Impact of Cryotherapy on Incidence and Severity of Oral Mucositis in Hematopoietic Stem Cell Transplantation: Retrospective Observational Study

Impact of Cryotherapy on Incidence and Severity of Oral Mucositis in Hematopoietic Stem Cell Transplantation: Retrospective Observational 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 Article Impact of Cryotherapy on Incidence and Severity of Oral Mucositis in Hematopoietic Stem Cell Transplantation: Retrospective Observational Study Oliwia Piotrowska, Alina Zuchmańska, Piotr Kulig, Tomasz Michowski, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6813382/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 23 Oct, 2025 Read the published version in Scientific Reports → Version 1 posted 10 You are reading this latest preprint version Abstract Oral mucositis (OM) is a common and significant complication of chemotherapy and radiotherapy, particularly in patients undergoing hematopoietic stem cell transplantation (HSCT). This retrospective observational study assessed the effectiveness of oral cryotherapy in reducing the incidence and severity of OM in 258 HSCT recipients treated at a single transplant center in Poland between 2018 and 2024. Patients were divided into two groups: 199 received cryotherapy as part of their conditioning regimen, while 59 did not. Cryotherapy was administered using ice chips from 10 minutes before chemotherapy infusion to two hours afterward. OM occurred in 48% of the cryotherapy group versus 68% in the control group, representing a statistically significant 20% relative risk reduction (p = 0.008). Furthermore, the incidence of severe OM (grades 3–4) was significantly lower in the cryotherapy group (p = 0.006). No significant differences were observed in platelet engraftment or hospitalization duration. Although neutrophil engraftment was slightly delayed in the cryotherapy group, this finding lacked clinical relevance. Overall, the results support cryotherapy as a safe, cost-effective, and easily implementable strategy for OM prevention in the HSCT setting. Further prospective studies are warranted to validate these findings and optimize treatment protocols. Biological sciences/Stem cells/Haematopoietic stem cells Health sciences/Diseases/Cancer/Cancer therapy/Chemotherapy Oral Mucositis Cryotherapy Hematopoietic Stem Cell Transplantation Chemotherapy Radiotherapy Side Effects INTRODUCTION Hematopoietic stem cell transplantation (HSCT) represents a complex therapeutic strategy for the management of hematological malignancies 1 and selected non-hematological disorders 23 . In recent years, there has been a consistent increase in the total number of HSCTs performed, accompanied by the emergence of a broader spectrum of conditioning regimens 4 . The conditioning phase, which is essential before the HSCT, may involve the utilization of chemotherapy and radiation therapy, including total body irradiation (TBI) 5 . The short- and long-term adverse effects associated with this treatment are significant and include myelotoxicity, mucositis, nausea, vomiting, diarrhea, cutaneous rashes, alopecia, and peripheral neuropathies 1 . Oral mucositis (OM), an ulcerative and inflammatory disease of the oral mucosa, is recognized as one of the most prevalent complications in patients undergoing chemotherapy and/or radiotherapy. OM is associated with direct stoma toxicity and usually develops within 3 to 7 days after chemotherapy and resolves within approximately 2 to 3 weeks, in parallel with neutrophil recovery. The incidence of OM is associated with heightened morbidity and can adversely influence treatment adherence and overall patient outcomes. The associated pain and debilitating symptoms significantly diminish patients' quality of life, often leading to anorexia and necessitating the implementation of enteral or total parenteral nutrition. The presentation of OM varies according to the severity grade. Clinical manifestations may include alterations in taste perception, restricted range of motion in the jaw, difficulties in swallowing and speaking, and disturbances in sleep patterns. These lesions can be portals for systemic infections, including bacteremia 67 . Various interventions have been tested and implemented for the prevention and treatment of oral mucositis (OM) 8679 . The Mucositis Study Group of the Multinational Association for Supportive Care in Cancer and the International Society of Oral Oncology (MASCC/ISOO) has provided clinical guidelines for managing mucositis 10 . Oral cryotherapy is commonly used to prevent OM, with minimal risk of side effects. This therapy involves placing ice in the form of ice cubes in the mouth before or during chemotherapy treatment 1112 . The cooling effect causes local hypothermia, leading to vasoconstriction of the oral mucosal blood vessels, which decreases blood flow to the tissues. As a result, the concentration of cytotoxic agents in the oral mucosa is reduced. Additionally, oral cryotherapy may lower the metabolic rate in the oral epithelium, helping to decrease inflammation. Following the increasing incidence of mucositis, new clinical practice guidelines for managing mucositis secondary to cancer therapy were published by MASCC/ISOO in 2020. The safety and effectiveness of recombinant human keratinocyte growth factor-1 (KGF-1/palifermin) in OM prevention have been established. Palifermin has proven effectiveness in significantly reducing the incidence and duration of grade 3–4 OM after myeloablative therapy. Furthermore, apart from palifermin, there are two human fibroblast growth factors (velafermin and repifermin), which may open the door to a focused strategy for mucositis prevention 1314 . Limited data on the successful OM treatment in patients receiving HSCT are available. Morphine is indicated for pain treatment due to oral mucositis in patients undergoing HSCT. Borowski et al. state in their article that a 2% morphine oral mouthwash may be used to treat mucosal pain accompanying OM 15 . MATERIALS AND METHODS STUDY DESIGN 1.1. PATIENTS From 23.07.2018 to 01.02.2024, a retrospective observational study was conducted at the University Clinical Hospital No. 1 of the Pomeranian Medical University in Szczecin (Poland). We investigated 258 consecutive autologous and allogeneic peripheral blood stem cell transplantation (PBSCT) procedures. All patients suffered from hematological malignancies or solid tumors. Detailed patients and cryotherapy characteristics are presented in Table 1 in the Results section. The participants in the study were categorized into two distinct groups: the study group comprised 199 patients who underwent cryotherapy as part of their conditioning regimen, whereas the control group included 59 patients who did not receive cryotherapy. The study was approved by the Bioethics Committee of the Pomeranian Medical University in Szczecin. As the study was retrospective in its nature the opinion of the ethics committee was not mandatory. No organs were harvested from prisoners in the study. Both donors and recipients of hematopoietic stem cells signed informed consents before the procedures were performed. All the research involving our participants was performed in accordance with the Declaration of Helsinki. 1.2. METHOD OF PERFORMING CRYOTHERAPY Oral cryotherapy introduces various ice forms—such as chips, cubes, or ice-cold water—into the mouth before or during chemotherapy treatment. Ice cubes are prepared with an ice machine with no unique solution. Cryotherapy was provided from 10 minutes before until 2 hours after any chemotherapy infusion. Apart from cryotherapy, the study group and the control group had oral care protocols implemented. Basic oral care protocols generally include brushing teeth, flossing, and at least one mouth rinse to uphold oral hygiene. 1.3. STATISTICAL ANALYSIS Continuous variables are expressed as mean (median); interquartile range (IQR). The Shapiro-Wilk test was implemented to assess the distribution of continuous variables. As constant variables were not normally distributed, the Mann-Whitney U test was implemented to compare the differences between the groups. Fisher exact test was used to assess differences in the categorical variables between the groups. When relevant post hoc pairwise comparison with Bonferroni correction for multiple testing was implemented. P value < 0.05 was considered statistically significant. All calculations were performed in RStudio. DEFINITIONS According to CTCAE, oral mucositis is defined as a disorder characterized by ulceration or inflammation of the oral mucosa. The severity of oral mucositis was defined as per the CTCAE oral toxicity scale, separating mucositis into 5 Grades. Grade 1 = Asymptomatic or mild symptoms; intervention not indicated, Grade 2 = oral ulcers, patients able to take solids; Grade 3=Severe pain; interfering with oral intake, Grade 4 = Life-threatening consequences; urgent intervention indicated; Grade 5=Death. RESULTS 3. 1. CHARACTERISTICS OF THE STUDY GROUP The characteristics of the group are presented in Table 1. 3.2. Cryotherapy reduces the incidence rate of oral mucositis. Cryotherapy has been demonstrated to significantly reduce the incidence of oral mucositis (OM) among recipients of stem cell transplants, regardless of the transplant modality employed (as shown in Table 1). Our investigation revealed that 48% of patients undergoing cryotherapy developed OM, in stark contrast to a 68% incidence observed in patients who did not receive this intervention. This finding corresponds to a relative risk reduction of 20% (RRR 20%, p = 0.008). Furthermore, cryotherapy has been shown to mitigate the risk of developing severe oral mucositis, specifically in grades 3-4 (p = 0.0056). Post-hoc analysis further elucidated statistically significant differences between individuals who did not develop OM and those who experienced OM graded as G1-2 and G3-4, with p-values of 0.044 and 0.029, respectively. In our investigation, we did not observe statistically significant differences regarding the length of hospitalization (p = 0.37) or platelet engraftment (p = 0.537). It is noteworthy that neutrophil engraftment within the cryotherapy cohort was observed to occur slightly later compared to the non-cryotherapy cohort, with mean durations of 12.38 days and 11.63 days, respectively (p = 0.045). However, this delay lacks clinical significance, as it does not correlate with an extension of the hospitalization period. It should be emphasized that the cryotherapy group was more diverse as it included patients undergoing alloSCT and patients treated for lymphomas where both subgroups are characterized by a more extended period of neutropenia compared to autoHSCT in myeloma. The control group included only patients undergoing the autoHSCT procedure, usually after melphalan conditioning for multiple myeloma. 3.3. Oral mucositis occurs less frequently in alloSCT patients with reduced intensity conditioning regimen. Next, we wanted to analyze if OM mucositis occurred more frequently in any subgroup regardless of cryotherapy (Table 4). We did not detect any differences in age (p = 0.2), type of SCT in the whole cohort (p = 0.86), and among patients who received cryotherapy (p = 0.045). Among alloSCT patients (all alloSCT individuals received cryotherapy) OM occurred less frequently in the RIC (reduced intensity conditioning) subgroup compared to the MAC (Myeloablative Conditioning) conditioning group (RRR 61%, p = 0.006). DISCUSSION The incidence of mucositis in patients undergoing hematopoietic stem cell transplantation (HSCT) is closely linked to the exacerbation of infectious and nutritional complications. By compromising the integrity of the mucosal barrier, mucositis is a potential conduit for the onset of bloodstream infections. These infections pose significant risks to patient health and extend the duration of hospitalization substantially. The management of these complications often necessitates intravenous antibiotic therapy and, in some cases, the administration of vasoconstrictor agents, thereby escalating the overall costs associated with patient care and hospitalization 16 17 18 19 . The findings of our study did not demonstrate a statistically significant relationship between the use of cryotherapy and the duration of stem cell engraftment or the length of hospital stay (p = 0.37). As mentioned earlier, this is most likely related to the characteristics of the study and control groups - the cryotherapy group included patients undergoing alloSCT and patients treated for lymphomas, where both subgroups are characterized by a longer period of neutropenia compared to classic autoSCT recipients and have longer hospitalization time. Further studies on the effectiveness of cryotherapy are required, comparing groups of patients homogeneous in terms of diagnosis and transplant type. Research has demonstrated that cryotherapy effectively reduces both the incidence and severity of oral mucositis in patients undergoing high-dose chemotherapy during hematopoietic stem cell transplantation (HSCT) 16 20 21 . In our study, we also confirmed this relationship, noting a 20% relative reduction in the risk of mucositis among patients who used cryotherapy compared to those who did not (RRR 20%, p = 0.008). The prevalence and severity of OM could vary depending on the type of transplant and conditioning regimen. The incidence of severe oral mucositis (SOM) is greater in patients undergoing alloSCT compared to autoSCT recipients due to prolonged neutropenia in the alloSCT group. SOM frequency reached 98% in the group receiving a conditioning regimen consisting of total body irradiation 22 . In a single-center retrospective study by Nakagaki et al., SOM (grade 3-4) was common in myeloablative total body irradiation (TBI) based regimens cyclophosphamide/TBI (71%) and fludarabine/TBI with PTCy (46%). In contrast, SOM occurred less frequently in reduced-intensity haploidentical regimen melphalan/fludarabine/TBI with PTCy (19%) 23 . Multicentre and retrospective study by L. Vagliano and colleagues demonstrated that 71% of patients who underwent HSCT were diagnosed with OM, and 21.6% developed SOM 24 . Moreover the duration and severity of mucositis are associated with the intensity of conditioning - they are both diminished in RIC setting 22 25 . Increased rates of OM were found in 86,5% HSCT patients who received myeloablative regimens versus 73.2% of patients who received reduced-intensity regimens. HSCT conditioning regimens, including those that utilize melphalan, busulfan, or radiotherapy, are significant contributors to the pathogenesis of oral mucositis 21 . In our research, we found no differences in the incidence of mucositis between alloSCT and autoSCT (p = 0.86). Notwithstanding, among alloSCT patients (all alloSCT individuals received cryotherapy) OM occurred less frequently in RIC subgroup (RRR 61%, p = 0.006). The absence of statistically significant differences in the incidence of mucositis between the autoSCT and alloSCT groups may be explained by the use of both RIC and MAC regimens in the alloSCT group, in contrast to the exclusive use of MAC regimens in the autoSCT group. Mucositis is frequently correlated with heightened levels of pain in patients, which subsequently diminishes their quality of life and necessitates the administration of supplementary analgesics 25 . The implementation of cryotherapy during the conditioning phase of hematopoietic stem cell transplantation has the potential to significantly reduce the requirement for pain management, particularly the utilization of opioids. Opioids themselves are associated with a range of adverse effects, including constipation, nausea, and vomiting. Furthermore, by mitigating both the incidence and severity of mucositis, we can enhance patient comfort and overall quality of life (QoL) 19 26 . The pain itself may lead to the development of anorexia and then malnutrition, which may prolong the patient's stay in the hospital. All this together leads to the subsequent need to implement TPN (Total Parenteral Nutrition). The use of cryotherapy supports the patient's physiological alimentation of food, which helps reduce the incidence of thrombosis or infections in central vein access lines, TPN complications. However, in our patients, we did not demonstrate a relationship between the occurrence of mucositis and an increased risk of using TPN, which may be caused by a small study sample (p = 0.87). According to some publications, e.g. “ Current Trends in Management of Oral Mucositis in Cancer Treatment” by Shankar A. and colleagues, mucositis leads to prolonged regeneration of hematopoiesis, including myelopoiesis and thrombopoiesis as well as prolonged hospitalization 6 . In conclusion, the application of cryotherapy during the conditioning phase for patients during the HSCT procedure represents a highly economical approach to the prevention of mucositis, which yields several advantages for patient care. Consequently, we advocate for the routine implementation of cryotherapy in all patients undergoing hematopoietic stem cell transplantation. Declarations Data availability statement: The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. Author contributions: Oliwia Piotrowska: investigation, patient care, data curation, conceptualization, study design, writing- original draft; Alina Zuchmańska : investigation, patient care, data curation, conceptualization, study design, writing- original draft; Piotr Kulig: investigation, formal analysis, writing - original draft, patient care, tables preparation; Tomasz Michowski: investigation, data curation; Jacek Szulc: investigation, data curation; Patryk Skórka: investigation, data curation; Dominika Dorsz: investigation, data curation; Bogusław Machaliński: supervision, writing-review and editing; Sławomir Milczarek: investigation, conceptualization, study design, writing- original draft. All authors reviewed the manuscript; Additional Information Competing Interests Statement: The authors declare no conflicts of interest. Funding: This research received no external funding. References Arnaout, K. et al. Complications of Allogeneic Hematopoietic Stem Cell Transplantation. 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Oncol. 27 , v119–v133 (2016). Villa, A. & Sonis, S. T. Pharmacotherapy for the management of cancer regimen-related oral mucositis. Expert Opin. Pharmacother. 17 , 1801–1807 (2016). Herrstedt, J. et al. 2023 MASCC and ESMO guideline update for the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting. ESMO Open 9 , 102195 (2024). Elad, S. et al. MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy. Cancer 126 , 4423–4431 (2020). Walladbegi, J. et al. Cooling of the oral mucosa to prevent adverse effects of chemotherapeutic agents: An in vitro study. J. Oral Pathol. Med. 47 , 477–483 (2018). Johansson, J.-E. et al. Cryotherapy as prophylaxis against oral mucositis after high-dose melphalan and autologous stem cell transplantation for myeloma: a randomised, open-label, phase 3, non-inferiority trial. Bone Marrow Transplant. 54 , 1482–1488 (2019). Braun, S. et al. 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Inflamm. 2014 , 378281 (2014). Reuss, J. M. et al. Oral Mucosa in Cancer Patients—Putting the Pieces Together: A Narrative Review and New Perspectives. Cancers 15 , 3295 (2023). Svanberg, A., Öhrn, K. & Birgegård, G. Oral cryotherapy reduces mucositis and improves nutrition – a randomised controlled trial. J. Clin. Nurs. 19 , 2146–2151 (2010). Niscola, P. et al. Mucositis in patients with hematologic malignancies: an overview. Haematologica 92 , 222–231 (2007). Spielberger, R. et al. Palifermin for Oral Mucositis after Intensive Therapy for Hematologic Cancers. N. Engl. J. Med. 351 , 2590–2598 (2004). Nakagaki, M., Kennedy, G. A., Gavin, N. C., Clavarino, A. & Whitfield, K. The incidence of severe oral mucositis in patients undergoing different conditioning regimens in haematopoietic stem cell transplantation. Support. Care Cancer 30 , 9141–9149 (2022). Vagliano, L. et al. Incidence and severity of oral mucositis in patients undergoing haematopoietic SCT—results of a multicentre study. Bone Marrow Transplant. 46, 727–732 (2011). Ali, M. et al. Oral Mucositis in Patients Undergoing Hematopoietic Stem Cell Transplantation. J. Coll. Physicians Surg. Pak. 33 , 804–808 (2023). Wysocka-Słowik, A., Gil, L., Ślebioda, Z., Kręgielczak, A. & Dorocka-Bobkowska, B. Oral mucositis in patients with acute myeloid leukemia treated with allogeneic hematopoietic stem cell transplantation in relation to the conditioning used prior to transplantation. Ann. Hematol. 100 , 2079–2086 (2021). Tables Table 1. Patient and mucositis characteristics G1-4– mucositis stage according to CTCAE, PCM-plasma cell myeloma, AML-acute myeloid leukemia, ALL-acute lymphoblastic leukemia, PCL-plasma cell leukemia, CMML-chronic myelomonocytic leukemia, MPN- myeloprofiferative neopalsm, MDS–myelodysplastic syndrome, LL-lymphoblastic lymphoma, DLBCL-diffuse large B-cell lymphoma, WM-Waldenström macroglobulinemia, FL-follicular lymphoma, BL-Burkitt lymphoma, NHL- Non- Hodgkin lymphoma, HL-Hodgkin lymphoma, PCNSL-primary central nervous system lymphoma, MCL–mantle cell lymphoma, PTCL- peripheral T-cell lymphoma, SGF- secondary graft failure GCT—germ cell tumor, BPDCN-blastic plasmacytoid dendritic cell neoplasm, HGBCL-high-grade B-cell Lymphoma, alloSCT-allogeneic stem cell transplantation, autoSCT-autologous stem cell transplantation, MAC-myeloablative conditioning regimen, Non-MAC- non myeloablative conditioning regimen, TPN- total parental nutrition. Cryotherapy (+) n = 199 Cryotherapy (-) n = 59 Mucositis (+) n = 95 (48%) Mucositis (-) n = 104 (52%) Mucositis (+) n = 40 (68%) Mucositis (-) n = 19 (32%) Grade - CTCAE V G1/G2 89 - 34 - G3/G4 6 - 6 - Age (years) Mean (x̄) 52,27 (σ = 12,87) 56,90 (σ = 11,93) 63,33 (σ = 8,78) 61,58 (σ = 8,75) Median 56 61 65 63 Sex Male/Female 113 (57%)/86 (43%) 30 (51%)/29(49%) Hospital stay duration Mean (x̄) 27,11 (σ = 13,13) 24,27 (σ = 6,80) 25,08 (σ = 8,00) 23,32 (σ = 6,25) Median 24 22 22 21 Plasma Cell dyscrasias (PCM + PCL) 105 50 Acute leukemias (AML+ALL+ blast crisis) 22 - MDS/MPN (CMML+ MDS/AML+AML) 4 - NHL (LL+DLBCL+FL+PCNSL+MCL+PTCL+HGBCL+BL+WM) 39 8 HL 14 1 SGF 1 - GCT 13 - BPDCN 1 - Auto/AlloSCT Auto 76 88 40 19 Allo 19 16 - - MAC allo 13 3 - - Non-MAC allo 6 13 - - TPN Yes 32 26 11 7 No 63 78 29 12 Table 2. Analysis of thrombo- and myelopoiesis regeneration in patients after autoSCT and alloSCT transplants in the group after cryotherapy and without intervention. alloSCT- allogeneic stem cell transplantation, autoSCT- autologous stem cell transplantation. AutoSCT AlloSCT Cryotherapy (+) Cryotherapy (-) Cryotherapy (+) Cryotherapy (-) Myelopoiesis regeneration (days after transplant) Mean (x̄) 11,46 (σ = 2,11) 11,63 (σ = 2,27) 16,69 (σ = 4,82) - Median 11 11 16 - Thrombopoiesis regeneration (days after transplant) Mean (x̄) 14,98 (σ = 6,10) 15,25 (σ = 5,84) 17,42 (σ = 11,30) - Median 14 13 13 - Table 3. Analysis of the incidence rate of oral mucositis between the patients who received cryotherapy and those who did not. Continuous variables were analyzed with Mann-Whitney U test while categorical variables with Fisher exact test which were applicable was followed by post-hoc pairwise comparison with Bonferroni correction for multiple testing. p < 0.05 was considered statistically significant. OR – odds ratio; RRR – relative risk reduction; TPN – total parenteral nutrition; IQR – interquartile range; G1-4 – mucositis stage according to CTCAE; MAC – myeloablative conditioning regimen; RIC – reduced intensity conditioning regimen. Cryotherapy (n = 199) No cryotherapy (n = 59) OR RRR p Mucositis YES/NO 95/104 40/19 0.4 20% 0.008 Length of stay mean(median); IQR 25.62(23), 19-29 24.51(22), 19-25 0.37 Platelet engraftment mean(median); IQR 15.37(14), 12-16 15.25(13), 12-16.5 0.537 Neutrophil engraftment mean(median); IQR 12.38(11), 11-12 11.63(11), 11-12 0.045 Mucositis stage G1-2 89 34 0.0056 G3-4 6 6 No mucositis 104 19 Mucositis stage; post-hoc comparison G1-2 / G3-4 89/6 34/6 0.181 G1-2 / No mucositis 89/14 34/19 0.044 G3-4 / No mucositis 6/104 6/19 0.029 Table 4. Analysis of the incidence rate of oral mucositis. Continuous variables were analyzed with Mann-Whitney U test while categorical variables with Fisher exact test. p < 0.05 was considered statistically significant. OR – odds ratio; RRR – relative risk reduction; IQR – interquartile range; MAC – myeloablative conditioning regimen; RIC – reduced intensity conditioning regimen. Mucositis No mucositis OR RRR p age mean(median), IQR 55.55(59), 46-65 57.63(61), 51-66 0.2 autoSCT/alloSCT 116/19 107/16 0.91 1% 0.86 autoSCT/alloSCT (cryotherapy group) 76/19 88/16 0.73 5% 0.45 MAC/RIC (alloSCT) 13/6 3/13 0.11 61% 0.006 Additional Declarations No competing interests reported. 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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-6813382","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":477490260,"identity":"27230089-3629-402b-9e2c-9e4f60c763ec","order_by":0,"name":"Oliwia Piotrowska","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+klEQVRIiWNgGAWjYDACdsYGICkB5R1gkANTD/BpYYZq4YFqMQZTCXi1QGmYlkSQCQz4tPAzM7dJMO6wkLOXPnxM8scZu/T5YYcfAm2xk9NtwK5FspkRqOWMhDEPX1qaNM+N5NyNt9MMgFqSjc0OYNdicJix7QZQV2IPD4/ZbYYPzLkbZyeAtBxI3EaMlps/PtSnG85O/0C8lhs8Nw4nyEvn4LcF6Jf2H4kgv5xhS//Nc+a44QbpnIIDCQa4/cLP3v7Y4OOOOjn2HubDhj+OVcvLz07f/OFDhZ0cLi1gAIkLmFPBKg3wKAcBRmQt8g04VI2CUTAKRsGIBQCc4V6FEb0oOgAAAABJRU5ErkJggg==","orcid":"","institution":"Pomeranian Medical University","correspondingAuthor":true,"prefix":"","firstName":"Oliwia","middleName":"","lastName":"Piotrowska","suffix":""},{"id":477490261,"identity":"f4adcb5b-452f-4ed4-8c2e-f0c8f395f647","order_by":1,"name":"Alina Zuchmańska","email":"","orcid":"","institution":"Pomeranian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Alina","middleName":"","lastName":"Zuchmańska","suffix":""},{"id":477490263,"identity":"a652c262-1adb-44cc-bfbf-62d765227b8b","order_by":2,"name":"Piotr Kulig","email":"","orcid":"","institution":"Pomeranian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Piotr","middleName":"","lastName":"Kulig","suffix":""},{"id":477490264,"identity":"19a6391d-f9fd-43fb-adac-3064c5eac3bd","order_by":3,"name":"Tomasz Michowski","email":"","orcid":"","institution":"Pomeranian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Tomasz","middleName":"","lastName":"Michowski","suffix":""},{"id":477490265,"identity":"596147dd-e10e-451e-a0e0-b75d77081bc2","order_by":4,"name":"Jacek Szulc","email":"","orcid":"","institution":"Pomeranian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jacek","middleName":"","lastName":"Szulc","suffix":""},{"id":477490266,"identity":"405e77d6-49e5-40b3-96ee-fc1eee358a2c","order_by":5,"name":"Patryk Skórka","email":"","orcid":"","institution":"Pomeranian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Patryk","middleName":"","lastName":"Skórka","suffix":""},{"id":477490267,"identity":"620e4a09-cea6-4eee-b7fd-fcd64d43e122","order_by":6,"name":"Dominika Dorsz","email":"","orcid":"","institution":"Pomeranian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Dominika","middleName":"","lastName":"Dorsz","suffix":""},{"id":477490268,"identity":"065fefa4-ccc7-4180-a699-addae613b4e2","order_by":7,"name":"Bogusław Machaliński","email":"","orcid":"","institution":"Pomeranian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Bogusław","middleName":"","lastName":"Machaliński","suffix":""},{"id":477490269,"identity":"c1e76c87-09e6-4903-bfe1-b5d48736f575","order_by":8,"name":"Sławomir Milczarek","email":"","orcid":"","institution":"Pomeranian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Sławomir","middleName":"","lastName":"Milczarek","suffix":""}],"badges":[],"createdAt":"2025-06-03 16:38:18","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6813382/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6813382/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-025-20927-5","type":"published","date":"2025-10-23T16:17:11+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":94490071,"identity":"386dc37e-4b62-4c99-aefa-cae91610127e","added_by":"auto","created_at":"2025-10-27 17:07:20","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":930237,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6813382/v1/6763dfe8-a766-4a32-914e-27fdb87a8216.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Impact of Cryotherapy on Incidence and Severity of Oral Mucositis in Hematopoietic Stem Cell Transplantation: Retrospective Observational Study","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eHematopoietic stem cell transplantation (HSCT) represents a complex therapeutic strategy for the management of hematological malignancies\u003csup\u003e1\u003c/sup\u003e and selected non-hematological disorders\u003csup\u003e23\u003c/sup\u003e. In recent years, there has been a consistent increase in the total number of HSCTs performed, accompanied by the emergence of a broader spectrum of conditioning regimens\u003csup\u003e4\u003c/sup\u003e. The conditioning phase, which is essential before the HSCT, may involve the utilization of chemotherapy and radiation therapy, including total body irradiation (TBI)\u003csup\u003e5\u003c/sup\u003e. The short- and long-term adverse effects associated with this treatment are significant and include myelotoxicity, mucositis, nausea, vomiting, diarrhea, cutaneous rashes, alopecia, and peripheral neuropathies\u003csup\u003e1\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eOral mucositis (OM), an ulcerative and inflammatory disease of the oral mucosa, is recognized as one of the most prevalent complications in patients undergoing chemotherapy and/or radiotherapy. OM is associated with direct stoma toxicity and usually develops within 3 to 7 days after chemotherapy and resolves within approximately 2 to 3 weeks, in parallel with neutrophil recovery. The incidence of OM is associated with heightened morbidity and can adversely influence treatment adherence and overall patient outcomes. The associated pain and debilitating symptoms significantly diminish patients' quality of life, often leading to anorexia and necessitating the implementation of enteral or total parenteral nutrition. The presentation of OM varies according to the severity grade. Clinical manifestations may include alterations in taste perception, restricted range of motion in the jaw, difficulties in swallowing and speaking, and disturbances in sleep patterns. These lesions can be portals for systemic infections, including bacteremia\u003csup\u003e67\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eVarious interventions have been tested and implemented for the prevention and treatment of oral mucositis (OM)\u003csup\u003e8679\u003c/sup\u003e. The Mucositis Study Group of the Multinational Association for Supportive Care in Cancer and the International Society of Oral Oncology (MASCC/ISOO) has provided clinical guidelines for managing mucositis\u003csup\u003e10\u003c/sup\u003e. Oral cryotherapy is commonly used to prevent OM, with minimal risk of side effects. This therapy involves placing ice in the form of ice cubes in the mouth before or during chemotherapy treatment\u003csup\u003e1112\u003c/sup\u003e. The cooling effect causes local hypothermia, leading to vasoconstriction of the oral mucosal blood vessels, which decreases blood flow to the tissues. As a result, the concentration of cytotoxic agents in the oral mucosa is reduced. Additionally, oral cryotherapy may lower the metabolic rate in the oral epithelium, helping to decrease inflammation.\u003c/p\u003e \u003cp\u003e Following the increasing incidence of mucositis, new clinical practice guidelines for managing mucositis secondary to cancer therapy were published by MASCC/ISOO in 2020. The safety and effectiveness of recombinant human keratinocyte growth factor-1 (KGF-1/palifermin) in OM prevention have been established. Palifermin has proven effectiveness in significantly reducing the incidence and duration of grade 3\u0026ndash;4 OM after myeloablative therapy. Furthermore, apart from palifermin, there are two human fibroblast growth factors (velafermin and repifermin), which may open the door to a focused strategy for mucositis prevention\u003csup\u003e1314\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eLimited data on the successful OM treatment in patients receiving HSCT are available. Morphine is indicated for pain treatment due to oral mucositis in patients undergoing HSCT. Borowski et al. state in their article that a 2% morphine oral mouthwash may be used to treat mucosal pain accompanying OM\u003csup\u003e15\u003c/sup\u003e.\u003c/p\u003e"},{"header":"MATERIALS AND METHODS","content":"\u003cp\u003e\u003cstrong\u003eSTUDY DESIGN\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e1.1. PATIENTS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFrom 23.07.2018 to 01.02.2024, a retrospective observational study was conducted at the University Clinical Hospital No. 1 of the Pomeranian Medical University in Szczecin (Poland). We investigated 258 consecutive autologous and allogeneic peripheral blood stem cell transplantation (PBSCT) procedures. All patients suffered from hematological malignancies or solid tumors. Detailed patients and cryotherapy characteristics are presented in Table 1 in the Results section.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe participants in the study were categorized into two distinct groups: the study group comprised 199 patients who underwent cryotherapy as part of their conditioning regimen, whereas the control group included 59 patients who did not receive cryotherapy. The study was approved by the Bioethics Committee of the Pomeranian Medical University in Szczecin. As the study was retrospective in its nature the opinion of the ethics committee was not mandatory. No organs were harvested from prisoners in the study. Both donors and recipients of hematopoietic stem cells signed informed consents before the procedures were performed. All the research involving our participants was performed in accordance with the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e1.2. METHOD OF PERFORMING CRYOTHERAPY\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOral cryotherapy introduces various ice forms\u0026mdash;such as chips, cubes, or ice-cold water\u0026mdash;into the mouth before or during chemotherapy treatment. Ice cubes are prepared with an ice machine with no unique solution. Cryotherapy was provided from 10 minutes before until 2 hours after any chemotherapy infusion.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eApart from cryotherapy, the study group and the control group had oral care protocols implemented. Basic oral care protocols generally include brushing teeth, flossing, and at least one mouth rinse to uphold oral hygiene.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003e1.3. STATISTICAL ANALYSIS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eContinuous variables are expressed as mean (median); interquartile range (IQR). The Shapiro-Wilk test was implemented to assess the distribution of continuous variables. As constant variables were not normally distributed, the Mann-Whitney U test was implemented to compare the differences between the groups. Fisher exact test was used to assess differences in the categorical variables between the groups. When relevant post hoc pairwise comparison with Bonferroni correction for multiple testing was implemented. P value \u0026lt; 0.05 was considered statistically significant. All calculations were performed in RStudio.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDEFINITIONS\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAccording to CTCAE, oral mucositis is defined as a disorder characterized by ulceration or inflammation of the oral mucosa. The severity of oral mucositis was defined as per the CTCAE oral toxicity scale, separating mucositis into 5 Grades. Grade 1 = Asymptomatic or mild symptoms; intervention not indicated, Grade 2 = oral ulcers, patients able to take solids; Grade 3=Severe pain; interfering with oral intake, Grade 4 = Life-threatening consequences; urgent intervention indicated; Grade 5=Death.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003e\u003cstrong\u003e3. 1. CHARACTERISTICS OF THE STUDY GROUP\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe characteristics of the group are presented in Table 1.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.2. Cryotherapy reduces the incidence rate of oral mucositis.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCryotherapy has been demonstrated to significantly reduce the incidence of oral mucositis (OM) among recipients of stem cell transplants, regardless of the transplant modality employed (as shown in Table 1). Our investigation revealed that 48% of patients undergoing cryotherapy developed OM, in stark contrast to a 68% incidence observed in patients who did not receive this intervention. This finding corresponds to a relative risk reduction of 20% (RRR 20%, p = 0.008). Furthermore, cryotherapy has been shown to mitigate the risk of developing severe oral mucositis, specifically in grades 3-4 (p = 0.0056). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePost-hoc analysis further elucidated statistically significant differences between individuals who did not develop OM and those who experienced OM graded as G1-2 and G3-4, with p-values of 0.044 and 0.029, respectively.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn our investigation, we did not observe statistically significant differences regarding the length of hospitalization (p = 0.37) or platelet engraftment (p = 0.537). It is noteworthy that neutrophil engraftment within the cryotherapy cohort was observed to occur slightly later compared to the non-cryotherapy cohort, with mean durations of 12.38 days and 11.63 days, respectively (p = 0.045).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHowever, this delay lacks clinical significance, as it does not correlate with an extension of the hospitalization period. It should be emphasized that the cryotherapy group was more diverse as it included patients undergoing alloSCT and patients treated for lymphomas where both subgroups are characterized by a more extended period of neutropenia compared to autoHSCT in myeloma. The control group included only patients undergoing the autoHSCT procedure, usually after melphalan conditioning for multiple myeloma.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.3. Oral mucositis occurs less frequently in alloSCT patients with reduced intensity conditioning regimen.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNext, we wanted to analyze if OM mucositis occurred more frequently in any subgroup regardless of cryotherapy (Table 4). We did not detect any differences in age (p = 0.2), type of SCT in the whole cohort (p = 0.86), and among patients who received cryotherapy (p = 0.045). Among alloSCT patients (all alloSCT individuals received cryotherapy) OM occurred less frequently in the RIC (reduced intensity conditioning) subgroup compared to the MAC (Myeloablative Conditioning) conditioning group (RRR 61%, p = 0.006). \u0026nbsp;\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThe incidence of mucositis in patients undergoing hematopoietic stem cell transplantation (HSCT) is closely linked to the exacerbation of infectious and nutritional complications. By compromising the integrity of the mucosal barrier, mucositis is a potential conduit for the onset of bloodstream infections. These infections pose significant risks to patient health and extend the duration of hospitalization substantially. The management of these complications often necessitates intravenous antibiotic therapy and, in some cases, the administration of vasoconstrictor agents, thereby escalating the overall costs associated with patient care and hospitalization\u003csup\u003e16\u003c/sup\u003e\u003csup\u003e17\u003c/sup\u003e\u003csup\u003e18\u003c/sup\u003e\u003csup\u003e19\u003c/sup\u003e. \u003c/p\u003e\n\u003cp\u003eThe findings of our study did not demonstrate a statistically significant relationship between the use of cryotherapy and the duration of stem cell engraftment or the length of hospital stay (p = 0.37). As mentioned earlier, this is most likely related to the characteristics of the study and control groups - the cryotherapy group included patients undergoing alloSCT and patients treated for lymphomas, where both subgroups are characterized by a longer period of neutropenia compared to classic autoSCT recipients and have longer hospitalization time. Further studies on the effectiveness of cryotherapy are required, comparing groups of patients homogeneous in terms of diagnosis and transplant type.\u003c/p\u003e\n\u003cp\u003eResearch has demonstrated that cryotherapy effectively reduces both the incidence and severity of oral mucositis in patients undergoing high-dose chemotherapy during hematopoietic stem cell transplantation (HSCT)\u003csup\u003e16\u003c/sup\u003e\u003csup\u003e20\u003c/sup\u003e\u003csup\u003e21\u003c/sup\u003e. In our study, we also confirmed this relationship, noting a 20% relative reduction in the risk of mucositis among patients who used cryotherapy compared to those who did not (RRR 20%, p = 0.008).\u003c/p\u003e\n\u003cp\u003eThe prevalence and severity of OM could vary depending on the type of transplant and conditioning regimen. The incidence of severe oral mucositis (SOM) is greater in patients undergoing alloSCT compared to autoSCT recipients due to prolonged neutropenia in the alloSCT group. SOM frequency reached 98% in the group receiving a conditioning regimen consisting of total body irradiation\u003csup\u003e22\u003c/sup\u003e. In a single-center retrospective study by Nakagaki et al., SOM (grade 3-4) was common in myeloablative total body irradiation (TBI) based regimens cyclophosphamide/TBI (71%) and fludarabine/TBI with PTCy (46%). In contrast, SOM occurred less frequently in reduced-intensity haploidentical regimen melphalan/fludarabine/TBI with PTCy (19%)\u003csup\u003e23\u003c/sup\u003e. Multicentre and retrospective study by L. Vagliano and colleagues demonstrated that 71% of patients who underwent HSCT were diagnosed with OM, and 21.6% developed SOM\u003csup\u003e24\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eMoreover the duration and severity of mucositis are associated with the intensity of conditioning - they are both diminished in RIC setting\u003csup\u003e22\u003c/sup\u003e\u003csup\u003e25\u003c/sup\u003e. Increased rates of OM were found in 86,5% HSCT patients who received myeloablative regimens versus 73.2% of patients who received reduced-intensity regimens. HSCT conditioning regimens, including those that utilize melphalan, busulfan, or radiotherapy, are significant contributors to the pathogenesis of oral mucositis\u003csup\u003e21\u003c/sup\u003e. \u003c/p\u003e\n\u003cp\u003eIn our research, we found no differences in the incidence of mucositis between alloSCT and autoSCT (p = 0.86). Notwithstanding, among alloSCT patients (all alloSCT individuals received cryotherapy) OM occurred less frequently in RIC subgroup (RRR 61%, p = 0.006). The absence of statistically significant differences in the incidence of mucositis between the autoSCT and alloSCT groups may be explained by the use of both RIC and MAC regimens in the alloSCT group, in contrast to the exclusive use of MAC regimens in the autoSCT group.\u003c/p\u003e\n\u003cp\u003eMucositis is frequently correlated with heightened levels of pain in patients, which subsequently diminishes their quality of life and necessitates the administration of supplementary analgesics\u003csup\u003e25\u003c/sup\u003e. The implementation of cryotherapy during the conditioning phase of hematopoietic stem cell transplantation has the potential to significantly reduce the requirement for pain management, particularly the utilization of opioids. Opioids themselves are associated with a range of adverse effects, including constipation, nausea, and vomiting. Furthermore, by mitigating both the incidence and severity of mucositis, we can enhance patient comfort and overall quality of life (QoL)\u003csup\u003e19\u003c/sup\u003e\u003csup\u003e26\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eThe pain itself may lead to the development of anorexia and then malnutrition, which may prolong the patient\u0026apos;s stay in the hospital. All this together leads to the subsequent need to implement TPN (Total Parenteral Nutrition). The use of cryotherapy supports the patient\u0026apos;s physiological alimentation of food, which helps reduce the incidence of thrombosis or infections in central vein access lines, TPN complications. However, in our patients, we did not demonstrate a relationship between the occurrence of mucositis and an increased risk of using TPN, which may be caused by a small study sample (p = 0.87).\u003c/p\u003e\n\u003cp\u003eAccording to some publications, e.g. \u0026ldquo;\u003cem\u003eCurrent Trends in Management of Oral Mucositis in Cancer Treatment\u0026rdquo; \u003c/em\u003eby Shankar A. and colleagues, mucositis leads to prolonged regeneration of hematopoiesis, including myelopoiesis and thrombopoiesis as well as prolonged hospitalization\u003csup\u003e6\u003c/sup\u003e. \u003c/p\u003e\n\u003cp\u003eIn conclusion, the application of cryotherapy during the conditioning phase for patients during the HSCT procedure represents a highly economical approach to the prevention of mucositis, which yields several advantages for patient care. Consequently, we advocate for the routine implementation of cryotherapy in all patients undergoing hematopoietic stem cell transplantation. \u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData availability statement:\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eThe datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions:\u003c/strong\u003e Oliwia Piotrowska: investigation, patient care, data curation, conceptualization, study design, writing- original draft; Alina Zuchmańska\u003cstrong\u003e:\u0026nbsp;\u003c/strong\u003einvestigation, patient care, data curation, conceptualization, study design, writing- original draft; Piotr Kulig: investigation, formal analysis, writing - original draft, patient care, tables preparation; Tomasz Michowski: \u0026nbsp;investigation, data curation; Jacek Szulc: \u0026nbsp;investigation, data curation; Patryk Sk\u0026oacute;rka: \u0026nbsp;investigation, data curation; Dominika Dorsz: investigation, data curation; Bogusław Machaliński: supervision, writing-review and editing; \u0026nbsp;Sławomir Milczarek: investigation,\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003econceptualization, study design, writing- original draft. All authors reviewed the manuscript;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdditional Information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests Statement:\u0026nbsp;\u003c/strong\u003eThe authors declare no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eThis research received no external funding.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eArnaout, K. \u003cem\u003eet al.\u003c/em\u003e Complications of Allogeneic Hematopoietic Stem Cell Transplantation. \u003cem\u003eCancer Investig.\u003c/em\u003e \u003cstrong\u003e32\u003c/strong\u003e, 349\u0026ndash;362 (2014).\u003c/li\u003e\n\u003cli\u003eBoyadzhieva, Z., Ruffer, N., K\u0026ouml;tter, I. \u0026amp; Krusche, M. How to treat VEXAS syndrome: a systematic review on effectiveness and safety of current treatment strategies. \u003cem\u003eRheumatology\u003c/em\u003e \u003cstrong\u003e62\u003c/strong\u003e, 3518\u0026ndash;3525 (2023).\u003c/li\u003e\n\u003cli\u003eBagnato, G. et al. Autologous Haematopoietic Stem Cell Transplantation and Systemic Sclerosis: Focus on Interstitial Lung Disease. \u003cem\u003eCells\u003c/em\u003e \u003cstrong\u003e11\u003c/strong\u003e, 843 (2022).\u003c/li\u003e\n\u003cli\u003eMaffini, E. et al. Neurologic Complications after Allogeneic Hematopoietic Stem Cell Transplantation. \u003cem\u003eBiol. Blood Marrow Transplant.\u003c/em\u003e \u003cstrong\u003e23\u003c/strong\u003e, 388\u0026ndash;397 (2017).\u003c/li\u003e\n\u003cli\u003eShimoni, A., Radici, V. \u0026amp; Nagler, A. Conditioning. in 125\u0026ndash;134 (2024). doi:10.1007/978-3-031-44080-9_13.\u003c/li\u003e\n\u003cli\u003eShankar, A. et al. Current Trends in Management of Oral Mucositis in Cancer Treatment. \u003cem\u003eAsian Pac. J. Cancer Prev. : APJCP\u003c/em\u003e \u003cstrong\u003e18\u003c/strong\u003e, 2019\u0026ndash;2026 (2017).\u003c/li\u003e\n\u003cli\u003eRoila, F. et al. 2016 MASCC and ESMO guideline update for the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting and of nausea and vomiting in advanced cancer patients. \u003cem\u003eAnn. Oncol.\u003c/em\u003e \u003cstrong\u003e27\u003c/strong\u003e, v119\u0026ndash;v133 (2016).\u003c/li\u003e\n\u003cli\u003eVilla, A. \u0026amp; Sonis, S. T. Pharmacotherapy for the management of cancer regimen-related oral mucositis. \u003cem\u003eExpert Opin. Pharmacother.\u003c/em\u003e \u003cstrong\u003e17\u003c/strong\u003e, 1801\u0026ndash;1807 (2016).\u003c/li\u003e\n\u003cli\u003eHerrstedt, J. et al. 2023 MASCC and ESMO guideline update for the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting. \u003cem\u003eESMO Open\u003c/em\u003e \u003cstrong\u003e9\u003c/strong\u003e, 102195 (2024).\u003c/li\u003e\n\u003cli\u003eElad, S. et al. MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy. Cancer \u003cstrong\u003e126\u003c/strong\u003e, 4423\u0026ndash;4431 (2020).\u003c/li\u003e\n\u003cli\u003eWalladbegi, J. et al. Cooling of the oral mucosa to prevent adverse effects of chemotherapeutic agents: An in vitro study. \u003cem\u003eJ. Oral Pathol. Med.\u003c/em\u003e \u003cstrong\u003e47\u003c/strong\u003e, 477\u0026ndash;483 (2018).\u003c/li\u003e\n\u003cli\u003eJohansson, J.-E. et al. Cryotherapy as prophylaxis against oral mucositis after high-dose melphalan and autologous stem cell transplantation for myeloma: a randomised, open-label, phase 3, non-inferiority trial. \u003cem\u003eBone Marrow Transplant.\u003c/em\u003e \u003cstrong\u003e54\u003c/strong\u003e, 1482\u0026ndash;1488 (2019).\u003c/li\u003e\n\u003cli\u003eBraun, S. et al. Nrf2 Transcription Factor, a Novel Target of Keratinocyte Growth Factor Action Which Regulates Gene Expression and Inflammation in the Healing Skin Wound. \u003cem\u003eMol. Cell. Biol.\u003c/em\u003e \u003cstrong\u003e22\u003c/strong\u003e, 5492\u0026ndash;5505 (2002).\u003c/li\u003e\n\u003cli\u003eB\u0026uuml;ltzingsl\u0026ouml;wen, I. von et al. Growth factors and cytokines in the prevention and treatment of oral and gastrointestinal mucositis. \u003cem\u003eSupport. Care Cancer\u003c/em\u003e \u003cstrong\u003e14\u003c/strong\u003e, 519\u0026ndash;527 (2006).\u003c/li\u003e\n\u003cli\u003eBorowski, G. et al. Oral mucositis \u0026ndash; characteristics and management of a common complication of cancer treatment. \u003cem\u003ePalliat. Med.\u003c/em\u003e (2024) doi:10.5114/pm.2024.142027.\u003c/li\u003e\n\u003cli\u003eTartarone, A., Matera, R., Romano, G., Vigliotti, M. L. \u0026amp; Renzo, N. D. Prevention of high-dose melphalan-induced mucositis by cryotherapy. \u003cem\u003eLeuk. Lymphoma\u003c/em\u003e \u003cstrong\u003e46\u003c/strong\u003e, 633\u0026ndash;634 (2005).\u003c/li\u003e\n\u003cli\u003eRapoport, A. P. et al. Analysis of Factors That Correlate With Mucositis in Recipients of Autologous and Allogeneic Stem-Cell Transplants. \u003cem\u003eJ. Clin. Oncol.\u003c/em\u003e \u003cstrong\u003e17\u003c/strong\u003e, 2446\u0026ndash;2446 (1999).\u003c/li\u003e\n\u003cli\u003eHaverman, T. M. et al. Oral Complications in Hematopoietic Stem Cell Recipients: The Role of Inflammation. \u003cem\u003eMediat. Inflamm.\u003c/em\u003e \u003cstrong\u003e2014\u003c/strong\u003e, 378281 (2014).\u003c/li\u003e\n\u003cli\u003eReuss, J. M. et al. Oral Mucosa in Cancer Patients\u0026mdash;Putting the Pieces Together: A Narrative Review and New Perspectives. \u003cem\u003eCancers\u003c/em\u003e \u003cstrong\u003e15\u003c/strong\u003e, 3295 (2023).\u003c/li\u003e\n\u003cli\u003eSvanberg, A., \u0026Ouml;hrn, K. \u0026amp; Birgeg\u0026aring;rd, G. Oral cryotherapy reduces mucositis and improves nutrition \u0026ndash; a randomised controlled trial. \u003cem\u003eJ. Clin. Nurs.\u003c/em\u003e \u003cstrong\u003e19\u003c/strong\u003e, 2146\u0026ndash;2151 (2010).\u003c/li\u003e\n\u003cli\u003eNiscola, P. et al. Mucositis in patients with hematologic malignancies: an overview. \u003cem\u003eHaematologica\u003c/em\u003e \u003cstrong\u003e92\u003c/strong\u003e, 222\u0026ndash;231 (2007).\u003c/li\u003e\n\u003cli\u003eSpielberger, R. et al. Palifermin for Oral Mucositis after Intensive Therapy for Hematologic Cancers. \u003cem\u003e N. Engl. J. Med.\u003c/em\u003e \u003cstrong\u003e351\u003c/strong\u003e, 2590\u0026ndash;2598 (2004).\u003c/li\u003e\n\u003cli\u003eNakagaki, M., Kennedy, G. A., Gavin, N. C., Clavarino, A. \u0026amp; Whitfield, K. The incidence of severe oral mucositis in patients undergoing different conditioning regimens in haematopoietic stem cell transplantation. Support. Care Cancer \u003cstrong\u003e30\u003c/strong\u003e, 9141\u0026ndash;9149 (2022).\u003c/li\u003e\n\u003cli\u003eVagliano, L. et al. Incidence and severity of oral mucositis in patients undergoing haematopoietic SCT\u0026mdash;results of a multicentre study. Bone Marrow Transplant. 46, 727\u0026ndash;732 (2011).\u003c/li\u003e\n\u003cli\u003eAli, M. et al. Oral Mucositis in Patients Undergoing Hematopoietic Stem Cell Transplantation. \u003cem\u003eJ. Coll. Physicians Surg. Pak.\u003c/em\u003e \u003cstrong\u003e33\u003c/strong\u003e, 804\u0026ndash;808 (2023).\u003c/li\u003e\n\u003cli\u003eWysocka-Słowik, A., Gil, L., Ślebioda, Z., Kręgielczak, A. \u0026amp; Dorocka-Bobkowska, B. Oral mucositis in patients with acute myeloid leukemia treated with allogeneic hematopoietic stem cell transplantation in relation to the conditioning used prior to transplantation. \u003cem\u003eAnn. Hematol.\u003c/em\u003e \u003cstrong\u003e100\u003c/strong\u003e, 2079\u0026ndash;2086 (2021).\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1. Patient and mucositis characteristics\u0026nbsp;\u003c/strong\u003e G1-4\u0026ndash; mucositis stage according to CTCAE,\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003ePCM-plasma cell myeloma, AML-acute myeloid leukemia, ALL-acute lymphoblastic leukemia, PCL-plasma cell leukemia, CMML-chronic myelomonocytic leukemia, MPN- myeloprofiferative neopalsm, MDS\u0026ndash;myelodysplastic syndrome, LL-lymphoblastic lymphoma, DLBCL-diffuse large B-cell lymphoma, WM-Waldenstr\u0026ouml;m macroglobulinemia, FL-follicular lymphoma, BL-Burkitt lymphoma, \u0026nbsp;NHL- Non- Hodgkin lymphoma, HL-Hodgkin lymphoma, PCNSL-primary central nervous system lymphoma, \u0026nbsp;MCL\u0026ndash;mantle cell lymphoma, PTCL- peripheral T-cell lymphoma, SGF- secondary graft failure GCT\u0026mdash;germ cell tumor, BPDCN-blastic plasmacytoid dendritic cell neoplasm, HGBCL-high-grade B-cell Lymphoma, alloSCT-allogeneic stem cell transplantation, autoSCT-autologous stem cell transplantation, MAC-myeloablative conditioning regimen, \u0026nbsp;Non-MAC- non myeloablative conditioning regimen, TPN- total parental nutrition.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"633\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 170px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 175px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCryotherapy (+)\u003cbr\u003e\u0026nbsp;n = 199\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 188px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCryotherapy (-)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003en = 59\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 170px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003eMucositis (+)\u003c/p\u003e\n \u003cp\u003en = 95 (48%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003eMucositis (-)\u003c/p\u003e\n \u003cp\u003en = 104 (52%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 83px;\"\u003e\n \u003cp\u003eMucositis (+)\u003c/p\u003e\n \u003cp\u003en = 40 (68%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003eMucositis (-)\u003c/p\u003e\n \u003cp\u003en = 19 (32%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 100px;\"\u003e\n \u003cp\u003eGrade - CTCAE V\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 170px;\"\u003e\n \u003cp\u003eG1/G2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 83px;\"\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170px;\"\u003e\n \u003cp\u003eG3/G4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 83px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 100px;\"\u003e\n \u003cp\u003eAge (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 170px;\"\u003e\n \u003cp\u003eMean (x̄)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e52,27\u003cbr\u003e(\u0026sigma; = 12,87)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e56,90\u003cbr\u003e(\u0026sigma; = 11,93)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 83px;\"\u003e\n \u003cp\u003e63,33\u003c/p\u003e\n \u003cp\u003e(\u0026sigma; = 8,78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003e61,58\u003c/p\u003e\n \u003cp\u003e(\u0026sigma; = 8,75)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170px;\"\u003e\n \u003cp\u003eMedian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 83px;\"\u003e\n \u003cp\u003e65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003e63\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 170px;\"\u003e\n \u003cp\u003eMale/Female\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 175px;\"\u003e\n \u003cp\u003e113 (57%)/86 (43%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 188px;\"\u003e\n \u003cp\u003e30 (51%)/29(49%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 100px;\"\u003e\n \u003cp\u003eHospital stay\u0026nbsp;\u003cbr\u003e\u0026nbsp;duration\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 170px;\"\u003e\n \u003cp\u003eMean (x̄)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e27,11\u003c/p\u003e\n \u003cp\u003e(\u0026sigma; = 13,13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e24,27\u003c/p\u003e\n \u003cp\u003e(\u0026sigma; = 6,80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 83px;\"\u003e\n \u003cp\u003e25,08\u003c/p\u003e\n \u003cp\u003e(\u0026sigma; = 8,00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003e23,32\u003c/p\u003e\n \u003cp\u003e(\u0026sigma; = 6,25)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170px;\"\u003e\n \u003cp\u003eMedian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 83px;\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"8\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 170px;\"\u003e\n \u003cp\u003e\u0026nbsp;Plasma Cell dyscrasias (PCM + PCL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 175px;\"\u003e\n \u003cp\u003e105\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 188px;\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170px;\"\u003e\n \u003cp\u003eAcute leukemias (AML+ALL+ blast crisis)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 175px;\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 188px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170px;\"\u003e\n \u003cp\u003eMDS/MPN (CMML+ MDS/AML+AML)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 175px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 188px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170px;\"\u003e\n \u003cp\u003eNHL (LL+DLBCL+FL+PCNSL+MCL+PTCL+HGBCL+BL+WM)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 175px;\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 188px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170px;\"\u003e\n \u003cp\u003eHL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 175px;\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 188px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170px;\"\u003e\n \u003cp\u003eSGF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 175px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 188px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170px;\"\u003e\n \u003cp\u003eGCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 175px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 188px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170px;\"\u003e\n \u003cp\u003e\u0026nbsp;BPDCN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 175px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 188px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"4\" style=\"width: 100px;\"\u003e\n \u003cp\u003eAuto/AlloSCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 170px;\"\u003e\n \u003cp\u003eAuto\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e88\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 83px;\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170px;\"\u003e\n \u003cp\u003eAllo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 83px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170px;\"\u003e\n \u003cp\u003eMAC allo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 83px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170px;\"\u003e\n \u003cp\u003eNon-MAC allo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 83px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 100px;\"\u003e\n \u003cp\u003eTPN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 170px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 83px;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 83px;\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. Analysis of thrombo- and myelopoiesis regeneration in patients after autoSCT and alloSCT transplants in the group after cryotherapy and without intervention.\u003c/strong\u003e alloSCT- allogeneic stem cell transplantation, autoSCT- autologous stem cell transplantation.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"602\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 201px;\"\u003e\n \u003cp\u003eAutoSCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 201px;\"\u003e\n \u003cp\u003eAlloSCT\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003eCryotherapy (+)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003eCryotherapy\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(-)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003eCryotherapy (+)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003eCryotherapy\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;(-)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 100px;\"\u003e\n \u003cp\u003eMyelopoiesis regeneration (days after transplant)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003eMean (x̄)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e11,46\u003cbr\u003e(\u0026sigma; = 2,11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e11,63\u003cbr\u003e(\u0026sigma; = 2,27)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e16,69\u003cbr\u003e(\u0026sigma; = 4,82)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003eMedian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 100px;\"\u003e\n \u003cp\u003eThrombopoiesis regeneration (days after transplant)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003eMean (x̄)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e14,98\u003cbr\u003e(\u0026sigma; = 6,10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e15,25\u003cbr\u003e(\u0026sigma; = 5,84)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e17,42\u003cbr\u003e(\u0026sigma; = 11,30)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003eMedian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 100px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3. Analysis of the incidence rate of oral mucositis between the patients who received cryotherapy and those who did not.\u003c/strong\u003e Continuous variables were analyzed with Mann-Whitney U test while categorical variables with Fisher exact test which were applicable was followed by post-hoc pairwise comparison with Bonferroni correction for multiple testing. p \u0026lt; 0.05 was considered statistically significant. OR \u0026ndash; odds ratio; RRR \u0026ndash; relative risk reduction; TPN \u0026ndash; total parenteral nutrition; IQR \u0026ndash; interquartile range; G1-4 \u0026ndash; mucositis stage according to CTCAE; MAC \u0026ndash; myeloablative conditioning regimen; RIC \u0026ndash; reduced intensity conditioning regimen.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"547\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 197px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCryotherapy\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n = 199)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo cryotherapy\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n = 59)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 41px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRRR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 197px;\"\u003e\n \u003cp\u003eMucositis YES/NO\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003e95/104\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003e40/19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003e0.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 41px;\"\u003e\n \u003cp\u003e20%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.008\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 197px;\"\u003e\n \u003cp\u003eLength of stay mean(median); IQR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003e25.62(23), 19-29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003e24.51(22), 19-25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 41px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e0.37\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 197px;\"\u003e\n \u003cp\u003ePlatelet engraftment mean(median); IQR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003e15.37(14), 12-16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003e15.25(13), 12-16.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 41px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e0.537\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 197px;\"\u003e\n \u003cp\u003eNeutrophil engraftment mean(median); IQR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003e12.38(11), 11-12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003e11.63(11), 11-12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 41px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.045\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 197px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMucositis stage\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 41px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 197px;\"\u003e\n \u003cp\u003eG1-2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003e89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 41px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.0056\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 197px;\"\u003e\n \u003cp\u003eG3-4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 41px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 197px;\"\u003e\n \u003cp\u003eNo mucositis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003e104\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 41px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 197px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMucositis stage; post-hoc comparison\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 41px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 197px;\"\u003e\n \u003cp\u003eG1-2 / G3-4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003e89/6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003e34/6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 41px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e0.181\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 197px;\"\u003e\n \u003cp\u003eG1-2 / No mucositis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003e89/14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003e34/19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 41px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.044\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 197px;\"\u003e\n \u003cp\u003eG3-4 / No mucositis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003e6/104\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003e6/19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 41px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.029\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4. Analysis of the incidence rate of oral mucositis.\u003c/strong\u003e Continuous variables were analyzed with Mann-Whitney U test while categorical variables with Fisher exact test. p \u0026lt; 0.05 was considered statistically significant. OR \u0026ndash; odds ratio; RRR \u0026ndash; relative risk reduction; IQR \u0026ndash; interquartile range; MAC \u0026ndash; myeloablative conditioning regimen; RIC \u0026ndash; reduced intensity conditioning regimen.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"486\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 188px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMucositis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo mucositis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRRR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 42px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 188px;\"\u003e\n \u003cp\u003eage mean(median), IQR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e55.55(59), 46-65\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e57.63(61), 51-66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 42px;\"\u003e\n \u003cp\u003e0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 188px;\"\u003e\n \u003cp\u003eautoSCT/alloSCT\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e116/19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e107/16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e0.91\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e1%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 42px;\"\u003e\n \u003cp\u003e0.86\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 188px;\"\u003e\n \u003cp\u003eautoSCT/alloSCT (cryotherapy group)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e76/19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e88/16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e0.73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e5%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 42px;\"\u003e\n \u003cp\u003e0.45\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 188px;\"\u003e\n \u003cp\u003eMAC/RIC (alloSCT)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e13/6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e3/13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e0.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e61%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 42px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.006\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Oral Mucositis Cryotherapy, Hematopoietic Stem Cell Transplantation, Chemotherapy, Radiotherapy, Side Effects","lastPublishedDoi":"10.21203/rs.3.rs-6813382/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6813382/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eOral mucositis (OM) is a common and significant complication of chemotherapy and radiotherapy, particularly in patients undergoing hematopoietic stem cell transplantation (HSCT). This retrospective observational study assessed the effectiveness of oral cryotherapy in reducing the incidence and severity of OM in 258 HSCT recipients treated at a single transplant center in Poland between 2018 and 2024. Patients were divided into two groups: 199 received cryotherapy as part of their conditioning regimen, while 59 did not. Cryotherapy was administered using ice chips from 10 minutes before chemotherapy infusion to two hours afterward. OM occurred in 48% of the cryotherapy group versus 68% in the control group, representing a statistically significant 20% relative risk reduction (p\u0026thinsp;=\u0026thinsp;0.008). Furthermore, the incidence of severe OM (grades 3\u0026ndash;4) was significantly lower in the cryotherapy group (p\u0026thinsp;=\u0026thinsp;0.006). No significant differences were observed in platelet engraftment or hospitalization duration. Although neutrophil engraftment was slightly delayed in the cryotherapy group, this finding lacked clinical relevance. Overall, the results support cryotherapy as a safe, cost-effective, and easily implementable strategy for OM prevention in the HSCT setting. Further prospective studies are warranted to validate these findings and optimize treatment protocols.\u003c/p\u003e","manuscriptTitle":"Impact of Cryotherapy on Incidence and Severity of Oral Mucositis in Hematopoietic Stem Cell Transplantation: Retrospective Observational Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-30 13:17:54","doi":"10.21203/rs.3.rs-6813382/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-08-29T07:52:19+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-26T16:26:42+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"190091097436575686364617428688124682448","date":"2025-08-18T03:16:07+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-13T20:03:14+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"229909950148670926547241506003676148487","date":"2025-06-30T06:23:08+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-06-25T15:01:26+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-06-25T14:55:37+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-06-18T06:13:49+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-06-10T14:52:33+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2025-06-10T14:49:23+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"87355794-ac2b-4555-a130-21e3137e45b1","owner":[],"postedDate":"June 30th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":50706659,"name":"Biological sciences/Stem cells/Haematopoietic stem cells"},{"id":50706660,"name":"Health sciences/Diseases/Cancer/Cancer therapy/Chemotherapy"}],"tags":[],"updatedAt":"2025-10-27T16:33:36+00:00","versionOfRecord":{"articleIdentity":"rs-6813382","link":"https://doi.org/10.1038/s41598-025-20927-5","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2025-10-23 16:17:11","publishedOnDateReadable":"October 23rd, 2025"},"versionCreatedAt":"2025-06-30 13:17:54","video":"","vorDoi":"10.1038/s41598-025-20927-5","vorDoiUrl":"https://doi.org/10.1038/s41598-025-20927-5","workflowStages":[]},"version":"v1","identity":"rs-6813382","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6813382","identity":"rs-6813382","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}