Cell-free and Concentrated Ascites Reinfusion Therapy (CART) Shows Enhanced Efficacy in Gynecological Cancer Patients: A Post-marketing Surveillance Study

Cell-free and Concentrated Ascites Reinfusion Therapy (CART) Shows Enhanced Efficacy in Gynecological Cancer Patients: A Post-marketing Surveillance Study | 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 Cell-free and Concentrated Ascites Reinfusion Therapy (CART) Shows Enhanced Efficacy in Gynecological Cancer Patients: A Post-marketing Surveillance Study Nami Tamura, Takashi Hirayama, Emiko Yoshida, Junna Terao, Misato Kawata, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6609092/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: Cell-free and concentrated ascites reinfusion therapy (CART) is an established method for managing malignant ascites. Ascites management is particularly important for gynecological cancer patients as ovarian cancer is the most common cause of malignant ascites, and patients with gynecological cancers often require long-term treatment. This study evaluates the efficacy and safety of CART specifically in gynecological cancer patients compared to patients with other cancers. Methods: This subgroup-analysis of a prospective post-marketing surveillance was conducted between January 2014 and January 2015. The study included 147 patients who underwent 356 CART sessions across 22 centers in Japan. After excluding non-cancerous patients, subjects were divided into two groups: gynecological cancer patients (Group G) and other cancer patients (Group O). Results: The final analysis included 128 patients who underwent 300 CART sessions (Group G: 46 patients/85 sessions; Group O: 79 patients/211 sessions). Group G had significantly higher rates of concurrent chemotherapy. The amount of total protein and albumin in both original and processed ascites was significantly larger in Group G. Group G showed significant improvements in renal function parameters (serum creatinine, blood urea nitrogen, estimated glomerular filtration rate) and increased daily urine volume. The interval between ascites removal procedures was longer in Group G, and no severe adverse events were observed in either group. Conclusion: CART demonstrates particular efficacy and safety in gynecological cancer patients. The improvement in renal function observed in this study may help reduce side effects of anticancer drugs, potentially contributing to better tolerability. Cell-free and concentrated ascites reinfusion therapy (CART) gynecological cancer post-marketing surveillance (PMS) Figures Figure 1 Introduction Malignant ascites accounts for approximately 10% of all ascites cases [ 1 ]. Symptoms associated with massive ascites include abdominal distension, pain, loss of appetite, leg edema, respiratory discomfort, and fatigue, all of which significantly deteriorate a patient's quality of life (QOL). While paracentesis temporarily alleviates these symptoms, repeated paracenteses induce hypoproteinemia and intravascular dehydration, potentially leading to pre-renal failure and consequently exacerbating edema and fatigue [ 2 ]. Additionally, the loss of immunoglobulins contained in the ascitic fluid can increase susceptibility to infection [ 2 ]. Cell-free and concentrated ascites reinfusion therapy (CART), approved by the Japanese national health insurance system since 1981, is a therapeutic approach that rapidly removes ascitic fluid while selectively collecting proteins and eliminating malignant cells before reinfusion, thereby improving symptoms [ 3 ]. CART also has the potential to elevate serum protein and albumin levels while increasing urine volume in patients with malignant refractory ascites [ 4 ]. The most common cause of malignant ascites is peritoneal dissemination, accounting for approximately 53% [ 5 ], and among all cancers, ovarian cancer is most frequently associated with the production of malignant ascites [ 6 ]. One study demonstrated that ascites accompanies 73.1% of advanced ovarian cancer or peritoneal cancer cases in Stage III and IV [ 7 ]. Notably, malignant ascites in gynecological cancers presents unique clinical characteristics. Gynecological cancers with malignant ascites demonstrate a relatively favorable prognosis compared to other malignancies [ 8 ][ 9 ]. The interval from first paracentesis to mortality is significantly prolonged in these patients [ 10 ], necessitating ascites management for substantially longer periods [ 11 ]. These gynecological malignancies require long-term ascites control and may have different intervals between paracentesis procedures compared to other malignancies. However, the potential differences in CART outcomes between gynecological and other cancers remain inadequately investigated. Given these distinct features, we hypothesized that the clinical significance and efficacy of CART might differ between gynecological and other malignancies. This study aimed to evaluate the efficacy and safety of CART in gynecological cancer patients by comparing their outcomes with those of other cancer types. Patients and Methods Ethics This study represents a sub-analysis of data collected during a previously reported post-marketing surveillance (PMS) study conducted in compliance with Good Post-marketing Surveillance Practice (GPSP) guidelines [ 12 ]. As established in the original study, the protocol was exempt from ethics committee approval under the GPSP ordinance by the Ministry of Health, Labour and Welfare (MHLW) of Japan. This research adhered to the principles of the Declaration of Helsinki, and written informed consent was obtained from all patients for both the CART procedure and the use of their medical records, in accordance with the ethical guidelines of each participating institution. Patients and study design The original multicenter PMS study enrolled patients who underwent CART between January 2014 and January 2015 at 22 selected Japanese medical centers. The current sub-analysis utilized data from this cohort, focusing specifically on cancer patients. Patients who received multiple CART sessions were registered as separate entries. After excluding patients with non-malignant conditions, subjects were categorized into two groups for analysis: patients with gynecological malignancies (ovarian, fallopian tube, endometrial, cervical, and peritoneal cancer) designated as Group G, and patients with other cancer types designated as Group O. CART Procedure The standardized CART procedure consisted of three sequential steps: collection, concentration and reinfusion [ 12 ]. In this study, paracentesis was performed under local anesthesia using either a catheter or needle. The AHF-MO ascitic filtration filter and AHF-UP ascitic concentration filter (Asahi Kasei Medical Co., Ltd., Tokyo, Japan) were employed for the filtration and concentration processes, respectively. Processing conditions, including filtration direction, filtration and concentration speed, and driving force varied according to institutional protocols. Data Collection and Assessment We collected patient background information including age, sex, primary disease, clinical stage, history of ascites therapy, and concurrent chemotherapy during or one month prior to CART procedures. For technical parameters, we documented total ascites volume, concentration ratio, total protein and albumin levels before and after processing, and their recovery rates calculated by comparing amounts in processed fluid to those in original ascites. Clinical parameters evaluated before and after CART included body weight, abdominal circumference, ECOG performance status (PS), dietary intake, daily urine volume, and laboratory values. Dietary intake was assessed by monitoring dinner consumption using a 5-point scale (0%, 25%, 50%, 75%, and 100%). Laboratory tests included complete blood counts (white blood cells, red blood cells, hemoglobin, hematocrit, platelets) and serum biochemistry (total protein, albumin, BUN, Cre, eGFR). Body temperature was measured at four timepoints: before reinfusion, immediately after reinfusion completion, 1 hour after completion, and one day after reinfusion. To account for circulating blood volume changes due to colloidal osmotic pressure alterations during CART, laboratory values were adjusted according to the following formula: Adjusted post-CART value = post-CART value × (pre-CART Hct value)/(post-CART Hct value) CART-associated adverse events as determined by attending physicians were recorded and classified according to the Medical Dictionary for Regulatory Activities/Japanese version 18.0 (MedDRA/J version 18.0). Statistical Analysis All data were expressed as mean ± standard deviation (SD) or proportion (%). Continuous data were analyzed by Student's t-test and categorical data were analyzed by Wilcoxon signed rank test, Mann-Whitney U test or Fisher's exact test. Paired t-test was used for comparisons between before and after CART within the same patient. Missing data were excluded from all analyses and P values less than 0.05 (two-sided test) were considered statistically significant. Data were analyzed using Bell Curve for Excel version 4.08. Results Patient Background Questionnaires were collected from 147 registered patients, and clinical data on 356 sessions of CART were retrieved. Nineteen patients who underwent 56 sessions for conditions other than malignancies were excluded. Three patients who underwent 4 sessions were excluded due to insufficient data for evaluation. A total of 125 patients who underwent 296 sessions were included in the study. Group G comprised 46 patients who underwent 85 sessions, and Group O comprised 79 patients who underwent 211 sessions. Figure 1 illustrates the selection process of the study patients. The background of the patients is shown in Table 1. The mean age of patients in Group G was 63.8 ± 12.0 years compared to 67.1 ± 11.7 years in Group O. This difference was not statistically significant (p = 0.162). The primary cancers of Group G included ovary (71.7%), peritoneum (13.0%), and cervix (6.5%), whereas Group O included pancreas (27.8%), liver (24.1%), and stomach (16.5%). Anticancer drug use during or within one month prior to CART was more frequent in Group G (35/85 sessions [41.2%]) than in Group O (26/211 sessions [12.3%]) (p < 0.001). Regarding clinical stage, Stage 4 disease was present in 30.4% of Group G and 88.6% of Group O. Efficacy of CART procedure The conditions of 296 CART procedures are summarized in Table 2. The amount of ascites collected was 3,051 ± 1,102 g in Group G and 3,506 ± 1,345 g in Group O. The concentration of total protein was significantly higher in Group G compared to Group O in the original ascites (4.2 ± 1.1 g/dL vs. 2.4 ± 1.2 g/dL, p < 0.001) and in the processed ascites (15.1 ± 4.0 g/dL vs. 14.2 ± 7.4 g/dL, p < 0.001). Similarly, albumin concentration was significantly higher in Group G in the original ascites (2.1 ± 0.5 g/dL vs. 1.3 ± 0.7 g/dL, p < 0.001) and in the processed ascites (8.2 ± 4.5 g/dL vs. 7.8 ± 4.3 g/dL, p < 0.001). In comparing the calculated total protein amount between groups, the amount was significantly higher in Group G in the original ascites (127.8 ± 60.9 g vs. 88.7 ± 52.4 g, p < 0.001) and also in the processed ascites (83.4 ± 43.2 g vs. 65.3 ± 40.6 g, p = 0.003). The same trend was also observed for albumin, with amounts in Group G significantly higher both in the original ascites (63.9 ± 26.6 g vs. 49.0 ± 32.0 g, p < 0.001) and in the processed ascites (44.7 ± 21.3 g vs. 38.1 ± 26.8 g, p = 0.011). The concentration ratio and the retention rates of total protein and albumin are shown in Supplemental Table 1. The concentration ratio was significantly lower in Group G compared to Group O (6.4 ± 2.3 vs. 9.7 ± 5.2, p < 0.001). The recovery rates of total protein (65.1 ± 16.0% vs. 73.8 ± 18.0%, p < 0.001) and albumin (69.3 ± 15.5% vs. 76.6 ± 16.9%, p < 0.001) were both significantly lower in Group G. Hemorrhagic ascites was more frequent in Group G (31.8% vs. 24.2%), though not statistically significant (p = 0.18). The changes in blood test values between before and after CART are shown in Table 3. The level of Cre (from 0.7 ± 0.3 mg/dL to 0.6 ± 0.3 mg/dL, p < 0.001) and BUN (from 17.9 ± 8.7 mg/dL to 14.5 ± 9.0 mg/dL, p < 0.001) after the procedure of CART were significantly decreased and the eGFR was significantly elevated (from 72.7 ± 24.8 mL/min/1.73m² to 81.3 ± 27.6 mL/min/1.73m², p < 0.001) in Group G, indicating an improvement in renal function. Hct decreased significantly in both Group G (from 32.1 ± 6.5% to 29.5 ± 4.8%, p < 0.001) and Group O (from 32.8 ± 4.7% to 30.6 ± 5.0%, p < 0.001), indicating plasma volume expansion due to the increase in plasma colloid osmotic pressure caused by the reinfusion of proteins. In both groups, the levels of total protein and albumin were significantly elevated after the CART procedure by the reinfusion of the patient's own proteins from the processed ascites. The clinical changes before and after CART are shown in Table 4. Both groups showed significant reduction in body weight, abdominal circumference, improved ECOG PS scores, increased dietary intake, and increased urine output after CART. The intervals between removal procedures (including both CART and paracentesis alone) were significantly longer in Group G than in Group O (20.0 ± 13.8 days versus 11.7 ± 10.9 days, p < 0.001). Safety of CART procedure Adverse events were recorded in 45.7% (21/46) of patients in Group G versus 27.8% (22/79) in Group O, and in 35.3% (30/85) of Group G sessions compared to 10.9% (23/211) in Group O sessions. Fever occurred significantly more frequently in Group G than Group O (29.4% versus 5.2%, p < 0.001). All adverse events were non-severe, with complete recovery observed in all patients. Discussion This study compared the efficacy and safety of Cell-free and Concentrated Ascites Reinfusion Therapy (CART) between gynecological cancer patients and other cancer types with massive ascites, revealing four key findings: 1) The gynecological cancer group had a significantly higher proportion of patients undergoing chemotherapy during or one month prior to CART procedure; 2) Both original and processed ascites contained significantly higher levels of total protein and albumin in the gynecological cancer group; 3) The gynecological cancer group demonstrated significant improvement in renal function along with increased daily urine volume following CART; and 4) The gynecological cancer group exhibited a longer interval between ascites drainage procedures. While many studies have evaluated the efficacy and safety of CART, to our knowledge, this is the first study to demonstrate enhanced efficacy in gynecological cancer patients with respect to renal function, suggesting a potential role of CART as a supportive therapy for chemotherapy beyond its established palliative benefits. Higher rate of chemotherapy uses in gynecological cancer patients Our first finding regarding the higher proportion of patients undergoing chemotherapy in the gynecological cancer group reflects clinical practice patterns for gynecological malignancies where chemotherapy remains essential even in advanced disease. Many anticancer drugs used in gynecological cancers (paclitaxel, docetaxel, cisplatin, doxorubicin, etoposide) have high binding rates (> 70%) to serum albumin [ 13 ]. Serum albumin concentration significantly influences these drugs' pharmacokinetics, and low levels increase the fraction of unbound anticancer drugs, potentially causing excessive toxicity. CART serves dual roles in chemotherapy patients: improving serum albumin levels directly (Table 3) and potentially optimizing drug pharmacokinetics for patients with low albumin. This benefit is particularly relevant for gynecological cancer patients given their high rates of concurrent chemotherapy. Hypoalbuminemia frequently accompanies malignant ascites and is a risk factor for febrile neutropenia [ 14 , 15 ], hypovolemia, hypotension, and increased mortality [ 16 ]. While Japanese guidelines discourage "administration of albumin preparation to patients with hypoalbuminemia due to malignant tumors or terminally ill patients" [ 17 ], CART offers a valuable alternative by reducing the need for exogenous albumin while providing comparable efficacy [ 18 ]. Furthermore, autologous albumin represents a more physiological approach to replenishment compared to commercial preparations, reducing allergic reactions [ 19 ]. CART improves clinically important parameters including ECOG PS and dietary intake (Table 4), potentially enabling patients to begin or resume primary treatments more effectively [ 20 ]. This is significant given evidence that ascites from ovarian cancers may confer platinum chemoresistance [ 21 ], highlighting benefits beyond symptom palliation. Higher protein and albumin content in gynecological cancer ascites Our second finding revealed significantly higher concentration and total amount of protein and albumin in ascites from gynecological cancer patients compared to other malignancies. As shown in Table 2, Group G demonstrated significantly higher concentrations of total protein and albumin in both original and processed ascites than Group O, representing a distinctive biochemical characteristic with important clinical implications. Previous studies have established that protein quantity returned during CART positively correlates with urine production and improved renal function [ 12 , 22 ]. This relationship helps explain why CART appears particularly beneficial for gynecological cancer patients with malignant ascites. Beyond albumin, replenishment of other bioactive components may provide additional therapeutic benefits. Cytokines and interleukins in processed ascites may modulate immune function, with one report indicating that IL-10 in ascites correlated with longer survival after CART [ 23 ]. Further investigation into specific immunomodulatory components could provide insights into the mechanisms underlying CART's beneficial effects in gynecological cancer patients. Despite higher protein content, our findings in Supplemental Table 1 demonstrated significantly lower protein recovery rates in Group G. Several factors likely contribute to this observation. First, the characteristic high protein concentration in gynecological cancer ascites may itself impede filtration efficiency through increased viscosity. Second, gynecological cancer ascites more frequently presented with hemorrhagic characteristics, although this difference did not reach statistical significance. The presence of blood components, including fibrin and cellular debris, is known to affect recovery rates through filter clogging [ 12 ]. For gynecological cancer patients, adjusting processing parameters such as reducing filtration speed [ 24 ] may improve protein recovery, while developing enhanced filtration technology specifically designed for the unique characteristics of gynecological cancer ascites could further optimize CART efficacy in this patient population. Significant improvement in renal function in gynecological cancer patients Our third finding was the significant improvement in renal function observed specifically in gynecological cancer patients following CART. As shown in Table 3, Group G demonstrated significant decreases in Cre and BUN levels along with elevations in eGFR after CART, a finding with substantial clinical implications for patients concurrently receiving chemotherapy. The improvement in renal function likely results from several physiological mechanisms. The reduction in abdominal pressure following massive ascites removal contributes to improved renal function through renal decongestion [ 25 , 26 ], relieving renal vessel compression and enhancing perfusion. In addition, reinfusion of concentrated proteins, particularly albumin, elevates blood colloid osmotic pressure, facilitating fluid movement from the third space into blood vessels. Current evidence suggests that albumin in processed ascites contributes to endothelial glycocalyx layer formation, preventing plasma leakage [ 27 ]. Additionally, albumin's anti-inflammatory and antioxidant properties may improve vascular permeability [ 28 ]. Through these mechanisms, CART prevents third-space fluid accumulation while maintaining adequate circulating plasma volume, improving renal blood flow and increasing urine output [ 12 ]. This is supported by our observation of a significant increase in the urine volume. The clinical importance of improved renal function extends beyond symptomatic relief. Enhanced renal function potentially facilitates more efficient anticancer drug clearance, which may reduce toxicity without compromising efficacy. This is particularly relevant for gynecological cancer patients who more frequently undergo concurrent chemotherapy. Additionally, CART may facilitate completion of planned chemotherapy regimens by avoiding delays due to renal dysfunction. When calculating anticancer drug dosages, body surface area (BSA) and creatinine clearance are commonly used [ 29 ]. By controlling ascites volume, stabilizing body weight, and improving renal function, CART may contribute to more appropriate and consistent chemotherapy dosing, potentially optimizing treatment outcomes in gynecological cancer patients with malignant ascites. Extended intervals between ascites removal in gynecological cancer Our fourth finding regarding longer intervals between ascites removal in gynecological cancer patients has significant implications for maintaining QOL and stabilizing body weight. Malignant ascites significantly impacts QOL and daily activities [ 29 – 31 ], while also increasing hospitalization rates—particularly emergency admissions—and healthcare costs [ 32 ] Since treatment for malignant ascites is primarily palliative, minimizing hospital stays benefits patients, their families, and healthcare systems. Given that malignant ascites secondary to ovarian cancers is associated with longer life expectancy compared to other cancer types [ 8 – 10 ], effective ascites management through CART is particularly valuable for gynecological cancer patients. Adverse events Regarding adverse events, fever represents the most frequent complication of CART. Refractory ascites contains inflammatory substances such as cytokines (including interleukins) derived from cancer cells or released from activated white blood cells during filtration and concentration, potentially causing fever [ 34 , 35 ]. The higher frequency of fever observed in Group G may result from greater cytokine content in ascitic proteins, affecting serum cytokine levels [ 36 ]. Additionally, our data showed that steroids or NSAIDs, which may reduce fever [ 37 ], were used before reinfusion in 24.7% of Group G versus 54.0% of Group O (data not shown), potentially contributing to the higher fever incidence in gynecological cancer patients. However, none of these adverse events were severe, and all patients fully recovered. Limitations Our study has several limitations. Differences in disease stage and sex distribution between the gynecologic and other cancer groups may introduce bias in comparisons of parameters such as ECOG PS, dietary intake, and serum creatinine levels. However, total protein and albumin levels in ascites are less affected by these differences. Future studies with matched stage distributions and controlled demographic factors would help validate these findings and further clarify the specific benefits of CART in different cancer populations. Future Research Our findings highlight the potential of CART in gynecological cancer patients, particularly for improving renal function, restoring albumin levels, and stabilizing body weight. While CART has traditionally been viewed as a palliative intervention, our results suggest a supportive role for CART in chemotherapy management. For patients with advanced ovarian or peritoneal cancer with malignant ascites, CART may be particularly beneficial when administered before neoadjuvant chemotherapy. By managing ascites and improving protein balance prior to treatment, CART could potentially reduce chemotherapy-related adverse events, improve tolerance, and facilitate treatment completion without dose modifications. Future studies should evaluate the efficacy of CART by comparing the incidence of chemotherapy dose reductions, postponements, or discontinuations between patients undergoing CART versus those receiving paracentesis alone prior to neoadjuvant chemotherapy in advanced gynecological malignancies. Such research would help identify additional therapeutic benefits of CART beyond its established palliative role and could optimize treatment strategies for patients with gynecological malignancies complicated by ascites. Conclusion CART demonstrates particular efficacy and safety in gynecological cancer patients with malignant ascites. The improvement in renal function observed in this study may help reduce side effects of anticancer drugs, potentially contributing to better treatment tolerability. The significantly higher protein and albumin content in gynecological cancer ascites and longer intervals between drainage procedures further support CART as an important supportive therapy for gynecological malignancies. Declarations Nothing to declare Acknowledgements Statistical analysis was performed by the Blood Purification Division, Asahi Kasei Medical Co., Ltd. Conflict of interests All authors declare no conflict of interest with regards to this article. Data availability statement We understand the importance of openness of data. However, unfortunately, the data for this manuscript cannot be made publicly available, because it was collected from the participating medical facilities and public availability would compromise patient confidentiality or participant facility privacy. 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Int J Clin Oncol 30(3):559–569. 10.1007/s10147-024-02682-1 Kawata Y, Nagasaka K, Matsumoto Y et al (2019) Usefulness of cell-free and concentrated ascites reinfusion therapy in the therapeutic management of advanced ovarian cancer patients with massive ascites. Int J Clin Oncol 24(4):420–427. 10.1007/s10147-018-1371-7 Tables Table 1 to 4 are available in the Supplementary Files section. Supplementary Files Table1.tiff Table2.tiff Table3.tiff Table4.tiff Table5.tiff Supplementaltable1.tiff 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. 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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-6609092","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":453996021,"identity":"8bce1335-ecda-4f95-a74a-5b1f62a7a4b0","order_by":0,"name":"Nami Tamura","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9klEQVRIiWNgGAWjYDADfoYDYJqxAUzx4FPLDKEkG4BaDpCkxQBkCUILHmDOwH/w0822e/LGB8+YPf5QcUe2n4H54QcGmTs4tVg2MDNL57YVG247cMbc4MCZZ8YzG9iMJRh4nuHUYnD/MQNQSwIjUIuZxMG2w4kbDjCYAf1yGLeWA8zMv4Fa7Dc3gLT8A2lh/0ZICxvIlsQNDCAtDSAtPARtMbPOOZeQPOPAsTKJM8cOG89s5imWSMDnlwOMj2/nlCXY9s84vE2iouawbD97+8YPH3twhxgCSByAMkARldhzALdKOOBvQOb9IEbLKBgFo2AUjBAAAOJFW7GA1OF9AAAAAElFTkSuQmCC","orcid":"https://orcid.org/0009-0001-4235-6780","institution":"Juntendo University: Juntendo Daigaku","correspondingAuthor":true,"prefix":"","firstName":"Nami","middleName":"","lastName":"Tamura","suffix":""},{"id":453996022,"identity":"dc8e6ede-b69d-49ea-9848-04f26aad0397","order_by":1,"name":"Takashi Hirayama","email":"","orcid":"","institution":"Juntendo University: Juntendo Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Takashi","middleName":"","lastName":"Hirayama","suffix":""},{"id":453996023,"identity":"cd462dba-153c-4721-8448-ed9099f080c4","order_by":2,"name":"Emiko Yoshida","email":"","orcid":"","institution":"Juntendo University: Juntendo Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Emiko","middleName":"","lastName":"Yoshida","suffix":""},{"id":453996024,"identity":"2080a222-39d1-45e5-b09d-85e8b3e47da9","order_by":3,"name":"Junna Terao","email":"","orcid":"","institution":"Juntendo University: Juntendo Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Junna","middleName":"","lastName":"Terao","suffix":""},{"id":453996025,"identity":"693fa82e-f3c8-4301-a954-19c3a27a635a","order_by":4,"name":"Misato Kawata","email":"","orcid":"","institution":"Juntendo University: Juntendo Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Misato","middleName":"","lastName":"Kawata","suffix":""},{"id":453996026,"identity":"059b74cf-39b6-4a41-8b79-5ab6a8d37321","order_by":5,"name":"Kengo Hiranuma","email":"","orcid":"","institution":"Juntendo University: Juntendo Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Kengo","middleName":"","lastName":"Hiranuma","suffix":""},{"id":453996027,"identity":"746a0e87-e94b-4882-a131-481cd4108449","order_by":6,"name":"Toshiyuki Okumura","email":"","orcid":"","institution":"Juntendo University: Juntendo Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Toshiyuki","middleName":"","lastName":"Okumura","suffix":""},{"id":453996028,"identity":"42a61655-c6d5-4e18-b751-88592ea03ee8","order_by":7,"name":"Kazunari Fujino","email":"","orcid":"","institution":"Juntendo University: Juntendo Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Kazunari","middleName":"","lastName":"Fujino","suffix":""},{"id":453996029,"identity":"9d11eb1b-22a4-49fb-bd0b-28160f6d8dac","order_by":8,"name":"Naoko Torii","email":"","orcid":"","institution":"Asahi Kasei Medical Co Ltd: Asahi Kasei Medical Kabushiki Kaisha","correspondingAuthor":false,"prefix":"","firstName":"Naoko","middleName":"","lastName":"Torii","suffix":""},{"id":453996030,"identity":"04624d7a-ef90-4335-a8a1-62716aec4c03","order_by":9,"name":"Noriko Soneda","email":"","orcid":"","institution":"Asahi Kasei Medical Co Ltd: Asahi Kasei Medical Kabushiki Kaisha","correspondingAuthor":false,"prefix":"","firstName":"Noriko","middleName":"","lastName":"Soneda","suffix":""},{"id":453996031,"identity":"8dd6380e-68a6-4a04-beae-524c902d2680","order_by":10,"name":"Go Murayama","email":"","orcid":"","institution":"Juntendo University: Juntendo Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Go","middleName":"","lastName":"Murayama","suffix":""},{"id":453996032,"identity":"04dc87c5-0e50-4a16-912b-651804e70af4","order_by":11,"name":"Makio Kusaoi","email":"","orcid":"","institution":"Juntendo University: Juntendo Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Makio","middleName":"","lastName":"Kusaoi","suffix":""},{"id":453996033,"identity":"5ffd4414-7f7f-4462-af37-f67c7f28ae69","order_by":12,"name":"Ken Yamaji","email":"","orcid":"","institution":"Juntendo University: Juntendo Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Ken","middleName":"","lastName":"Yamaji","suffix":""},{"id":453996034,"identity":"b84f6398-dafa-4fc9-acc8-905605dad98b","order_by":13,"name":"Yasuhisa Terao","email":"","orcid":"https://orcid.org/0000-0002-9126-3361","institution":"Juntendo University: Juntendo Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Yasuhisa","middleName":"","lastName":"Terao","suffix":""}],"badges":[],"createdAt":"2025-05-07 07:21:56","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6609092/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6609092/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":82714677,"identity":"af3f5970-91db-4755-b7f7-66f29eda562e","added_by":"auto","created_at":"2025-05-14 12:06:37","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":12700,"visible":true,"origin":"","legend":"\u003cp\u003eSelection of study patients.\u003c/p\u003e\n\u003cp\u003eAmong cases collected via a questionnaire survey, those with missing data were excluded. Efficacy and safety were evaluated in the remaining 125 patients (296 sessions)\u003c/p\u003e\n\u003cp\u003eCART: Cell-free and concentrated ascites reinfusion therapy.\u003c/p\u003e\n\u003cp\u003eGroup G: Group of gynecological and peritoneal cancer patients.\u003c/p\u003e\n\u003cp\u003eGroup O: Group of other cancer patients.\u003c/p\u003e","description":"","filename":"OnlineFigure1.png","url":"https://assets-eu.researchsquare.com/files/rs-6609092/v1/7262b97f6d48dd13b8c72e19.png"},{"id":83677325,"identity":"dd11dc9a-f2f7-49da-b237-8e6fce855db0","added_by":"auto","created_at":"2025-05-30 15:07:36","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":710079,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6609092/v1/81e90674-094b-48f1-bff0-f7796521ad36.pdf"},{"id":82714681,"identity":"b72269ae-4eef-4a74-8d37-d53262968573","added_by":"auto","created_at":"2025-05-14 12:06:37","extension":"tiff","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":878246,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.tiff","url":"https://assets-eu.researchsquare.com/files/rs-6609092/v1/0a37b6942432ac3ce863f445.tiff"},{"id":82716187,"identity":"109ad215-c2a7-4f3e-825b-e4a3dbe0108a","added_by":"auto","created_at":"2025-05-14 12:14:38","extension":"tiff","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":878246,"visible":true,"origin":"","legend":"","description":"","filename":"Table2.tiff","url":"https://assets-eu.researchsquare.com/files/rs-6609092/v1/6c56b2daa2845faef4bcf92a.tiff"},{"id":82714682,"identity":"fc82521b-de01-4ff6-b4cf-5b8085b522c1","added_by":"auto","created_at":"2025-05-14 12:06:37","extension":"tiff","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":878246,"visible":true,"origin":"","legend":"","description":"","filename":"Table3.tiff","url":"https://assets-eu.researchsquare.com/files/rs-6609092/v1/c2e147097d90cb1db42232c3.tiff"},{"id":82714680,"identity":"6bb8f9d9-0828-4a60-b6cb-7c18eee5315f","added_by":"auto","created_at":"2025-05-14 12:06:37","extension":"tiff","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":878246,"visible":true,"origin":"","legend":"","description":"","filename":"Table4.tiff","url":"https://assets-eu.researchsquare.com/files/rs-6609092/v1/ec4ec6f7e68042290497dd79.tiff"},{"id":82714688,"identity":"a7095bc3-c7c8-46bd-a8fd-e64860720a09","added_by":"auto","created_at":"2025-05-14 12:06:37","extension":"tiff","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":878246,"visible":true,"origin":"","legend":"","description":"","filename":"Table5.tiff","url":"https://assets-eu.researchsquare.com/files/rs-6609092/v1/fba3b66341b0a6eaee0fd9c4.tiff"},{"id":82714687,"identity":"30286a83-afe3-49c4-8d40-4ae7ab710880","added_by":"auto","created_at":"2025-05-14 12:06:37","extension":"tiff","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":878246,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementaltable1.tiff","url":"https://assets-eu.researchsquare.com/files/rs-6609092/v1/1527d2360442f70c99e88a26.tiff"}],"financialInterests":"","formattedTitle":"Cell-free and Concentrated Ascites Reinfusion Therapy (CART) Shows Enhanced Efficacy in Gynecological Cancer Patients: A Post-marketing Surveillance Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMalignant ascites accounts for approximately 10% of all ascites cases [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Symptoms associated with massive ascites include abdominal distension, pain, loss of appetite, leg edema, respiratory discomfort, and fatigue, all of which significantly deteriorate a patient's quality of life (QOL). While paracentesis temporarily alleviates these symptoms, repeated paracenteses induce hypoproteinemia and intravascular dehydration, potentially leading to pre-renal failure and consequently exacerbating edema and fatigue [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Additionally, the loss of immunoglobulins contained in the ascitic fluid can increase susceptibility to infection [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Cell-free and concentrated ascites reinfusion therapy (CART), approved by the Japanese national health insurance system since 1981, is a therapeutic approach that rapidly removes ascitic fluid while selectively collecting proteins and eliminating malignant cells before reinfusion, thereby improving symptoms [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. CART also has the potential to elevate serum protein and albumin levels while increasing urine volume in patients with malignant refractory ascites [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe most common cause of malignant ascites is peritoneal dissemination, accounting for approximately 53% [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], and among all cancers, ovarian cancer is most frequently associated with the production of malignant ascites [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. One study demonstrated that ascites accompanies 73.1% of advanced ovarian cancer or peritoneal cancer cases in Stage III and IV [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Notably, malignant ascites in gynecological cancers presents unique clinical characteristics. Gynecological cancers with malignant ascites demonstrate a relatively favorable prognosis compared to other malignancies [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e][\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The interval from first paracentesis to mortality is significantly prolonged in these patients [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], necessitating ascites management for substantially longer periods [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. These gynecological malignancies require long-term ascites control and may have different intervals between paracentesis procedures compared to other malignancies. However, the potential differences in CART outcomes between gynecological and other cancers remain inadequately investigated. Given these distinct features, we hypothesized that the clinical significance and efficacy of CART might differ between gynecological and other malignancies. This study aimed to evaluate the efficacy and safety of CART in gynecological cancer patients by comparing their outcomes with those of other cancer types.\u003c/p\u003e"},{"header":"Patients and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eEthics\u003c/h2\u003e \u003cp\u003eThis study represents a sub-analysis of data collected during a previously reported post-marketing surveillance (PMS) study conducted in compliance with Good Post-marketing Surveillance Practice (GPSP) guidelines [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. As established in the original study, the protocol was exempt from ethics committee approval under the GPSP ordinance by the Ministry of Health, Labour and Welfare (MHLW) of Japan. This research adhered to the principles of the Declaration of Helsinki, and written informed consent was obtained from all patients for both the CART procedure and the use of their medical records, in accordance with the ethical guidelines of each participating institution.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003ePatients and study design\u003c/h3\u003e\n\u003cp\u003eThe original multicenter PMS study enrolled patients who underwent CART between January 2014 and January 2015 at 22 selected Japanese medical centers. The current sub-analysis utilized data from this cohort, focusing specifically on cancer patients. Patients who received multiple CART sessions were registered as separate entries. After excluding patients with non-malignant conditions, subjects were categorized into two groups for analysis: patients with gynecological malignancies (ovarian, fallopian tube, endometrial, cervical, and peritoneal cancer) designated as Group G, and patients with other cancer types designated as Group O.\u003c/p\u003e\n\u003ch3\u003eCART Procedure\u003c/h3\u003e\n\u003cp\u003eThe standardized CART procedure consisted of three sequential steps: collection, concentration and reinfusion [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. In this study, paracentesis was performed under local anesthesia using either a catheter or needle. The AHF-MO ascitic filtration filter and AHF-UP ascitic concentration filter (Asahi Kasei Medical Co., Ltd., Tokyo, Japan) were employed for the filtration and concentration processes, respectively. Processing conditions, including filtration direction, filtration and concentration speed, and driving force varied according to institutional protocols.\u003c/p\u003e\n\u003ch3\u003eData Collection and Assessment\u003c/h3\u003e\n\u003cp\u003eWe collected patient background information including age, sex, primary disease, clinical stage, history of ascites therapy, and concurrent chemotherapy during or one month prior to CART procedures. For technical parameters, we documented total ascites volume, concentration ratio, total protein and albumin levels before and after processing, and their recovery rates calculated by comparing amounts in processed fluid to those in original ascites.\u003c/p\u003e \u003cp\u003eClinical parameters evaluated before and after CART included body weight, abdominal circumference, ECOG performance status (PS), dietary intake, daily urine volume, and laboratory values. Dietary intake was assessed by monitoring dinner consumption using a 5-point scale (0%, 25%, 50%, 75%, and 100%).\u003c/p\u003e \u003cp\u003eLaboratory tests included complete blood counts (white blood cells, red blood cells, hemoglobin, hematocrit, platelets) and serum biochemistry (total protein, albumin, BUN, Cre, eGFR). Body temperature was measured at four timepoints: before reinfusion, immediately after reinfusion completion, 1 hour after completion, and one day after reinfusion. To account for circulating blood volume changes due to colloidal osmotic pressure alterations during CART, laboratory values were adjusted according to the following formula:\u003c/p\u003e \u003cp\u003eAdjusted post-CART value\u0026thinsp;=\u0026thinsp;post-CART value \u0026times; (pre-CART Hct value)/(post-CART Hct value)\u003c/p\u003e \u003cp\u003eCART-associated adverse events as determined by attending physicians were recorded and classified according to the Medical Dictionary for Regulatory Activities/Japanese version 18.0 (MedDRA/J version 18.0).\u003c/p\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eAll data were expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD) or proportion (%). Continuous data were analyzed by Student's t-test and categorical data were analyzed by Wilcoxon signed rank test, Mann-Whitney U test or Fisher's exact test. Paired t-test was used for comparisons between before and after CART within the same patient. Missing data were excluded from all analyses and P values less than 0.05 (two-sided test) were considered statistically significant. Data were analyzed using Bell Curve for Excel version 4.08.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003ePatient Background\u003c/h2\u003e \u003cp\u003eQuestionnaires were collected from 147 registered patients, and clinical data on 356 sessions of CART were retrieved. Nineteen patients who underwent 56 sessions for conditions other than malignancies were excluded. Three patients who underwent 4 sessions were excluded due to insufficient data for evaluation. A total of 125 patients who underwent 296 sessions were included in the study. Group G comprised 46 patients who underwent 85 sessions, and Group O comprised 79 patients who underwent 211 sessions. Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e illustrates the selection process of the study patients.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe background of the patients is shown in Table\u0026nbsp;1. The mean age of patients in Group G was 63.8\u0026thinsp;\u0026plusmn;\u0026thinsp;12.0 years compared to 67.1\u0026thinsp;\u0026plusmn;\u0026thinsp;11.7 years in Group O. This difference was not statistically significant (p\u0026thinsp;=\u0026thinsp;0.162). The primary cancers of Group G included ovary (71.7%), peritoneum (13.0%), and cervix (6.5%), whereas Group O included pancreas (27.8%), liver (24.1%), and stomach (16.5%). Anticancer drug use during or within one month prior to CART was more frequent in Group G (35/85 sessions [41.2%]) than in Group O (26/211 sessions [12.3%]) (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Regarding clinical stage, Stage 4 disease was present in 30.4% of Group G and 88.6% of Group O.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eEfficacy of CART procedure\u003c/h3\u003e\n\u003cp\u003eThe conditions of 296 CART procedures are summarized in Table\u0026nbsp;2. The amount of ascites collected was 3,051\u0026thinsp;\u0026plusmn;\u0026thinsp;1,102 g in Group G and 3,506\u0026thinsp;\u0026plusmn;\u0026thinsp;1,345 g in Group O. The concentration of total protein was significantly higher in Group G compared to Group O in the original ascites (4.2\u0026thinsp;\u0026plusmn;\u0026thinsp;1.1 g/dL vs. 2.4\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2 g/dL, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and in the processed ascites (15.1\u0026thinsp;\u0026plusmn;\u0026thinsp;4.0 g/dL vs. 14.2\u0026thinsp;\u0026plusmn;\u0026thinsp;7.4 g/dL, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Similarly, albumin concentration was significantly higher in Group G in the original ascites (2.1\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5 g/dL vs. 1.3\u0026thinsp;\u0026plusmn;\u0026thinsp;0.7 g/dL, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and in the processed ascites (8.2\u0026thinsp;\u0026plusmn;\u0026thinsp;4.5 g/dL vs. 7.8\u0026thinsp;\u0026plusmn;\u0026thinsp;4.3 g/dL, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). In comparing the calculated total protein amount between groups, the amount was significantly higher in Group G in the original ascites (127.8\u0026thinsp;\u0026plusmn;\u0026thinsp;60.9 g vs. 88.7\u0026thinsp;\u0026plusmn;\u0026thinsp;52.4 g, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and also in the processed ascites (83.4\u0026thinsp;\u0026plusmn;\u0026thinsp;43.2 g vs. 65.3\u0026thinsp;\u0026plusmn;\u0026thinsp;40.6 g, p\u0026thinsp;=\u0026thinsp;0.003). The same trend was also observed for albumin, with amounts in Group G significantly higher both in the original ascites (63.9\u0026thinsp;\u0026plusmn;\u0026thinsp;26.6 g vs. 49.0\u0026thinsp;\u0026plusmn;\u0026thinsp;32.0 g, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and in the processed ascites (44.7\u0026thinsp;\u0026plusmn;\u0026thinsp;21.3 g vs. 38.1\u0026thinsp;\u0026plusmn;\u0026thinsp;26.8 g, p\u0026thinsp;=\u0026thinsp;0.011).\u003c/p\u003e \u003cp\u003eThe concentration ratio and the retention rates of total protein and albumin are shown in Supplemental Table\u0026nbsp;1. The concentration ratio was significantly lower in Group G compared to Group O (6.4\u0026thinsp;\u0026plusmn;\u0026thinsp;2.3 vs. 9.7\u0026thinsp;\u0026plusmn;\u0026thinsp;5.2, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The recovery rates of total protein (65.1\u0026thinsp;\u0026plusmn;\u0026thinsp;16.0% vs. 73.8\u0026thinsp;\u0026plusmn;\u0026thinsp;18.0%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and albumin (69.3\u0026thinsp;\u0026plusmn;\u0026thinsp;15.5% vs. 76.6\u0026thinsp;\u0026plusmn;\u0026thinsp;16.9%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) were both significantly lower in Group G. Hemorrhagic ascites was more frequent in Group G (31.8% vs. 24.2%), though not statistically significant (p\u0026thinsp;=\u0026thinsp;0.18).\u003c/p\u003e \u003cp\u003eThe changes in blood test values between before and after CART are shown in Table\u0026nbsp;3. The level of Cre (from 0.7\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3 mg/dL to 0.6\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3 mg/dL, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and BUN (from 17.9\u0026thinsp;\u0026plusmn;\u0026thinsp;8.7 mg/dL to 14.5\u0026thinsp;\u0026plusmn;\u0026thinsp;9.0 mg/dL, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) after the procedure of CART were significantly decreased and the eGFR was significantly elevated (from 72.7\u0026thinsp;\u0026plusmn;\u0026thinsp;24.8 mL/min/1.73m\u0026sup2; to 81.3\u0026thinsp;\u0026plusmn;\u0026thinsp;27.6 mL/min/1.73m\u0026sup2;, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) in Group G, indicating an improvement in renal function. Hct decreased significantly in both Group G (from 32.1\u0026thinsp;\u0026plusmn;\u0026thinsp;6.5% to 29.5\u0026thinsp;\u0026plusmn;\u0026thinsp;4.8%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and Group O (from 32.8\u0026thinsp;\u0026plusmn;\u0026thinsp;4.7% to 30.6\u0026thinsp;\u0026plusmn;\u0026thinsp;5.0%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), indicating plasma volume expansion due to the increase in plasma colloid osmotic pressure caused by the reinfusion of proteins. In both groups, the levels of total protein and albumin were significantly elevated after the CART procedure by the reinfusion of the patient's own proteins from the processed ascites.\u003c/p\u003e \u003cp\u003eThe clinical changes before and after CART are shown in Table\u0026nbsp;4. Both groups showed significant reduction in body weight, abdominal circumference, improved ECOG PS scores, increased dietary intake, and increased urine output after CART. The intervals between removal procedures (including both CART and paracentesis alone) were significantly longer in Group G than in Group O (20.0\u0026thinsp;\u0026plusmn;\u0026thinsp;13.8 days versus 11.7\u0026thinsp;\u0026plusmn;\u0026thinsp;10.9 days, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eSafety of CART procedure\u003c/h2\u003e \u003cp\u003eAdverse events were recorded in 45.7% (21/46) of patients in Group G versus 27.8% (22/79) in Group O, and in 35.3% (30/85) of Group G sessions compared to 10.9% (23/211) in Group O sessions. Fever occurred significantly more frequently in Group G than Group O (29.4% versus 5.2%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). All adverse events were non-severe, with complete recovery observed in all patients.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study compared the efficacy and safety of Cell-free and Concentrated Ascites Reinfusion Therapy (CART) between gynecological cancer patients and other cancer types with massive ascites, revealing four key findings: 1) The gynecological cancer group had a significantly higher proportion of patients undergoing chemotherapy during or one month prior to CART procedure; 2) Both original and processed ascites contained significantly higher levels of total protein and albumin in the gynecological cancer group; 3) The gynecological cancer group demonstrated significant improvement in renal function along with increased daily urine volume following CART; and 4) The gynecological cancer group exhibited a longer interval between ascites drainage procedures. While many studies have evaluated the efficacy and safety of CART, to our knowledge, this is the first study to demonstrate enhanced efficacy in gynecological cancer patients with respect to renal function, suggesting a potential role of CART as a supportive therapy for chemotherapy beyond its established palliative benefits.\u003c/p\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eHigher rate of chemotherapy uses in gynecological cancer patients\u003c/h2\u003e \u003cp\u003eOur first finding regarding the higher proportion of patients undergoing chemotherapy in the gynecological cancer group reflects clinical practice patterns for gynecological malignancies where chemotherapy remains essential even in advanced disease. Many anticancer drugs used in gynecological cancers (paclitaxel, docetaxel, cisplatin, doxorubicin, etoposide) have high binding rates (\u0026gt;\u0026thinsp;70%) to serum albumin [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Serum albumin concentration significantly influences these drugs' pharmacokinetics, and low levels increase the fraction of unbound anticancer drugs, potentially causing excessive toxicity. CART serves dual roles in chemotherapy patients: improving serum albumin levels directly (Table\u0026nbsp;3) and potentially optimizing drug pharmacokinetics for patients with low albumin. This benefit is particularly relevant for gynecological cancer patients given their high rates of concurrent chemotherapy. Hypoalbuminemia frequently accompanies malignant ascites and is a risk factor for febrile neutropenia [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], hypovolemia, hypotension, and increased mortality [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. While Japanese guidelines discourage \"administration of albumin preparation to patients with hypoalbuminemia due to malignant tumors or terminally ill patients\" [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], CART offers a valuable alternative by reducing the need for exogenous albumin while providing comparable efficacy [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFurthermore, autologous albumin represents a more physiological approach to replenishment compared to commercial preparations, reducing allergic reactions [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. CART improves clinically important parameters including ECOG PS and dietary intake (Table\u0026nbsp;4), potentially enabling patients to begin or resume primary treatments more effectively [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. This is significant given evidence that ascites from ovarian cancers may confer platinum chemoresistance [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], highlighting benefits beyond symptom palliation.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eHigher protein and albumin content in gynecological cancer ascites\u003c/h2\u003e \u003cp\u003eOur second finding revealed significantly higher concentration and total amount of protein and albumin in ascites from gynecological cancer patients compared to other malignancies. As shown in Table\u0026nbsp;2, Group G demonstrated significantly higher concentrations of total protein and albumin in both original and processed ascites than Group O, representing a distinctive biochemical characteristic with important clinical implications.\u003c/p\u003e \u003cp\u003ePrevious studies have established that protein quantity returned during CART positively correlates with urine production and improved renal function [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. This relationship helps explain why CART appears particularly beneficial for gynecological cancer patients with malignant ascites. Beyond albumin, replenishment of other bioactive components may provide additional therapeutic benefits. Cytokines and interleukins in processed ascites may modulate immune function, with one report indicating that IL-10 in ascites correlated with longer survival after CART [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Further investigation into specific immunomodulatory components could provide insights into the mechanisms underlying CART's beneficial effects in gynecological cancer patients.\u003c/p\u003e \u003cp\u003eDespite higher protein content, our findings in Supplemental Table\u0026nbsp;1 demonstrated significantly lower protein recovery rates in Group G. Several factors likely contribute to this observation. First, the characteristic high protein concentration in gynecological cancer ascites may itself impede filtration efficiency through increased viscosity. Second, gynecological cancer ascites more frequently presented with hemorrhagic characteristics, although this difference did not reach statistical significance. The presence of blood components, including fibrin and cellular debris, is known to affect recovery rates through filter clogging [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. For gynecological cancer patients, adjusting processing parameters such as reducing filtration speed [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] may improve protein recovery, while developing enhanced filtration technology specifically designed for the unique characteristics of gynecological cancer ascites could further optimize CART efficacy in this patient population.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eSignificant improvement in renal function in gynecological cancer patients\u003c/h2\u003e \u003cp\u003eOur third finding was the significant improvement in renal function observed specifically in gynecological cancer patients following CART. As shown in Table\u0026nbsp;3, Group G demonstrated significant decreases in Cre and BUN levels along with elevations in eGFR after CART, a finding with substantial clinical implications for patients concurrently receiving chemotherapy.\u003c/p\u003e \u003cp\u003eThe improvement in renal function likely results from several physiological mechanisms. The reduction in abdominal pressure following massive ascites removal contributes to improved renal function through renal decongestion [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e], relieving renal vessel compression and enhancing perfusion. In addition, reinfusion of concentrated proteins, particularly albumin, elevates blood colloid osmotic pressure, facilitating fluid movement from the third space into blood vessels. Current evidence suggests that albumin in processed ascites contributes to endothelial glycocalyx layer formation, preventing plasma leakage [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Additionally, albumin's anti-inflammatory and antioxidant properties may improve vascular permeability [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Through these mechanisms, CART prevents third-space fluid accumulation while maintaining adequate circulating plasma volume, improving renal blood flow and increasing urine output [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. This is supported by our observation of a significant increase in the urine volume. The clinical importance of improved renal function extends beyond symptomatic relief. Enhanced renal function potentially facilitates more efficient anticancer drug clearance, which may reduce toxicity without compromising efficacy. This is particularly relevant for gynecological cancer patients who more frequently undergo concurrent chemotherapy.\u003c/p\u003e \u003cp\u003eAdditionally, CART may facilitate completion of planned chemotherapy regimens by avoiding delays due to renal dysfunction. When calculating anticancer drug dosages, body surface area (BSA) and creatinine clearance are commonly used [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. By controlling ascites volume, stabilizing body weight, and improving renal function, CART may contribute to more appropriate and consistent chemotherapy dosing, potentially optimizing treatment outcomes in gynecological cancer patients with malignant ascites.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eExtended intervals between ascites removal in gynecological cancer\u003c/h2\u003e \u003cp\u003eOur fourth finding regarding longer intervals between ascites removal in gynecological cancer patients has significant implications for maintaining QOL and stabilizing body weight. Malignant ascites significantly impacts QOL and daily activities [\u003cspan additionalcitationids=\"CR30\" citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e], while also increasing hospitalization rates\u0026mdash;particularly emergency admissions\u0026mdash;and healthcare costs [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e] Since treatment for malignant ascites is primarily palliative, minimizing hospital stays benefits patients, their families, and healthcare systems. Given that malignant ascites secondary to ovarian cancers is associated with longer life expectancy compared to other cancer types [\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], effective ascites management through CART is particularly valuable for gynecological cancer patients.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eAdverse events\u003c/h2\u003e \u003cp\u003eRegarding adverse events, fever represents the most frequent complication of CART. Refractory ascites contains inflammatory substances such as cytokines (including interleukins) derived from cancer cells or released from activated white blood cells during filtration and concentration, potentially causing fever [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. The higher frequency of fever observed in Group G may result from greater cytokine content in ascitic proteins, affecting serum cytokine levels [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Additionally, our data showed that steroids or NSAIDs, which may reduce fever [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e], were used before reinfusion in 24.7% of Group G versus 54.0% of Group O (data not shown), potentially contributing to the higher fever incidence in gynecological cancer patients. However, none of these adverse events were severe, and all patients fully recovered.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eLimitations\u003c/h2\u003e \u003cp\u003eOur study has several limitations. Differences in disease stage and sex distribution between the gynecologic and other cancer groups may introduce bias in comparisons of parameters such as ECOG PS, dietary intake, and serum creatinine levels. However, total protein and albumin levels in ascites are less affected by these differences. Future studies with matched stage distributions and controlled demographic factors would help validate these findings and further clarify the specific benefits of CART in different cancer populations.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eFuture Research\u003c/h2\u003e \u003cp\u003eOur findings highlight the potential of CART in gynecological cancer patients, particularly for improving renal function, restoring albumin levels, and stabilizing body weight. While CART has traditionally been viewed as a palliative intervention, our results suggest a supportive role for CART in chemotherapy management. For patients with advanced ovarian or peritoneal cancer with malignant ascites, CART may be particularly beneficial when administered before neoadjuvant chemotherapy. By managing ascites and improving protein balance prior to treatment, CART could potentially reduce chemotherapy-related adverse events, improve tolerance, and facilitate treatment completion without dose modifications. Future studies should evaluate the efficacy of CART by comparing the incidence of chemotherapy dose reductions, postponements, or discontinuations between patients undergoing CART versus those receiving paracentesis alone prior to neoadjuvant chemotherapy in advanced gynecological malignancies. Such research would help identify additional therapeutic benefits of CART beyond its established palliative role and could optimize treatment strategies for patients with gynecological malignancies complicated by ascites.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eCART demonstrates particular efficacy and safety in gynecological cancer patients with malignant ascites. The improvement in renal function observed in this study may help reduce side effects of anticancer drugs, potentially contributing to better treatment tolerability. The significantly higher protein and albumin content in gynecological cancer ascites and longer intervals between drainage procedures further support CART as an important supportive therapy for gynecological malignancies.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eNothing to declare\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStatistical analysis was performed by the Blood Purification Division, Asahi Kasei Medical Co., Ltd.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors declare no conflict of interest with regards to this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe understand the importance of openness of data. However, unfortunately, the data for this manuscript cannot be made publicly available, because it was collected from the participating medical facilities and public availability would compromise patient confidentiality or participant facility privacy. These restrictions are compliant with the Ethical Guidelines for Medical and Health Research Involving Human Subjects that was issued by Ministry of Health, Labour and Welfare (MHLW) of Japan and with the Good Post-marketing Surveillance Practice, which was also issued by MHLW of Japan.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eRunyon BA (1994) Care of patients with ascites. 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Int J Clin Oncol 24(4):420\u0026ndash;427. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s10147-018-1371-7\u003c/span\u003e\u003cspan address=\"10.1007/s10147-018-1371-7\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 to 4 are available in the Supplementary Files section.\u003c/p\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":"Cell-free and concentrated ascites reinfusion therapy (CART), gynecological cancer, post-marketing surveillance (PMS)","lastPublishedDoi":"10.21203/rs.3.rs-6609092/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6609092/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground:\u003c/h2\u003e \u003cp\u003eCell-free and concentrated ascites reinfusion therapy (CART) is an established method for managing malignant ascites. Ascites management is particularly important for gynecological cancer patients as ovarian cancer is the most common cause of malignant ascites, and patients with gynecological cancers often require long-term treatment. This study evaluates the efficacy and safety of CART specifically in gynecological cancer patients compared to patients with other cancers.\u003c/p\u003e\u003ch2\u003eMethods:\u003c/h2\u003e \u003cp\u003eThis subgroup-analysis of a prospective post-marketing surveillance was conducted between January 2014 and January 2015. The study included 147 patients who underwent 356 CART sessions across 22 centers in Japan. After excluding non-cancerous patients, subjects were divided into two groups: gynecological cancer patients (Group G) and other cancer patients (Group O).\u003c/p\u003e\u003ch2\u003eResults:\u003c/h2\u003e \u003cp\u003eThe final analysis included 128 patients who underwent 300 CART sessions (Group G: 46 patients/85 sessions; Group O: 79 patients/211 sessions). Group G had significantly higher rates of concurrent chemotherapy. The amount of total protein and albumin in both original and processed ascites was significantly larger in Group G. Group G showed significant improvements in renal function parameters (serum creatinine, blood urea nitrogen, estimated glomerular filtration rate) and increased daily urine volume. The interval between ascites removal procedures was longer in Group G, and no severe adverse events were observed in either group.\u003c/p\u003e\u003ch2\u003eConclusion:\u003c/h2\u003e \u003cp\u003eCART demonstrates particular efficacy and safety in gynecological cancer patients. The improvement in renal function observed in this study may help reduce side effects of anticancer drugs, potentially contributing to better tolerability.\u003c/p\u003e","manuscriptTitle":"Cell-free and Concentrated Ascites Reinfusion Therapy (CART) Shows Enhanced Efficacy in Gynecological Cancer Patients: A Post-marketing Surveillance Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-14 12:06:33","doi":"10.21203/rs.3.rs-6609092/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":"0be8c161-b91d-4595-8c41-cae8d4437507","owner":[],"postedDate":"May 14th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-05-30T14:59:29+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-14 12:06:33","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6609092","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6609092","identity":"rs-6609092","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}