line represents an HR of 1.0 (no effect).\u003c/p\u003e\n\u003cp\u003eAbbreviations: SII, Systemic Immune-Inflammation Index; NLR, Neutrophil-to-Lymphocyte Ratio; SIRI, Systemic Inflammation Response Index; PFS, Progression-Free Survival; OS, Overall Survival; ECOG, Eastern Cooperative Oncology Group.\u003c/p\u003e","description":"","filename":"figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8935041/v1/527de47563fe0bf513de3d9b.jpg"},{"id":104878889,"identity":"1329ce28-bac0-41c3-be30-048a6c426ec2","added_by":"auto","created_at":"2026-03-18 08:59:02","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":83157,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier estimates of survival outcomes stratified by the Systemic Inflammation Response Index (SIRI), truncated at 12 and 24 months.\u003c/p\u003e\n\u003cp\u003e(A) Progression-free survival stratified by median SIRI (displayed up to 12 months).\u003c/p\u003e\n\u003cp\u003e(B) Progression-free survival comparing extreme quartiles (Q1 vs Q4) (displayed up to 12 months).\u003c/p\u003e\n\u003cp\u003e(C) Overall survival stratified by median SIRI (displayed up to 24 months).\u003c/p\u003e\n\u003cp\u003eCurves were truncated at prespecified time points (12 months for PFS and 24 months for OS) to improve visualization of early survival patterns, and the full follow-up curves are provided in Supplementary Fig. 2. Survival probabilities were estimated using the Kaplan–Meier method and compared using the log-rank test.\u003c/p\u003e","description":"","filename":"figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8935041/v1/8fe3f40abd08cb1dd21bf283.jpg"},{"id":106093498,"identity":"581ba84d-012c-4982-addd-6d0b31bcc63d","added_by":"auto","created_at":"2026-04-03 11:37:36","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1162220,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8935041/v1/c2bf6ee5-2d27-4b62-a8b9-60f406a45ddd.pdf"},{"id":104878906,"identity":"982b030d-de70-4748-a1b1-caafbd549a18","added_by":"auto","created_at":"2026-03-18 08:59:07","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":57463,"visible":true,"origin":"","legend":"\u003cp\u003eFile name: Additional file 1\u003c/p\u003e\n\u003cp\u003eFile format: docx (Microsoft Word Document)\u003c/p\u003e\n\u003cp\u003eTitle of data: Supplementary tables and figures for the association of inflammatory markers with survival outcomes\u003c/p\u003e\n\u003cp\u003eDescription of data: This file contains supplementary tables and figures that support the primary findings of the study.\u003c/p\u003e\n\u003cp\u003eTable S1. Robustness checks for the association between the Systemic Inflammation Response Index (SIRI) and overall survival using different statistical models (Primary Cox, Time-varying coefficient, and 3-month Landmark analysis).\u003c/p\u003e\n\u003cp\u003eTable S2. Sensitivity analysis using a multivariable Cox proportional hazards model adjusted for PD-L1 expression status to verify the independent prognostic value of SIRI.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFig. S1\u003c/strong\u003e. Frequency distribution histograms of peripheral blood inflammatory markers (SII, SIRI, and NLR) before and after natural log transformation, justifying the use of log-transformed variables.\u003c/p\u003e\n\u003cp\u003eThe left panels (blue) display the raw values, exhibiting a distinct right-skewed distribution.\u003c/p\u003e\n\u003cp\u003eThe right panels (red) display the values after natural logarithmic transformation, demonstrating a reduction in skewness and an approximation to a normal distribution, which justified the use of log-transformed variables in the subsequent regression analyses.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFig. S2\u003c/strong\u003e. Full-length Kaplan-Meier survival curves (up to 80 months) for progression-free survival and overall survival, stratified by SIRI median and extreme quartiles.\u003c/p\u003e\n\u003cp\u003eSurvival curves are plotted over the entire follow-up period (up to 80 months) to illustrate the long-term clinical course. Survival probabilities were estimated using the Kaplan–Meier method and compared using the log-rank test. Shaded regions represent 95% confidence intervals.\u003c/p\u003e\n\u003cp\u003e(A) Progression-free survival (PFS) stratified by median SIRI\u003c/p\u003e\n\u003cp\u003e(B) PFS comparison between extreme quartiles (Q1 vs. Q4)\u003c/p\u003e\n\u003cp\u003e(C) Overall Survival (OS) stratified by median SIRI\u003c/p\u003e","description":"","filename":"Additionalfile1.docx","url":"https://assets-eu.researchsquare.com/files/rs-8935041/v1/b5eeb821e6bc0475f0d827d4.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Association of inflammatory markers with survival and durable benefit in heavily pretreated platinum- resistant ovarian cancer receiving pembrolizumab","fulltext":[{"header":"Background","content":"\u003cp\u003eEpithelial ovarian cancer (EOC) exhibits the highest lethality among gynecologic malignancies. The 5-year relative survival rate is 51.6% (2015\u0026ndash;2021), dropping significantly to 31.8% for distant-stage disease, which accounts for 55% of cases.[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] The standard primary treatment consists of cytoreductive surgery followed by platinum-based chemotherapy. Treatment outcomes have improved with the introduction of maintenance therapies, such as bevacizumab[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] (GOG218), or poly (ADP-ribose) polymerase (PARP) inhibitors (SOLO1[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], PRIMA[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], PAOLA-1[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]), tailored to BRCA mutation or homologous recombination deficiency (HRD) status. However, more than 80% of patients with advanced ovarian cancer eventually experience recurrence, with 15\u0026ndash;30% recurring as platinum-resistant disease.[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] Even among patients with initially platinum-sensitive recurrence, resistance eventually develops through repeated relapses.[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/p\u003e \u003cp\u003ePlatinum-Resistant Ovarian Cancer (PROC) is characterized by limited therapeutic options and a very poor prognosis. The median Overall Survival (OS) for patients with PROC is approximately 12\u0026ndash;18 months, which is only half that of patients with platinum-sensitive disease.[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] To overcome this poor prognosis, various agents with novel mechanisms, including immune checkpoint inhibitors (ICIs) and antibody-drug conjugates (ADCs), as well as conventional cytotoxic agents, are being investigated. However, for heavily pretreated patients, additional chemotherapy often increases the treatment burden without providing a substantial survival benefit.[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] Therefore, determining whether to continue active treatment or transition to palliative care in later-line settings is a critical clinical decision for both clinicians and patients.\u003c/p\u003e \u003cp\u003eVarious factors, such as albumin and C-reactive protein (CRP), have been studied to assess patient condition.[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] Recently, peripheral blood-based inflammatory markers\u0026mdash;such as the Systemic Inflammation Response Index (SIRI), Neutrophil-to-Lymphocyte Ratio (NLR), and Systemic Immune-Inflammation Index (SII)\u0026mdash;have gained attention as prognostic factors in various cancers.[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] Calculated using combinations of platelets, lymphocytes, and neutrophils, elevated levels of these markers have been reported to correlate with poor survival outcomes.[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eCytotoxic chemotherapy acts directly on tumor cells, potentially causing temporary tumor reduction even if the host\u0026rsquo;s immune competence is limited. In contrast, ICIs induce antitumor effects by enhancing T-lymphocyte activation;[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] thus, functional immune activation is a prerequisite for therapeutic efficacy. Consequently, rapid disease progression may be observed in the early stages of treatment in patients with insufficient immune functional reserve.[\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] In particular, repeated cytotoxic therapies can induce lymphocyte depletion, leading to the failure of immunotherapy.[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] Therefore, ICI monotherapy in later-line settings can be considered a clinical scenario that most sensitively reveals the host\u0026rsquo;s immune functional reserve.\u003c/p\u003e \u003cp\u003eIn this context, this study aimed to evaluate the association between peripheral blood-based inflammatory markers and survival outcomes in patients with platinum-resistant ovarian cancer treated with pembrolizumab monotherapy, and to explore their potential as indicators reflecting the host\u0026rsquo;s functional immune status in later-line immunotherapy settings.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003eStudy designs and patient population\u003c/h2\u003e\n \u003cp\u003eThis retrospective observational study included patients with advanced platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who received pembrolizumab monotherapy at Samsung Medical Center from July 2018 to December 2023. Inclusion criteria were age\u0026thinsp;\u0026ge;\u0026thinsp;18 years. Patients with underlying autoimmune or hematologic diseases were excluded. Additionally, patients were excluded if inflammatory markers could not be calculated due to missing baseline blood tests, if they received combination therapy, or if they had other confirmed malignancies. Platinum resistance was defined as disease recurrence within 6 months of completing platinum-based chemotherapy. All patients met at least one of the following criteria: mismatch repair deficiency (dMMR) or PD-L1 positivity. This cohort reflects a real-world population selected for immunotherapy eligibility in clinical practice.\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eTreatment and response assessment\u003c/h3\u003e\n\u003cp\u003ePembrolizumab 200 mg was administered intravenously every 3 weeks. Radiologic assessment was performed using CT or MRI every 2\u0026ndash;3 cycles, with serum CA-125 levels measured at the same intervals. Imaging was generally performed every 3 cycles; however, additional evaluations were conducted after 2 cycles in cases of rising CA-125 levels or changes in clinical symptoms. Tumor response was assessed according to RECIST version 1.1 based on the initial follow-up imaging, consistent with clinical decision-making regarding treatment continuation.\u003c/p\u003e\n\u003cp\u003eProgression-Free Survival (PFS) was defined as the time from the initiation of pembrolizumab to radiologic disease progression or death. Patients who did not experience an event were censored at the last follow-up date. Overall Survival (OS) was defined as the time from treatment initiation to death. To account for the non-proportional hazards and long-term disease control patterns often observed with immune checkpoint inhibitors (ICIs), survival probabilities over time and mean survival times were evaluated in addition to median survival. Follow-up continued until December 2024.\u003c/p\u003e\n\u003ch3\u003eData collection and definitions\u003c/h3\u003e\n\u003cp\u003eClinical and pathological data were collected from electronic medical records. Collected variables included age, FIGO 2017 stage, histology, tumor grade, completeness of surgery (residual disease status), number of prior chemotherapy lines, Eastern Cooperative Oncology Group (ECOG) performance status, prior PARP inhibitor use, PD-L1 expression status, and MMR status.\u003c/p\u003e\n\u003cp\u003ePD-L1 expression was evaluated using the 22C3 pharmDx assay, with positivity defined as a Combined Positive Score (CPS)\u0026thinsp;\u0026ge;\u0026thinsp;1 or a Tumor Proportion Score (TPS)\u0026thinsp;\u0026ge;\u0026thinsp;1%. MMR status was assessed by the expression of MLH1, MSH2, MSH6, and PMS2 proteins; the loss of any protein was classified as dMMR.\u003c/p\u003e\n\u003cp\u003eMeasurement of Inflammatory Markers\u003c/p\u003e\n\u003cp\u003eInflammatory markers were calculated using peripheral blood tests performed within 1\u0026ndash;2 days prior to pembrolizumab administration using the following formulas:\u003c/p\u003e\n\u003cp\u003e\u003cimg 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Bg8ePPy4hDiMDsPWZwqBd7s5BJD01gImZ+eHAFa389yUOvNAsGFoFFljo8SqTx9/8IMfJMx23nnnzUcpnOUeNGhQ3n51DEbfbevydGG4sNRH41aH4OjYtNNO6zUH8wNHDNQRF1gSgFVVjXBGnEKgb1sNU2qLYIYRBSxX1MofmDrKpC/ef/SjHyVzROmkqCoOF8dQPNdff/185El8PRBQBL+xm/OhQ4cmgtKcoiPYUPaMn5caDZgbBteSSy6Zz75TEghSyrO6p59++nz8DQZzzjlnQge2wNEMY2TIkCH53LzyhHVRjCkaM888c9IP8zXHHHMkZdTp3oc5duTGWOWRvsACCyT0LY/A80spWXzxxRMBC19KqF0M64QxxfiGvXXgDD/8xRHa6mhLMOfuL1jniy22WFplmDddPRQnSos6rBtGF7ykwU5/zIl0gZLMGED31iS6QMcMbrhTbLTDyIIdQU5JgKHy9WDeORP0rapGPDYBJ3MmPzqxVhlevjsaYEmR0V91GDdvZ3PrluFkTGhW/hLgxxBBY2jFCghCGAAAEABJREFU/RzKMV5BGcUfSt76kwLmDhBawBNhQ+E0rzB35Eq90gX48cArYy7QB6wo3fV6yzuly9ygu6HD1gUFDl1xFsgDU/RYaBZd4h/SSkADDHy8xNxTxGecccbEgKQMqmuZZZZJ6MOdFPmsA0YnfK0fBlepz+72ZJNNVj6T42RLLbVU/rYO0LNjVI7z8ThLwJvxAPwPL4QFJ5S0xuDOB2NWm/ij/lJsjZ3C2ZjfNz6EX1J01Yu2GMDaw1/ksU4o1/qO1xjrSiutlBhP6AaOeKm8AgXY8TjjK9/4xeSTT56PXxmD42/wsT6qqsr8jcJsJ55hwChkBGiLUYsPm2/GWVVVicyDi3nebLPN8i4c48adJvxHuyXYKSL71ltvvcQAIVvIUunol+z13paADsle40GDHBfmUD/sFuknGhYPd5exGUPWBBmkXL0dcsZ8lzj9x6utS7zYPKpHHvyUY1F/ySk0hmbgiceWOqqqyseD0Whz66/k9cRP8VA82dyJixAI9BUEetx4YLFj5nWACCzCxGKqx3fVe1VViRHAi0DxIggxOt6QqqoShkuIXHvttdnDT1mm8GKUhDFma+udAsFTg5FTLJvqH6bBs4ixY54EAUXP2HhAlamqKmHUhIZ4AobSiKFhdBiJOHnkF6pqRMWGwotJYWIUVuUJbQqU/G0JpR3Cr6qqfD9Au4SNfqlTaOwH5knhL3m0T8ARnqXOxjJV9f/9r6pqhCMY+lpVlUciqLSpTvPCKybBWHmNMG8KHIVXe5Q/WMjTllBVVb7MZ77lJwh50glj320JlNCiNDMaKGBwq8+veihF+ggT42FcUKrKd1V9TQfyClVVZU8hLOWxVpQzH+oXhx4pHIIylEFKFFqDC8VBn+xCSG8qVNXXWJc0+ZVnUGnHvBKe2oOzfFX1dRk0qk/yUEAIde3K05ZQVVXSx4K/d3NOsUAzDFNzau71paqqZE2giVK/9YUG4al/8utr2SGz9niQecAp1tqiBJTy9ac2KWnK1+O9iyPc1csbyWC07hl90jsatFnmjwLkHfZN1UdpqarqW+tFXnNgLqzFqvp6/VJE0DKalKcx6Puiiy6ajV1GA1xh2JivfDs6qT7Gi3y+lXHspOSpP9ERHus4D6NMqKoqMQjKzmQ9f1PvaAFNrrvuuvmOhzEyDiigdiLwVGMwfnPkndJd6q+qEfGqqhG/tVlVX8fhfejMmNRDEYWLPO0J1iqHgLXA0GEMqLelOvQdbTMOvRsnY0AdnGzomzFDdukTLOWxY1TWd1VVIzRRVVWTtDJCpmEfVVXlnTZyV9/tJuwwbFeKokx5ZtykYf9ZO2jUvA/7zHXrK0eS4N0Y8FF9LP2S1xr+3ve+l+8QyYPOrTVpgrKebQl4vz4su+yymSZgS37b4UIrDEtOK/xRvXAcPMzhht7VX1WVxwihqkaMUw4W+C960AY6JnvI9REKt/BRX9/1bPQAssOPSbQU7Mg0t37r9fWi9+jKAERglJ4eM2WBV4MSom1MheeIt9Z3dwfCgqeEl81xEO3xKPCEULwJD94R3jJ9w1B4TnhgMUJHi2xFy4MZKl8PGIdtWkyf59hxJx5cDLiMuZ6/o+/6iRFjdh2toy+Vg6n+UpZhKvAs8Y4RrtJ6KtgpQwc827zGaINS01Pt19uBB0XZ1rqjUYRsPb0t7wyA3iKszDPvH+HdXN/tVFAYyvpCCwx9Bk8pw3Czg8WwoPg2tVZL3taeDMA11lgj/2wvT6e13VqZkZlOSbEj0dgH2DrOwZtt5wBuFLLGfPVvCiyDgGNCfgH+lKB6vvIuv3T0KK/A6MBD8dKSr6UnA1IdZEVjPmMwp43xI/ubxx4vYlziy3Yi6op0R/uHrzj2CkfBETNGFcW9o3U2V84a6UyflWf0NFd/Z+IZB1VVjbD7XurDvxjZ5bu3PsnqslNut7y5wMlJ9+it44h+BQIQ6HHjgWeAseA4AMWLMHPMgGKuQ90ReCBt9RJs6ue11F4RsJQDDJnHS794GnhNqqrK9xScz6aM2Ep3vpyiRViU+jwJDHUbHwNFeVumlMwSbH/L0xWBt5aCxVM0vL5e/lK8N/CjBLSnu46t2Fq2/Vzw9ISxIwztqaszedGMc7zmH83YzreLxfPZmXo7UpanzxEJ2Dh24TiH4xaNddXpszHNt50NygiPrm+Bx44hzLD23VPB0QPrkbe7tNmoDBsv76BjN2igHpShTKALnkfHXhy7cQ+CciO9HghpnntlGtPxKbtSJT+PMhrsjKKC7tWBT5R6W3pyOFgvbW0T78Lb8LjGevFB/AsujnnAzbw35qO4F36mHrzPkRH566GxnG/5tW9t1PN658WVR4CDZ1NBeXRgB6MxXf3mvz4vjnzhLbzo9fyMUN/S2oqf/PUAB+unHtf47miZX/KzBskIx10pho7X1Om4sVxr34wtO0nkhjsnMCyhvi6NzVpVn7kzXu/1IL7+3dS79sw1YxHNyWPsjtnB3HdTQd3mw26FuWsqT2fj0I65QN+NdXEeWcd1WYhn2Ck0npLf+sa/yzdHQHlvz9N4C971cqV+Rq8donpaU+/64rioHRQ4N5Un4gKB3opAjxsPgKAcEGDOQzpW0N2Kl+1e25u8NhY9RcIxJOeE9UdwBMOREgqJXQIKlXiMwh0GxodvjJp3hlCnvDuCRXhhVJgXY8jWqmMtvMLK2LK3FVmO16hTPcWDholgHkXYKUMA6Csvd/2bkuOboIQhJck2t/x2UoxLej1oTxsYfD2ehw9DxmjFa1+bdcGuPd6kksd3qU8Z5eUXME/fBA+h6V0ex0gIFkqcsi4UUlS1L11QRnnj8C3orzq0TWlwDp/i7j4F/AhoXhrCTf7GoH7jtktT0vRfX5UXx/OqT+VbfuVKf+Qp6ZR1fTT/BCwFEPbOWouDn/zq0G+4+RakKat936V+9fgW5FdOe771w7fx+xbgo64yBu1rT32OHrhDYSzoSX5nzNElOmIEu3sjv3T1yENBYZTZkXNxVx/RFYHMkyqP+vVf+74F3n/9K/0VVw/Goy31lXhjkV/74qQbp/p9oxNHBh0T4m0k4K0l4y39tT558awpa886cpyQgqUeCrK+4i+UWOvaeXJ1aaMeKPLWMu+4MvU03nOXg9Gysbg3ob8cAyWfsWlf/8QVPJTx3RgcOaHQwFaa+xsULjTtuzE4MolGtd+Y5htNMmThaQfMmnCU0W4Lutcv+Mqrn+K882ibb/MBM+XF44N4GexdUtZPR1KsXetMfdqDtfxlvOrzbSxoiVKE36nXMTPrVDq8Kb6OI+qLufUurQTtyeMsvvWh/37oAD8Q79w/+vQNfzyBAVh2nsy34zZ2WNAr/o1WtVfaMG7z7Vni5NFfcyyOUwJ9WRPu6Vnn4usBHzM290HwJ3wK/fohBnPB6GqK7tRhTuvt6Y+81gdcyRfn8N1hYaBIdy8O9nCh7GsLDaFfc6Zd/Ve3NshW9O1IrjopqvoMF/WZe/kE9Tk+p09oSToDTllHI+UpQX/wE7zGzrqjvtaHoz7qVAd6KfkLztJKnPlQHk2J02fv+ua7HtzDQZtOB5gT885ZYuzki50tdODfYNGWS/Toxp0o9VhHaNn4lfWrTMrqJ7zkkb/eH+PXR32CnTwMFfPC0Yinake8IA9eC29tiWspyE8XQV/kbkt5Iy0Q6G0IjBTjoadBcDETc+cldrwBs3c+tTAW/cEQeIoYDQyaqvr6PCQlxVlK240YtTwuJzvTWlVVPqPvchzPE4WHsiXN5WNKjPbkd3baOUdKhR0Xwk5dGBcmTPi6qEaxJiAYOgSlPJglRYkg4HnBrJ339UsbFClHCAhUTBPzN556sO1NuBijS2DSHEPA/DB7x28YOC6ZuX9CEaOU8KLpH+HPeMLs4MazYgza03cKrHSCRjlnxCkJLmFry/lTghXjLoqNeyeEBKWOMNOm3RRHUQjG/fffPxEmVVUluKqHMsOT7OwzYUJBcYSM8JBeD7BRjzjb/eripSccCD7CTrvmifeVsCQkHDcwR8ZF0YM9pYGn2wVBipw7LxQUFx4Zm5Qlx94oY4QHwUToKEcpdMwFhrxnlAmGBiFovBQb57kpJzDgsWIEUJTRp10sRigBI5/69JuRqrw54o1Ed85OM4id/eZlJpDQPgNC3ylHcNM/9IOmzB0vL1qlIFgnxgMn9VgP+mteKL3m1hjNv36hKUJbf2FdAqXQeLRDwFJs1OddfWgSPZkb3+o1RvRn7s2Jy4iMfsqkwFtO2DqTzVBGawxol0DhjTYoOvrmSRkyf5RYtOYYU+lfeaJ/awemlOsS74leKRDWv7s2lEG4U0Sku5wJYwaZNSmvuwCUEhgZh3wlOOpIcTGuEgcfCqdnias/8RzpHCD1+PJufVKk9cmatiaMs6qqRKFCI2ibUcmYQh/mGZb4huOZ+gx7dQ4dOjTvtjK60I57WQwotOWoJz6GN6E3+dG49YJm8S4GtTVt7VN80Z7dXPfF5Dcn+mU+tQ13eaSVYLzWr7FT4B0ZwwuNBV3oj4vW5g2WVVXlXzGzdtTBoWOd4RvGTJnTbzSCT6NF65YDBt3hjeiJ4wWelHVKrjsQxolvoGf9UH89qNPFWevGWpBWVVXSpmOVxlBVX8sSaSVQrM0B+iNb1GNcaMzRQwYVrNA03M0ZWeK4mW/rUrpdCfhpHy/w9K0u6w1e5BPaJis47vBta9N6tq7tMpZ+2blkKFoz5t6uqvlUR8njaScCZvgJ+sM/zLk0fbS2YYi/og9HK61bvMfa0C6egUfjtfgaWhLHANJfdZUAW31mnJp3c0E2MyisHfNKfmnPGNAznutdHXDWXzxDWTwPVuQC+Wdd6j8+jzfhG/ojMFL1UT0cLdaIX31i0JJn4gXGx2OPPZbwT+tAXEuBgWHd0EcK7baUP9ICgd6EwIAwHjByjJqChnERlhiABY6JUxIxOhded9999xF+iQazdXyhlKV4YqQEnInk4cNI1EF5FI8REFoEDiZMsSYEMTnMybd+EFbyMhCUF8fw4Nmk/PgmWHhjMSoeQYKbcqBtgoHAoLQTNgSm+MaAKZb6MWbpFFPKjHgGAWFA2GmTsIcZJd23fBit/jNsxKkH86ZI+xZcSiWQKMu+jU9bcHbPRVvGRSnhNZLHOf0ixH0T3ASjn7KFnTLwUY9AYSv18ywSqOIbA2VZWXU4RsCYgaE2GA4UF+2W8VDmzTUhKA8BTvDAnjIqTjnjIwQJSPNhHAQ44SKdoYTW5BcIEoYFLHzDloJMiVbeWCgDBDucCT1KJ+FGeVWGUUloyedbMDcEKmPQ/DMsGDOOAKqH0kO5gCUlyngoItom7NWBlowHduiYEEPfyvvFIwauNGUozcqYP2OkMOmrYK70V94SKHW8c8rwlFI+GVy+BV5l9ETZ9a1/FBHlHQ8yH/Axx5RcGMhn3uSR186AOGvTmjRec1HiKAzooyjzxqtsY6BsUWZhx8go6TzZ6JzirQY5jaEAABAASURBVE5KRv1uFkNTvHTKbFVV+VeyxAnmsdRFOaHQyaetEm+ty4tGSlz9ydPJ0EY3jQqVfLCi7KjDjgBDSrxgrsQbf2mTd1gcQ8M8Usjq6bBQDu/Cs9TDOKf8KYc+KNNoQhrHiHgB7xKHbtCnONhQFBnO0gR0oF3zi39Yd+LrgaGgnDr0BT8t6eovawzt4yHWaUlXH6VXWcqfcaAV7eHVaJHRXtL1jXHjG82qm2KHnhi3xmDMpf76E8/DS+Wvx3vn7EFTnr7rAabaE/TfTgkF2LcxFR4PZ04TirD+mwdzXuqyfq1v69Dc2vXGxxm0cJYPD4IhwxsPQQuFH1nXDDP5SjAmDgF9sbYYezAt6Z7wZnjJQ54ySsUL1iIeor9onsyDv7zmA92V+TEu8kkfpQvGQbapqx7Ug5eoW5twr6c7NsYIUYe1WsZf8nAKSlcWrXJomW99JLfxb2Xxe+OzVn0L5Jd68Dl8kmzBI8lN8YxOfYMdo1NchECgPyPQf42HNs4ahQLzoDTy/vBKtLFoZAsEAoF+gADDkpLHc2inw9GRrhyW3UIeUYYAo4nDoK31M7w5L3hceZ95QUtZXlseXopLiYtnINCdCDhSxcC2e9Gd7fSluu2scFDZwWLo2ZnvS/2PvgYCHUFgwBsPhLPtdp5PXibe9I4AGWUCgUCgaxHoydrstDmu4fgPj6LjaV3RvmNhdk8cJ3RUpikvdGvt8LTb3XFEj5ODJ9wuI+8nLyzPc2t1RHog0FkEHNGzg+CojR1duzidrbOvl3cMyvq2m+L4qB2lvj6m6H8g0BYEBrzxYKfBOUvb6Lx7bQEt8gQCgUD/Q8CRBEchKOp2CbpihI6VcErgM00dbWlrG8o6kuSIi2MnFBb3UhyHckykrfVEvkCgowg4xuX4qjtKaM8xq1bq6vfJnA5wcIzTDma/H3AMMBD4BoEBbzx8g0M8AoFAIBAIBAKBQCAQCAQCgUAgI9D8nzAemscmUgKBQCAQCAQCgUAgEAgEAoFAoIZAGA81MOI1EOitCES/AoFAIBAIBAKBQCAQ6A0IhPHQG2Yh+hAIBAKBQCDQnxGIsQUCgUAg0G8QCOOh30xlDCQQCAQCgUAgEAgEAoFAoOsRiBrrCITxUEcj3gOBQCAQCAQCgUAgEAgEAoFAoFkEwnhoFppI6K0IRL8CgUAgEAgEAoFAIBAIBEYOAmE8jBzco9VAIBAIBAYqAjHuQCAQCAQCgT6MQBgPfXjyouuBQCAQCAQCgUAgEAj0LALR2kBHIIyHgU4BMf5AIBAIBAKBQCAQCAQCgUCgjQiE8dBGoHprtuhXIBAIBAKBQCAQCAQCgUAg0FMIhPHQU0hHO4FAIBAIfBuBiAkEAoFAIBAIBPoUAmE89Knpis4GAoFAIBAIBAKBQO9BIHoSCAw8BMJ4GHhzHiMOBAKBQCAQCAQCgUAgEAgEOoRAvzIeOoRAFAoEAoFAIBAIBAKBQCAQCAQCgTYhEMZDm2CKTIFAINADCEQTgUAgEAgEAoFAINDLEQjjoZdPUHQvEAgEAoFAIBDoGwhELwOBQGAgIBDGw0CY5RhjIBAIBAKBQCAQCAQCgUAg0BICbUwL46GNQEW2QCAQCAQCgUAgEAgEAoFAYKAjEMbDQKeAGH9vRSD6FQgEAoFAIBAIBAKBQK9DIIyHXjcl0aFAIBAIBAKBvo9AjCAQCAQCgf6JQBgP/XNeY1SBQCAQCAQCgUAgEAgEAh1FIMo1i0C/Nx7ef//9tNtuu6Upp5wyHXjggc0C0RMJRx55ZJp44onTJptskt54442eaDLaCAQCgUAgEAgEAoFAIBAIBLoMgX5vPIwzzjhpu+22S7PPPnv66KOPugy4jlS0ww47pPXWWy+999576csvv+xIFQO1TIw7EAgEAoFAIBAIBAKBQKAXINDvjQcYf/e7302C95Edxh577JHahY8//jhdccUV6fHHHx+p/ehs42+++WY68cQT02uvvdbZqqJ8IBAIdDsC0UAgEAgEAoFAf0FgQBgP/WWyumIcjksdcMAB6d577+2K6kZaHffcc0/aeeed0/PPPz/S+hANBwKBQCAQCAQCAwKBGGQgUENgwBkPr7zySlp++eXTRBNNlAYNGpQee+yx9PTTT6cf/OAHOW7JJZdMxx57bJpmmmnSRhttlG666aa0+OKLp6mnnjqdfvrp6e23304/+9nP0hRTTJF++MMfpnfeeSfDeeedd6bpp58+zTnnnOm6665Lm2++eZp00knTiiuu2KSiLv/SSy+dvve976V99913eD0qc6zpj3/8Y/r+97+fJplkkrTCCiukW2+9dYSjTg888EBu3zimm266tNdee+X++Rb22GOP9Mknn6SrrroqTTXVVHlsZ511VlpnnXXS3Xffnfsn37zzzpueeuqp7MHfZ599krpmmWWWdMwxx6RPP/1Ud5oMV155ZcZFHfKfcsop6fPPP0+fffZZuuyyy9JSSy2V73eo/+yzzx5e1xZbbJH7Io+KH3300dy/ZZZZJh/nevfdd9NOO+2UJp988nT88cenv/zlL2nuuedOs802W7r++usVSdr++c9/nj788MM0ePDgXN/WW2+dx5szxJ9AIBAIBAKBQCAQCAQCgW5BYJRuqbUXV0opdffAMabf//73ieI7aNCgtMEGG2SD4fzzz08U00UXXTQbFQwLyurGG2+c40899dSs7F9zzTXp9ttvT+ow3IUXXjgbHRTxSy+9NO2///6Jgi9t9913H8FDftddd6X//Oc/6dprr00nnHBConjfdtttsmYF+KijjsqGgL5of7755kubbrpp7s9XX32VGB5bbrllWmuttdKLL76YDQF1rbnmmnkcM888c76UPfroo6clllgiid9ll13S+uuvn84555w066yzJuNw9Oe+++5LY401Vq6D8n///fenk08+OR8JOu+883Kf6n/c1dCv/fbbLx1yyCHpySefTLC6+eabs+Fw9dVX5wvqu+66azZItt122+Qdhl999VXac8890/jjjz/cmJhpppnSDjvskBgN0scbb7z8bQw33HBDmmyyyZK6F1hggfSjH/0od2XVVVdNhx9+eBpzzDHTjTfemIwDjsabM8SfQCAQCAQCgUAgEAgEAoFuQWDAGQ9QpOgLlH/fPNh33HFHVnqnGLajMNpooyXBDgClfYIJJshKOGWVIm9XYp555kmU1ZdfflkVOdhpoIivvPLK2RDxC092FR5++OH0xBNP5Dz+UN4p8mOMMUaaf/7504QTTjh85+H1119PF154YTYC5HPh268zUaovuuiirHRT0Bk9Ll+rQ10MHu+bbbZZcq/hhRdeSJTxV199NV8Ut0sy6qijav5bwdgZPdtss00y1kUWWSRR6s8444xv5YWJXQMGyWKLLZb7zutv54ZBdvTRR6cFF1wwLbfccmmUUUbJBg6sGVt2Qr7zne9kpb9U7Fu/y7enesTbMbFzo0/qUz7uOEAoQt9GIHofCAQCgUAgEAj0XQQGpPFAyXdMhmedsu7oEmPB8aD6VPpZ1fq3d0q8Z3OhqqpUV9J5zinw7hqUMuOOO25q7uI0Q8ZRHuUo0MrobzEwpD/yyCPJbklph5HhKBXjZvrpp8+Kv2NOjhDZ5ZhhhhnyDou6mgovvfRS3sHYaqutsrJvF0Y5dTTmZzw8+OCDacYZZxw+TkaEMvrzr3/9K+8slPHpE2Prgw8+yMZMY30tfTMaSrq5YIzEHYeCSDwDgUAgEAgERgoC0WggMMARGJDGAyV0ww03zMds3ANwR4ECTkHtDnpoyVhobE/fKNyN8eWbQcFT71lVVYke/nQHYY011sj3DijsJ510UvLNOBqeqeHliy++yPcO3DE47bTTkvDQQw8luxcNWfNugv7ZHWhM892acSVPhEAgEAgEAoFAIBAIBAKBvolAXzce2oS64ztC/QKwIzEuD//ud7/LR4rcDaCQq1BeZ/sp1b4FcZ7i6896neKVcYna/QFpLizbDdBeSVdHqU+cb8G7Y0qORDlK5B6AeJ5+uxeDBw9ODAdHihy5spuhHkaCc//eq6pKCy20UKqqKv/7FtpVn7oFxok6XBzXV7sOLmZXVZWeffbZvCPC2FGX/itTD3YUGFruI+iffG+99dbwY1f66B6EY1DKuZPhXoU7C3YmSvsME+0r616HccovqNOzHgdP8SWOAVNVVd4xcZxJPdKVixAIBAKBQCAQCAQCgUAg0D0I9HvjgYLqcvJzzz2XXK6llBcoHdOheNtxoBCXePkdHaIEy88Y8KSkunfgX632yz/KOt5TLjsrL81uhgu9/kVrZ/3dR3BHQX2O9ajbkSAKscvAFHlGhvr0Zfvtt08U6oMOOigdccQRyQXlIUOGJMeD7CCsvvrqiYJ/6KGHJncMXLhWr7Hqg2NK7hm4pOyCsrgSHH9yP+GSSy7JF7Uvv/zy5JeMXL7WljaPO+649Le//S1R+ku58tTuuuuumy+AH3zwwbn9P/3pT8mYKO9+PtXuw2GHHZb77t9iUL87F3Yr7Izo/7nnnpu0Y9fHPQZGhmNkMPEzrObrlltuyTg4quRCuGNY7nvAmIHkboY+n3766fkXrYphUfoaz76AQPQxEAgEAoFAIBAIBPoSAv3eeKiqKt8P8KtIfs60fo7evQE/weqXlFx+LhNHwfZrSY7xeKf0Urj9UtGyyy6b7FC4DH3mmWcmCrw8pSzPvDxzzDFHvgwt3U++qt9lar88ZLfD7kFVVVlxd0zIpWftCKusskqu18/GMjr87Otuu+02/KKxn4NVr3wMBb925KdRldUPOwt+ctVF5tlnn13U8KAP4v36krJrr712MhY/jyr4aVVt+jnbxjsgKrFzYHza9xO27j6stNJKye5GVVX5Z1WNz4Vq9Tsy5d+V8K48fLTvIjkM7Ej4iVgGkLqqqsr3KRgFfoVJf42HwcKIgolxMkL8wtIvf/nL3CZjybxoI0IgEAgEAoFADyEQzQQCgcCAQ6DfGw+UXcowzzeF1s+EMgxclPaTpDzujQq2C74lvx0JCi/lXHm//uPIDAWeYixfvTzFluGw2mqr5Z9I9W8UyI+yKOnqEOaaa65shFCefcvPwJDP7oJ2eejVz8PuOJM0wZgchfKrTvV047HrwWvvH4GjWMtfD1VV5fsNyhqLnQ7pcHF0S18YJdrXjrTGoH9lN0EfjbH0XZlpp502MSjU5d+ycOG71FFVVTZWpPvJVQaDn2WVd/DgwRkTx6h8Cy6Ol3/rwreL7owJ9ZlXc2BHpo6PtAiBQCAQCAQCgUAgEAgEAi0j0JHUfm88NILiaI3jMI4GXXDBBfleQFV9++JxY7nWvh05crTJPQHKu2drZbo63ZEfOwJ2N+wK8M53dRtRXyAQCAQCgUAgEAgEAoHAwEVgwBkPPNS8/HYL/DsGU0wxRZfMvnP77i44YuRsPmOiSypuRyXuATheZXz+bQgXlNtRPLKOdASiA4FAIBAIBALqIRngAAAQAElEQVSBQCAQCPRuBAac8eAy74477pj23nvvfLa+q6bH/QkXpF2Udqa/fg+iq9porR7/OJu7He5wjIz2W+tfpAcCgUAg0K8RiMEFAoFAIDAAEBhwxsMAmNMYYiAQCAQCgUAgEAgEAoFAOxGI7G1DIIyHtuEUuQKBQCAQCAQCgUAgEAgEAoEBj0AYDwOeBHorANGvQCAQCAQCgUAgEAgEAoHehkAYD71tRqI/gUAgEAj0BwRiDIFAIBAIBAL9EoEwHvrltMagAoFAIBAIBAKBQCAQ6DgCUTIQaA6BMB6aQybiA4FAIBAIBAKBQCAQCAQCgUBgBATCeBgBjt76Ef0KBAKBQCAQCAQCgUAgEAgERj4CYTyM/DmIHgQCgUB/RyDGFwgEAoFAIBAI9BMEwnjoJxMZwwgEAoFAIBAIBAKB7kEgag0EAoH/RyCMh//HIt4CgUAgEAgEAoFAIBAIBAKBQKAFBPqg8dDCaCIpEAgEAoFAIBAIBAKBQCAQCAS6DYEwHroN2qg4EAgEmkQgIgOBQCAQCAQCgUCgzyIQxkOfnbroeCAQCAQCgUAg0PMIRIuBQCAwsBEI42Fgz3+MPhAIBAKBQCAQCAQCgUBg4CDQ6ZGG8dBpCKOCQCAQCAQCgUAgEAgEAoFAYGAgEMbDwJjnGGVvRSD6FQgEAoFAIBAIBAKBQB9CIIyHPjRZ0dVAIBAIBAKB3oVA9CYQCAQCgYGGQBgPA23GY7yBQCAQCAQCgUAgEAgEAhCI0AEEwnjoAGhRJBAIBAKBQCAQCAQCgUAgEBiICITxMBBnvbeOOfoVCAQCgUAgEAgEAoFAINCrEQjjoVdPT3QuEAgEAoG+g0D0NBAIBAKBQKD/IxDGQ/+f4xhhIBAIBAKBQCAQCAQCrSEQ6YFAmxAI46FNMA3cTF999VX63//+l0477bT0u9/9Lh166KE5PProowMXlBh5r0Hg7bffTmeddVamyWeffbbb+/Xvf/873Xzzzenjjz/u9rbqDRjnmWeemZ555pl6dLvfv/zyy/T000+n888/P3300UftLt9XCsDpqKOOSieddFJ64YUX2tRt2Jx88smZltpapk0VR6ZAoJsRII+vvPLK9MYbb3RzS1F9IPA1AgPGeHj11VfTkUcemX70ox+lH/zgB2nHHXdM//znP79GoTf+baJPG2ywQSIQm0hqMeqaa65JP/zhD/O499577xbzNia+/PLL6aCDDkoE62uvvZbOOeecdPjhh6f//Oc/jVn75DelbL/99svj+uKLL7plDE899VT6xS9+kfFHeyX89re/TQ899FC3tNnbK6WEF5rcf//905tvvtmhLo8++uhZkbe2n3zyyQ7V0ZZCH374Ydp3330znYwzzjjpO9/5Ti525513pu233z6tvvrqeX5POOGE4crq+uuvn+N+/OMfp//+9785/ymnnJLjCg14brnllskaZajnTMP+HHDAATnfmmuumS6++OI02mijpXHHHTf94Q9/SBdddFH6/PPPU0f+u/HGG/P61VYZQ0fq6e1lzNEHH3yQfv/736eWjMp77703bbHFFjlPVVWpqqrsJHl6mIHV28cY/QsECgLjjz9+ouPgGw888ECJjmcg0G0IDAjjgWKyww47pPvvvz8df/zx6cQTT0yEg4XWbch2Q8U33HBDevDBB9td85JLLpmF4sMPP5wVoPZUcNlll2XFbo011kiHHHJIOvfcc9PEE0/cnip6dd5PP/003XPPPXl3hULVHZ0dNGhQWnjhhdM//vGPtN8wQ4Xyt88++6Q//vGPaZ111kmPPPJIdzTbq+tcYIEF0jzzzJMef/zxrHhPOOGEHervmGOOmeaaa6403njjdah8WwsdfPDBiaHgOd9886VRRx01G9CbbbZZWmSRRdLf/va3tOuuu2bF0zyr94gjjkiUdXM/22yziUrLLrtsev/999Pyyy+fLrzwwnTqqacmRutaa62VrrrqqpzHn2222SZdd911iXHEyBprrLHSkCFD0s9+9rPsTcfL5GtPwAd32WWX7EDhRGGQtKd8X8qLRy2xxBKtdvn1119Pt9xyS56TqqrS/PPPnyaYYIJWy0WGQKA3ITDFFFOkjTfeOC2++OIJj3rllVd6U/eiL/0QgZFiPHz22WdZYbrjjjvS3XffnRl3d2JL4Sb4KW6TTz55mm666dLOO++c5p133k43S/FcdNFFE8W805W1UoFdANvqrWT7VvLYY4+dKFkzzDBD9mB+K0MLEXYYquprjxxPJaWphey9Ounvf/97mnnmmbOhUDo62WSTpUsvvTTtscce6bvf/W6J7tJnVVVZua2qKiuDY4wxRmbyp59+enrxxRfzMZgubbAPVDbKKKOkiSaaKMGColdVVa/ttWNKFHvGHvqvqq/7eswxx2RF0w6DXQGGwW677TbcuJ5yyinzukNjxmuAjAGGgHqMXR60N+uss46wqwgT+aeddtrhuxxVVaXZZ589rbTSSjkvPipPWwIjWT+XWmqptMwyy6TSn7aU7Yo8dlzwj66oqyvrWHHFFdNjjz2Wvv/973dltd1a1yeffJKdEXaAW2po9913T2eccca3jqcxIsm/yy+/vKXi/S6Nc+jss89OHGFtVK57JQZOAfzkJz9J66677gj9I79WWWWVLGP+/Oc/j5DW0sdbb72V7rvvvoSuWsoXaYFAHYFR6h898U7gUdZsxy+22GJp8ODBWRDyAHVX+wRlVVWJ8lja4JVyhv+JJ55IPOpCYaYMAYxZnPd33303lz3ssMOyZ5ECbyuc8XP00UdnBZBwlJ+SoQ1nZv/617/m/Bi4/JjXO++8kxxtUL/zibBQjheSgKesq5Niooy6nE3WN/29+uqrRQ0PDCP1qcNTf4cntvBy00035S39M844IznuwQPqPsOtt946vNTtt9+eFVvnKfWJh254Yu2FJ5WCpc+OCTh76ciALI6nOGrhWAas7fzwyN43jFk5CnLJJZdk/Hnj0YYyxnDkkUemI4cFdPGXv/wl5+HRhdGNN96Yj17YQSIIlSmBJ9sZeP2Q/vzzz+ck4zr22GMTRikeXuLMl3djxZRlxkT123hg7qy5esyfs+7mQP133XVXskVsTOp2PEn5tgbtUSYnnXTS4UWMx24PzPTT/JZEbUszF/rM+NDm008/nWlKnPKw1D/pvkt5T3Pp/oq8jfXD2XjtcBmbdmBAuVJWgM1tt92WpKnD2GEgTYATL3xp3zoQ35ZgBwZt2N3ST/NozVm3xl7q8P6vf/0r90G6OSz0VvKgSZ579ZkbTgrz99JLL+WjP/qOJtGc+n3Do5QvT21de+21Ca+aZpppSnR+Etbw1dccMezPVlttlVZdddVhb23/X7/knmWWWTxaDNrEM2FunbSYuZbIeWKcP//5z2uxKeErxq4+mB533HF5R8w9p3pGRxbLWv3Tn/6UrGXpxo+HqMO3gC+iI/NovVpnlDbjlE/gdCnlbhrGixwfst7RLH6LztSjP/Ir71iG+vUFD8av8C7zgw7cbyg8U74S8Fw0Ir9jl3iKNM4YtKFciRPfWnjuuecS5Uy/0Jfjr8apnD5efPHFSX+0Z2z4nDRHFJVBd/Jb/2SEOOsEPnissngcXqZvjqqSC+qAN16tD/ihsvKQJdLrwXE5c6YNMkSacTqGKv+CCy4oaoSgX+rVB7wGjVkXxonOHfM0r+b3ggsuSPKXCowHH4WpfsEIxiXd3OIL6AwPMd9kFv5V8tiFQ3t4rjrMP1lRP6ZnzZby8uBn+I76fONNxqnMeeedl2WHeTcuWKBdfM0YzJ228VH16B9aU158UwFvsZa0VfK/9957Oasn+YB/q9/6Qn8S9ZHchxuaMFa0oB7zCz9jNQ4YcyzBUF3WkDrUj7+jE/xSWcGakO740nLLLZfvgeFd4loLMLADXp+r1spEeiDQ48YD5mNxFIXEQsRsCJNmp6OTCbxKSy+9dHJMyflkTLBUyQNI8cWAy9EJnnpKPeHFo0ixx8RsDU4yyST5qAHl0i7G1FNPneTnEXScgadQ/byJGLR49ey5557JwndUgAJrzBinsvry61//OmHQmIidEQJo2223lZQ94ryXtiMxnhw57A8G5ngDoUMBVQeBPCyp1f+/973v5fPb5gJjGjRoUN4F+tWvfjX8HL7xzTTTTGmCCSbIR0N4SRsrNkZjhZejGZjiTjvtlCif8jp7DF9jI0h5/qU5PgFT6TyS+++/f6IEKGMeKDv6hvnrB+bubDgjDQ2JwzQPPPBARXKgUGy33XbZq6qv0mEi0dxNNdVU2SszxxxzJHMlTvvaIKwxbwwd9nvttVeSZvzGpl7MWF/NIUFIqDrLjgbUsfnmm2uqTYFRoH+YNo91KQQXzByWhI12yxEVYydIzDXPNMzghEbh4ygUurLLBEPp7rjot/r1lXJLKBmXNYfGzId0cwNDglXbc845Zz5vTwhSiuRBy9YRJVYdBJkgjfDRX2XtchHW7ha11cs3wTA6I9jhQqjOOOOM2djbYYcd8hEhbZgfWBurMVK4KRt1YY+n6KN1i64Jb/2gIDPWKJi/+c1v8rrlWIAL2oO5NuoBrVmTjkZV1dc7DiUdlhQUTwaTdVjS2vrUNwoCejb3bSmHpzimRUkp+Sn0vI7ooMTVn9dff32yJuBVj4cHo9GcU0DQMtzq64piCz84WTvw2HrrrRMlX3kKPLxLveaR8kcZs16sM3xTunUn+EZv8lCo8FP8QT9gTkFGm/ijdWu9bbrppvkIJfpmXOA7+Ar6ZtgxZMUZh7YEdVGgKbl4qHsrlEN0ZAcI/hTlQt/KtBTgu/swj74xO3aHxq05PF2d+Lx5gbOx24misFJ4KXbo2nrR/6qq8t0VCiia1K4+XXHFFQkOFHH0i3/ifdLtVpExnnCBJfnmW3o9OILlKJ36KKNoleHAKDEG81LP7916MDf4AH5D0YctubPRRhsljiHjwCutdd/pm/+sAfzWGPTRHGoHX5DFWOzeGRsjCB2bC8q+eZCH7CSD4AFfOP/yl79M6EO6MVgv6M18whh+eCZ+bf6NDx7GQh6hMd9knjFbO9bzvPPOm9cEHorHWL/4Fv6Pb2qvMXBSoFdyFn8i/8wxnofGGHqcHtNPP32Wm3gnOaEf+sA4sDbUU1VVvkuof3hxVVUJtmiKbNQP/WV0MvqfeeaZfFwSbRmbdWb+BWui9NW8o3v8rsS19HRyQh/g2VK+SAsE6gj0uPFAgaas1juBuVggGEM9vqveHY+gdFFqLVzKGsaIoVPUN9lkk6xwUoa0WVVVVhxdaKWk8b6ow7lk24UUPswfg8C4LXg7GSuvvHKysAlfglVe55VddMag1GORY4oEHg+BIJ+FK93RAtuqzkRTaPSHgePcNEHtW6AgYd68kJQXiqvdHMxMemuB4Mb8MDFKh35gmLxAvLPKY6SDhhkVFBuYFXyklaAflAljdwTgpz/9aaLcFgEOX/XIzxMmj6cy+q7dDTfcoKSphwAAEABJREFUMDPNosRimASLfvDiwoIAIeAJHfgo49w8pUjdArwolNIIurXXXjsbRNKM1dEQgs3RDf0tcYSwPAJaxLgd7XCGVB3wxfQJYHOhHvRA2Ng6NserrbZaaqRr9TUG5+MJEcYsgUCQEgLyUSooCuhBfZR/HkZeU+mECmXK+OGMbtEhGkUfBApMjc0lUIJU2WJ8GA8FB5bOvFO2CGdrgXBTB8VBfSussEIyN0OHDs1eZvOsD4x+ioP+qYOgV1YaIU7oUyzhRlEzHgaH9NaCeZ977rlzNm07v0thNK5C1+pndK+33nrJHMNCe5SVXHDYH0oXTyNFzj0B6eaK4mLeKDTqZowTshQX/GHwsF3QYcVH+B+98fBZ61U1ovFAAfGrRda/9YcHwHOECpr5cGwEL6DQGBPluD6GZorlaPSDDu0Q5Yhhf8wL+i/zNCxqhP/NA2OQ0VdPYDAxKmBvrcHTWjfmkg9d4s8UUbRurAwKSjJ6xEv0qeRXJzryTbmzziigVVUltCkYq90c2MEA3zOvymiLQo7Pmn90i3cbH0Wckmj9yEsB1CfrkAPIGqmvQ/PuzpdxWVfWPqUK36NEonn1tCWoiyOBnEJTLrtzRlmD4tAcj7B1qT0KKT5CiaZcwhkWpa2qqhJjDAbiqqpKeGXhR+jbETVryfzKg38pA3d8CJbG51t6PVRVle/jcIQwGvSJk4RhSE7V85Z39GEN4kmMcmNBF/gNh4e50ie0gB/bMVKWQwLPgedmm22WyDxKNqOjGBh4n7GiBfyFLDA2yj55CEPymVxWF3wZrZwjlHLtUKAp7owpbbgDRFnGg+AFD21w8FRVlZVt7ZAh6BS+ZK21bhzmhKGE5+F1+iOQ4drSZj2QW3ZkjB994uHmlOHAuCY78EW6gjHgU3CwxmFqbZT68DVlyUtxVVUlfIbMJYeNUb/hiU+RTdYZvmO+rVnjFawJdQhoxLqjc/huLWjfusCPWssb6YFAQaDHjQdEztItHfC0mCmLGJfv7ggWLkZPMGEyPJeYvbYwH8KOh4aAsOhY8xgNhX2hhRbKv8ykHEaDMRBWyjYGQgmDUR8hRZHBCOTjxfEUtKP+qqqy4VJVVcJUMZSqqvIF59TCf8ZBucYYSxl9E1ooNkJSVX3NXOEvgdDQf94f320JjANCnRFF4TBm/fFOCJQ6tEHh8S3ds4y/qr4eL0zEl+Bb/VVVZYzSsP8IVuWrqspx8qRv/uORphDzXjumItp4CEHvbQmMW4KagC79NTYe2SJMqqrKVelb6QvDCsMuwjRnaOIPGmAQEJ777bdf4sks2QgsdTA80Q06xND1h1JIEBkL2qOQUOIoRMpX1dd9ohBVVZXph5AhVAkdnnnzStkijKuqyjtaaFl7hLd6BAaYdeqdgkLwFeXdurCTQDBSuGHAiy8vDzYc0D+DgQHJI4tWpbc1EP6Eo/z6AXt1MFoo+o5gUIRhL49nVVVec9A+HKw7/TBuwp3iJwOFgTLCqGJcMI5hJa2pUKexenpVVfnSN7rjJTRHFBrzVc/X1Dtvt3Ew3Cj2DIHm2mmqvDh4eAqOyPhubhzqrqr/x0iZerA+C47wtn6lGxOlkUKDHtElGqTo8aLL09lgPswXZaisW8oShaaqqkzLFD1joISX9qqqyr9AVVVf58HHrV/0XvKg5TqfMcaS1t4nfCnfFEDKpvLWMeMKX4IN2mUYSSPPGMHWXn19SauHqqrqn/kdJniBD/NhPTiq47s9oaq+VkjJMLyHoUVhrapvt9lYL9z0oaoqvDbPAzqpqq+/07D/zMmwR0Iv3vGHqqpyXryDkcIAl6cE2FGCzYW+MB7wII4NCjhaw6PkJxPpBniQb0958eSqqrJ3304EXshg8Ktn1jzew6gzZk41fET5xoCXoWdGkbzKMoqMpRFv848P6T+Fu6q+NvYYrByC+Ik0PLGqqnxXCR54uL6kNv5XVVUy5wV7tAUv66+NVeRsxpBfGv4w6BglHCgtBWNtKBqfgcBwBHrceKDEO2qDMekFpsh7YJH57u6ASdhaZa3bZtUeZkVQ8Vxh9JQPi8qix+AoGDwiGIQtcIzKNmNTixODwSgoLM478lJgrLwUmKD2uiJgoNrnZeiK+jpaB+WC19S2J2ZLoWDUdLS+zpTDxHnYGDP6YR7bWx+DB7btLdee/AQP7zchxftNiVQelpRjNFMCYU9xQoeMB3TorDLjgaeMYqdsc4FAprgYE3ppLl9b4ylo1o0+mW8eYx5o7VDcCOLSd087E8q0tf7W8llbDCKKWXN55bGOy/rTD8KyGFrK4QPLLrtsUpdv69azI4GDAT/RDqW3HLFoS12rrLJKvsDMmGBotaVMT+YxrwwvhrPxCZQY/IzHuzv6Yh1Yhx2pm1GD3jtStrUy1o85Mt8Uu8b8FNHGuJH9TXF3dEa/HQdkpNq9KTynq/qH7jtblzXYWj3WtnxN4S8OTeJDFHnKL1qy49Fc3wp921lG24JdFDoJI6Bezvyrm5GCH9fTvBcHi/feHOyM2LHHv1sKHGi9eRzRt/Yi0LX5e9x4sPAcW+Gto+Dx9jvry/vXtUP7/9oc3aB0FYHEC0GBIxTlIgwIQx4QZ4d5LCloVVXlewqOq8jvWA9vK8ZBUSWolPcUvPMQYDq8U4wUymwJdgnk6YqgDQpURxTkrmi/1MFbw/PD+KLMUop5i0p6Tz0Jbmekza1+2KpvSmgQPGXem+obY5YxycNFsMijbkLNnPruimCXhzJrDfBYqtOOnGM1jhUVmvGkoDMShwwZkn8Vxths3VNSnRlWtqnAaIWH8fBe8eZR7uvKFSFrl4yh3FQdjXHWAoXbMRLHTBwFYFDb4UEDPKaNdE9Bbqyno9/GYL3Wvcvars8pzy8nBb4Cv3rQrrnkqeelhDXvv/P2lAPp9YAejIkSVo/37jgHPL0L1qR5KrxAXGtBP+3+oDHOi9byS6dAaQP2vtsSeIApRW3JW89j/Lyg+F8dR++OU9TzMlB9U9jq8yGuBLRT3pt7MuzQLS90yeNIp3c7W55NBcqinQb03lR6Z+OqqsrHUu1+GGNjfY5RokWGqzT0xIlkPHAUJ8Cm8BZzSSEV397QGpZ4nd1AfXBUydEjx4A4e6zj9rbXUn7zor36euAIsQNgR6mlsiWN8q8ea6HwKGuVMwr9ymd+0b56fTcG5Tkr8EV8yBq1q1XPB3N9FWf90T04L9F0PXAgylMCuY+32Dluav4p22XMyph/aw6/whfECfX2vbc2j8o0FZqjG/RlfPraVLnGOLstQ4cOTXBvTIvvQKA5BHrceNARBoQFznvpTKitXvHdFTB7RysoaZi2YwKUNmdpS5vOatpmdW7bVjRhKY3BwcBxxAkzwBwwBNutjrUwMnwTXAJFhJeTMlKOSWA2DA9HetSJYVjgvEG+vWunzgwwJwxA3+Up39r3TXHQT5eKnbOW7rwlL7D0esCItckoqsdrHx4EnviiMJdvccamfxi275Kf19y7fivHk6U+Rpr++IaXPNrHIH2rw7c65fetDvXDybcAC/nLeEt9xildUF49xeOjrwSN+s2ZOSjty8/TTAnkOXUumgAt6aV+iqIzrxQ5CgsszD3mTxCpB5b6W5QlcYSZ+ZLfd2MwfnFw82T4MQKqqsr/9oh4R4H0zzyq27t+8BQqw2B1uVDbhLS+O4YkrQTn+pXTd3cOKPRomwBzVMe9EkdsYE6JcGyKUVKMB+3CQro6Yeobzr4Zi/pkfsQzuCmXBDQaZ9DASxp6Y2xbb8o2Bm2p17OkwangK867eRbv2/wQ9PoAM4E31ZyXeoxZf4xf/ykgLjHqi3oYDngOh4Gxw9CRRnVpox7UwyhA0+ixnuYHC7TBkNG2Y2hwYwTKZx7g4OlbMGfGVBTMqqry3RL3JeAHX/nU5+lugWc9WCfWRV25QUscF83tROFT0kq9pT60pD9wKXH6q9/WFTrFp43fkUjlKRnu0/BaKsOoZoDaPbE+OYbwBOWlC8YHP3PlDLy7Ab7Vpy39kE8wH+YQHniq+TdnDGtzJo9gvdkFg4d174w4o7zch1A3uoCV/IL1Kc48+EbHxm7efHvqj/p81wPlFg8w7/iH/vtFL+tInZwB8uOB6rU2YIZPo1vKJ7kHNwo9enPnydj1VVnv1oR++hbQrzlSp2/0qD7rDH0zEIqckF4CvmFHmOyDaVVVCb2jdfPn+ErJW3/CQz/QQYkv/ZEmDqbGX3ByXM749YWck2494A1kvDLyG4M61G/+0JJv80Ge4r129dGIdB5yyq27L+pgHFDS8TL9E8hsvEY6o9NRMfIdJuoTL6Bl/WSUyu+InF1q88MZY17lwzvdJ7Tb5ruEqqqS45IMQfnFW5/6ggfY9dA3afplbuBvV9J8aR994pGcNmjGDrJ8BV9zLx5+6hfMP7osNCLOmsQr0BheaA2IFxzbhamTEr5bC2SXC+fabS1vpAcCBYGRYjyUxnvqieFjmIQbweICE2HrfHLpQ1VVifDBnHgkSzxGgeEyPCifvBnKFm8q5uhoBi+ss6+ONNlhIOwINkIQE3XBFGOhNFBsCVzCEbOgFGoPU8EsMRYMwDlVeSxuSiPvCwaCyVVVlRgq+ubSlrFQAEu/1FeC/AQwBsZjLJ7irG1eF14azE8axcxuBuFGiaUEYPiEPQZPUBqz8/nyYZiOoTl+Awfefp5yjA2TxqAJE0JGP4yfAuEIl3L6IJ5g5ilXv7LOjVN6CT7Mk6DEeOGjXd5uAojSQkCbJ0oxpZqggZN/1ZnHnRFHqSE4/DIGhm08sLNNjXET6IQGDF1mRS/6Z97gRdASTIQ4wUYRQBP6aoyUCAqa/hujMiVQvKTzTGL0xiZN39EibMwvhdYYCAKXBc0rr2URgC7waw99uVDKUKgrU+o0FnGEn50YdFlVlaRkXrQPy8GDByfGFVokbGVQP0+c/sFYv9GAI4b6RYBZG7D1dAeIwaMt5dGCXxZBGwSyX0Sx3gTp9QA7dMBIp3BQNLXnAnJVVck8Ux7MLaz1FU3yPLpIzniHi1/boZhSUBzPsIZ43MwD+rDLSampqirxuqqHMWO+KTPoHt7qRTf1PnoXD2/9JZDFlWBH0xlwF/TNF4EPW04IeVw2pSxSZOApzlEqOFrzaEIcwxRfYXQ4WmIMPKDWkv5Zq/IJ+ky5Yijga+IEdI6+0K/vxoDW0Zv5rqfpD5ysQTyHso6+8QGXguUt86q/xmmdm99ivFiX1ow5U8b40QdlkGKnDhhaUww480ixwRedEXdkBC3IJ1jL7i6pUxnHLPAc9IE+5RGq6utfK3LEBM3jfdY2I4PiiHbRgrVLyTNGSqN6zKdxa4cyjgeiN3ldWrW24KGdeqC0HXjggfnnxfF2fMTYzAf+ynBifOAbLkyTFXbAYFFVVSrHEMVZm9YOZ5N37alPX61BNMK4t/bQuzVP0ayqKqEPvMEat9Or7Xo/vTNO7KRTeH0LVVUlWFkrcBLXGMgtc0VyPtMAABAASURBVFBVVf6HDCmo5gctw5csQafoFb/FX6uqyj/xi+aNDW3qn/Wsf9qw+2G9MwYo5vittqTbva6qKplDc4Ivw5dMpYwXHoJeyFbzCku7X+itPn4X8e12cKxV1de8T/sCmYIfuPDMALQueN3xFLSKj5gLP5KBLpSpBzKYsWAerAs77fi+ccEMv1IOb8IX7Crig2SHerSPps2fdSSfPphjvMnatz7IAvNtDmEDI3NAlqrHjim+TWZrmxwXj6bREP7e1h04OKI9/VZHhECgLQgMCOOBYMVkMTkMw0J1ftwOCMZowVIMLF7MoC6geGwpIKUsAYpBOj4BYIIfE1CWoo9JqBfToOBayBg4hkZBJsB96wdBJS/mpbw4goRgpYT4pgRhDn45hnfAzgLBrW19oHQQ2pgtw0V8YyDIS/2UVeku3WJG4imAmC1Gr01eWgyZ8uzbJUEY6D9GKI4gnnfeefOvUhEW6tFXzJdgKemYmPyCX/swfszZN6XK+LWvvDhYUJrMkW8Gn/kgMIxfPCPAJTj9gq85g7u2eJIoRIwpoZ5u3PIq56ltCrp29JcSJI/2KCT6JK/xUF6koYeCi3L6Smkr2DHojFHeEgh+AlB++QigkgZX8RR3Cob64ChOXnNHMZGfwDB+aeixKWWXMKF0GA9DCS7KlmAOCGR18IrBsqShX/HmhaKg3+hdHMGqf+iToiVO0Kf6eM1L6SNFgwFc6q8/rQf4qsPcUgq051sgvBkNhKxv42FwqmPQoEH53/lAD4xWCm3pU2lPXoaSsrCyy6g+eUscTyA6ZwSIs7bU3xiMGe1Taupp4q0neCvPkKkrahR18eotONdphyJa6nMB1HjMjTGgOWWtUWu15ONIMCeUJnRa4hnK8sOwxNWf5gjOeA8FuqRRXpVTJ8cJB4f+iqsbLXiOb/GUGWMvdVgTZR3hHYwKRqS8eIN8FCv4wIoRZ0en8BL4U8DlK0F+Zc27MtYHhaqke1ZVlfDi0l/GCF4vzXot8RQ68fDWJ4Fya/7V7xsdoQ9Kte+Ch7rqAb+3ZhlY5ssY1F3ymEdjZ6DKw2CHT0mnBHIUSMe7YcXgsGbgT5nUvkA5ZMhYp77xeAq5utCIdcpQp1ijT/H1gBcwAutx5d164Awr3/Unfqx/gv7Y5S5zbw0wqOGlT2QPnqI8PMlC/ZJmV670VzrjQTxc0ClaK/ibX3nUwVMPE3nRGiW9Pj7rv8wTGat9GDNM1cEAhit54LseyFL9IBfwLvOJv1pP+o0nmR99q5erv+P3aMr8o3fOi9I/82vtkhvqclSsvk45G+AinXHLQEIv5BbZqS5pxk5nkR+P8Q2rIqMYT+QDmqBrkGUcC4wLBp11Xe9zvDciEN+dRWBAGA8tgcTrhXFRUnjWKRct5Y+0QKA3ImB3hvCIreeunx0KECWRgKcY2Inr+lZar9EOFQ8pLyMFtvUSI+YoCiPFj2d7xNS+9WWXJ+i9b81Zd/eW84OizfmC1ru7vd5WvyOpnDwcOHY4elv/oj/9C4EBbzzwOlAKCFPbkb771xT37tFE7zqPAO8fb5rjMI56UDI7X2vUUEeAx4+H3O4LD7pjcPX07n7nTeQFdsSBIdPckZOW+qHvvPmOAfEQU75byt9b09zdcDxK/ymLjkf21r5Gv3oOAbLb2rRG7OD2XMsjvyWnGOzoOybnOKmdiJHfq+hBf0ZgwBsPzvs5o2pbtr692J8nPcbWvxBwhIRySZmylV4//9u/RjpyR+NIBaXbsYPG42Dd3TP3TpzTd7zH8ZqOtkepcHzHcYeqGvE8eAfr7PFijoYxINC7+2GOCvV4J6LBXoeAuxjuLzmSbK32ug52Y4c4BBwTtTaqqm+u626EJ6ruBgQGvPHQDZhGlYFAIBAIBAKBQCAQCPQBBKKLgUD7EQjjof2YRYlAIBAIBAKBQCAQCAQCgUBgQCIQxkMvmvboSiAQCAQCgUAgEAgEAoFAINCbEQjjoTfPTvQtEAgE+hIC0ddAIBAIBAKBQKDfIxDGQ7+f4hhgIBAIBAKBQCAQCLSOQOQIBAKBtiAQxkNbUIo8gUAgEAgEAoFAIBAIBAKBQCCQeq3xEHMTCAQCgUAgEAgEAoFAIBAIBAK9C4EwHnrXfERvAoH+gkCMIxAIBAKBQCAQCAT6IQJhPPTDSY0hBQKBQCAQCAQCnUMgSgcCgUAg0DQCYTw0jUvEBgKBQCAQCAQCgUAgEAgEAn0TgW7sdRgP3QhuVB0IBAKBQCAQCAQCgUAgEAj0JwTCeOhPsxlj6a0IRL8CgUAgEAgEAoFAIBDoFwiE8dAvpjEGEQgEAoFAINB9CETNgUAgEAgEAgWBMB4KEvEMBAKBQCAQCAQCgUAgEOh/CMSIuhSBMB66FM6oLBAIBAKBQCAQCAQCgUAgEOi/CITx0H/ntreOLPoVCAQCgUAgEAgEAoFAINBHEQjjoY9OXHQ7EAgEAoGRg0C0GggEAoFAIDCQEQjjYSDPfow9EAgEAoFAIBAIBAYWAjHaQKCTCITx0EkAo3ggEAgEAoFAIBAIBAKBQCAwUBAI42HkznS0HggEAoFAIBAIBAKBQCAQCPQZBMJ46DNTFR0NBAKB3odA9CgQCAQCgUAgEBhYCITxMLDmO0YbCAQCgUAgEAgEAgWBeAYCgUC7ERhwxsNzzz2Xpp9++lRVVXrhhRfaDVhXFXjmmWfSQgstlMYZZ5x0zDHHdFW1UU8gEAgEAoFAIBAIBAKBQCDQbQj0JuOh2wZZr3iaaaZJRx11VJpkkknq0T3+Pt1006V//OMfPd5uNBgIBAKBQCAQCAQCgUAgEAh0FIEBZzwAatRRR02C95EZxh133JHZfG77gQceSOecc0768MMP83df/XPTTTels846q692v5/0O4YRCAQCgUAgEAgEAv0dgQFpPPT3SW3P+C644IJ07rnn9mnj4dNPP01nnHFGOvPMM9sz9MgbCAQCgUAgUEcg3gOBQCAQaAMCA954uOyyy9Ioo4yS70AMHTo0Q8YTP9544+X44447Lq222mo5/brrrkt77LFHsmMwzzzzpMcffzz9/e9/T3PNNVeOO/HEE3N5f3baaae8u7HWWmulq6++Os0666y5vu233z69//77sgwP77zzTjr66KNzHTPOOGO6+OKLh6d98cUX6ZZbbkkrr7xyGm200dIEE0yQDj300PTWW28Nz/PRRx+l448/Pk011VTpO9/5Tpp55pnTJZdckp9VVeUyV111Vc6/4YYb5rEsueSSeVy/+c1v0kUXXZQmn3zyXPa0007L+f75z3+mZZZZJre5yCKLpBtvvDF9+eWXOa3xz9NPP5023XTTNProo6cxxhgj/fjHP07/+9//cra333477bbbbmniiSfO9a+++urpwQcfzGkPPfRQ7tsSSyyRHnvssRz361//OuN00EEHpc8//zxdeumlabLJJkv6e8cdd6RVV101jTnmmGm77bZLH3/8cVL/rrvums4777x0/fXX5zZgUMcwVxx/AoFAIBAIBAKBQCAQ6McI9NTQRumphnprOyussELaZZdd0hxzzJEOO+yw3E0KqviDDz44bbPNNumAAw5Ic845Z2JobLbZZonSO+GEE6atttoqvfnmm+nWW29Nu+++e9phhx3Sk08+mes4/PDD01JLLZUefvjh9Morr6T77rsvXXPNNYmn/4gjjsiKsYy85pReBsjzzz+fFXaGgIvd0pXbcccds0LuaJHyf/3rX9Oxxx6blP3kk0/yHQ59o+AzaFwIv//++9MNN9yQjYL11lsvrbTSSqpL++67b6KsG+sVV1yRGDkMHH1kqDCgrrzyymwkGf97772X29YHeXIltT/6bNyMHnkp8cb84osvZuUeRs8880w2GMSNP/746Re/+EV64oknMuYMoVp1OY2hVOIYbjvvvHM2lu6999509tln5+NJcLj99tsTY+rII49MK664Ylp22WWTMQhDhgwpVcQzEAgEAoFAIBAIBAKBQKCLEBjwxgMvNmX1q6++Sk8P86DD9dFHH012HjbZZBOf6bvf/W4OCy+8cJplllnStNNOm738DId1110355177rmzl54nPBca9meKKabI3voNNtgge8spuIySu+++OyvDw7JkL/vSSy+dBIq1dEp42Z2gJDNUKP/6wQO/5pprJrsZdhzeeOONZEfkJz/5SaLA6xtDZvDgwWnKKadMW265ZaLgF8X/zjvvTHYS9Ff7jeGDDz5Idimkzz///Hk3QZu8/HfddVdj9vTvf/87vfvuu8kY7YzYrWCg6Md///vf3Le1114798XuBiPkqaeeykaVyuDvWYJdIDsY5dsugt0MhtJGG22UsZ5vvvmSC+cMkJKv9z2jR4FAIBAIBAKBQCAQCPQ/BAa88WBKef39ChOPvqMyFGI/o+q4jPQS/Kxqeffk9fZsKVCGKdUlz6STTpoo/MXIYBD45SdKcslTfzI0tDvWWGPlaIo1o4CS7xgRQ4NnX5y21LfccstlY0SdPPCOED3yyCO5/Pnnn58V/VJfjqz9sZNhh8CuBGOHUWOnwE6Iy9W1rPmVQQEHQQSji0HFeLBTYOwTTTSRpByM1bEvxkCOaOMfGFRVlXMzONQ7Mn9qN3ck/gQCgUD/RSBGFggEAoFAINAkAmE8DIOFQr/++uunk046KR+nsfPgyBFFfFhyl/5vh4OCTRluS8XuCsinnGc9VFWVd0TsWFTV14p1Pd273YjFF1887wA48kPxXnDBBSUND/W6vTNKtthii/xTsjfffHO655578j2Nvfbaa3iZ8mJXpKqqfI+ixJUno0F95duzfFdV5bPJUPI0mRiRgUAgEAgEAoFAIBAItIJAJHcfAgPSeKAcC47iFGiXX375fKl3zz33zOfmXTouafJSaJ2lF+db+Oyzz3zmUNIaPeryODIk/8svv5wVckefeOqlqbdexs6HvOJV7H4Cr7+dA3EvvfRSvkBtR8BxHl58Srp7F44x6QePvEvYyjNSHDtyH8Jl5F/96leihweGh10QOxivvfZa0qdFF100H0fSloxwckSoHKUSV4KL43Y+3APRP31wTEoZx4sYKy5fi1e3S892RKaffvpchf7r6+uvv56Ud6TJzodxyCAOHuVbnPfGOOOAkx2ZV199NR+lkjdCIBAIBAKBQCAQCAQCgUDXITDgjAfKJW+6c/ouDVOYwenYkrP5LuG660DpFU8J9mtHFFqXgeV3GdmlYAq1+wHuPlDOHfnxa0WUd2UFab/97W8Tr727CLPNNlvaeuut8x0IF6OVcX/Bbgel168EPfvss4nCTdnWJ7sgJ5xwQtp7773TIYccksYee+zk4rYjTDz/W221Vd4d8EtQLnfrJ2Vc+44yLbbYYtkgYhS4tyG+BJfDYaJeR5pcyl5jjTXyReR99tknX7D2j+r5VSn5SrnytIvhmJRdG/1zGfy2227Ll7kHDRqU/JrT/fffn8evf+pxSRsO6ijHw8yFX7bwzZasAAAQAElEQVSCLeMCno49MbxgzCBxlMp8wMtRLHc9XBBXj0vh+s74c0/E0TDxEQKBQCAQCAQCgUAgEAgEug6BAWc8OCu/8cYbp2uvvTb/vCjPfIFz9tlnT355iMe8xDm6tMoqq6QLL7ww+VUh+aeeeupEmadsU4LdH9h8883zT4X+9Kc/TbzgpTzl3hEgvxq07bbbJsq1nQfpLjVTkinYjk6pu/zsKIWcEu3StQvIfhGKos+wYYzw+FdVlX8O1s+f+mUkP5Gqr+uss06+UKwNwS6HC8YMGN/14GL0qaeemoYOHZp/utUxJz8r61eQ/NKUy+TqpJw33gFRj7oZBX4RSf+M0+VuR7OkK6cufXP/Qh9cfC7GmfGdcsop+Rev7JDIxwAzRvcm1LPffvvln2xdYIEF8jGtwYMH53/YjsHhDoV2xPnFKcfP4KGs+AiBQCDQBQhEFYFAIBAIBAKBwDcIDDjjYdRRR83/LgNFlSee95pC70iRJ0VYnm/wycoqZb/kp/RS9HnzxTl+4/gQJdw3zz4jQHlHbhgr8847b/53Cnjp/eKQNIEBoIx+OHrECPEubqaZZsq/xFRVVWKAMGgcYSp12FFQh2AHwjEr6frFuGH0aMvxHjstLoUzIOSvB2P1M7XKFYVb3S5gG4s69VMfqqqqF83vVTVi/+RlUOTEYX/UDz/1G9cMM8yQf5VqWFL+Xz/FSYeTsow43/oPE+/KGqP8nr4F/VKROYCRvHaRGF7iIwQCgUAgEAgEAgMdgRh/INCVCAw446ERPMeGTj755GRXQKB4NubpyLd/9MyvEznq4z5AR+robBmKtmNPl19+ef7H1RgZna0zygcCgUAgEAgEAoFAIBAIDFwEBrzxwNvtX0f2Ly87ctRVpOASseNRjv6U+wdf191zf91B4J3ffvvtE698z7UcLQUCgUAgEAgEAoFAIBAI9EcEBrzx4AjMbrvtlnjou9Iz799IcARq9913z/9q9MggHhez3UVwVyCO8YyMGYg2+yUCMahAIBAIBAKBQGAAIzDgjYcBPPcx9EAgEAgEAoFAYMAhEAMOBAKBziEQxkPn8IvSgUAgEAgEAoFAIBAIBAKBwIBBYCQbDwMG5xhoIBAIBAKBQCAQCAQCgUAg0OcRCOOhz09hDCAQGIkIRNOBQCAQCAQCgUAgMKAQCONhQE13DDYQCAQCgUAgEPh/BOItEAgEAoH2IhDGQ3sRi/yBQCAQCAQCgUAgEAgEAoHAyEdgpPQgjIeRAns0GggEAoFAIBAIBAKBQCAQCPQ9BMJ46HtzFj3urQhEvwKBQCAQCAQCgUAgEOjnCITx0M8nOIYXCAQCgUAg0DYEIlcgEAgEAoFA6wiE8dA6RpEjEAgEAoFAIBAIBAKBQKB3IxC96yEEwnjoIaCjmUAgEAgEAoFAIBAIBAKBQKCvIxDGQ1+fwd7a/+hXIBAIBAKBQCAQCAQCgUC/QyCMh343pTGgQCAQCAQ6j0DUEAgEAoFAIBAINIVAGA9NoRJxgUAgEAgEAoFAIBAI9F0EoueBQLchEMZDt0EbFQcCgUAgEAgEAoFAIBAIBAL9C4EwHnpiPqONQCAQCAQCgUAgEAgEAoFAoB8gEMZDP5jEGEIgEAh0LwJReyAQCAQCgUAgEAh8jUAYD1/jEH8DgUAgEAgEAoFAoH8iEKMKBAKBLkQgjIcuBDOqCgQCgUAgEAgEAoFAIBAIBPozAj1vPPRnNGNsgUAgEAgEAoFAIBAIBAKBQD9GIIyHfjy5MbRAoDsQiDoDgUAgEAgEAoFAYOAiEMbDwJ37GHkgEAgEAoHAwEMgRhwIBAKBQKcQCOOhU/D1jsKvv/56Oumkk9Kuu+6a7rzzzjZ36uSTT85lLrroojaX6S8Z77nnnrTnnnumQw89NL355pv9ZVi9ehwPPPBAOvPMM9Nbb701Uvp57LHHprvuuit99tlnI6X93tjo3//+97wOLrjggjZ371//+lfae++9M+9oc6EBlPG9995Lp556atptt93S1VdfPdJG/tVXX2V633fffRPaH2kdiYYDgUCgixEY+dUNCOPh3//+d1pjjTXSwgsvnC6++OIRUC/xv//979Mnn3wyQlpf+Rh33HHTlFNOmU488cT0n//8p8VuL7PMMum8887LebxTGq6//vr83R1/XnnllbTJJptk7Jdbbrn0zDPPdEcz7a5zuummS2+//Xb605/+lJ/trqCXFNhuu+0ytmhbWGyxxdIWW2yRbr755vTll192qpeU/R/+8IeJodWZiqyrY445JlljM888cxprrLHSHnvskfu9/vrrp5deeml49ddee21aaqmlEtr873//mw07RrGxCU0ZxzfddFP6wQ9+kOuTRxg8eHA6+OCD03PPPTe87gUXXDCh98MPPzx9+OGHw+MH8svUU0+d7r///nTddde1CMNWW22VfvnLX+Y8M8wwQ3rkkUfSYYcdlr/jz4gIjDHGGGm++ebL+Nxyyy0jJvbgV1VVyfw++eST6S9/+UsPthxNBQKBQH9HYJT+PkDjW2ihhdK8886bFWsC8OmnnxadA68MT+RKK62URh999BzX2T+Uto8++ijx/HS2rraU129K2aijjtpqdkK/eNpnmWWWbHS0VOjjjz/ulKd28sknTxTQJ554Iu+OUNpbaq+n0iaeeOI066yzps7+19ny8P388887XM0vfvGL9PLLLyd0TLH+85//nBXj1VdfPdN7WyvWD+ugnh8NP/744+mDDz6oR7fr3Rq48MIL0zXXXJMNNcYNerXrw9C97LLLstHLwFAxxX+mmWZKK664YpptttnSRBNNlIzljTfeSHvttVc2EOSrB4YG+rerAAPGxM4775x+85vfpI033jjZmZN/0UUXTTvuuGPG5fzzz++x9Zna8d+nn36ahHYU6VRWTocpppii1ToY/c8++2zON+mkk6bpp58+v/f2P2gYP+7JfuLDjIeebLO5tsztNNNM01xyj8TjASNjHrpjcPjkF1980R1VR52BQJ9CYKQYDxQFQv6KK65Its3fHuYB7m7Uxh577DRkyJDcDA99UYjGH3/8NNpooyUMPyd2wR87HQsssEBW6rqgui6twk7Alltu2aY6KZPLL798VvrbVKCZTDxxMJ5wwgmbyTEwowu+jjh0FIHvfve72ZNfys8444zJbgSlkGJe4lt6EohrrrlmPsJVz7fIIotkD7OdgHp8e96ff/759Le//S3vhtTXmN2yqqryjgE+wPut3u985zsJvYw55pg+c2BsKKtMjmjij7SqqnKKsgwOuxuUXjsYOWHYn8kmmywbFKeffnp67bXXhsX0rv8322yz9Nvf/rZ3dWpYb6666qpv7doOi+7V/5vfueeeOzlm1UJHm02i9N56660j7F41mzkSmkXg4YcfTp2Zh2Yr7uEETjdOjUsvvbSHW47mAoHeh0CPGw+8auecc05ab731skexKC2U2u6G5/vf/37ikXR0gVAgHCgr44wzzghN83JSeJxZPfDAAxNjoHiHfRPutoIVeuihh9Iuu+ySt4WN7dFHH03uEvDSHXDAATnttNNOSzyd6nPGnhf+6KOPzmmUK3U7IvKHP/whxx1yyCHpvvvuy8dOKHbnnntujr/33ntzX/bbb7+0//77NykUKaS2yrV90EEHZeVPP50zP/LII7P31tjFtRSefvrpfMxEv9yJMEZBGX0qbThSYiz/+9//OuTJPeWUU/LYeJWfeuqppG70oa199tknwffXv/51Ou644xJMnd2lFF555ZWJB+jyyy/PZ7aPOOKIVIxQ+Dqyog5e57POOiufP5aHQmEM9SCOAm8sZ5xxRnr33XeHJ5tTePFiq89Y1T88w7AXQgW9KL/77rsn3v877rgjH81RxtGod955JxuTzoqLO/vss5N5hi/aECcMqy7Ja3zoxY6CI0hwkdaWABeBN77kdw77kksuyYop/LQpj7b++Mc/JgLe+Wx9QDc33nhjprE6ravLcR9GibmRlxL+6quvSmoycBJImH/++VNVfa3c+y5ho402SuONN1464YQTknVgPTIWSnpnnpwUDAme8no9diC0ZUekHt/cu7Ve6Mm7IyB2TqzzOq0of9NNN+UdD/SMz5R5M9/wgp18eAx6gTW69422brjhhnyESF7h7rvvzvV55/CwNszfP//5T9VkmkJv4uSxHsy1RDxE3F//+tfMB9CbfI4tvv/++7KMEPRDH9DcP/7xj5yG/hkOyhlvjmzjH2Mp6+Z3v/tdUr+ieJRx6Y/+4XvFwNOvM844I/MEPEh+huV+++03/I6FY25HHXVU/rbbBFN446124ZSx/uBr/eMZ2rEOpbU1WB877LBDno+2lmkqHxpxVE4frCcyQr5CU9aQY2PS8Tk8wZEw/WdYow3rtaQXWelInnFzhuFJ7r3hGcZZeKF2SsDnpKFdNFDiPdGp46vkhnbUBWdpJaArfUUL8uB55rF8m0d57SiaL31xx8mRRX0u84DXqsuOkDb3HybL8EVKuTWrjqbCgw8+mHmmtuFILsuHRvGZgic+XzA2LtjBksyS/5lnnsl8EHb6ZX6MV3/tkN50000Jf4NFqccTDRtboU951BdhZCMQ7Y8MBHrceMDUKApPD1NODZgygplQjH13d1h//fXT7LPPni+QYRo84lNNNdXwZvVv/2HMjDBba621shcUsyr9c96XskWRVcixCu+YPCbG4+tsNaWFYcRI4rl1dIrAx7QpEspgppjX7bffns8Tl90RAvBnP/tZVuh4XNWJqWHShATvhyfFyzEk/SiBoH/ssccSBYnRwQtty1jd4igHZSylTFPPSSaZJO/UYPB2UYxDIFAxY4wXjquttlrS/5///OeJ4G+qrpbiBg0alBgQlFg7E8brTDwlaM4550y23aWhEUoQHKuqSttuu22iQIwxxhj5KIu0IrwclTIXxkoIOyrlOAwhRhmAR+kTxZdC5qgM43L3Ycp/XamEJ+NFHaussko22AiiogihF4KMsr322mtneqEUoWuGIUFjPIJdLkorhYdij74YsMYEWwGGFA2KvPqcWTbvBJq8pd/NPQnG008/PS277LJJf+Wz1n76058mBon5oqAbA8MMnaJXdDzXXHNlo94xM0eG4EioUlLUI8CcArLEEkvkuwnmhUHNOJXeGNAGb79jYo1pvuE6dOjQRFmlbJvPRmVfvvYECgj89I1CYG7r5SeYYILEmLEWS7wdUDst5rvElaf+WwfmhSGNZh3bUTflqOSjxLnXgdYcWzFvlEHpaJlSc+ONN/pMHBbmFu2/8MIL+du6Ng9zzDFHngf0oC3zjr9wfFAkrY1yD2WnnXbK91vc+TBnFBpKPgymnXbabFBTgijY5h4vQc+Nd78ogebVWtcG/mPd2dlyvBH/MT+pjf/pgzVqLPqFZ5oTxdWFLxm/PuFhaAAODEc8mcHvW37jQKvw923+jMPaxkvRjLmz/q1FeezALbnkksmO1AorrJDx11EOJAAAEABJREFUXHrppSW1OVgn5te9uDYXaiKjNYa36T+eoO+yLbroonlXDm+AE16ERijFjuJVVZWdHmgIXRjH8ccfn/AU/E2dsIKDeDSHJ1uzymijBHLGvDuqiceiTWuzpFvXaAkPIK/w+A022CChBXnwJd8cGYMHD076ih7xOfJGHwq/Ma8MV2sKn7AeYKD/aFr95gw/pgssvvjiSbvkrDWrvcaAPygLB+VhoKx8aBs94SXWgbZ/8pOfpBdffDGfKCDLGDplzeBFjApj5vjRNzzQ/JAj6N6OO/5AF8DjySF0gCbQlb7gz9qPEAgMRAR63HjgPeMlqIPNI8LzSbGqx3fHO0WAYOSZIsyqqkoEZGlL33iaf/zjH2cF3GXfqqoSxV//CNeS15Mgw7S8C7yohB0GPc888yRMifIij4BZbbbZZmm//fbL9w3gQdlzLlVbmK17GYQoTwdmpTyFimDAwOWhsGFqBIV2SyCYXJh1h4PCyMjARAkZwqrka+1JuaFMjzLKKMl4jEMghChJBAXll5Dbeuut80VoDLq1ehvTKc6YsHFi4p4ElfoZXxg9g40XTDuUhB/96EeJMUQZJ5CGDBmS4Hfbbbfl6ikMtsnV5fgKpUEZmBN+RYjIrB7KsjxDhw5N2uLplEZp23777dO8886bGJ0ECg8Z+nCxl0IpL1qiKMHX3BKE+kCRqaoq6Qd6IDAJW+fw0RGFUhq6gK1gB4fxsu666yZjRYcUIZ5J9Jea+U8+baqTgKWEwEd2CgCPOcWSgqH9CYYp0DBFF4MGDcpHnxjR+qD/hCUMlS9B39AkIWp+PH/1q18lih4cSr76E1aEN3qqx5d34zfP+uVSrvUhrqS39wkDSpU1YI7MKewb66GwFUVeGkcC76Kn73pQJ2Ovqqp8Edb6w0OsUbjKS9FFA9bEyiuvnNZZZ50EI2sC/ualqv5/50VZNKCs4Nv6Ro/f+973Mt8wF+jf/Ft36J+Rbr0YE0XHkZxNN900oV9jliaeEYkO8CA8D/2bV3mWHWZYMhTQd/rmPzwQvRrbhhtumGN5Wa1/7Rdaygmt/GGsUl4pXvqjTfPLoDEOCqJvdDh48ODEoLfm8TTjspbNT2nGfFoj5RufYJD4xpsYXWjR+mSIGBd+iW/CVV5YmkNlWgr6UQLerC/WbYnzpLi3VEdjmjHhC4wwjgv0JA9at8bxH3NOsbdOKNP4Ivw4KaxFPzZhfIsOMzjEwVJeirl3GCuD3hlkDCk4aEfQFnwpvvpi3eNb0jiTGHubb755Qr+w5ESxdhln8lCkOTB499E3XgIHOFPUORpgLS9a4nBg0KAd/EV79XnAezgwtGf+KONkCaOFXFNPCTC3G7bqqqsm9K9/aJQBYN2hZZiJgxMjiE7BkMdL0AiaKfXBrU4L5oczAT9Hd+pHl+SncaAD9E8eGpsxoSc0XOqMZyAw0BDocePBwiWg6kBjjoSrhVmP7653jAHTwmQYLfV2MEzMhODk4ePxwCQpFp71vB15x2ApaXCgjBEYFBCCTrvqpMASWnYnfJdQhI5vDBFejf0nQKR3V8BIeZoIQu1rByPmbcLIfbcnGBN6oNQTcLw+FFECBValLsKJIlO+PRlKni0FylhJ12cCh+AqcdLrikmJ9+Ql1CdzQ/iJo5AR+DzthA0BrB/6J11dFEbz4J2wRkMEIEPOfDFo5G0qOLJA6MuH/mzra4uAt+vTVBlxhLujABQOnl1eRfVIo6Sia4YLA8vOByWGh1N6WwOjy3yhz1KGQkCBUHeJa++TYGaUoX8eUX1rbx0lPwxghSZ5MmFX0lp6UnIpLZSYlvIZa0mHKyx9e8Jb382bYK0wRijy8nQ2FB5pjhkS5th84BWlbgqYcehHibOOylpF74wJF+FLuicjI6XktdPBLgHljZJZKqMUMhKsb+uKIlbSeN3hSikucW15VlWVyrqT3xhK/b7bGxjnnDOtBcf/2lu3/JRlvI2Bgw/xdPOY1xVbhoo5lV+gzDL0vTcX5KEkl3S8GG+i+JY4hikjrHzXn+gTf8KzSjwlHD0z9sShZ4ZKwRtPNMfWP4MGDTIW5LXjQJnHJ303FfBN8daHugU8BL9FH9JKwDc5wOwqlDhrgJEsP37OMC5p6MBYjavEteVJvtBFSl6yGf9Qf4mLZyAQCHyNQI8bDxihXzyxMHUBo+RpZ/n77omgTV5CzIIntW4UELoYKYWewUAhpljwDlFuurp/FEJMs6P18jp1tGxHynW2v/U2ebH03zY0BYcAodTAg6Cqqv/31NbLdeadUKUktKUOgq21fGiFYlYX3vUyvMIMAoYib6AdjCKA6/nKOzzQIEUK/RGAjF3eQu2UfM09ed8YLdoqdO2IAS+coyoMP33RRnN1NBffFjyaK9taPE8eY95uIEOntfzSKQ+83N7rAW+xvikxjTtz9Xxd+U4ZVJ/+mDeBgkxhbGm+lelooNh0tGyhjY6Wb6kcLKwxfLYxn/sOHaG9xnq649v6cgSmtWCXryPtkyGMAx58u2KMOEp2R+pqS5m2zrH5MF8t1WntNzWfyqBvO6WcJgxHhoGdLmnNBTTCOCl8znrhybfTa6eyXk5efLtuZJV09CS9fMczEAgEegaBHjceKOA8rxg0b53jQLwvtud7Zshft8Lb5TKfS30UtK9jU3JEZYIJJki8T45klGArWN/lw5QxLe+YLsbqvTE0F1/PR5jY1tUHdUlz54FXR198NxUoKfK35N1pqlx74xgLhEspx8vlvHdpXzzPjKMZMPXdlqAMBZdHnyebguzbuWrHZbqDHgg2nlf9b0sfea8ZBXaAynzzbBu73SPGp90MXjEesKbq5J22y+TMt92VRs92I748hPpI+Bba83TEg3LTVBv1OAqJsrzvFHFpntYbw8LROAZMo4CWj6fcs7nAuydP3TOIVtEhT19T5YwHZm0R8BR+eLXVeHAMrTkF2nqlmFFoGKSNfTMOXtPG+I5+MxSqqkraNF8lOPqAVkq9jM3yzqgr7/UnrGBaj2vqnafYOMxBSbdj6giM45Mlrv7UvvwUtXp8V75rn6LZ1Dzql3TOmdKm9WXHwHhKnKexeQrNYSWtpWB94dct5WkuTVnrxUXe5vK0J96uJe+5+yvuH7g3hv+1p47W8qIbsgT+5Epr+aXbqcBzXEj2Ldghwd/wQN94siNy9TkRX4L7d3B2aV0e676klaf48o6XqN9OWVkrno5d1b3/8qMXhoP2fdcDWS1/fY0zSNB5o0Oy3j75Wq+nre/kgHG2NX/kCwT6KwI9bjwAkhKOKVEUMCWMS3x3BUKAksFQ4NnVDsaFUWFedWZAiZXfuVy/1EFouVhFgIgn/Jx5dLGSwije8YG6gkQZxrgdJaFouhSpffVhPsrxuuiHIxuOUFEsXWiVZoufQHU0QZ4S/KoKgUxZdUGNIk/hUhfhyzuDcRIg+qo979LkofT5dqxBOiy0R/EXV9qpPx0fwrQxZ/3hZWJYuUjo2At8XDimPDrjXS/rXbuMKG1h6HDCuI888sj8q0aUc2HIkCH5Hwuz+wCPqvp61wFesFMHI0Z9hID61GPM6rRbQSGRR7sluJRHmLoQ6ky3OxIMLuOHj3qMQb3e4VHaItid7XUMyPl48egCBpRENOTIFfph9MDQLgNDgXGkD45j+LcNxDmSw5AQXwJ6K/g6R+84gLWBZozHGHnPKcH6XMqVJ0wFYzS3+sQ4J5yHDh2abPmLN/f6ZKzo0rfxS6PcomkX7LVpPnkC5YU/fOFDuTPH6NCxKjTq0r811JSyoI8MYEcfYOe7BHWrkwPBHIqHjaMt+INvQR7tw9gcexfcu7GDYrzGYN7k1X9PyoZjFMaBBqwB9Qnoxzw5++9bMHbGmV9S8l0PcEeD6i3tUPDt4qAZdcPb3Q3rkuFmThhs6EdZ9TEAOUtc6LSO3XWCr/IFA8dFGADWMS+snU/p8jmGUvKpj2JLeXLmWz7KH7pxXIhCKI/guJl1BTeGJFr2c81VVeV/GBMe6MGYjFE+7Zk37WlfmjkzDwVvdZsDZbyXYM45Euwk4Rvq9gs/Tz/9dKLoOVPuXo97POgbL4GXuVcH+mcEcyagsUKP0vRBn8o8wNa3fmnLU136VNYmzCnDnEXqaGtQh/aNv61lSj7YlfKwFI9W8R/ygtPBbpt4AaawqPcfbr61b4zq8W7dGqNygnG7m2CNFTniMj96Nm/ijcM861OZX+1plxzWL/jg6fL60Qc7mPiyNvAS5a0p5fAs/EqaQMHnGPGDAurDI8ULeANnhV8dtD6tNfLRvTxHt9Ct8aAJvz6mv8qV4Iiu+w7uceEXaMAdDcfH0Dl+Z906Hgp3PBpW22yzTa6iyOPCM9Cd46CwKPTDoPaNrqx3uKBt69u4pZEHaNvOivXpjlZuIP4EAgMQgZFiPPQ0zjzOGB7lhJJXbx/zci6dp0Y84eayH0XFJTQKH0aP0VFyecQJQkzKkQT5Cb2qqhLGqQ6KmN0USgRmSwEnwBgejCXCUP3yqtPlSgoOZcOlNYxJPwlReUrQD4oCpsVwsPVN8cN4MU6XJjFnwoli42wtD6PjG9qjPOsLRkmQU0gpqwSUn7HDNEtb5eksuiNFlETHy7wzWFyocxRGX2DnCInxlXLlyTChuDuaBBMeKrhSPimiJR9BSsD4BQ8Yl3gKL2WKMkJAGgdliNcYRtJdctcH2OpTKes5xhhjJB4tHjHKDJzFUyrh43ws44DQIIBgzghAM/IZn3IEEuWPUurdHEsnYNVJeXNxkCLEWHAPQjqBY2yEnx0BcfUA36qq8k/ROqNPaSK4YaBdCiSPJQGJVuplvaM5HjZHIcy9ODjyalKO9Q0NqMf8o3dKlb4SjrBVhrIhnjcfTVsrLkIzGChehKx86AANucCIDiiqFGZKrPTGYN0QvhScehpFQj3mjuFT0ige6oZvVVX5Z2vlcd6fEYV+BIY2TNEchQJdwEge86c+NONonLnh7aUAiDdmfXL50rdA+VHeevKdUhr+sFZgYDeD8q1+iggadNabMi4zY4AB4WKqdUzZd0STYS2dt5mh5agk7PXN3FD4KETymBfKkjrQmz5bK4MHD07i8B35BHRhTXiaC+noyRqqG2DoAYZwo3BZI7BTB8WNokSxNScUN8YNJckv2mgP/0ATFDVOE+l4BbzwIwqtukqwRuCD3q09fcJjKYz6ZTeGYWAdmQNzYQ0ahzoons60+1YWfo7t6TPjCL04gqd9/adkowc8nqKI/1H6rBdjxS/MPz6t/rYGyrd1xUhra5mSDy3oH2cG/Eo8enHxua54S0PD1i9+QjHHk/Es9IJe8WxKq3hjQzPKCeYGBugF/eOz8JLGeWDtWlfWuP6QRdYG/oeuyRJ8ovB0fAddwg1fVQ/jmLxRH/4NT3MjrQT0hV9Y1yXOU//QJqOFbFW3OYURY9m6UCdZwUFlTStXD34xDH+0dqwpdGSt4a9o3zwzKPBra4ajUBulDjwVr8IX4cba2KIAABAASURBVKGMeWBUkyEchOgLLeL9nAvWOsMHDuLJEhjK75ee6Aal/ngGAgMNgVEGwoAplYScXQJHN+pjlkaQYeriCVHKGGZC0CpnqxnjkI5pEQqUZYIMA8Ko1V0Egjy885RbzI5AcN7VjgLvCgZZ322RXxuENaGoP5h1VX3tfdeu4B4Agast9VJexGPwGJn+Mggo6pgexUJeRo72CHTfFEDKGW+Sb/3UP8JWffVAGPA0w0Od0jB3OBqLQIg0pXTJS3HhMdJOUwGOhAbhaTwUDuVKoEjBTVnGi3FQAnwL2jUHvOm+KZ6lrKc5UZ63i1BVXrxjJqUM4UVZp/CpAx4UfvkIVkIRrtJ4kgutSIeZeSF8pVOk0RThQ4Dx/FGc0UOhIeVKcNmQ0WInhnEongFD0Tef8GFcmmNpjYFQ1a7xOetf0hkO5sa8EdZoQH2ELEUU/SgnTRnKOcOHwUBhgSsc5DG/FDn5CGQKYcGOIljSpDcG82eXRt2U1JJOCKvbjkz9GJlxUn55PKuqSowSxrq8TQVlYWjtSKdw6WNpB60YB3qtqipRYCgMjBpjLvkot9YebEpceVornADqp4SoX72+1U2JkVffjavQm3/9u44N5Vk95pRCigbVoc8ULHVYYzChWFl7FPZCWxTDYpTKK+gbI4QRiUatHwa+tBLMQaET84t/FVqkvOmvfuBLdkIpkb4F7alT/b6N1drQP9+UQnNU2ipP5dCcPPJSzEqa/qlTf9Wr/8ZR0j0petLRjbmiFKoLLZhz68U3XmZ8Q4YMSb7VZx0bX1VV+fipOVLO/Ki7JwI60B/Y2unkMKLUMhCs77LuSl/QsPz6754UjCjD4vzkNOPWmvYt8PKXssZlzYjH8xmghc+hcThKgxV+Zp7ROv7AqFCPeJ56fESfzZ16pZWgj2hTXeiJXGPY4nPy6Lt+oVnf9WD+leO8MH5p1gZl3vzAB6+2tqQ1BuOh8Osffjl06NDhWWClXePUB7xT31IaniX/NDM85XE/gyNAf+x04HVo0DeZjn/TAXwLjBXOFLoBuoQx/tnYxv+3Fm+BQP9HYEAYD319GnmLeJt4P/r6WBr7T5HCiAkjChkm3ZinI9+8S7b6YdeR8p0tw0PH0KD4MSQo0IRPZ+vta+UpJZQCXlwCn3d4ZI2BhxytMVYpowNhPqwD3mo7BSML94Hert0cSjMjinJKCac4dxYXxgha5qAYWfNrB41DgoPBjglHS2fHFeUDgUCg9yPQI8ZD74eh9/aQp5TgsXVN8Ng67r29bX/PeI14nniGeUHbX8O3SziCxTOpbh5H28zfztW9MXZn7Dg4W+sYwED2UvGqO65gB8XRA0cwuhf9pmvXPs++9dSUd7TpUn031rqyE+aYESO9746kb/fcMS7GszsFPPB2fqpqxF3ljozQcRo7BI7R2RHrSB2dLWNsdo0dH+Ol7yrnT2f7FeUDgUCgexEI46F78e107baObTfzmgq28DtdaS+qgILDS++8riNAXdE1x7Z4++HlPLojFF1Rb3vqcAHReXHnZm2Dt6dsL8zbJV1ytIT3lTHRJRW2sxIXJRmpFJ52Fu2T2R0NsgYEx0P65CD6Qafd4XBBnpe+Kz3zjhz58Qzz6zjayICKw8d9HcegmjtyNDL6FW0GAoFA9yIQxkP34hu1BwKBQCAQCAQCIxmBaD4QCAQCga5DIIyHrsMyagoEAoFAIBAIBAKBQCAQCAS6FoFeVlsYD71sQqI7gUAgEAgEAoFAIBAIBAKBQG9FIIyH3joz0a/eikD0KxAIBAKBQCAQCAQCgQGLQBgPA3bqY+CBQCAQCAxEBGLMgUAgEAgEAp1BIIyHzqAXZQOBQCAQCAQCgUAgEAgEeg6BaGmkIxDGw0ifguhAIBAIBAKBQCAQCAQCgUAg0DcQCOOhb8xTb+1l9CsQCAQCgUAgEAgEAoFAYAAhEMbDAJrsGGogEAgEAiMiEF+BQCAQCAQCgUD7EAjjoX14Re5AIBAIBAKBQCAQCAR6BwLRi0BgJCAQxsNIAD2aDAQCgUAgEAgEAoFAIBAIBPoiAmE8dN2sRU2BQCAQCAQCgUAgEAgEAoFAv0YgjId+Pb0xuEAgEGg7ApEzEAgEAoFAIBAIBFpDIIyH1hCK9EAgEAgEAoFAIBDo/QhEDwOBQKBHEAjjoUdgjkYCgUAgEAgEAoFAIBAIBAKBvo9AdxkPfR+ZGEEgEAgEAoFAIBAIBAKBQCAQCIyAQBgPI8ARH4FAIPA1AvE3EAgEAoFAIBAIBAKBbyMQxsO3MYmYQCAQCAQCgUCgbyMQvQ8EAoFAoJsQCOOhm4CNagOBQCAQCAQCgUAgEAgEAoGOINCby4Tx0JtnJ/oWCAQCgUAgEAgEAoFAIBAI9CIEwnjoRZMRXemtCES/AoFAIBAIBAKBQCAQCAQgEMYDFGrh888/T3fccUfaaqut0k033ZRTXn755XTkkUemrbfeOn+39GeNNdZIf/nLX1rK8q20119/Pe2///5pvvnmS6uuumo69thj0zrrrJPefPPNFP+NPATeeeeddPbZZ6f99tsvPfvssyOvIx1o+YUXXkiHHHJI2mKLLZot/fjjj6c111wz/fvf/04ffPBBuvDCC9PPfvazpGxzhXbeeed0+OGHp88++6y5LG2O186+++6bLrroojaXKRn12Xp59NFHS1Szz/feey9dcsklafXVV0+PPfZYs/k6mvDuu++ma6+9Nq222mrdUn9H+6XcXXfdlXbdddfUFpzkx/9uv/32zH98C0888USmk3vuucdnlwR9KvwUHe61117ptNNO65K6SyW/+c1v0jbbbJM+/vjjlEpkH3yau8033zzdd999fab3zzzzTOabu+yyS5/pc0c7+vzzz6df/vKXae65504bbrhh+u9//9vRqrql3Ntvv511Cry7tQbkPfTQQ9OCCy6Yll9++XTDDTe0VmSkpr/22mt5bL/4xS863Q9yQj1k/pdfftnp+vp7BQPSeLDYDzvssGShNE4wonnyySfTNddck9566630xRdfJMrBZZddlh555JHG7N/6/vTTT9OHH374rfjmIj766KN00kknpdlnnz1df/31abrppktHHXVUVkbU1Vy53hRP4YBTb+pTV/TFvFM2zUtfmYsy7vfffz/99a9/TQ888ECJ+tZz9NFHTwxXY7MmCL1//vOfyfe3Mn8TYZ7V/c1n+uqrr7Ih4Vni2vJ89dVXs0J/wgkn5HXWljL1PN/97ncTox7t1eObeqc8UqKvuuqqFhVJ425LfY1tfPLJJ+n+++9PV199dYv1N5br7u9nhilwHBkMJxi0pb1XXnkl/fGPf8xjKflHGWWUzCvbYjCij7bkgzP+ymh98cUX08UXX5xpsbTZkWcj362qqkO01ZG2u6uM+fjzn/+c10rj+Lqrza6olyKG9toiMzvbnnVLbne2no6U5+CjbG+88cZ5zVgrdAd9Sr3gPzSDp//+979v1QFm3Z555plpookmyvrHnHPOmdCeuewFQ0mNfTDnZDS8//Of/zQmt/u7qqqEl8OsvfKs3Y31gwIDznhAcLfcckv6wx/+kHcYGudwtNFGSxbNBBNMkJO+853vpFlmmSVNMcUU+bu1PxQI3tvW8pV0lvM//vGPNPnkk+dFS5k6ctgux9hjj12y9OonZcHibUlJ7dUDaKFz00wzTVphhRVayNF7k2adddY044wzttjBaaedNt16661piSWWSPLzNLVYYFjiEUcckewWjDrqqMO+UmIE2LFoyhDPGZr5M9lkkyVengUWWKCZHC1H23V46aWX0hxzzNFyxmGpk046aZprrrlSVVXDvpr/nxHPgGo+R9Mp6l9uueVarb/p0t0XyxHBYz399NO3uZGpppoq7z7hR6XQDDPMkHdhF1lkkRLV7PPBBx9Ml156abPpJcHuFQ8fPrfMMsukSSaZpCR16GmXcLfddhuh7N57750N6DHGGGOE+L70YR7sHk455ZR9qdtZhg4aNKjb+0xJP/fcc1vcLe3OTuAXDCT0+73vfS8r2zvuuGOiR3Rnu22te6yxxso7rj/4wQ9aLcKQ52ig6zAgODH/9Kc/pXHHHbfVsiMjA0ONjJt66qm7pPlxxhknGS+eSe/rkkr7cSUDznhgRVvwPJcHHnjgSJ9aOw//+9//Rno/2t6BEXM+/fTT+ZgWxjNiSv/4wnz7x0i6ZxSM5Ztvvrl7Ku/BWim9DKOONmkXp6Nl+1O5M844o007tF05ZgrkiSeemPoyH+1KPAZKXbzDjnIxVnmMR8a47Z5xYoyMtru6TbuBdtq7ut6or38iMOCMB+dHect32GGHfIb0ppu+vtfQFdNrB2GnnXbK3gf1le9TTz01nXPOOfkc4aabbppsRUt3HtQ5bEdGhg4dmr014hsDry5PHW8rT62zvHYs5LvyyivT9ttvnyhwPKfOXTp/iaE5bsNzPmTIkOHnMMVTkg466KAsbDfZZJO06KKL5v7BRd2LL754YlgVhqx9OzWl/d/+9rf5iIHjBmuvvXY+s/6Tn/wksdj1Sf7jjjsu3+FQt36Jk/bQQw+lX/3qV+mss85Kxx9/fDKeFVdcMY/djs9aa60lW+4bT+fCCy+c+5Yja38YK9ddd1366U9/mv7+97/nc/jzzjtvPuPPG3755ZenwYMH57Pa99577/CStnB/+MMf5vbcKynnuD133333xFupv7yhaGV4wW9e9LEEx3ds9RJePM/if/e73yVjdRzI+HgNHXlzHt5ROWU8F1poofTjH/84n5U1/99U/62HLVTHSBZbbLEk2EZmcG677bZ5DNpER+eff37G2+7BnXfeOUI9FOP1118/mdfbbrstp8HvggsuSD//+c/znYcc+c2fp556KqFTdcNCe5IIaudmza1v4/PteIK63RVCQzD+0Y9+lPvHC+dug/wCTDfbbLNkruzQwUN8c8Eakh8tO79u7uxy8VrDVH2lrHal63cJaKB+btc2t2MGzvRaB8q6P7Hlllsm40bPe+65Z+JkkNYYHn744bTBBhskdAm7gkU9n+NU6623Xh4/XHjzpKND/UPz2qB4/O1vf8v59Fd99W9xhPkVV1yRd4d8q8cYeAV9L7XUUum8887L2+3SKADuX2hHunsv3zqyJGNDwEd4J/XtyCOPHH70Eg+wzjbaaKNkjSiGtvEJ9Vuv3suY0cvRRx+dxySvo3P4kflTvzHefffdCQ/ZaqutZBkhWLcwg7G5xWOsIW2VOxLHHHNMrh+v0z9YmFM8cMkll0zGArcDDjgg88bSAGVTf5ZddtmEt+BxhY/W8+ufcakLbZTyN954Y1LWWje/5rOkNT7R9f7775/7aWfPsRF5zJ05drfNWtFH4z355JMlDw/W2rrrrpvXCZ6EVoYnNrzY+cMbYOTMvd3r8o0+7AzDUjq6cMRD/8gUdIxnoDHVwgO+dgXlw5utcwbav/71r3wnz9r59a9/nez2KNPWYNcfLemDvuBNjmhZAAAQAElEQVS3jgiX8vBwbAbvlV6CI0HkVslXnu7KkDtoBp7oTBy80PDFF1+cz+0b29NPP51lgzrJRJipxxjw1FVWWSUf1zQu81G/f6OPQ4cOTfPMM08y72gcT0SXeJI7Qcorp07y5+CDD85zD1vzLb/x483oHo2SFeS/9QpzdeCVsEfb+D4+hE9Zl3SWN954QxM5GCv5bUz4l7WSE4b9UW6fffZJ5Ix7mHZHhkU3+z9aRe/WcZEtMpNv+NdKK62Ux293z3FIacaJhpQl45SHu7SmAl6pP+hHPdaC+t2xIsfpBGSp+TEu6aUesgpN00HIDby6pJUnWekuFTwE79LsrlsH1rw17Bsvmn/++RPacpxVPrIRjzFe33ipd3NoHcClK/VFbfTlMKCMB8Lj9NNPzwzFRdHxxhsvYRaIpLOTSBkbf/zx8/0F5yDLN0bOO6t+ghzzxCh8EygWnW1C/aLkia+HwlAxmxuHCS+CkjFCUaKkEgKUB8qUYzaUOYYKxmGHxSLVFwwIAyOECCYLBtO0EN23IEiVtTgJLe1YTNrnTZSfcFaPrT0L0DYtxdERFExfv7RFMSCMKZOYC8ODgkEAwcb5c/211WuRYxSzzTZbopip2/gdldAPDBXDFlcPGAVBh6lgOI6W6b/Lt4QIAw0Dx4wp64QExotZqI9CSWlneFGueI4xN8xdP/XN2Ottwo/Bob+OvtnmJJjVpR/mkOKEgZoXQoVgI7gdC1KeEkU5ITDMjbPyGGi9nfo7IWbOKNHbbbddMkZC0diGDBmSjAkTJDzVz3ilEJQ64EABwhTtohBclD/zhDmbV+8lv7b02bxYHxgw5YHg00/5y+VxQo5RQolHKwxFij0hAAc0i9k65gQPwg3+6rYO0A0aLW039TTHjEM0jombJ3OvD7A3d8pRbCl1jB60SdiqG41T+OQRrKGZZpopKwGMLvNAoKED2+CUCoZ1c1v1aJng0fbEE0+cKCXqrYcJJ5wwzTzzzFnRUh9eAwdzQ0k0pzBmWJm3lVdeOeFN6I9BSZAS0DBC19pzbIUSYq6sQbwGv2CwM8attTTsP/S13377JYLOelWvNTAsqcn/pVszjBnlKFoyUgw88Ubzpv9wF2fN4z3aR0/WEdqwpr///e/n42jSrHX5GLbWiLGW+bJejFF9JVgX6JyybQ4pY+pF6+a95IcPGje/4s0jmlp66aUTvqgd/YaxPOpHv/iAvqMJc0A5o2yjsZLfvOq7uaqqKpkja8IYKVDWAn5obAUP9TcGCqwx4hPWHl5vrcObA0W8uihS6rWuKanqwYMYa5Q+uDtCYs1KayqgD3RDmcQjtIf/48EMb/SF/1ireAZ+b+06EqV+6Yw1WDHGtG++pFlH+CBatI7xOLihRfwLrk31qak469jF+CIH0Swejz/Kj/bghH9qD1b66AdE0L889WBtUMAdv8RrlMPn9Z/MNW/WOh6J7zhtIA2fQrfq0n9GkvlgFEjDL8gQO1nWG3mGt+AxlFC8RzmyCp9zLFB7eKC28BLpeKF1CCdjMB7ryrjRoWOFZCg+bK3qg3GQMY5jokFjwifRON6B9vSbbDEmc4LOtYUPWy/WHBllXGQFWjK3yjUX6EHaJ/f01RowBmuabBenb+YKz8ETYI3GtP/cc89lhwo+31Qbp5xySsJf8Brr0Di8k7XGr270YS3CHp+Gu7qsSfSK9hxRYwgpL60eyDe0X2iFQ0E6PoIOrDFzZSzoEI+ZYIIJUjFM9R3dkZnKmUtrFL/VNnpglEmLkNKAMh4sJkRPOCEmC8yiwiQ7SwzO7mK0pZ7yXVVV3nGgsLKoMXpEWfK19sRwMBnMnXJI+GImFh3CZ40TBjy96sZALBYGCW8EhYsw5VEgBAh3Frh0SgeBy9taFi1PiLrUiSHU28dICRdnvDGppvoOT0yUEkewE/IYKGGD6TISKFfOoBNkmADvEUapXoxCvcbJI1GYvLh6kJfg14Zx6zdmqt+ErfZhwzjCnAh6zNBYKRrmwBPDcCYasyZc9E1/CX5YaVM5zBQDGTx4cCIM5JNG4Iw55ph594M3hJA2foooocbAYAAxogh0ZWBqPtAL4YdWxDcGzJnxqX8YtHsGQsEIc6WYyuNdX8x/vR7CAE68eRQh84YBoiFzUc/rXV/MB2FlHBQb60N/KdkMCvmaC4QNRUxZnkoeNAIb46UEUrjha/4YrIRnc3WJ5+0jFODOG0wRJeAJgaqqZMmB0myejJ9ibQzOrVLycoZv/hgP+qaAmiN0/01Smx7qNC/aMh7rp16QgksxoGwQXtYZWmaMW3cENAFMwKF9Cg7eADPCDA3iT87yMtTUbU0ZF3plrPB4o1sGFZ6Axihe6IqQlhevsQ54KwutqqsxGL/+8qDqn/5aO57yoge80jrzLeijdvEHypTdBHMkrR60bz3ql3VHsaWIoPum6Eh+64QCWbCh/KBV/Sh1W2/ylu+mntZufdww3GOPPbLx7V6HdEYumUBp8S0/esRrjct6wWdhjXfit9aBfPppbTXVtjh8AO9RzvrVZ/wTbZpbGFLs8WYKNHqgtGjL2M0hfiY/Dzdeot6mgrqHDh2a5EEz2uQpNYfWIJ5tvhgteIG1Sfl0Lh9fMbeMZUqS8+MwUId1StE3Dkqs9Y8XWMvymEtGVVN9aowzLkqnfuK1xoufGrM+oH8yggMMnUunhOs73Brra+rbeuZ0QhtoBr4MHXwD/7PO8H08yPjUYS6VMR/6RpaYf/yJom+dmz8KOQMOfpR7fED5ekDnjC5tWEP6Y34ZbehFHejCerXW9AfPVp985sGc4x2cNupjIFH+1YEX0l+0aT70myOQc8g6M6f4C/nAEcdIRuvaYaQq155ATuAn8NMPdVHAGbnWzKBBgxI6sC7wVGNkNDfVhnywM3bjRHtowrrGX3ybd7TOaNZf/EVd5pNxjL7RAt7hKa0xkAt0Blgz9qRbs+SeOnybF3MpzhqnL4nHl/THu1BVVb7HhkbRiblCl9IipIFjPGBCFCzCktJMWLLWCW+KIkJuP0G0XgKhYj4lp4VQ3tvyxNSKIsAKpjgYS70shVK+epzFWFVV0r7FaiFi0Omb/8RVVfXN19cPC9ubujBHTMJ7aZ9nFLNqbF+ZEjCwqqpSWYTK84wTTrwUJZ9vfSvfBBPGgSkyMjBBiiemU/I09VSHsdbTfGtXnHGaY/NLIFAaMVeeDkaFPPVAsNS/vcvHW0IwY/riSuBFYpigKwET5f0g9OXRj4KFb1u7hABa5DXCCAk6aY2BJxGTw8TVLVCACBNjlJ+S70lJYKh5rwfzCANxbaE99Za+KzN4mLFk/BRg360F9EHh0ldBnxhbFBnKLoOl9EddlBXP1gIBVVUj0mu9DAEAR3NEsKB3igiBV89X1iJhUFXN12e7Go8ogUecMKeQUP4JHcpOo/GgnHES7FX1df0MGEqWdQMTgdFnPVkH6IFBZHeOUsM4oexQ3Mw/BZexXVVV/vUga0we9RgbJY+yWVVV/hEIQta8S6NYtjTv6ufJs1MivwCbgpPvxqDvPMKOnVD00bf5acxXvvEVPKp8N/ck+EsaA8p78Qp670xgPCiPB3gK2oA/Zdi3YL1aA97ruHHgMAYZHOiZQkIRlK+pQBFlXFDIKXIUlcZ8cBHH8NKud7RifhkYvgXrsb5mxDUGfaXYMaLRPn6AN1AsGQ14HiUQPRiv9Yx+BHPDE8vAK/XW+SAl2u5VnX4ZPHh1GUMp19yT0astdFPyUMTwU04X/XGcCa+zQ2MNK0NBRVvWT1mLnvhxqaepJxou8eaYIQIHhhkD3zor6eVZxlKfD2WteX1Rh119/W5qfagTtjAuNGTe0Jk0/Ly0ZU7Le3lWVZWUrX8rX76l6YdvckedMBUo25R3a8gOHpzLeOTHEzzbE9Cs8dT7iq8x/sxRqUs7hX5LXOOTccRxg2Y4k8iIxjxwL3HWTnmnGzA88Ec7EgyDktbU004a45+sRE9kPdqXlz7BOLRThI6MQ5y0xoDurGNHHa0t+hADpzHfQP0eMDsPvHoIydYfohEwIMoegsTgeyMRWGS22CkvvBI8EBZwT/WVwNA+jwpvLi8GBtVc+xgOAQjrkgfTw0zrzKGklScBRhmhzJgjChhPVUnviifmTdGiwGIKmHpb6sUc7eJgyo538OKVctIoerZVS3D0C24lT/1JyBNCGFtVVYmHiqCv5ynvMKGYUdZK3YwfigxhKx9Di3HG28WTL64rgz4YY12ItVS//O4zlP56Uuyrqso/eVyni5bqaW8aJQSulFkeJPRji7uuBDVZZzORlG90W0LJxhiy/W4d8Gpqs8yFPHaZ0DpBx2spjoEr2AmDRwk8bOYNtnZBGcyOMaIvdEpw21VSDyWq1IWGKG+lHk/KDOOGUVHvjzItBQoIWmVct5SvnsbgI0yddVbOjgKFt56ns+8wVEdd2ffd0cBxAp/iuS31UFLgX75bepojY6ao8QzznDeVH/5ohCGLb/B4mrOm8jbGmQ88Hw00prX2jSYo3Y7icYzhn3iFo3N2G/ARdVD0qqrKx8vQTgloVHpjsBak4ZclrycvPcdMY/6mvuGPjhk2Jb2qqsR5Yq7Vbz1Yu3ayPBkM7oTggXApa9ETnyn1tPZk/JgH7XNQ6bc6WytX0s03R481SY/gXSfjSnr9aZwMS2uqxOOfMG9J/pW8bX3CjMfePJRAppkP9Neagt2WdqwX/Eko+bWL17R3LPiYI5/4JhlWN+5K3c09Kf+MW+uIIcd4aS6veHiT02jeESWGL74tDd2Yf3RF9+PA0bf6fMknGKs8HH1kOp3Rbpu0CGlg7DxQWCjAGL/t6XrgRcLQitBGFJiMhYNhlW9xvsWLayqUdHnlK6F8K4O5yCeufMtXvsV5FyevvlPceVUJ7aqqknhKuqAu38ooKyhbvsu7ZwnKCL7ll9e7eurf8mif4cKTUdoXr22hqqq8tUfgUSQoisowyMSpG762PQmEUr+2tOm7BF4eyhgPivfWFAftq0Mb6vAs357i9NW7wNugL7wHBFDpH8ahP/J7qse7IA/BRjnl1eN5dCbeGKXbHbEjxLNpB4JXi+BWv3q0q055BbjIiwadM7XdzLMsrTHwSOsbPAhS9fN+MHThw2Pnvof+YK6MYbto2tNuad9T3fV43wWbki7OuzaVp8DY6TJv6E+a+PKUn2KhXgJLkBdGGLf+Etz6C0deekfRKJrqMX/KSvNUX2MobTWmi5fXGDwp2o40Udh45RyfgnEp15i/lNMH5Y3D0xgEnjJ4luAoQVVVibAhnKT7hR/4GKMxKM9jzHBgaFLeYGDtiKfAuO9jndjNMa/WhXJ29whF7emznQBrgcA1H5Rc+TwpiNpmKHin0ChTVVWiUMCeES6/8Qn6V8YsvgReRQom3My3eVGXp74r411+8Z7WETrnxHDcEC3a2pcGR/n0S1m4ewrSBfUJ4jzFCdpXVrwxwdmOijTKlzHAQj5Kknhj5YJZqwAAEABJREFUU4d2vZs7+cRpuzz/j727SW4bBwIoLNwg66xylBzBR/AyB86BZj5VdRVHlifjsS2T0lugJJIg0HjdaDR+ZNOfPmkcUIZn+rBPk39l+T75XZPDPUmfFoTbQTPhF6g7sy3fZcJCwGPFlO49V4Z6yagOSVvnmU/PBNN2yxzXwtB78vnUbt/lvZa8KwBnV+oV4NlNcC6f3DNJsnii7exxbIgdCxLJpS71aL96yGPByHEQ+cjlPYEZu5bnMinH+z6VZ0GBr8NQcO2+cvQDvzEgq7LpznijDwvqrPJ7n43qG5P0DXXyzT69p18pVyK/9zyz42C12+TdJG7kog/55Jd8l997rukDE7pUvl1jO47aPsG5suSX2KgdRH6Zn/NM4rPVbaxQrqRsdU2auuV3T3nyzfV89ynxF/iTTbslk1ljJh/AH25lUL42qNf76rhM80zdntGJevwOwO6Ge+PrZiKqLDJKnr+W+E065DPozHuX8pDR+56RwbXvYjNBP3/Ohj0jK/157lr9vntfslNrsm+SYBJg/HLfWCSe4rO0wYTATjJf531JeT7p2ZFO75p0Or5ngUc5eNtlV6/rR0x3v/PAQXFCBm2D6gw6o2xOyqBiFdG5ZCtTgkSzVYOD5zohA7O9bzWT4cz788kZG5h0CM7PYGO7a3vtSIMzo4xOHX7c5xwdB+UZo2awzoD69Iw8OpzAiHyCRXUpxwCrDoGK98nsvuNBylaeZ+QxoDkDaRvbypTzgMrkBF1rEwYcrUDCirbynfU3QFjJteWofg5fEIyH4MPxENvBAhoTDDsIgliDFvm01aqI1R7y2QFQB/mG33w+PT2d/7KMwV6nn/uXn9pqkCSLgda1ukwODELqwYBzFXi71g764FCsIHjHChLn5AgKZ6RdznPKR07MDQYGPe+bRPjBu5UobBwN4HjsCjmuhCEe+Gkfp2urm461QZ1++8BW/OCOLg2qnl1Ljj1oj2DF+XVttBKmXQJYAwUnz7EKtjhDwTsm7IDefbe7oY2CSm1hn+6zM4MDDlbpDT7ax2nii4Mgg/NmP1jqS7Z7OViTBQ6ZrbpvS9gWucDZCpOjHvQoAGEP6jBhF9zTj8HI5Ml2vPIuGbAj7LSJbXpOx/TEybN7jLUTc8GTo1Z4WcH0I352Kr/y2bw+oTyO37X6Be4CFbyxZVfqukxsmf7w4Vesxuo72k8e8goi7AaxMQOOfsROTAYdOTMQWblmM9vy7RzRpS1398lvoiu4ci1hK4hzDIX+2QS/xg48Z9s4WfnWDv3c0R/BE93Ls030QleeC8j8doK9WV3EzkQPO36T7WGsTBMkwQoO+rVgda11EmDJz3Zwpx82j7f6Dfqekwl3ExHyWNnj9wQZuJmQ24EU6Hpu1ZGM2uU5u+Vr+Gf9j78gF/351HYBFHn1Q3ZHR2xHGWzZhNtuKr3wkfKbFGHA5+sv/K9+wh7ojA/0rjqsYJLtMvGJJoX6kfz6F9/CNtiC5Jpv0Q+1mw3jjcvz8/P5n5OyHeONdrNd+ch/Wd9cm0DZ+RKk8hFrrRM7dI+tTD6BFRtiy454CIjJpu/SifGJDeGl3d5jm2yM/erX+rCjJJ5dS3yqMjDl603qlCevRTxs+QN+ayZvfIC85P358+eJbshGfwJJ714mR07YH7/Ln/JB/DYfzjblZ5tshf7III/yRo90zc8JxunDGMfe+WgLPa7ZOz/OnvUZEzU2gxudeaYf4m0cMOk3HhoX+Rs7deo0DvGh2q9e8ulvxleM3Ndv2K++om764Kf4WTy9xzYwwkeQbCebjRt7rO47pmNHQj8ipz6Ir7pMQtW7TWSkD/2K/eMnLjKe6BP8OJ+Nqd/T0Jvxj20qU5/clnf53bjJZzmKqa1rrZO+ry3GAT6UfeND3+IU/URsYtLx+/fv819C1B9MPj3zI3O6pDM655+Mp1O3H17bceCjTTrmPr2Sg87Upy38nbYZR7QdZ35F/9VP+Tq+hn9TjgU7x+zI4voR091PHiiV8TEkBqQDu7dNnJkBhdPnRHRAgzCjY9Scss4qn+eCju37vrsnnw5oUNHx5d1eC9CUY+ttrXX+c5ACR47G+VmGb5CwSmPwFcwoU/BmhY9cT09PJ7LZTrM6afuPIXtfnWb1jhF4zhmRQWe3yi2o0X4DiaBD51CfAMVxD07WPUEoZycA07Zfv36d/+qIwIVT4kitaJHdrNzAYoXCwKITCkb8mNTsXv2uDVJk0x66sHpHPuVvkzx2LwQTa63to398V65VJCtR5Hct2a40qAnkDHzkMpn59u3byco3Z2CwUgemtiQFjmSlB85YRd4nH2chWGQbWPlhtrYJDjznFP2oDE/lqpvsHLS8dOPICe7KtTLF2bMX+mBTyvDsWrI6IogyYCtfQGnwGo5WFL1Hb9pCz7gITnDGQ152LEiiOwOu/NrgB9v4kc+1AU+b2aKVU0zkV4cyBVxjF+7Rq4ELT0kZnK124S3om+DXMwESG2arVjPVb7Bl22u91LeVdu0yUKpfnT4NCgZ7fUBZ2sz+DJj6i0kEPRjcBEQYy28CiAVfILizso2FCboARN9QNntR12XSFwRf+Ajy8TSxUr7AVzl0r1zXWLJLfcUAiwtm9CjQ2JYvAPZcm93Xp5WPjWtJ/zLpYHPsiH0L+vRdz50r1k5ttzDAh9EHnzR55JvENviKeYfsWHtHEEcWbdLHlaktBk2JHjxnYwJLZWoXH4cjnWi3Puc5G9OH5NP3TMDpzrU+pg6+h0zKFAR5JulXbJMNsSv9FAOMBI98DFvClJ0rlw+TTz9TL07seWxGmWQ1ueUrJj8fxEZMjMnFx+lnfA1/q92CqufnZ6K9SGyH3rRRXXwlf44JXQrsXWsr2xP0GX+sTrv++XfgbGJKt5ixN23DVt9/UeHmhkBI3dNn9TE+ge+ebGzfERzBNr9ifDBx9JzfIy9OuPFT7puQmAA6ssPG9FmcPbuW8NcmY9Fa66RcfYQO+UBBqr5hUi0QVwY2xkZl68Paj40AT355LhP988d8FX3qi3TKH7NV+dkMfo78ys9W2KRxlm7JY9LJjiw2uocheddaJ3qmMxMKHPxmklzy8gECa7bOZujec/2YHZGHLORjg54bj/xImg8hn3KMq+xLfuOKmEXsQDbPtQVPNqAcsYFxQd3sip+lN+Xp59qjD5kAGNvIxB+xRwsU8m0T2dXJLvVz1+Tnk0xA9GM68AdY6EgZbNMYpx7stuVdfmeD/Dj+ysCfntgn/eNNfv1QW9mAvue7fksu7+KhLH2LnGut8yRTTCTv2Kv6yaQP05lrST9m82xNe/g4izk48QMYkw9jujLhnD7P9/O5yuGb2BS9u37EdPeTBwZE0YxRsrK6VbR72/Tjx4/zn3GcexwYg51rxiOQ3JbhO0PTqSYfZ/Nv18o1oE9+nwIe5fg+yWBg4BVsCxoMChwWozeQTD6fZBeY+S4pT0Dn+6TLax1jnvnk5DhZ3yUD2dQvOPv+/fs5CBcAGVx0OIM5LhwaFhyL9wwAHDUnLZ9nnKRyJfK5t01WM7RRJ9/ev/zO6XA+ypFcq8t3idPjVH2XOFeDtfrlMyAbUHHlGLfcDI6CNHm8O0kb5rtPOsbA+1bJlCsQJ6tn2i8fvXHo7mNpkDMIyK8OZXh2LalTMCsv/pyefGM7Aj/X9Db1mXBsdeiaQ5znymHTZCCfawOmcsjPWbuPw9bWt7zpdK118p78AhCDjUQX+hxnq55t+wxebAUv9sqO1SmgUf9lIsckgaHnGE7fwpZeBaLq27bboE0ug8zkx9EkjMxTriABZ/ZCNquU6rmWyEt27woABBHatC3fgEUv8khsUfvYG/nIMG3Z1sHmBJDbeyZeW36eGehw1V6ct/JqB3sxILIztomBCYB3ryWyYUBW/YRuvYOz9inHM8k9Njv3BFbqEPArGwt8MOAPvDNJnyafNs298QHqUSe5vW9Cr7xJ7FCdOKvPpIgPZX/y8IW48kv4bPszfat3rXX+/w7yqUfw6r73t/lN/MgyMrIV7aZvgYd+wL/Rl3evJX6bfgREZNMH2ZfJ65SrP9Kj/uee/HRH3/oEOdk33iZr2j3yXqvTPeOHIEsQ6povxtKn60nKwUV76Ny4uNY60T1ZJO00Psw7+vXo4N8mDvJv7V+71b/WOuHC5yqfTxI4ym/Flz/CZJ7L41pfmfbIu03Gd34KJ23Q17wn0bG8eGorvvLqL9rBRvkgeSXt1f+U5VrdbMSYSSbvswHvr7VOdCLfJGWrT5v4Cff5E3ojgzZg7b40+dXhWtKf6UAfcC2x9bGRuVaeMYXdktsYrO5JJvXqol82pq8oZ6vPyesTH2VPUq77ZBZ8Y4kHviYjnhlzJr9P915LfB975v/0B/0US+OZPuJ9CdNhN9cmNd7TFhNB9eqT2miclU/iG779vUg4Mti90S6+Y+5pP/+jLO0xjrrnuTIm6e/8CDvRdveV5Z687J8Mc+3eo6W7nzw8mkKP2F7bj4IOQZ7ZPAciCD1iW5L59gTs6FkVNFDbXrbVb0vcro8jTwaC20u13xqTLAJ7I+BojH5sp8LxGH3YESa7IyaWAvK9yZw8+yNgwmA3wATMcS2Tpv1JeR8SNXm4Dz0euhUmDo7CWIlxDtWK5aEblPA3JWD10NliK4bO0zv76jceVj8dY7qpMFUWgQi8mYAdF8eT7LI4c68PO3duVd1O+5sLvO8Xat0rBPxGanY4/LbBztQrWbv9TgJNHt4JsNffT8BkwXln5zcdWXp/iZXwaARsf1u1tPNg5dK5WEckHo1D7Y3AUQk4XuWcu99W6MN+V+KI0FHbk9y3J+B4pt+O+F1JE4fP5d/k4T18ezcCEYhABCIQgQhEIAIPRKDJwwMpu6ZGIAL/JNBVBCIQgQhEIAJvI9Dk4W28yh2BCEQgAhGIwD4IJEUEIvAFBJo8fAH0qoxABCIQgQhEIAIRiMARCXzc5OGIrU/mCEQgAhGIQAQiEIEIROA/E2jy8J9RlTEC902g1kUgAhGIQAQiEIE/EWjy8CdCPY9ABCIQgQjsn0ASRiACEbgJgSYPN8FcJRGIQAQiEIEIRCACEXiNwHHuN3k4jq6SNAIRiEAEIhCBCEQgAl9KoMnDl+Kv8r0SSK4IRCACEYhABCIQgZcEmjy8ZNKdCEQgAhE4NoGkj0AEIhCBTyLQ5OGTwFZsBCIQgQhEIAIRiMD/IdA7eybQ5GHP2km2CEQgAhGIQAQiEIEI7IhAk4cdKWOvoiRXBCIQgQhEIAIRiEAEEGjygEIpAhGIwP0SqGURiEAEIhCBDyPQ5OHDUFZQBCIQgQhEIAIR+GgClReBfRFo8rAvfSRNBCIQgQhEIAIRiEAEdkugycMbVVP2CEQgAhGIQAQiEIEIPCqBJg+PqvnaHYHHJFCrIxCBCEQgAhF4B4EmD++A16sRiEAEIhCBCNySQHVFIAJfTaDJw1droPojEIEIRCACEYhABCJwEFWbG/YAAAEdSURBVALvmjwcpI2JGYEIRCACEYhABCIQgQh8AIEmDx8AsSIicFACiR2BCEQgAhGIQATeRKDJw5twlTkCEYhABCKwFwLJEYEIROD2BJo83J55NUYgAhGIQAQiEIEIPDqBg7a/ycNBFZfYEYhABCIQgQhEIAIRuDWBJg+3Jl59eyWQXBGIQAQiEIEIRCACfyDQ5OEPgHocgQhEIAJHIJCMEYhABCJwCwJNHm5BuToiEIEIRCACEYhABF4n0JPDEGjycBhVJWgEIhCBCEQgAhGIQAS+lkCTh6/lv9fakysCEYhABCIQgQhEIAIvCDR5eIGkGxGIQASOTiD5IxCBCEQgAp9DoMnD53Ct1AhEIAIRiEAEIvD/CPRWBHZM4C8AAAD//0QR73UAAAAGSURBVAMA0BtbrXFtxawAAAAASUVORK5CYII=\"\u003e\u003c/p\u003e\n\u003cp\u003eAll inflammatory markers exhibited right-skewed distributions and were log-transformed for analysis. The primary analysis was based on continuous variable models; dichotomization by median values was used solely for descriptive visualization. Serum albumin (g/dL) was also collected to adjust for nutritional status and the influence of cachexia.\u003c/p\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\n \u003ch2\u003eStatistical analysis\u003c/h2\u003e\n \u003cp\u003eAssociations between inflammatory markers and survival outcomes were evaluated using Cox proportional hazards regression. Multivariate models were adjusted for age, ECOG performance status, line of therapy, and albumin to reflect host status at baseline. Given the high correlation among inflammatory markers, each marker was analyzed in separate models. Markers showing consistent associations were selected as representative variables for further analysis. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated. The proportional hazards assumption was assessed using Schoenfeld residuals.\u003c/p\u003e\n \u003cp\u003eSensitivity analyses were performed using models further adjusted for PD-L1 expression status. PD-L1 status was categorized as negative (reference), positive, or unknown. The unknown category was retained to avoid case-wise deletion.\u003c/p\u003e\n \u003cp\u003eSurvival curves were estimated using the Kaplan\u0026ndash;Meier method and compared using the log-rank test. As average hazard ratios may not fully capture the clinical course of immunotherapy, survival probabilities at specific time points (2, 3, 6, and 12 months) were presented. To quantify differences in treatment courses given the non-proportional hazards often observed with ICIs, Restricted Mean Survival Time (RMST) was calculated at 6 and 12 months. A 3-month landmark analysis was performed to minimize guarantee-time bias resulting from early events.\u003c/p\u003e\n \u003cp\u003eStatistical significance was defined as a two-sided p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05. All analyses were performed using R version 4.4.1.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003eStudy population and clinical efficacy\u003c/h2\u003e\n \u003cp\u003eOf the 121 patients treated with pembrolizumab, 95 were included in the final analysis after excluding those with platinum-sensitive disease (n\u0026thinsp;=\u0026thinsp;17), those receiving combination therapy (n\u0026thinsp;=\u0026thinsp;6), and those with other confirmed malignancies (n\u0026thinsp;=\u0026thinsp;3) (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n \u003cp\u003eBaseline characteristics are summarized in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. The most common histology was serous carcinoma (76.8%), with high-grade tumors accounting for 92.6% and FIGO stage III\u0026ndash;IV disease for 91.6%. The majority of patients (95.8%) received pembrolizumab as third-line therapy or later, with a median of 3 prior lines of systemic therapy (range 1\u0026ndash;9). An ECOG performance status of \u0026ge;\u0026thinsp;2 was observed in 24.2% of patients. The median follow-up duration was 54 months (range 15\u0026ndash;77).\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eBaseline characteristics of patients with recurrent platinum-resistant ovarian cancer treated with pembrolizumab monotherapy\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eAge, year\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTotal (n\u0026thinsp;=\u0026thinsp;95)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e56.1 (10.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ge;\u0026thinsp;65 years \u0026ndash; no. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e18 (18.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eECOG performance status \u0026ndash; no. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u0026ndash;1 (good)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e72 (75.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ge;\u0026thinsp;2 (poor)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e23 (24.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHistologic type \u0026ndash; no. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSerous carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e73 (76.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eClear cell carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e14 (14.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOther \u0026para;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8 (8.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTumor histologic grade \u0026ndash; no. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 or 2 (low grade)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7 (7.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (high grade)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e88 (92.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSurgical optimality \u0026ndash; no. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOptimal surgery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e39 (41.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSuboptimal surgery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e56 (58.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFIGO Stage (2017) \u0026ndash; no. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eI-II\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8 (8.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIII-IV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e87 (91.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo. of previous lines of systemic chemotherapy \u0026ndash; no. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4 (4.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u0026ndash;3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e45 (47.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ge;\u0026thinsp;4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e46 (48.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMedian CA125 (IQR) \u0026ndash; U/mL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e310 (89.5\u0026ndash;695)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMedian albumin (IQR) \u0026ndash; g/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.0 (3.5\u0026ndash;4.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePD-L1 expression \u0026ndash; no. (%)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCPS 0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8 (11.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCPS 1\u0026ndash;9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e35 (51.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCPS\u0026thinsp;\u0026ge;\u0026thinsp;10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e25 (36.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePD-L1 Positive, CPS not available \u0026ndash; no. (%)\u0026dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e27 (28.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMMR status\u0026ndash; no. (%)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003edMMR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e31 (64.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epMMR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e17 (35.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNot available\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e47 (49.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBRCA 1/2 mutation \u0026ndash; no. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNegative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e69 (72.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e18 (18.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNot available\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8 (8.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePrevious PARP inhibitor use \u0026ndash; no. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e16 (16.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\"\u003eValues are presented as mean (SD), median (IQR), or number (%).\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\"\u003e\u0026para; Includes mucinous carcinoma, malignant Brenner tumor, or mixed histology.\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\"\u003e* Percentages were calculated based on the number of patients with available results, excluding those with unknown or missing data.\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\"\u003e\u0026dagger; Indicates patients confirmed as PD-L1 positive, but for whom the specific Combined Positive Score (CPS) was not available. Percentages for this category are calculated relative to the total cohort (n\u0026thinsp;=\u0026thinsp;95).\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\"\u003eAbbreviations: SD, standard deviation; ECOG, Eastern Cooperative Oncology Group; FIGO, International Federation of Gynecology and Obstetrics; IQR, interquartile range; PD-L1, programmed death-ligand 1; CPS, combined positive score; MMR, mismatch repair; dMMR, mismatch repair deficient; pMMR, mismatch repair proficient; BRCA, breast cancer gene; PARP, poly (ADP-ribose) polymerase.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003e[Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e near here].\u003c/p\u003e\n \u003cp\u003eIn the overall cohort, the median Progression-Free Survival (PFS) was 2 months, and the median Overall Survival (OS) was 7 months. The objective response rate was 8.3%, and the disease control rate was 28.5%. The median duration of response was 12 months (IQR 5.0\u0026ndash;41.5). The 6-month and 12-month PFS rates were 10.5% and 7.4%, respectively. At the time of analysis, 79 patients (83.2%) had died.\u003c/p\u003e\n \u003cp\u003e\u003cem\u003eBaseline inflammatory marker profiles\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003eThe median (IQR) values for inflammatory markers in the overall cohort were as follows: SII 752 (364.5\u0026ndash;1647.7), SIRI 1.6 (0.7\u0026ndash;3.8), and NLR 2.7 (1.6\u0026ndash;5.7). All inflammatory markers exhibited a right-skewed distribution, which was reduced after natural log transformation (skewness: -0.76, 0.57, and 0.73, respectively) (Fig. S1 in Additional file 1). Consequently, all subsequent analyses were performed using log-transformed continuous variables.\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eAssociation between inflammatory markers and survival\u003c/h3\u003e\n\u003cp\u003eIn multivariable Cox analysis, log-SIRI was significantly associated with both PFS (HR 1.35, 95% CI 1.04\u0026ndash;1.75, p\u0026thinsp;=\u0026thinsp;0.025) and OS (HR 2.02, 95% CI 1.53\u0026ndash;2.67, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Log-NLR was associated with PFS (HR 1.42, p\u0026thinsp;=\u0026thinsp;0.026) and OS (HR 2.42, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), while log-SII was associated only with OS (HR 1.53, p\u0026thinsp;=\u0026thinsp;0.002) (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). In the multivariable model using log-SIRI as the representative marker, the proportional hazards assumption was satisfied for the PFS model (global p\u0026thinsp;=\u0026thinsp;0.107). Age (p\u0026thinsp;=\u0026thinsp;0.564), ECOG\u0026thinsp;\u0026ge;\u0026thinsp;2 (p\u0026thinsp;=\u0026thinsp;0.106), line of therapy (p\u0026thinsp;=\u0026thinsp;0.153), and albumin (p\u0026thinsp;=\u0026thinsp;0.408) did not show statistically significant associations with PFS (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2.\u003c/strong\u003e Multivariable Cox proportional hazards analysis of inflammatory markers and clinical factors associated with survival outcomes\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariable\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePFS HR (95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eOS HR (95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e(A) Comparative Multivariable Analysis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003elog-SIRI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.35 (1.04\u0026ndash;1.75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.025\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2.02 (1.53\u0026ndash;2.67)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003elog-NLR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.42 (1.04\u0026ndash;1.92)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.026\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2.42 (1.71\u0026ndash;3.43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003elog-SII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.09 (0.87\u0026ndash;1.36)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.442\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.53 (1.17\u0026ndash;1.99)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e(B) Representative Multivariate Model (SIRI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003elog-SIRI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.35 (1.04\u0026ndash;1.75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.012\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2.13 (1.59\u0026ndash;2.85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.99 (0.98\u0026ndash;1.01)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.565\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.98 (0.96\u0026ndash;1.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.088\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAlbumin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.84 (0.56\u0026ndash;1.27)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.408\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.40 (0.26\u0026ndash;0.60)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTreatment line\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.91 (0.80\u0026ndash;1.04)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.153\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.89 (0.77\u0026ndash;1.01)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.074\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eECOG\u0026nbsp;\u0026ge;\u0026nbsp;2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.61 (0.90\u0026ndash;2.88)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.106\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.26 (0.69\u0026ndash;2.32)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.458\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e(C) Sensitivity Analysis (PD-L1 adjusted)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003elog-SIRI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.37 (1.07\u0026ndash;1.75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.012\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2.01 (1.52\u0026ndash;2.66)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ePD-L1 Positive (vs. Negative)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.92 (0.40\u0026ndash;2.12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.848\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.84 (0.78\u0026ndash;4.33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.164\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e(A) Comparative Multivariable Analysis: Each inflammatory marker (natural log-transformed) was analyzed in a separate multivariable model adjusted for age, serum albumin, line of chemotherapy, and ECOG performance status.\u003c/p\u003e\n\u003cp\u003e(B) Representative Multivariable Model: Presents the detailed results of the model using log-SIRI as the representative inflammatory marker.\u003c/p\u003e\n\u003cp\u003e(C) Sensitivity Analysis: The model was further adjusted for PD-L1 expression status (Positive vs. Negative). The unknown category was retained to avoid case-wise deletion.\u003c/p\u003e\n\u003cp\u003eAbbreviations: HR, hazard ratio; CI, confidence interval; PFS, progression-free survival; OS, overall survival; SIRI, systemic inflammation response index; NLR, neutrophil-to-lymphocyte ratio; SII, systemic immune-inflammation index; ECOG, Eastern Cooperative Oncology Group; PD-L1, programmed death-ligand 1.\u003c/p\u003e\n\u003cp\u003eIn the OS model, a violation of the proportional hazard assumption was observed for albumin; therefore, a time-varying coefficient was applied (Table S1). Even after this adjustment, the effect of log-SIRI remained significant (HR 2.03, 95% CI 1.55\u0026ndash;2.66). In the 3-month landmark analysis (n=19), the effect size was HR 2.11 (95% CI 0.60\u0026ndash;7.40), although the confidence interval was wide due to the limited sample size.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSensitivity analysis and PD-L1 adjustment\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eSensitivity analysis further adjusting for PD-L1 expression status showed consistent associations (Table S2). Log-SIRI remained significantly associated with PFS (HR 1.37, 95% CI 1.07\u0026ndash;1.75, p=0.012), while PD-L1 positivity was not (HR 0.92, 95% CI 0.40\u0026ndash;2.12, p=0.848). Similarly, log-SIRI was associated with OS (HR 2.01, 95% CI 1.52\u0026ndash;2.66, p\u0026lt;0.001), whereas PD-L1 positivity was not (HR 1.84, 95% CI 0.78\u0026ndash;4.33, p=0.164). The proportional hazards assumption was generally met in the sensitivity analysis models (Global test: OS p=0.104, PFS p=0.087).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSurvival outcomes stratified by SIRI\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eWhen stratified by the median SIRI, the median PFS was 2 months in both the low and high SIRI groups (Table 3), but survival curves diverged thereafter (Fig. 3, Fig. S2 in Additional file 1). When comparing the extreme quartiles (Q1 vs. Q4), the low SIRI group showed a significantly superior PFS compared to the high SIRI group (p \u0026lt; 0.001).\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3.\u003c/strong\u003e Survival outcomes stratified by the systemic inflammation response index (SIRI)\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eOutcome\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eLow SIRI (n=47)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eHigh SIRI (n=48)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eProgression-Free Survival (PFS)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eMedian PFS, months (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (2\u0026ndash;3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (2\u0026ndash;2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2-month PFS rate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e38%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e25%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3-month PFS rate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e23%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e16%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6-month PFS rate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e17%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e12-month PFS rate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e13%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eOverall Survival (OS)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eMedian OS, months (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e11 (7\u0026ndash;22)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e4 (4\u0026ndash;7)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3-month OS rate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e81%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e63%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6-month OS rate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e72%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e33%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e12-month OS rate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e49%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e13%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003ePatients were dichotomized into Low and High SIRI groups based on the median value of the cohort (median SIRI = 1.6). Data represent median survival times and survival rates at specific time points estimated using the Kaplan-Meier method.\u003c/p\u003e\n\u003cp\u003eAbbreviations: SIRI, systemic inflammation response index; PFS, progression-free survival; OS, overall survival; CI, confidence interval.\u003c/p\u003e\n\u003cp\u003eFurthermore, in the median-stratified analysis, the PFS rates at specific time points diverged: 2-month PFS was 38% vs. 25%, 6-month PFS was 17% vs. 3%, and 12-month PFS was 13% vs. 3% (Low vs. High SIRI). The median OS was 11 months vs. 4 months, with 12-month survival rates of 49% vs. 13%, respectively.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRestricted Mean Survival Time (RMST) analysis revealed that the mean PFS was significantly shorter in the high-SIRI group at both the 6-month (2.10 vs. 2.81 months, p=0.037) and 12-month (2.29 vs. 3.66 months, p=0.028) time points.\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis retrospective study evaluated the association between peripheral blood-based inflammatory markers and survival outcomes in patients with platinum-resistant ovarian cancer treated with pembrolizumab monotherapy. Focusing on the substantial heterogeneity in clinical courses among patients receiving identical treatment in later-line settings, we aimed to explore whether baseline systemic inflammatory status could be related to these differences.\u003c/p\u003e\n\u003cp\u003eIn this study, SIRI and NLR were associated with PFS, and all three markers (SIRI, NLR, SII) were associated with OS. These associations persisted even after adjusting for albumin and ECOG performance status, which reflect general patient condition. This suggests that, in addition to the biological characteristics of the tumor, the patient\u0026rsquo;s systemic inflammatory burden may be related to the clinical course in later-line treatment settings. Previous studies have similarly reported that elevated levels of these inflammatory markers are associated with poor prognosis in various malignancies, including ovarian, cervical, and colorectal cancers.[18-21] Although this single-arm study cannot strictly distinguish between predictive and prognostic roles, our results indicate that inflammatory markers serve as critical indicators of the host\u0026rsquo;s functional immune reserve in later-line treatment.\u003c/p\u003e\n\u003cp\u003eConsistent with the KEYNOTE-100 study, which reported a modest median PFS of 2.1 months, our cohort also demonstrated a limited median PFS of 2 months.[22] However, median values often fail to capture the \u0026ldquo;delayed survival benefit\u0026rdquo; characteristic of ICIs. Although ovarian cancer is classified as a representative \u0026ldquo;cold tumor,\u0026rdquo; where the response rate to ICI monotherapy is only 8\u0026ndash;15%, a subset of patients achieves durable survival benefits.[22-24] Consequently, there has been sustained interest in identifying information that can explain the differences in clinical courses among patients prior to treatment initiation. Our analysis revealed that survival curves between the high and low SIRI groups diverged over time, a pattern quantitatively confirmed by RMST analysis, which demonstrated a significant survival gain in the low SIRI group.\u003c/p\u003e\n\u003cp\u003eIt is well established that the therapeutic efficacy of pembrolizumab in various solid tumors, including ovarian cancer, is closely related to PD-L1 expression (CPS score).[22, 25, 26] In our study, the association between SIRI and survival outcomes was observed even after adjusting for PD-L1, a tumor-intrinsic marker. This suggests the possibility that SIRI representing the patient\u0026rsquo;s systemic status may be related to the clinical course independently of tumor characteristics. Therefore, peripheral blood-based markers could serve as complementary information alongside existing tumor-based data to aid in interpreting the patient\u0026rsquo;s clinical course.\u003c/p\u003e\n\u003cp\u003eWith the recent emergence of various therapeutic options, such as antibody-drug conjugates (MIRASOL, DESTINY-PanTumor02) and immunotherapeutic combinations (KEYNOTE-B96),[25, 27-29] the treatment landscape for platinum-resistant ovarian cancer is becoming increasingly complex. However, this later-line setting is characterized by the coexistence of limited treatment options, high symptom burden, decreased quality of life, and the financial toxicity of novel agents.[8, 30] Therefore, careful decision-making that balances the expected benefits of treatment attempts against the treatment burden is required. In this context, SIRI could be utilized as non-invasive, cost-effective adjunctive information in the clinical decision-making process.\u003c/p\u003e\n\u003cp\u003eThis study has limitations, including potential selection bias due to the single-center retrospective design and the lack of external validation. Additionally, blood markers can be influenced by infection, comorbidities, and medications, warranting caution in interpretation. Nevertheless, this study is significant as it provides real-world evidence in a heavily pretreated cohort, a population often underrepresented in clinical trials but frequently encountered in daily practice.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn conclusion, peripheral blood inflammatory markers, particularly SIRI, provide valuable insight into the heterogeneous clinical courses of patients with platinum-resistant ovarian cancer treated with pembrolizumab. In the context of later-line settings where therapeutic options are limited, these markers may serve as a practical reference for anticipating long-term outcomes and stratifying patient risk. Future prospective studies are needed to validate their utility in clinical practice.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eADC: Antibody-drug conjugate\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBRCA: Breast cancer gene\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCI: Confidence interval\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCPS: Combined positive score\u0026nbsp;\u003c/p\u003e\n\u003cp\u003edMMR: Mismatch repair deficient\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eECOG: Eastern Cooperative Oncology Group\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eEOC: Epithelial ovarian cancer\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFIGO: International Federation of Gynecology and Obstetrics\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHR: Hazard ratio\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHRD: Homologous recombination deficiency\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eICI: Immune checkpoint inhibitor\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIQR: Interquartile range\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMMR: Mismatch repair\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNLR: Neutrophil-to-lymphocyte ratio\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOS: Overall survival\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePARP: Poly (ADP-ribose) polymerase\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePD-L1: Programmed death-ligand 1\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePFS: Progression-free survival\u0026nbsp;\u003c/p\u003e\n\u003cp\u003epMMR: Mismatch repair proficient\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePROC: Platinum-resistant ovarian cancer\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRECIST: Response Evaluation Criteria in Solid Tumors\u003c/p\u003e\n\u003cp\u003eRMST: Restricted mean survival time\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSII: Systemic immune-inflammation index\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSIRI: Systemic inflammation response index\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTPS: Tumor proportion score\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eHuman Ethics and Consent to Participate declarations:\u0026nbsp;\u003c/strong\u003eThe study was conducted in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board (IRB) of Samsung Medical Center (IRB No. 2025-05-013-001). The requirement for informed consent was waived by the IRB due to the retrospective nature of the study and the use of de-identified data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number\u003c/strong\u003e: not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e: Not applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u0026nbsp;\u003c/strong\u003eThe datasets generated and analyzed during the current study are not publicly available due to institutional policy on patient data protection but are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of competing interests:\u0026nbsp;\u003c/strong\u003eThe authors have no conflicts of interest to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding sources:\u0026nbsp;\u003c/strong\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions:\u0026nbsp;\u003c/strong\u003eSL and YYL conceptualized the study. SL and HH were responsible for data curation. SL and YL performed the formal analysis and developed the methodology. JHS and YEC conducted the investigation. SL was responsible for the software, visualization, and validation of the data. TJK, JWL, CHC, and YYL provided the necessary resources for the study. YYL served as the project administrator and supervised the overall research. SL and YL were major contributors in writing the original draft. YYL reviewed and edited the final manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thank Joo-Ok Jung of the Future Medicine Research Institute, Samsung Medical Center, for administrative support.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eSEER Cancer Stat Facts: Ovarian Cancer [https://seer.cancer.gov/statfacts/html/ovary.html ]\u003c/li\u003e\n \u003cli\u003eBurger RA, Brady MF, Bookman MA, Fleming GF, Monk BJ, Huang H, Mannel RS, Homesley HD, Fowler J, Greer BE, et al: Incorporation of bevacizumab in the primary treatment of ovarian cancer. \u003cem\u003eN Engl J Med\u0026nbsp;\u003c/em\u003e2011, 365:2473\u0026ndash;2483.\u003c/li\u003e\n \u003cli\u003eDiSilvestro P, Banerjee S, Colombo N, Scambia G, Kim BG, Oaknin A, Friedlander M, Lisyanskaya A, Floquet A, Leary A, et al: Overall Survival With Maintenance Olaparib at a 7-Year Follow-Up in Patients With Newly Diagnosed Advanced Ovarian Cancer and a BRCA Mutation: The SOLO1/GOG 3004 Trial. \u003cem\u003eJ Clin Oncol\u0026nbsp;\u003c/em\u003e2023, 41:609\u0026ndash;617.\u003c/li\u003e\n \u003cli\u003eGonz\u0026aacute;lez-Mart\u0026iacute;n A, Pothuri B, Vergote I, Graybill W, Lorusso D, McCormick CC, Freyer G, Backes F, Heitz F, Redondo A, et al: Progression-free survival and safety at 3.5 years of follow-up: results from the randomised phase 3 PRIMA/ENGOT-OV26/GOG-3012 trial of niraparib maintenance treatment in patients with newly diagnosed ovarian cancer. \u003cem\u003eEuropean Journal of Cancer\u0026nbsp;\u003c/em\u003e2023, 189:112908.\u003c/li\u003e\n \u003cli\u003eRay-Coquard I, Leary A, Pignata S, Cropet C, Gonz\u0026aacute;lez-Mart\u0026iacute;n A, Marth C, Nagao S, Vergote I, Colombo N, M\u0026auml;enp\u0026auml;\u0026auml; J, et al: Olaparib plus bevacizumab first-line maintenance in ovarian cancer: final overall survival results from the PAOLA-1/ENGOT-ov25 trial. \u003cem\u003eAnn Oncol\u0026nbsp;\u003c/em\u003e2023, 34:681\u0026ndash;692.\u003c/li\u003e\n \u003cli\u003eSt Laurent J, Liu JF: Treatment Approaches for Platinum-Resistant Ovarian Cancer. \u003cem\u003eJ Clin Oncol\u0026nbsp;\u003c/em\u003e2024, 42:127\u0026ndash;133.\u003c/li\u003e\n \u003cli\u003eDavis A, Tinker AV, Friedlander M: \u0026quot;Platinum resistant\u0026quot; ovarian cancer: what is it, who to treat and how to measure benefit? \u003cem\u003eGynecol Oncol\u0026nbsp;\u003c/em\u003e2014, 133:624\u0026ndash;631.\u003c/li\u003e\n \u003cli\u003eLheureux S, Gourley C, Vergote I, Oza AM: Epithelial ovarian cancer. \u003cem\u003eLancet\u0026nbsp;\u003c/em\u003e2019, 393:1240\u0026ndash;1253.\u003c/li\u003e\n \u003cli\u003ePrigerson HG, Bao Y, Shah MA, Paulk ME, LeBlanc TW, Schneider BJ, Garrido MM, Reid MC, Berlin DA, Adelson KB, et al: Chemotherapy Use, Performance Status, and Quality of Life at the End of Life. \u003cem\u003eJAMA Oncol\u0026nbsp;\u003c/em\u003e2015, 1:778\u0026ndash;784.\u003c/li\u003e\n \u003cli\u003eMcMillan DC: The systemic inflammation-based Glasgow Prognostic Score: a decade of experience in patients with cancer. \u003cem\u003eCancer Treat Rev\u0026nbsp;\u003c/em\u003e2013, 39:534\u0026ndash;540.\u003c/li\u003e\n \u003cli\u003eYang R, Chang Q, Meng X, Gao N, Wang W: Prognostic value of Systemic immune-inflammation index in cancer: A meta-analysis. \u003cem\u003eJ Cancer\u0026nbsp;\u003c/em\u003e2018, 9:3295\u0026ndash;3302.\u003c/li\u003e\n \u003cli\u003eWang Y, Ni Q: Prognostic and clinicopathological significance of Systemic Immune-Inflammation Index in cancer patients receiving immune checkpoint inhibitors: a meta-analysis. \u003cem\u003eAnn Med\u0026nbsp;\u003c/em\u003e2023, 55:808\u0026ndash;819.\u003c/li\u003e\n \u003cli\u003eSharma P, Allison JP: The future of immune checkpoint therapy. \u003cem\u003eScience\u0026nbsp;\u003c/em\u003e2015, 348:56\u0026ndash;61.\u003c/li\u003e\n \u003cli\u003eMezquita L, Auclin E, Ferrara R, Charrier M, Remon J, Planchard D, Ponce S, Ares LP, Leroy L, Audigier-Valette C, et al: Association of the Lung Immune Prognostic Index With Immune Checkpoint Inhibitor Outcomes in Patients With Advanced Non-Small Cell Lung Cancer. \u003cem\u003eJAMA Oncol\u0026nbsp;\u003c/em\u003e2018, 4:351\u0026ndash;357.\u003c/li\u003e\n \u003cli\u003eChampiat S, Dercle L, Ammari S, Massard C, Hollebecque A, Postel-Vinay S, Chaput N, Eggermont A, Marabelle A, Soria JC, Fert\u0026eacute; C: Hyperprogressive Disease Is a New Pattern of Progression in Cancer Patients Treated by Anti-PD-1/PD-L1. \u003cem\u003eClin Cancer Res\u0026nbsp;\u003c/em\u003e2017, 23:1920\u0026ndash;1928.\u003c/li\u003e\n \u003cli\u003eDiakos CI, Charles KA, McMillan DC, Clarke SJ: Cancer-related inflammation and treatment effectiveness. \u003cem\u003eLancet Oncol\u0026nbsp;\u003c/em\u003e2014, 15:e493\u0026ndash;503.\u003c/li\u003e\n \u003cli\u003eVerma R, Foster RE, Horgan K, Mounsey K, Nixon H, Smalle N, Hughes TA, Carter CR: Lymphocyte depletion and repopulation after chemotherapy for primary breast cancer. \u003cem\u003eBreast Cancer Res\u0026nbsp;\u003c/em\u003e2016, 18:10.\u003c/li\u003e\n \u003cli\u003eChao B, Ju X, Zhang L, Xu X, Zhao Y: A Novel Prognostic Marker Systemic Inflammation Response Index (SIRI) for Operable Cervical Cancer Patients. \u003cem\u003eFront Oncol\u0026nbsp;\u003c/em\u003e2020, 10:766.\u003c/li\u003e\n \u003cli\u003eHayama T, Ochiai H, Ozawa T, Miyata T, Asako K, Fukushima Y, Kaneko K, Nozawa K, Fujii S, Misawa T, Fukagawa T: High systemic inflammation response index (SIRI) level as a prognostic factor for colorectal cancer patients after curative surgery: a single-center retrospective analysis. \u003cem\u003eSci Rep\u0026nbsp;\u003c/em\u003e2025, 15:1008.\u003c/li\u003e\n \u003cli\u003eNie D, Gong H, Mao X, Li Z: Systemic immune-inflammation index predicts prognosis in patients with epithelial ovarian cancer: A retrospective study. \u003cem\u003eGynecol Oncol\u0026nbsp;\u003c/em\u003e2019, 152:259\u0026ndash;264.\u003c/li\u003e\n \u003cli\u003eMao H, Yang F: Prognostic significance of systemic immune-inflammation index in patients with ovarian cancer: a meta-analysis. \u003cem\u003eFront Oncol\u0026nbsp;\u003c/em\u003e2023, 13:1193962.\u003c/li\u003e\n \u003cli\u003eMatulonis UA, Shapira-Frommer R, Santin AD, Lisyanskaya AS, Pignata S, Vergote I, Raspagliesi F, Sonke GS, Birrer M, Provencher DM, et al: Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: results from the phase II KEYNOTE-100 study. \u003cem\u003eAnn Oncol\u0026nbsp;\u003c/em\u003e2019, 30:1080\u0026ndash;1087.\u003c/li\u003e\n \u003cli\u003eYoon WH, DeFazio A, Kasherman L: Immune checkpoint inhibitors in ovarian cancer: where do we go from here? \u003cem\u003eCancer Drug Resist\u0026nbsp;\u003c/em\u003e2023, 6:358\u0026ndash;377.\u003c/li\u003e\n \u003cli\u003ePujade-Lauraine E, Fujiwara K, Ledermann JA, Oza AM, Kristeleit R, Ray-Coquard IL, Richardson GE, Sessa C, Yonemori K, Banerjee S, et al: Avelumab alone or in combination with chemotherapy versus chemotherapy alone in platinum-resistant or platinum-refractory ovarian cancer (JAVELIN Ovarian 200): an open-label, three-arm, randomised, phase 3 study. \u003cem\u003eLancet Oncol\u0026nbsp;\u003c/em\u003e2021, 22:1034\u0026ndash;1046.\u003c/li\u003e\n \u003cli\u003eColombo N, Zsiros E, Sebastianelli A, Bidzinski M, Araneda CEG, Matanes E, Hasegawa K, Kose F, Maciel MEM, Herbertson RA, et al: LBA3 Pembrolizumab vs placebo plus weekly paclitaxel \u0026amp;#xb1; bevacizumab in platinum-resistant recurrent ovarian cancer: Results from the randomized double-blind phase III ENGOT-ov65/KEYNOTE-B96 study. \u003cem\u003eAnnals of Oncology\u0026nbsp;\u003c/em\u003e2025, 36:S1582.\u003c/li\u003e\n \u003cli\u003eFuchs CS, Doi T, Jang RW, Muro K, Satoh T, Machado M, Sun W, Jalal SI, Shah MA, Metges J-P, et al: Safety and Efficacy of Pembrolizumab Monotherapy in Patients With Previously Treated Advanced Gastric and Gastroesophageal Junction Cancer: Phase 2 Clinical KEYNOTE-059 Trial. \u003cem\u003eJAMA Oncology\u0026nbsp;\u003c/em\u003e2018, 4:e180013\u0026ndash;e180013.\u003c/li\u003e\n \u003cli\u003eMoore KN, Angelergues A, Konecny GE, Garc\u0026iacute;a Y, Banerjee S, Lorusso D, Lee J-Y, Moroney JW, Colombo N, Roszak A, et al: Mirvetuximab Soravtansine in FR\u0026alpha;-Positive, Platinum-Resistant Ovarian Cancer. \u003cem\u003eNew England Journal of Medicine\u0026nbsp;\u003c/em\u003e2023, 389:2162\u0026ndash;2174.\u003c/li\u003e\n \u003cli\u003eMeric-Bernstam F, Makker V, Oaknin A, Oh DY, Banerjee S, Gonz\u0026aacute;lez-Mart\u0026iacute;n A, Jung KH, Ługowska I, Manso L, Manzano A, et al: Efficacy and Safety of Trastuzumab Deruxtecan in Patients With HER2-Expressing Solid Tumors: Primary Results From the DESTINY-PanTumor02 Phase II Trial. \u003cem\u003eJ Clin Oncol\u0026nbsp;\u003c/em\u003e2024, 42:47\u0026ndash;58.\u003c/li\u003e\n \u003cli\u003eNarayana RVL, Gupta R: Exploring the therapeutic use and outcome of antibody-drug conjugates in ovarian cancer treatment. \u003cem\u003eOncogene\u0026nbsp;\u003c/em\u003e2025, 44:2343\u0026ndash;2356.\u003c/li\u003e\n \u003cli\u003eSmith AJ, Sharma MH, Powell K, Doherty M, Hinkle SN, Ko EM: Financial toxicity in gynecologic oncology: a multi-practice survey. \u003cem\u003eInt J Gynecol Cancer\u0026nbsp;\u003c/em\u003e2024, 34:919\u0026ndash;925.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Platinum-resistant ovarian cancer, Systemic inflammation response index, Pembrolizumab, Late-line treatment","lastPublishedDoi":"10.21203/rs.3.rs-8935041/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8935041/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eThis study aimed to evaluate the association between peripheral blood inflammatory markers and clinical outcomes in patients with platinum-resistant ovarian cancer treated with pembrolizumab monotherapy, focusing on clinical heterogeneity in later-line settings. We retrospectively analyzed 95 patients with advanced platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer treated with pembrolizumab between July 2018 and December 2023. The systemic inflammation response index (SII), neutrophil-to-lymphocyte ratio (NLR), and systemic immune-inflammation index (SIRI) were calculated from baseline blood tests. Cox regression models, adjusted for age, Eastern Cooperative Oncology Group (ECOG) performance status, therapy line, and albumin levels, were utilized to assess associations with progression-free survival and overall survival.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eThe median progression-free survival was two months, and the median overall survival was seven months. SIRI and NLR were associated with progression-free survival, while all evaluated inflammatory markers correlated with overall survival. Although the median progression-free survival was similar when stratified by the median SIRI, the survival curves diverged over time. A high SIRI was associated with poorer overall survival (hazard ratio 2.02, 95% CI 1.53–2.67). Notably, long-term survival was predominantly observed in the low SIRI group, demonstrating a 12-month overall survival rate of 49% compared to 13% in the high SIRI group. This trend persisted after adjusting for albumin levels, performance status, and programmed death-ligand 1 expression.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003ePeripheral blood inflammatory markers were associated with distinct clinical courses in platinum-resistant ovarian cancer patients receiving pembrolizumab, particularly regarding long-term disease control. These findings suggest these markers may aid in interpreting later-line treatment outcomes, warranting prospective validation.\u003c/p\u003e","manuscriptTitle":"Association of inflammatory markers with survival and durable benefit in heavily pretreated platinum- resistant ovarian cancer receiving pembrolizumab","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-18 08:58:05","doi":"10.21203/rs.3.rs-8935041/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"cfb8eeb2-d900-414f-a11b-baf5a2212c64","owner":[],"postedDate":"March 18th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-04-01T13:57:11+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-18 08:58:05","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8935041","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8935041","identity":"rs-8935041","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}