Reappraisal of a renovated cell-free and concentrated ascites reinfusion therapy (KM-CART) for malignant ascites

Reappraisal of a renovated cell-free and concentrated ascites reinfusion therapy (KM-CART) for malignant ascites | 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 Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Reappraisal of a renovated cell-free and concentrated ascites reinfusion therapy (KM-CART) for malignant ascites Yongsik Kim, Tetsuo Ajiki, Yasuhiro Ueda, Yuko Yoshida, Tsuyoshi Takahashi, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3305757/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Renovated cell-free and concentrated ascites reinfusion therapy (KM-CART) has become widely practiced, but the actual clinical efficacy has been reported rarely. The aim of this study was to evaluate the outcomes of KM-CART for malignant ascites. Methods We performed 226 KM-CART procedures in 104 patients with malignant ascites in three hospitals from August 2013 to September 2018. Medical records were retrospectively reviewed for ascites data, related complications, symptoms before and after each CART and prognosis after the first CART. We reviewed the modified Glasgow Prognostic Score (mGPS) before every procedure, as an indicator of nutritional status. Results Pancreatic cancer was the most common indication for the CART procedure, followed by gastric cancer, hepatocellular carcinoma, ovarian cancer, and cholangiocarcinoma (five major diseases). The 50% survival times of these five major diseases after the first procedure were 25, 39, 31, 49, and 33 days, respectively. The mean survival time for all patients was 73.5 days, and 75.6 days for those with the five major diseases. All patients experienced symptomatic relief, and complications were rare. Repeated KM-CART was performed in 47.1% of the patients, most often in those with ovarian cancer (66.7%). As for the mGPS at the first CART procedure, 89% of patients were in the group with the poorest nutritional status. The mGPS score improved in only two patients during treatment and was not related to prognosis. Conclusions KM-CART gives the benefit of improved ascites-related symptoms and general condition, even in a short time and with a poor nutritional status. Renovated cell-free and concentrated ascites reinfusion therapy KM-CART Modified Glasgow Prognostic Score (mGPS) Prognosis Cumulative survival rate Figures Figure 1 Figure 2 Figure 3 Introduction Cell-free and concentrated ascites reinfusion therapy (CART) provides symptomatic treatment. Although CART was established for refractory ascites and reported by Inoue et al. in 1977 [ 1 ], malignant ascites contains many cellular components, and purification is a difficult process. Ito et al. reported that, among 37 patients receiving CART, various symptoms related to malignant ascites, especially fatigue, improved within the 24-h period following CART [ 2 ]. Recently the number of reports evaluating the efficacy of CART for malignant ascites has increased [ 3 – 8 ]. CART not only improves the symptoms caused by refractory ascites, but also was reported to enable the resumption of anticancer drug treatment [ 9 ]. Furthermore, the administration of tolvaptan, in combination with CART, leads to a significantly reduced rate of ascites accumulation [ 10 ]. In cancer therapy, the combination of CART followed by chemotherapy is safe and could be a treatment option for malignant massive ascites [ 11 , 12 ]. In particular, CART contributes to the relief of symptoms in gynecological cancer patients, without infection and/or allergic reaction [ 13 – 15 ]. Thus, CART has come to be used widely because of its expected symptom-relieving outcomes. Matsusaki et al. developed a renovated CART system, so called KM-CART. This renovated system has a simpler circuit and uses an external pressure system, with a membrane cleaning function [ 16 ]. KM-CART has made it possible to purify large volumes of malignant ascites, which is rich in cellular and mucous components and contains more than 20L of fluid. Although few papers have reported the outcomes of patients treated with KM-CART, Matsusaki et al. have reported its efficacy for alleviating clinical signs/symptoms [ 17 ]. The general status of patients improves with treatment and improvement of the Quality of Life could be expected. Although long-term survivors and cases of treatment cessation have been reported, careful selection is necessary for the adaptation of KM-CART. However, there are few prognostic data for KM-CART and the repeat rate in various cancers, in clinical settings, is unclear. The purpose of this study was to review retrospectively the clinical course of patients with malignant ascites after KM-CART, and to reveal the differences of clinical outcomes with prognosis, according to the primary disease. To investigate the association between a patient's nutritional status before treatment and prognosis, we analyzed the modified Glasgow Prognostic Score (mGPS) as an indicator of nutritional status before each CART procedure; this has been reported to influence the prognosis in various cancers [ 18 – 22 ]. Patients and methods Patients We analyzed the records and clinical courses of 104 patients, 58 men and 46 women, aged from 38 to 86 years (mean age 66 years), who underwent KM-CART therapy at Mitsubishi Kobe Hospital between October 2013 and June 2017, and at Fukuyama Hospital and Kobe University Hospital, International Clinical Cancer Research Center, between July 2017 and September 2018. Treatment criteria included the following, Performance status < 2, T.Bil < 5.0 mg/dl, Cr 8.0 g/dl. Transfusions of 2–4 units RCC were given to patients with Hb below 8.0g/dl, before each procedure. This study was approved by our institutional review board [#B100010-I]. Procedures Each patient was admitted to hospital a few days before KM-CART and evaluated by a blood biochemical examination, before and after each procedure. Chest and abdominal radiography and chest and abdominal computed tomography were evaluated. After confirmation by abdominal ultrasonography, each patient was punctured under local anesthesia with 5ml of 1% xylocaine. Ascites was drained through a catheter (14G, 50cm; Argyle LCV-UK Catheter Kit; Covidien, Dublin, Ireland). During peritoneal drainage, 500 to 1,000ml of acetated Ringer’s solution with 10mg of prednisolone sodium succinate was continuously drip-infused, and the patient’s vital signs, percutaneous oxygen saturation (SpO2), and signs /symptoms were monitored. As far as possible, the ascites was drained into a collection bag by intraperitoneal pressure, at a flow rate of 2.0–3.0 L/h. The ascitic fluid was immediately filtered using the KM-CART system equipped with AHF-MOW (polyethylene) and AHF-UP filters (Asahi Kasei Medical Co., Ltd., Japan). The concentrated ascites was infused into the patient intravenously at a rate of 100 mL/h while monitoring the patient’s signs/symptoms and hemodynamic parameters, which were recorded at 0, 5, 10, 15, and 60 minutes, and every 60 minutes thereafter. After confirming the absence of adverse events, the KM-CART therapy was completed successfully [ 17 ]. Parameters examined The following parameters were analyzed in the 226 KM-CART procedures: (1) volumes of drained and concentrated ascites, (2) amount and ratio of recovered protein and albumin, (3) related complications and symptom before and after each CART, (4) laboratory data, including serum creatinine and albumin levels, total protein, and total bilirubin before and after KM-CART, and (5) prognosis after the first CART procedure. Modified Glasgow Prognostic Score To estimate the relationship between nutritional status and practiced KM-CART procedures as well as prognosis, we determined the mGPS prior to each procedure. The patients were divided into four groups, according to their serum albumin and CRP values, as follows: Group A (Alb ≥ 3.5 g/dl and CRP < 0.5 mg/dl), Group B (Alb < 3.5 g/dl and CRP < 0.5 mg/dl), Group C (Alb ≥ 3.5 g/dl, CRP ≥ 0.5 mg/dl), Group D (Alb < 3.5 g/dl, CRP ≥ 0.5 mg/dl) [ 22 ]. Statistical analysis Data are reported as the mean ± standard deviation (SD) or median and range. We measured overall survival from the date of the first KM-CART procedure to the date of the death. Kaplan-Meier estimates were used in the analysis of survival data and the log-rank test was used to compare survival rates. P values of < 0.05 are considered significant. All statistical analysis were carried out using the JMP 17 software (SAS Institute Inc., Cary, HC, USA). Results Primary disease and repeat time of the KM-CART procedure The primary disease, procedure time and repeat rate of KM-CART are shown in Table 1. Pancreatic cancer was the most common and the total number of patients with pancreatic cancer, gastric cancer, hepatocellular carcinoma, ovarian cancer, or cholangiocarcinoma was 76, accounting for 73.0% of all patients (76/104). Therefore, we consider these diseases as the “five major diseases of malignant ascites” in this study. As for the maximum repeated treatment times, pancreatic cancer was 5, gastric cancer was 5, hepatocellular carcinoma was 22, ovarian cancer was 22, cholangiocarcinoma was 6, colon cancer was 4, unknown primary cancer was 2, breast cancer was 2, appendix cancer was 5, rectal cancer was 4, and lung cancer was 3. Among the pancreatic cancer patients, 12 could be treated more than twice, and the repeat rate was 52.2%. The repeat rate of gastric cancer was 42.9%, hepatocellular carcinoma was 53.3%, ovarian cancer was 66.7%, and cholangiocarcinoma was 50.0%. The mean ± SD procedure interval time in all patients was 19 ± 8 days. After the KM-CART procedure, all patients had symptomatic relief. Complications occurred only in two cases: one intra-abdominal hemorrhage in ovarian cancer and one acute renal failure in hepatocellular carcinoma. Figure 1 shows the first procedure in a gastric cancer patient with liver metastasis. This patient was able to sustain KM-CART therapy three times. After the KM-CART procedure, the abdominal distension disappeared quickly, and other subjective symptoms and the general condition of the patient improved. Ascites-related data from KM-CART procedures Table 2 shows the ascites related data from the 226 KM-CART procedures. The mean total volume of ascites drained was 7.6L, and the maximum volume of fluid drained during a single KM-CART procedure was 21.0L, from an ovarian cancer patient. The mean total volume of concentrated fluid was 0.5L. The mean amount of collected protein was 74.9 g, equivalent to 47.8% of ratio of recovery. Furthermore, the mean amount of albumin recovered was 37.9g, equivalent to 51.0% of ratio of recovery. Survival time after KM-CART Figure 2 shows the cumulative survival curves of the patients with the five major diseases using the Kaplan-Meier method. The mean survival time for all 104 patients was 73.5 days, and for the five major diseases was 75.6 days. Ovarian cancer patients had the longest 50% survival time after the first KM-CART procedure, 49 days. The shortest 50% survival time was 25 days for pancreatic cancer patients. The 50% survival time of gastric cancer patients was 39 days, hepatocellular carcinoma patients 31 days, and cholangiocarcinoma patients 33 days. Figure 3 shows the cumulative survival curves according to the repeat time of the KM-CART procedure for the five major diseases. The 50% survival time of patients with a single procedure was 22 days (37 patients), patients with two procedures was 33 days (24 patients), and those with three or more procedures was 88 days (15 patients). Although the prognoses of patients with single and two KM-CART procedures were similar, patients who were treated three or more times had predominantly longer survival times than those who were treated once or twice (p < o.o1). KM-CART procedures and modified GPS As for mGPS at the first procedure, there was no patient in Group A. There were 5 patients (1 pancreatic cancer, 2 unknown primary cancer, 1 gastric cancer, 1 fallopian cancer) in Group B, and 3 patients (1 pancreatic cancer, 1 hepatocellular carcinoma, 1 uterine sarcoma) in Group C. Of the 104 KM-CART cases, 96 (89%) were in Group D at the first procedure. Two patients with ovarian cancer improved from Group D to B or C during treatment, but the other patients did not improve. The nutritional status of the patients was found to be poor, but the nutritional status of two patients (2/104, 1.9%) improved during treatment. One pancreatic cancer patient in Group B maintained the same score through three procedures, and this patient survived 218 days after the first treatment. Another pancreatic cancer patient in Group C at the first procedure had declined to Group D at the second procedure. This patient survived 46 days after the first treatment. There was no relationship between the mGPS score and number of KM-CART procedures, nor with the prognosis. Discussion To the best of our knowledge, this is the first report of the survival time and repeat rate of KM-CART procedures in a clinical setting. Regarding the prognosis of patients with malignant ascites, a retrospective review of 76 patients showed that median survival was determined to be 11.1 weeks from time of diagnosis and prolonged survival was found in patients with ovarian cancer [ 23 ]. In another study by Garrison et al., it was demonstrated that tumors originating from the female reproductive system had the longest survivals, with a mean survival of 19 weeks, and foregut adenocarcinomas had the poorest survivals, with a mean survival of 10 weeks from the onset of ascites [ 24 ]. In this study, of the five major diseases (accounted for 73% of all cases), ovarian cancer had also the longest 50% survival time (49 days), followed by gastric cancer, cholangiocarcinoma, and hepatocellular carcinoma. Pancreatic cancer had the shortest 50% survival time (25 days). Our results of survival time of patients with malignant ascites were shorter compared to those of previous reports because our data were from first KM-CART and data of previous reports were from the onset of ascites. Therefore, prognostic impact of KM-CART is thought to be unclear in this study, and KM-CART mainly provides symptomatic treatment. Because KM-CART is often performed multiple times to improve the quality of life [ 17 ], we examined the repeat rate of this treatment. In this study, about half of the patients underwent repeated KM-CART therapy. Matsusaki et al. have already reported the improvement of treatment results and inspection data, and concluded that KM-CART therapy had the "quality of best supportive care" for patients with malignant ascites [ 17 ]. Maeda et al. suggested that higher albumin levels in ascites may lead to multiple treatments [ 25 ]. Furthermore, Ito et al. reported that the presence of IL-10 in ascites was related to longer survival after CART, and the immunological environment of cancer-related ascites may reflect the outcome of CART therapy [ 26 ]. From the results of this study, we consider the continuity of treatment to be critical. In this study, patients who were treated three or more times with KM-CART procedures had longer survival times than those who are treated once or twice. Thus, if possible, the longer the treatment period, the more benefit to the patient. Nutritional status is important in enabling terminal stage patients to maintain their quality of life. Ayantunde et al. reported that low levels of serum albumin and total proteins are significant factors affecting survival [ 27 ]. In particular, sarcopenia is an established adverse prognostic factor in cancer patients [ 22 ]. In this study, pancreatic cancer patients, whose mGPS were in Group B and Group C at the first procedure, had long survival times, with maintenance of QOL. In addition, we found that two ovarian cancer patients, in mGPS Group D before their initial procedures were temporarily assigned to Group B and Group C after treatment. This suggests that a nutritional index, such as mGPS, may be useful as an indicator of the expected treatment effect and the possibility of continuation of treatment. The outcomes of the 226 KM-CART procedures were almost the same as those in Matsusaki’s report [ 17 ]. Although this study does not assess the details of improvements of clinical findings, lower leg edema in many patients in our study improved promptly after KM-CART. Blood osmotic pressure is determined by the number of albumins per unit area, and albumin has the maximum osmotic pressure. It would be extremely important and useful to restore albumin concentrations in order to improve intravascular circulatory failure, by collecting albumin from the ascites fluid and infusing it intravenously. Therefore, KM-CART can be considered to be a very reasonable treatment for refractory ascites [ 17 ]. This clinical study suggests that most patients with refractory ascites are malnourished and have hypoalbuminemia, but repeated KM-CART therapy may improve general condition by supplementing albumin recovered from the massive ascites. This study has several limitations. Firstly, this retrospective study was conducted only in three centers and was based on a small number of cases. A follow-up study is required to determine the survival time after treatment with prognostic surveys from various facilities. Secondly, some patients in this study were also receiving various cancer treatments in addition to KM-CART therapy. Of course, the availability of additional cancer treatment is such that there is a nutritional effect, and it is fully expected that the prognosis will be that much more favorable. It is necessary to consider the post-treatment course of patients with and without such additional treatments. We conclude that KM-CART can improve rapidly the physical symptoms of patients with malignant ascites. Many malignant diseases with refractory ascites should be treated aggressively with multiple applications of the KM-CART procedure to achieve the good QOL and prognosis. Declarations Acknowledgements We are grateful for technical support and invaluable advice from Keisuke Matsusaki and Masahiro Yokoi, members of Japanese CART Study Group. Conflict of interest The authors have no conflict of interest to disclose. Institutional review board The study was conducted in accordance with the Declaration of Helsinki, and approved by the Ethics Committee of the Kobe University Hospital (#B100010-I). AUTHOR CONTRIBUTIONS Yongsik Kim and Tetsuo Ajiki designed the study, analyzed and interpreted the data. Yasuhiro Ueda, Yuko Yoshida, Tsuyoshi Takahashi, Hitoshi Fukuyama and Tsuyoshi Fukuyama collected the data. Tetsuo Ajiki carried out the statistical analysis. Yuichi Hori checked the initial draft of the manuscript. This manuscript was critically revised and approved by all authors. References Inoue N, Yamzaki Z, Oda T et al (1977) Treatment of intractable ascites by continuous reinfusion of the sterilized, cell-free and concentrated ascitic fluid. 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Curr Opin Clin Nutr Metab Care 12:223–226 Hacker UT, Hasenclever D, Baber R et al (2022) Modified Glasgow prognostic score (mGPS) is correlated with sarcopenia and dominates the prognostic role of baseline body composition parameters in advanced gastric and esophagogastric junction cancer patients undergoing first-line treatment from the phase III EXPAND trial. Ann Oncol 33:685–692 Mackey JR, Venner PM (1996) Malignant ascites: demographics, therapeutic efficacy and predictors of survival. Can J Oncol 6:474–480 Garrison RN, Kaelin LD, Galloway RH et al (1986) Malignant ascites. Clinical and experimental observations. Ann Surg 203:644–651 Maeda S, Yabuuchi J, Nobuta H et al (2015) Characteristics of Patients and Their Ascites Who Underwent Repeated Cell-Free and Concentrated Ascites Reinfusion Therapy. Ther Apher Dial 19:342–348 Ito T, Hanafusa N, Iwase S et al (2020) Ascitic IL-10 Concentration Predicts Prognosis of Patients Undergoing Cell-Free and Concentrated Ascites Reinfusion Therapy. Ther Apher Dial 24:90–95 Ayantunde AA, Persons SL (2007) Pattern and prognostic factors in patients with malignant ascites: a retrospective study. Ann Oncol 18:945–949 Tables Table 1 and 2 are available in the Supplementary Files section. Supplementary Files Table12.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies 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-3305757","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":231672226,"identity":"1af8a567-1386-49ab-b47b-e778d27c9b5f","order_by":0,"name":"Yongsik Kim","email":"","orcid":"","institution":"Kobe Minimally invasive Cancer Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yongsik","middleName":"","lastName":"Kim","suffix":""},{"id":231672227,"identity":"3d0bc47b-fc58-49a4-997c-72dbdbd932cc","order_by":1,"name":"Tetsuo Ajiki","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA8klEQVRIiWNgGAWjYFCCg80MCRVA+gAbAzNcUIKgljOkaQEqZGxD14IP8DcebjZ4OG+bHN8BtsTHBRUMiQ3shx8wWO7ArUXiwMHmhMRtt40lD7AdNp5xBqiFJ82AQfIMHmuAWg4AtSRuOMDeJs3b9j+xgSGHgUGyDbcOebCWObfrIVr+AW3hf4NfiwHYYQ23EwwOsB2T5m0AapEgYIshUItBwrHbhjMPsyUbzzjGYNwm8czgAD6/yN04/ljyR81teb7jbYaPC2oYZPv5kx8+lsQTYsAggzJgkcIGxIclG/Bo4ccmyfgRn5ZRMApGwSgYaQAA3aFXQkEPcrgAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-5807-6716","institution":"Kobe Medical Center: Kokuritsu Byoin Kiko Kobe Iryo Center","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Tetsuo","middleName":"","lastName":"Ajiki","suffix":""},{"id":231672228,"identity":"fd43ad42-5ca4-4961-b304-1d19ceecaa2f","order_by":2,"name":"Yasuhiro Ueda","email":"","orcid":"","institution":"Kobe University Hospital: Kobe Daigaku Igakubu Fuzoku Byoin","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yasuhiro","middleName":"","lastName":"Ueda","suffix":""},{"id":231672229,"identity":"e9b39041-3543-43fb-9735-06d391b8ba45","order_by":3,"name":"Yuko Yoshida","email":"","orcid":"","institution":"Mitsubishi Kobe Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yuko","middleName":"","lastName":"Yoshida","suffix":""},{"id":231672230,"identity":"50daf3cc-4f07-4202-a1b7-9c5790f271d3","order_by":4,"name":"Tsuyoshi Takahashi","email":"","orcid":"","institution":"Mitsubishi Kobe Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Tsuyoshi","middleName":"","lastName":"Takahashi","suffix":""},{"id":231672231,"identity":"32edb45d-0118-4c8f-b87b-b407be4c7330","order_by":5,"name":"Hitoshi Fukuyama","email":"","orcid":"","institution":"Fukuyama Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hitoshi","middleName":"","lastName":"Fukuyama","suffix":""},{"id":231672232,"identity":"599dee83-39e7-4fcc-89e8-4e8212aabf79","order_by":6,"name":"Tsuyoshi Fukuyama","email":"","orcid":"","institution":"Fukuyama Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Tsuyoshi","middleName":"","lastName":"Fukuyama","suffix":""},{"id":231672233,"identity":"db7c2d52-4531-4f42-b6b0-47b53ee5def3","order_by":7,"name":"Yuichi Hori","email":"","orcid":"","institution":"Kobe University Faculty of Health Sciences and Graduate School of Medicine Faculty of Health Sciences: Kobe Daigaku Daigakuin Hokengaku Kenkyuka Igakubu Hoken Gakka","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yuichi","middleName":"","lastName":"Hori","suffix":""}],"badges":[],"createdAt":"2023-08-29 07:44:24","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3305757/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3305757/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":43011151,"identity":"61288a14-c563-41b6-a1e9-96de184ab041","added_by":"auto","created_at":"2023-09-12 14:32:14","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":664875,"visible":true,"origin":"","legend":"\u003cp\u003eReduction of abdominal distension of a gastric cancer patient with liver metastasis．This patient was drained 5.78L of ascites, including 138.7g of protein and 57.8g of albumin. Drip infusion concentrated 0.35L of ascites, which is equivalent to 75g of protein and 33.5g of albumin. The ratio of protein recovery was 53.0% and albumin recovery was 58.1%. After procedure, the metastatic liver tumor became visible.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-3305757/v1/8ec976d76b9472249a9e134d.png"},{"id":43011669,"identity":"31769990-22bf-45d3-80c2-eaf9aab7b23b","added_by":"auto","created_at":"2023-09-12 14:40:14","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":21772,"visible":true,"origin":"","legend":"\u003cp\u003eThe cumulative survival rate of five major disease after the first KM-CART procedure (The Kaplan-Meier method).\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-3305757/v1/2e896ca02acce4aa384ae0a4.png"},{"id":43013062,"identity":"78ffe61c-7aaf-4d37-b747-28d38ff092b4","added_by":"auto","created_at":"2023-09-12 14:48:14","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":8637,"visible":true,"origin":"","legend":"\u003cp\u003eThe cumulative survival rate according to repeat time after the first KM-CART procedure.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-3305757/v1/e25a898d0892ae77cefd38e2.png"},{"id":45176393,"identity":"e854b96b-6d35-4f55-8ed0-b4e66eda2b73","added_by":"auto","created_at":"2023-10-24 20:07:15","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":983049,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3305757/v1/a6db49d8-ae93-489b-9aa8-b07724057ca7.pdf"},{"id":43009345,"identity":"fe206b75-8cea-4fb6-9b81-2d772983b829","added_by":"auto","created_at":"2023-09-12 14:24:14","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":13899,"visible":true,"origin":"","legend":"","description":"","filename":"Table12.docx","url":"https://assets-eu.researchsquare.com/files/rs-3305757/v1/69916e7d38a5660da7b2595f.docx"}],"financialInterests":"","formattedTitle":"Reappraisal of a renovated cell-free and concentrated ascites reinfusion therapy (KM-CART) for malignant ascites","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCell-free and concentrated ascites reinfusion therapy (CART) provides symptomatic treatment. Although CART was established for refractory ascites and reported by Inoue et al. in 1977 [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], malignant ascites contains many cellular components, and purification is a difficult process. Ito et al. reported that, among 37 patients receiving CART, various symptoms related to malignant ascites, especially fatigue, improved within the 24-h period following CART [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Recently the number of reports evaluating the efficacy of CART for malignant ascites has increased [\u003cspan additionalcitationids=\"CR4 CR5 CR6 CR7\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. CART not only improves the symptoms caused by refractory ascites, but also was reported to enable the resumption of anticancer drug treatment [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Furthermore, the administration of tolvaptan, in combination with CART, leads to a significantly reduced rate of ascites accumulation [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. In cancer therapy, the combination of CART followed by chemotherapy is safe and could be a treatment option for malignant massive ascites [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. In particular, CART contributes to the relief of symptoms in gynecological cancer patients, without infection and/or allergic reaction [\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Thus, CART has come to be used widely because of its expected symptom-relieving outcomes.\u003c/p\u003e \u003cp\u003eMatsusaki et al. developed a renovated CART system, so called KM-CART. This renovated system has a simpler circuit and uses an external pressure system, with a membrane cleaning function [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. KM-CART has made it possible to purify large volumes of malignant ascites, which is rich in cellular and mucous components and contains more than 20L of fluid. Although few papers have reported the outcomes of patients treated with KM-CART, Matsusaki et al. have reported its efficacy for alleviating clinical signs/symptoms [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. The general status of patients improves with treatment and improvement of the Quality of Life could be expected. Although long-term survivors and cases of treatment cessation have been reported, careful selection is necessary for the adaptation of KM-CART. However, there are few prognostic data for KM-CART and the repeat rate in various cancers, in clinical settings, is unclear.\u003c/p\u003e \u003cp\u003eThe purpose of this study was to review retrospectively the clinical course of patients with malignant ascites after KM-CART, and to reveal the differences of clinical outcomes with prognosis, according to the primary disease. To investigate the association between a patient's nutritional status before treatment and prognosis, we analyzed the modified Glasgow Prognostic Score (mGPS) as an indicator of nutritional status before each CART procedure; this has been reported to influence the prognosis in various cancers [\u003cspan additionalcitationids=\"CR19 CR20 CR21\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e"},{"header":"Patients and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003eWe analyzed the records and clinical courses of 104 patients, 58 men and 46 women, aged from 38 to 86 years (mean age 66 years), who underwent KM-CART therapy at Mitsubishi Kobe Hospital between October 2013 and June 2017, and at Fukuyama Hospital and Kobe University Hospital, International Clinical Cancer Research Center, between July 2017 and September 2018. Treatment criteria included the following, Performance status\u0026thinsp;\u0026lt;\u0026thinsp;2, T.Bil\u0026thinsp;\u0026lt;\u0026thinsp;5.0 mg/dl, Cr\u0026thinsp;\u0026lt;\u0026thinsp;2.0 mg/dl, no serious cardiopulmonary complication, and Hb\u0026thinsp;\u0026gt;\u0026thinsp;8.0 g/dl. Transfusions of 2\u0026ndash;4 units RCC were given to patients with Hb below 8.0g/dl, before each procedure. This study was approved by our institutional review board [#B100010-I].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eProcedures\u003c/h2\u003e \u003cp\u003eEach patient was admitted to hospital a few days before KM-CART and evaluated by a blood biochemical examination, before and after each procedure. Chest and abdominal radiography and chest and abdominal computed tomography were evaluated. After confirmation by abdominal ultrasonography, each patient was punctured under local anesthesia with 5ml of 1% xylocaine. Ascites was drained through a catheter (14G, 50cm; Argyle LCV-UK Catheter Kit; Covidien, Dublin, Ireland). During peritoneal drainage, 500 to 1,000ml of acetated Ringer\u0026rsquo;s solution with 10mg of prednisolone sodium succinate was continuously drip-infused, and the patient\u0026rsquo;s vital signs, percutaneous oxygen saturation (SpO2), and signs /symptoms were monitored. As far as possible, the ascites was drained into a collection bag by intraperitoneal pressure, at a flow rate of 2.0\u0026ndash;3.0 L/h. The ascitic fluid was immediately filtered using the KM-CART system equipped with AHF-MOW (polyethylene) and AHF-UP filters (Asahi Kasei Medical Co., Ltd., Japan).\u003c/p\u003e \u003cp\u003eThe concentrated ascites was infused into the patient intravenously at a rate of 100 mL/h while monitoring the patient\u0026rsquo;s signs/symptoms and hemodynamic parameters, which were recorded at 0, 5, 10, 15, and 60 minutes, and every 60 minutes thereafter. After confirming the absence of adverse events, the KM-CART therapy was completed successfully [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eParameters examined\u003c/h2\u003e \u003cp\u003eThe following parameters were analyzed in the 226 KM-CART procedures: (1) volumes of drained and concentrated ascites, (2) amount and ratio of recovered protein and albumin, (3) related complications and symptom before and after each CART, (4) laboratory data, including serum creatinine and albumin levels, total protein, and total bilirubin before and after KM-CART, and (5) prognosis after the first CART procedure.\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section3\"\u003e \u003ch2\u003eModified Glasgow Prognostic Score\u003c/h2\u003e \u003cp\u003eTo estimate the relationship between nutritional status and practiced KM-CART procedures as well as prognosis, we determined the mGPS prior to each procedure. The patients were divided into four groups, according to their serum albumin and CRP values, as follows: Group A (Alb\u0026thinsp;\u0026ge;\u0026thinsp;3.5 g/dl and CRP\u0026thinsp;\u0026lt;\u0026thinsp;0.5 mg/dl), Group B (Alb\u0026thinsp;\u0026lt;\u0026thinsp;3.5 g/dl and CRP\u0026thinsp;\u0026lt;\u0026thinsp;0.5 mg/dl), Group C (Alb\u0026thinsp;\u0026ge;\u0026thinsp;3.5 g/dl, CRP\u0026thinsp;\u0026ge;\u0026thinsp;0.5 mg/dl), Group D (Alb\u0026thinsp;\u0026lt;\u0026thinsp;3.5 g/dl, CRP\u0026thinsp;\u0026ge;\u0026thinsp;0.5 mg/dl) [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eData are reported as the mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD) or median and range. We measured overall survival from the date of the first KM-CART procedure to the date of the death. Kaplan-Meier estimates were used in the analysis of survival data and the log-rank test was used to compare survival rates. P values of \u0026lt;\u0026thinsp;0.05 are considered significant. All statistical analysis were carried out using the JMP 17 software (SAS Institute Inc., Cary, HC, USA).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003ePrimary disease and repeat time of the KM-CART procedure\u003c/h2\u003e \u003cp\u003eThe primary disease, procedure time and repeat rate of KM-CART are shown in Table\u0026nbsp;1. Pancreatic cancer was the most common and the total number of patients with pancreatic cancer, gastric cancer, hepatocellular carcinoma, ovarian cancer, or cholangiocarcinoma was 76, accounting for 73.0% of all patients (76/104). Therefore, we consider these diseases as the \u0026ldquo;five major diseases of malignant ascites\u0026rdquo; in this study.\u003c/p\u003e \u003cp\u003eAs for the maximum repeated treatment times, pancreatic cancer was 5, gastric cancer was 5, hepatocellular carcinoma was 22, ovarian cancer was 22, cholangiocarcinoma was 6, colon cancer was 4, unknown primary cancer was 2, breast cancer was 2, appendix cancer was 5, rectal cancer was 4, and lung cancer was 3. Among the pancreatic cancer patients, 12 could be treated more than twice, and the repeat rate was 52.2%. The repeat rate of gastric cancer was 42.9%, hepatocellular carcinoma was 53.3%, ovarian cancer was 66.7%, and cholangiocarcinoma was 50.0%. The mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD procedure interval time in all patients was 19\u0026thinsp;\u0026plusmn;\u0026thinsp;8 days.\u003c/p\u003e \u003cp\u003eAfter the KM-CART procedure, all patients had symptomatic relief. Complications occurred only in two cases: one intra-abdominal hemorrhage in ovarian cancer and one acute renal failure in hepatocellular carcinoma.\u003c/p\u003e \u003cp\u003eFigure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows the first procedure in a gastric cancer patient with liver metastasis. This patient was able to sustain KM-CART therapy three times. After the KM-CART procedure, the abdominal distension disappeared quickly, and other subjective symptoms and the general condition of the patient improved.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eAscites-related data from KM-CART procedures\u003c/h2\u003e \u003cp\u003eTable\u0026nbsp;2 shows the ascites related data from the 226 KM-CART procedures. The mean total volume of ascites drained was 7.6L, and the maximum volume of fluid drained during a single KM-CART procedure was 21.0L, from an ovarian cancer patient. The mean total volume of concentrated fluid was 0.5L. The mean amount of collected protein was 74.9 g, equivalent to 47.8% of ratio of recovery. Furthermore, the mean amount of albumin recovered was 37.9g, equivalent to 51.0% of ratio of recovery.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eSurvival time after KM-CART\u003c/h2\u003e \u003cp\u003eFigure\u0026nbsp;2 shows the cumulative survival curves of the patients with the five major diseases using the Kaplan-Meier method. The mean survival time for all 104 patients was 73.5 days, and for the five major diseases was 75.6 days. Ovarian cancer patients had the longest 50% survival time after the first KM-CART procedure, 49 days. The shortest 50% survival time was 25 days for pancreatic cancer patients. The 50% survival time of gastric cancer patients was 39 days, hepatocellular carcinoma patients 31 days, and cholangiocarcinoma patients 33 days.\u003c/p\u003e \u003cp\u003eFigure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e3\u003c/span\u003e shows the cumulative survival curves according to the repeat time of the KM-CART procedure for the five major diseases. The 50% survival time of patients with a single procedure was 22 days (37 patients), patients with two procedures was 33 days (24 patients), and those with three or more procedures was 88 days (15 patients). Although the prognoses of patients with single and two KM-CART procedures were similar, patients who were treated three or more times had predominantly longer survival times than those who were treated once or twice (p\u0026thinsp;\u0026lt;\u0026thinsp;o.o1).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eKM-CART procedures and modified GPS\u003c/h2\u003e \u003cp\u003eAs for mGPS at the first procedure, there was no patient in Group A. There were 5 patients (1 pancreatic cancer, 2 unknown primary cancer, 1 gastric cancer, 1 fallopian cancer) in Group B, and 3 patients (1 pancreatic cancer, 1 hepatocellular carcinoma, 1 uterine sarcoma) in Group C. Of the 104 KM-CART cases, 96 (89%) were in Group D at the first procedure. Two patients with ovarian cancer improved from Group D to B or C during treatment, but the other patients did not improve. The nutritional status of the patients was found to be poor, but the nutritional status of two patients (2/104, 1.9%) improved during treatment.\u003c/p\u003e \u003cp\u003eOne pancreatic cancer patient in Group B maintained the same score through three procedures, and this patient survived 218 days after the first treatment. Another pancreatic cancer patient in Group C at the first procedure had declined to Group D at the second procedure. This patient survived 46 days after the first treatment. There was no relationship between the mGPS score and number of KM-CART procedures, nor with the prognosis.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eTo the best of our knowledge, this is the first report of the survival time and repeat rate of KM-CART procedures in a clinical setting. Regarding the prognosis of patients with malignant ascites, a retrospective review of 76 patients showed that median survival was determined to be 11.1 weeks from time of diagnosis and prolonged survival was found in patients with ovarian cancer [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. In another study by Garrison et al., it was demonstrated that tumors originating from the female reproductive system had the longest survivals, with a mean survival of 19 weeks, and foregut adenocarcinomas had the poorest survivals, with a mean survival of 10 weeks from the onset of ascites [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. In this study, of the five major diseases (accounted for 73% of all cases), ovarian cancer had also the longest 50% survival time (49 days), followed by gastric cancer, cholangiocarcinoma, and hepatocellular carcinoma. Pancreatic cancer had the shortest 50% survival time (25 days). Our results of survival time of patients with malignant ascites were shorter compared to those of previous reports because our data were from first KM-CART and data of previous reports were from the onset of ascites. Therefore, prognostic impact of KM-CART is thought to be unclear in this study, and KM-CART mainly provides symptomatic treatment.\u003c/p\u003e \u003cp\u003eBecause KM-CART is often performed multiple times to improve the quality of life [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], we examined the repeat rate of this treatment. In this study, about half of the patients underwent repeated KM-CART therapy. Matsusaki et al. have already reported the improvement of treatment results and inspection data, and concluded that KM-CART therapy had the \"quality of best supportive care\" for patients with malignant ascites [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Maeda et al. suggested that higher albumin levels in ascites may lead to multiple treatments [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Furthermore, Ito et al. reported that the presence of IL-10 in ascites was related to longer survival after CART, and the immunological environment of cancer-related ascites may reflect the outcome of CART therapy [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. From the results of this study, we consider the continuity of treatment to be critical. In this study, patients who were treated three or more times with KM-CART procedures had longer survival times than those who are treated once or twice. Thus, if possible, the longer the treatment period, the more benefit to the patient.\u003c/p\u003e \u003cp\u003eNutritional status is important in enabling terminal stage patients to maintain their quality of life. Ayantunde et al. reported that low levels of serum albumin and total proteins are significant factors affecting survival [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. In particular, sarcopenia is an established adverse prognostic factor in cancer patients [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. In this study, pancreatic cancer patients, whose mGPS were in Group B and Group C at the first procedure, had long survival times, with maintenance of QOL. In addition, we found that two ovarian cancer patients, in mGPS Group D before their initial procedures were temporarily assigned to Group B and Group C after treatment. This suggests that a nutritional index, such as mGPS, may be useful as an indicator of the expected treatment effect and the possibility of continuation of treatment.\u003c/p\u003e \u003cp\u003eThe outcomes of the 226 KM-CART procedures were almost the same as those in Matsusaki\u0026rsquo;s report [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Although this study does not assess the details of improvements of clinical findings, lower leg edema in many patients in our study improved promptly after KM-CART. Blood osmotic pressure is determined by the number of albumins per unit area, and albumin has the maximum osmotic pressure. It would be extremely important and useful to restore albumin concentrations in order to improve intravascular circulatory failure, by collecting albumin from the ascites fluid and infusing it intravenously. Therefore, KM-CART can be considered to be a very reasonable treatment for refractory ascites [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. This clinical study suggests that most patients with refractory ascites are malnourished and have hypoalbuminemia, but repeated KM-CART therapy may improve general condition by supplementing albumin recovered from the massive ascites.\u003c/p\u003e \u003cp\u003eThis study has several limitations. Firstly, this retrospective study was conducted only in three centers and was based on a small number of cases. A follow-up study is required to determine the survival time after treatment with prognostic surveys from various facilities. Secondly, some patients in this study were also receiving various cancer treatments in addition to KM-CART therapy. Of course, the availability of additional cancer treatment is such that there is a nutritional effect, and it is fully expected that the prognosis will be that much more favorable. It is necessary to consider the post-treatment course of patients with and without such additional treatments.\u003c/p\u003e \u003cp\u003eWe conclude that KM-CART can improve rapidly the physical symptoms of patients with malignant ascites. Many malignant diseases with refractory ascites should be treated aggressively with multiple applications of the KM-CART procedure to achieve the good QOL and prognosis.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e We are grateful for technical support and invaluable advice from Keisuke Matsusaki and Masahiro Yokoi, members of Japanese CART Study Group.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u0026nbsp;\u003c/strong\u003eThe authors have no conflict of interest to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInstitutional review board\u0026nbsp;\u003c/strong\u003eThe study was conducted in accordance with the Declaration of Helsinki, and approved by the Ethics Committee of the Kobe University Hospital (#B100010-I).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAUTHOR CONTRIBUTIONS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYongsik Kim and Tetsuo Ajiki designed the study, analyzed and interpreted the data.\u0026nbsp;Yasuhiro Ueda, Yuko Yoshida, Tsuyoshi Takahashi, Hitoshi Fukuyama and Tsuyoshi Fukuyama collected the data.\u0026nbsp;Tetsuo Ajiki\u0026nbsp;carried out the statistical analysis.\u0026nbsp;Yuichi Hori\u003csup\u003e\u0026nbsp;\u003c/sup\u003echecked the initial draft of the manuscript. This manuscript was critically revised and approved by all authors.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eInoue N, Yamzaki Z, Oda T et al (1977) Treatment of intractable ascites by continuous reinfusion of the sterilized, cell-free and concentrated ascitic fluid. Trans Am Soc Artif Intern Organs 23:699\u0026ndash;702\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIto T, Hanafusa N, Iwase S et al (2015) Effects of cell-free and concentrated ascites reinfusion therapy (CART) on symptom relief of malignancy-related ascites. Int J Clin Oncol 20:623\u0026ndash;628\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang L, Okubo T, Shinsaka M et al (2015) Efficacy and safety of cell-free and concentrated ascites reinfusion therapy (CART) in gynecologic cancer patients with a large volume of ascites. J Obstet Gynaecol Res 41:1614\u0026ndash;1620\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHisakane K, Ohmatsu H, Umemura S et al (2017) Efficacy of Cell-Free and Concentrated Ascites Reinfusion Therapy for Palliative Care in a Patient with Malignant Pleural Mesothelioma: A Case Report. J Nippon Med Sch 84:231\u0026ndash;236\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIto T, Hanafusa N (2017) CART: Cell-free and Concentrated Ascites Reinfusion Therapy against malignancy-related ascites. Transfus Apher Sci 56:703\u0026ndash;707\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIto T, Hanafusa N, Soneda N et al (2021) Safety\u0026atilde;\u0026#128;\u0026#128;and efficacy of cell-free and concentrated ascites reinfusion therapy against cirrhotic ascites in comparison with malignancy-related ascites. J Gastroenterol Hepatol 36:3224\u0026ndash;3232\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYokomichi N, Imai K, Sakamoto M et al (2022) Feasibility of a fast-track randomized controlled trial of cell-free and concentrated ascites reinfusion therapy for patients with refractory malignant ascites. BMC Cancer 22:218\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTsubokura M, Adegawa Y, Kojima M et al (2022) Adverse effects of cell-free and concentrated ascites reinfusion therapy for malignant ascites: a single-institute experience. BMC Cancer 22:268\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYamaguchi H, Kitayama J, Emoto S et al (2015) Cell-free and concentrated ascites reinfusion therapy (CART) for management of massive malignant ascites in gastric cancer patients with peritoneal metastasis treated with intravenous and intraperitoneal paclitaxel with oral S-1. Eur J Surg Oncol 41:875\u0026ndash;880\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIwasa M, Ishihara T, Kato M et al (2019) Cell-free and concentrated ascites reinfusion therapy for refractory ascites in cirrhosis in post-marketing surveillance and the role of tolvaptan. Intern Med 58:3069\u0026ndash;3075\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNagata Y, Kato K, Miyamoto T et al (2020) Safety and efficacy of cell-free and concentrated ascites reinfusion therapy (CART) in gastrointestinal cancer patients with massive ascites treated with systemic chemotherapy. Support Care Cancer 28:5861\u0026ndash;5869\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIshitani K, Isoai A, Ito T et al (2021) Clinical usefulness of cell-free and concentrated ascites reinfusion therapy (CART) in combination with chemotherapy for malignant ascites: a post-marketing surveillance study. Int J Clin Oncol 26:1130\u0026ndash;1138\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTogami S, Hori S, Kamio M et al (2014) Clinical usefulness of concentrated ascites reinfusion therapy (CART) for gynecological cancer patients with refractory massive ascites due to cancerous peritonitis. Eur J Gynaecol Oncol 35:301\u0026ndash;303\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAbe Y, Kobayashi H, Kanno T et al (2019) Application of gamma-delta T cells obtained by ascites filtration for immunotherapy against malignant refractory ascites. Ann Cancer Res Ther 27:73\u0026ndash;79\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKawata Y, Nagasaka K, Matsumoto Y et al (2019) Usefulness of cell-free and concentrated ascites reinfusion therapy in the therapeutic management of advanced ovarian cancer patients with massive ascites. Int J Clin Oncol 24:420\u0026ndash;427\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJapanese CARTS, Group, Matsusaki K, Ohta K et al (2011) Novel cell-free and concentrated ascites reinfusion therapy (KM-CART) for refractory ascites associated with cancerous peritonitis; its effect and future perspectives. Int J Clin Oncol 16:395\u0026ndash;400\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMatsusaki K, Orihashi K (2020) Feasibility, efficacy, and safety of cell-free and concentrated ascites reinfusion therapy (KM-CART) for malignant ascites. Artif Organs 44:1090\u0026ndash;1097\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMcMillan DC, Forrest LM, O\u0026rsquo; Gorman P et al (2002) Performance status of male and female advanced cancer patients is independently predicted by mid-upper arm circumferences measurement. Nutr Cancer 42:191\u0026ndash;193\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eForrest LM, McMillan DC, McArdle CS et al (2003) Evaluation of cumulative prognostic scores based on the systemic inflammatory response in patients with inoperable non-small-cell lung cancer. Br J Cancer 89:1028\u0026ndash;1030\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eElahi MM, McMillan DC, McArdle CS et al (2004) Score based on hypoalbuminemia and elevated C-reactive protein predicts survival in patients with advanced gastrointestinal cancer. Nutr Cancer 48:171\u0026ndash;173\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMcMillan DC (2009) Systemic inflammation, nutritional status and survival in patients with cancer. Curr Opin Clin Nutr Metab Care 12:223\u0026ndash;226\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHacker UT, Hasenclever D, Baber R et al (2022) Modified Glasgow prognostic score (mGPS) is correlated with sarcopenia and dominates the prognostic role of baseline body composition parameters in advanced gastric and esophagogastric junction cancer patients undergoing first-line treatment from the phase III EXPAND trial. Ann Oncol 33:685\u0026ndash;692\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMackey JR, Venner PM (1996) Malignant ascites: demographics, therapeutic efficacy and predictors of survival. Can J Oncol 6:474\u0026ndash;480\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGarrison RN, Kaelin LD, Galloway RH et al (1986) Malignant ascites. Clinical and experimental observations. Ann Surg 203:644\u0026ndash;651\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMaeda S, Yabuuchi J, Nobuta H et al (2015) Characteristics of Patients and Their Ascites Who Underwent Repeated Cell-Free and Concentrated Ascites Reinfusion Therapy. Ther Apher Dial 19:342\u0026ndash;348\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIto T, Hanafusa N, Iwase S et al (2020) Ascitic IL-10 Concentration Predicts Prognosis of Patients Undergoing Cell-Free and Concentrated Ascites Reinfusion Therapy. Ther Apher Dial 24:90\u0026ndash;95\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAyantunde AA, Persons SL (2007) Pattern and prognostic factors in patients with malignant ascites: a retrospective study. Ann Oncol 18:945\u0026ndash;949\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 and 2 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Renovated cell-free and concentrated ascites reinfusion therapy, KM-CART, Modified Glasgow Prognostic Score (mGPS), Prognosis, Cumulative survival rate","lastPublishedDoi":"10.21203/rs.3.rs-3305757/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3305757/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eRenovated cell-free and concentrated ascites reinfusion therapy (KM-CART) has become widely practiced, but the actual clinical efficacy has been reported rarely. The aim of this study was to evaluate the outcomes of KM-CART for malignant ascites.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe performed 226 KM-CART procedures in 104 patients with malignant ascites in three hospitals from August 2013 to September 2018. Medical records were retrospectively reviewed for ascites data, related complications, symptoms before and after each CART and prognosis after the first CART. We reviewed the modified Glasgow Prognostic Score (mGPS) before every procedure, as an indicator of nutritional status.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003ePancreatic cancer was the most common indication for the CART procedure, followed by gastric cancer, hepatocellular carcinoma, ovarian cancer, and cholangiocarcinoma (five major diseases). The 50% survival times of these five major diseases after the first procedure were 25, 39, 31, 49, and 33 days, respectively. The mean survival time for all patients was 73.5 days, and 75.6 days for those with the five major diseases. All patients experienced symptomatic relief, and complications were rare. Repeated KM-CART was performed in 47.1% of the patients, most often in those with ovarian cancer (66.7%). As for the mGPS at the first CART procedure, 89% of patients were in the group with the poorest nutritional status. The mGPS score improved in only two patients during treatment and was not related to prognosis.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eKM-CART gives the benefit of improved ascites-related symptoms and general condition, even in a short time and with a poor nutritional status.\u003c/p\u003e","manuscriptTitle":"Reappraisal of a renovated cell-free and concentrated ascites reinfusion therapy (KM-CART) for malignant ascites","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-09-12 14:24:09","doi":"10.21203/rs.3.rs-3305757/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"2d03d48c-1bc2-4b67-925a-cdfbe6d0af74","owner":[],"postedDate":"September 12th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2023-10-24T19:59:08+00:00","versionOfRecord":[],"versionCreatedAt":"2023-09-12 14:24:09","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3305757","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3305757","identity":"rs-3305757","version":["v1"]},"buildId":"GqpaHPwrfC8PjnIFayRh5","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}