Reviving peritoneal cytology: Exploring its role in endometrial cancer molecular classification.

OBJECTIVE: The prognostic significance of positive peritoneal cytology in endometrial cancer has long been debated. In 2009, the Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) removed cytology as a staging criterion from the endometrial cancer staging system. However, there is still evidence that positive peritoneal cytology may decrease survival among patients with endometrial cancer. The aim of this study was to determine the prognostic significance of positive peritoneal cytology among the different molecular subgroups. METHODS: This study included patients with endometrial cancer who underwent primary surgical treatment between 2004 and 2015 at the Bern University Hospital, Switzerland, with molecular classification of the primary tumor and peritoneal cytology performed. RESULTS: A total, 250 patients with endometrial cancer were enrolled. Peritoneal cytology was assessed in 206 patients, of whom 24% were positive: 25% of the POLEmut, 16% of the MMRd, 41% of the p53abn, and 24% of the NSMP cases. The mean follow-up was 128.7 months. Presence of positive peritoneal cytology was associated with significantly decreased mean recurrence-free and overall survival in patients with p53abn (p = .003 and p = .001) and NSMP (p = .020 and p = .049) endometrial cancer. In multivariable Cox regression analysis, positive peritoneal cytology remained an independent predictor of recurrence (p = .033) and death (p = .008) in p53abn endometrial cancer patients. CONCLUSION: Positive peritoneal cytology is associated with worse oncologic outcomes in NSMP and p53abn endometrial cancer and remains an independent predictor of recurrence and death in patients with p53abn endometrial cancer.

Reproducibility of the peritoneal regression grading score for assessment of response to therapy in peritoneal metastasis.

AIMS: The four-tiered peritoneal regression grading score (PRGS) assesses the response to chemotherapy in peritoneal metastasis (PM). The PRGS is used, for example, to assess the response to pressurised intraperitoneal aerosol chemotherapy (PIPAC). However, the reproducibility of the PRGS is currently unknown. We aimed to evaluate the inter- and intraobserver variability of the PRGS. METHODS AND RESULTS: Thirty-three patients who underwent at least three PIPAC treatments as part of the PIPAC-OPC1 or PIPAC-OPC2 clinical trials at Odense University Hospital, Denmark, were included. Prior to each therapy cycle, peritoneal quadrant biopsies were obtained and three haematoxylin and eosin (H&E)-stained step sections were scanned and uploaded to a pseudonymised web library. For determining interobserver variability, eight pathologists assessed the PRGS for each quadrant biopsy, and Krippendorff's alpha and intraclass correlation coefficients (ICCs) were calculated. For determining intraobserver variability, three pathologists repeated their own assessments and Cohen's kappa and ICCs were calculated. A total of 331 peritoneal biopsies were analysed. Interobserver variability for PRGS of each biopsy and for the mean and maximum PRGS per biopsy set was moderate to good/substantial. The intraobserver variability for PRGS of each biopsy and for the mean and maximum PRGS per biopsy set was good to excellent/almost perfect. CONCLUSIONS: Our data support the PRGS as a reproducible and useful tool to assess response to intraperitoneal chemotherapy in PM. Future studies should evaluate the prognostic and predictive role of the PRGS.

Cachexia Anorexia Syndrome and Associated Metabolic Dysfunction in Peritoneal Metastasis.

: Patients with peritoneal metastasis (PM) of gastrointestinal and gynecological origin present with a nutritional deficit characterized by increased resting energy expenditure (REE), loss of muscle mass, and protein catabolism. Progression of peritoneal metastasis, as with other advanced malignancies, is associated with cancer cachexia anorexia syndrome (CAS), involving poor appetite (anorexia), involuntary weight loss, and chronic inflammation. Eventual causes of mortality include dysfunctional metabolism and energy store exhaustion. Etiology of CAS in PM patients is multifactorial including tumor growth, host response, cytokine release, systemic inflammation, proteolysis, lipolysis, malignant small bowel obstruction, ascites, and gastrointestinal side effects of drug therapy (chemotherapy, opioids). Metabolic changes of CAS in PM relate more to a systemic inflammatory response than an adaptation to starvation. Metabolic reprogramming is required for cancer cells shed into the peritoneal cavity to resist anoikis (i.e., programmed cell death). Profound changes in hexokinase metabolism are needed to compensate ineffective oxidative phosphorylation in mitochondria. During the development of PM, hypoxia inducible factor-1α (HIF-1α) plays a key role in activating both aerobic and anaerobic glycolysis, increasing the uptake of glucose, lipid, and glutamine into cancer cells. HIF-1α upregulates hexokinase II, phosphoglycerate kinase 1 (PGK1), pyruvate dehydrogenase kinase (PDK), pyruvate kinase muscle isoenzyme 2 (PKM2), lactate dehydrogenase (LDH) and glucose transporters (GLUT) and promotes cytoplasmic glycolysis. HIF-1α also stimulates the utilization of glutamine and fatty acids as alternative energy substrates. Cancer cells in the peritoneal cavity interact with cancer-associated fibroblasts and adipocytes to meet metabolic demands and incorporate autophagy products for growth. Therapy of CAS in PM is challenging. Optimal nutritional intake alone including total parenteral nutrition is unable to reverse CAS. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) stabilized nutritional status in a significant proportion of PM patients. Agents targeting the mechanisms of CAS are under development.

In Vivo Feasibility of Electrostatic Precipitation as an Adjunct to Pressurized Intraperitoneal Aerosol Chemotherapy (ePIPAC).

BACKGROUND: Intraperitoneal chemotherapy is limited by tissue penetration. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) has been shown to improve drug uptake by utilizing the physical properties of gas and pressure. This study investigated the effect of adding electrostatic precipitation to further enhance the pharmacologic properties of this technique. METHODS: A comparative study was performed using an in vivo porcine model. There were 3 cases in each group, PIPAC and electrostatic precipitation pressurized intraperitoneal aerosol chemotherapy (ePIPAC), plus 1 negative control comparing intraperitoneal distribution and tissue uptake of 2 tracer substances (toluidine blue and DT01). Tracer uptake was determined by measuring DT01 in tissue and peritoneal fluid at the end of each procedure. RESULTS: Electrostatic precipitation of the aerosol was technically feasible in all ePIPAC animals. The aerosol was cleared completely from the visual field within 15 s in the ePIPAC group versus 30 min in the PIPAC group. The peritoneal surface was homogeneously stained in both groups. After 30 min, 1.5 % remaining DT01 was measured in samples of ePIPAC-treated peritoneal fluid versus 15 % in PIPAC animals (p = 0.01). Tissue concentration was increased after ePIPAC versus PIPAC (p = 0.06). CONCLUSIONS: ePIPAC is technically feasible and improves tissue uptake of 2 tracer substances compared to PIPAC by up to tenfold. Intraperitoneal distribution was homogeneous in both groups. ePIPAC has the potential to allow more efficient drug uptake, further dose reduction, a significant shortening of the time required for PIPAC application, and improved health and safety measures.

Pressurized intraluminal aerosol chemotherapy with Dbait in the distal esophagus of swine.

BACKGROUND AND STUDY AIMS: A novel therapeutic concept, pressurized intraluminal aerosol chemotherapy (PILAC), and a corresponding device for distributing drugs to the mucosa and submucosa of the distal esophagus are presented. MATERIALS AND METHODS: The endoscopic device that was designed consisted of (i) a double-balloon catheter, similar to a Sengstaken-Blakemore tube; (ii) a carbon dioxide (CO2) line, used to create a gaseous, pressurized environment; and (iii) a micropump, used to generate a therapeutic aerosol. The device was inserted into the distal esophagus in three narcotized Landrace pigs. Dbait (short interfering DNA, or siDNA) was aerosolized under pressure (12 mmHg) in CO2 at 37 °C for 30 minutes. RESULTS: The procedure was well tolerated by all animals. At autopsy, no mucosal or muscular tear was observed. Fluorescence microscopy revealed a homogeneous intramural distribution of Dbait-cyanine 5 in the esophageal wall down to the circular muscular layer (400 - 600 µm). CONCLUSIONS: PILAC is feasible in a large animal model and appears to be safe. Therapy of the entire "tissue at risk" for the development of cancer in the distal esophagus is possible without the prior endoscopic identification of diseased tissue.

Pressurized intraperitoneal aerosol chemotherapy in women with recurrent ovarian cancer: A phase 2 study.

OBJECTIVE: Recurrent ovarian, fallopian or peritoneal cancer with peritoneal carcinomatosis (ROCPC) is resistant to systemic chemotherapy. We assessed the safety and activity of laparoscopic pressurized intraperitoneal aerosol chemotherapy (PIPAC) in women with this cancer. METHODS: In this open-label, single-arm phase 2 study, patients underwent 3 courses q 28-42 days of PIPAC with doxorubicin 1·5 mg/m(2) followed by cisplatin 7·5 mg/m(2). A pressure of 12 mm Hg and a temperature of 37 °C were applied for 30 min/course. The primary endpoint was the proportion of patients who had an objective tumor response (OTR) according to RECIST version 1.1 criteria. Analysis was by intention to treat. Secondary endpoints were tumor regression on histology, PC Index improvement on repeated video-laparoscopy, and quality of life measured with the EORTC QLQ-30 questionnaire. RESULTS: Sixty-four patients were enrolled. Laparoscopic non-access rate was 11/64 (17%). 53 patients were eligible for analyses. 33/53 (62%) patients had an OTR - three had a partial response and 30 patients had stable disease. Tumor regression on histology and PC Index improvement were observed in 26/34 (76%) and in 26/34 (76%) patients who underwent all 3 PIPACs. There were no treatment-related deaths. No grade 4 toxicity was observed. Grade 3 toxicities were trocar hernia (n=2), bowel obstruction (n=2), abdominal pain (n=2), hematoma (n=1), intraoperative bleeding (n=1), and cystitis with urosepsis (n=1). EORTC QLQ-30 global physical health scores, nausea/vomiting, appetite loss, diarrhea, and constipation improved during therapy. CONCLUSION: PIPAC is well tolerated and active in women with ROCPC and warrants further investigation in these patients.

Intraperitoneal chemotherapy of peritoneal carcinomatosis using pressurized aerosol as an alternative to liquid solution: first evidence for efficacy.

BACKGROUND: Peritoneal carcinomatosis (PC) is an unmet medical need. Despite recent improvements, systemic chemotherapy has limited efficacy. We report the first application of intraperitoneal chemotherapy as a pressurized aerosol in human patients. METHODS: Three end-stage patients with advanced PC from gastric, appendiceal, and ovarian origin were treated as a compassionate therapy. All patients had received previous systemic chemotherapy. A pressurized aerosol of CO2 loaded with doxorubicin 1.5 mg/m(2) and cisplatin 7.5 mg/m(2) (pressurized intraperitoneal aerosol chemotherapy, PIPAC) was applied into the abdomen for 30 min at a pressure of 12 mmHg and a temperature of 37 °C. RESULTS: No side-effects >2 CTCAE were observed, and the procedures were well tolerated. Early hospital discharge was possible (days 2-5). Nuclear presence of doxorubicin was documented throughout the peritoneum, reaching high local concentration (≤4.1 µmol/g) and plasma concentration was low (4.0-6.2 ng/ml). PIPAC created no significant adhesions, could be repeated, and was applied 6×, 4×, and 2×. Two patients showed a complete and one a partial histological remission. Mean survival after the first PIPAC was 288 days. One patient is alive after 567 days. CONCLUSIONS: PIPAC shows superior pharmacological properties with high local concentration and low systemic exposure. PIPAC can induce regression of PC in chemoresistant tumors, using 10% of a usual systemic dose.

Activity of Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) with cisplatin and doxorubicin in women with recurrent, platinum-resistant ovarian cancer: preliminary clinical experience.

OBJECTIVE: To assess the activity of laparoscopic Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) in women with recurrent, platinum-resistant ovarian cancer. METHODS: Prospective case series using repeated courses q 28-42 days of PIPAC containing cisplatin 7.5 mg/m(2) and doxorubicin 1.5 mg/m(2) at 12 mmHg and 37°C for 30 min. Objective tumor response was defined as tumor regression on histology and peritoneal carcinomatosis index (PCI) improvement on repeated video-laparoscopy. RESULTS: 34 PIPAC procedures were performed in 18 women, in 8 instances combined with cytoreductive surgery (CRS). Eight women had repeated PIPAC and objective tumor response was observed in 6 (complete remission: 1; partial remission: 2; stable disease: 3). Five adverse events WHO grade ≥ 2 were noted, 3 of them after combined CRS. No perioperative mortality occurred. Median follow-up was 192 days (min. 13-max. 639). Cumulative survival after 400 days was 62% and mean actuarial survival time was 442 days. In a multivariable regression analysis with objective tumor response (yes vs. no) as the dependent variable and PIPAC (1 vs.>1), patient age (<75 vs.≥75 years), serum CA-125 (<1000 vs.>1000 U/mL), and the presence of ascites (yes vs. no) as independent variables, PIPAC independently predicted objective tumor response. CONCLUSION: PIPAC has activity in women with recurrent, platinum-resistant ovarian cancer and should be investigated in prospective clinical trials.

Pressurized intraperitoneal chemotherapy (PIPAC) in women with gynecologic malignancies: a review.

OBJECTIVE: The objective of this study was to provide an overview of published and ongoing trials of pressurized intraperitoneal chemotherapy (PIPAC) in ovarian cancer. DESIGN: The study comprised a systematic literature review. RESULTS: We identified 10 studies, including 2 ex vivo and in vitro studies, 6 clinical studies, and 2 ongoing clinical trials using PIPAC in women with recurrent ovarian cancer and pseudomyxoma peritonei. Experimental evidence and clinical study data demonstrate that PIPAC increases peritoneal cavity coverage and depth of peritoneal infiltration, and is technically feasible. Occupational safety has been established. PIPAC has demonstrated antitumor activity based on histological, radiological, and clinical evidence. The toxicity of PIPAC is manageable and restricted to Common Terminology Criteria for Adverse Events grade 2-3 events when used without concomitant cytoreductive surgery. Further clinical trials assessing efficacy and dose escalation are ongoing. CONCLUSIONS: PIPAC is technically feasible, has a safe local and systemic safety profile, and has antitumor activity in women with peritoneal carcinomatosis from recurrent ovarian cancer.

Unveiling spatial complexity in solid tumor immune microenvironments through multiplexed imaging.

Deciphering cellular components and the spatial interaction network of the tumor immune microenvironment (TIME) of solid tumors is pivotal for understanding biologically relevant cross-talks and, ultimately, advancing therapies. Multiplexed tissue imaging provides a powerful tool to elucidate spatial complexity in a holistic manner. We established and cross-validated a comprehensive immunophenotyping panel comprising over 121 markers for multiplexed tissue imaging using MACSima™ imaging cyclic staining (MICS) alongside an end-to-end analysis workflow. Applying this panel and workflow to primary cancer tissues, we characterized tumor heterogeneity, investigated potential therapeutical targets, conducted in-depth profiling of cell types and states, sub-phenotyped T cells within the TIME, and scrutinized cellular neighborhoods of diverse T cell subsets. Our findings highlight the advantage of spatial profiling, revealing immunosuppressive molecular signatures of tumor-associated myeloid cells interacting with neighboring exhausted, PD1high T cells in the TIME of hepatocellular carcinoma (HCC). This study establishes a robust framework for spatial exploration of TIMEs in solid tumors and underscores the potency of multiplexed tissue imaging and ultra-deep cell phenotyping in unraveling clinically relevant tumor components.

Real-World Data on Institutional Implementation of Screening for Mismatch Repair Deficiency and Lynch Syndrome in Endometrial Cancer Patients.

Lynch syndrome is an inherited tumor syndrome caused by a pathogenic germline variant in DNA mismatch repair genes. As the leading cause of hereditary endometrial cancer, international guidelines recommend universal screening in women with endometrial cancer. However, testing for Lynch syndrome is not yet well established in clinical practice. The aim of this study was to evaluate adherence to our Lynch syndrome screening algorithm. A retrospective, single-center cohort study was conducted of all endometrial cancer patients undergoing surgical treatment at the Bern University Hospital, Switzerland, between 2017 and 2022. Adherence to immunohistochemical analysis of mismatch repair status, and, if indicated, to MLH1 promoter hypermethylation and to genetic counseling and testing was assessed. Of all 331 endometrial cancer patients, 102 (30.8%) were mismatch repair-deficient and 3 (0.9%) patients were diagnosed with Lynch syndrome. Overall screening adherence was 78.2%, with a notable improvement over the six years from 61.4% to 90.6%. A major reason for non-adherence was lack of provider recommendation for testing, with advanced patient age as a potential patient risk factor. Simplification of the algorithm through standardized reflex screening was recommended to provide optimal medical care for those affected and to allow for cascading testing of at-risk relatives.

Combined analysis of albumin in situ hybridisation and C reactive protein immunohistochemistry for the diagnosis of intrahepatic cholangiocarcinoma: towards a molecular classification paradigm.

AIMS: Intrahepatic cholangiocarcinoma (iCCA) is a diagnosis of exclusion that can pose a challenge to the pathologist despite thorough clinical workup. Although several immunohistochemical markers have been proposed for iCCA, none of them reached clinical practice. We here assessed the combined usage of two promising diagnostic approaches, albumin in situ hybridisation (Alb-ISH) and C reactive protein (CRP) immunohistochemistry, for distinguishing iCCA from other adenocarcinoma primaries. METHODS: We conducted Alb-ISH and CRP immunohistochemistry in a large European iCCA cohort (n=153) and compared the results with a spectrum of other glandular adenocarcinomas of different origin (n=885). In addition, we correlated expression patterns with clinicopathological information and mutation data. RESULTS: Alb-ISH was highly specific for iCCA (specificity 98.8%) with almost complete negativity in perihilar CCA and only rare positives among other adenocarcinomas (sensitivity 69.5%). CRP identified the vast majority of iCCA cases (sensitivity 84.1%) at a lower specificity of 86.4%. Strikingly, the combination of CRP and Alb-ISH boosted the diagnostic sensitivity to 88.0% while retaining a considerable specificity of 86.1%. Alb-ISH significantly correlated with CRP expression, specific tumour morphologies and small or large duct iCCA subtypes. Neither Alb-ISH nor CRP was associated with iCCA patient survival. 16 of 17 recurrent mutations in either IDH1, IDH2 and FGFR2 affected Alb-ISH positive cases, while the only KRAS mutation corresponded to an Alb-ISH negative case. CONCLUSIONS: In conclusion, we propose a sequential diagnostic approach for iCCA, integrating CRP immunohistochemistry and Alb-ISH. This may improve the accuracy of CCA classification and pave the way towards a molecular-guided CCA classification.

Renal and hepatic toxicities after pressurized intraperitoneal aerosol chemotherapy (PIPAC).

BACKGROUND: Both in animal models and in human patients, pressurized intraperitoneal aerosol chemotherapy (PIPAC) has been shown to improve local bioavailability of chemotherapy in peritoneal nodules, as compared with conventional peritoneal lavage. Pharmacokinetic studies show a low drug concentration in peripheral venous blood. However, hepatic and renal toxicities induced by delivering chemotherapeutic drugs into the abdomen as a pressurized aerosol have not yet been investigated. METHODS: Liver and renal function as well as toxicity parameters were monitored after eight PIPAC applications with doxorubicin (1.5 mg/m(2) body surface) and cisplatin (7.5 mg/m(2) body surface) in three end-stage patients suffering therapy-resistant peritoneal carcinomatosis. PIPAC was repeated at 4-week intervals (three times in two patients, twice in one patient). Peripheral venous blood was collected preoperatively and then daily until the 5th postoperative day, and sent to the hospital's clinical chemistry laboratory. Statistical analysis was performed by analysis of variance (ANOVA). RESULTS: Gamma-glutamyltransferase was significantly elevated (p < 0.05) in the early postoperative phase. Glutamic oxaloacetic transaminase [aspartate aminotransferase], glutamic pyruvic transaminase [alanine aminotransferase], and bilirubin levels were not influenced by the procedure. Quick-test remained normal. Serum creatinine levels were not altered. CONCLUSIONS: Under the above conditions, PIPAC did not induce clinically relevant liver cytotoxicity. Liver metabolism and function were not altered. Renal function remained within the normal range. No cumulative toxicity was observed after repeated PIPAC. PIPAC appears to be associated with very limited hepatic and renal toxicity, which might be a significant advantage over other administration routes.

Pressurized intraperitoneal aerosol chemotherapy (PIPAC): occupational health and safety aspects.

BACKGROUND: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a novel approach for treating peritoneal carcinomatosis. First encouraging results have been obtained in human patients. However, delivering chemotherapy as an aerosol might result in an increased risk of exposure to health care workers, as compared with other administration routes. METHODS: PIPAC was applied in two human patients using chemotherapeutic drugs (doxorubicin and cisplatin), and air contamination levels were measured under real clinical conditions. Air was collected on a cellulose nitrate filter with a flow of 22.5 m(3)/h. To exclude any risk for health care workers, both procedures were remote controlled. Toxicological research of cisplatin was performed according to NIOSH 7300 protocol. Sampling and analysis were performed by an independent certification organization. RESULTS: The following safety measures were implemented: closed abdomen, laminar airflow, controlled aerosol waste, and protection curtain. No cisplatin was detected in the air (detection limit < 0.000009 mg/m(3)) at the working positions of the surgeon and the anesthesiologist under real PIPAC conditions. CONCLUSIONS: For the drugs tested, PIPAC is in compliance with European Community working safety law and regulations. Workplace contamination remains below the tolerance margin. The safety measures and conditions as defined above are sufficient. Further protecting devices, such as particulate (air purifying) masks, are not necessary. PIPAC can be used safely in the clinical setting if the conditions specified above are met. However, a toxicological workplace analysis must be performed to confirm that the procedure as implemented complies with local regulations.

The Role of Additional Staining in the Assessment of the Peritoneal Regression Grading Score (PRGS) in Peritoneal Metastasis of Gastric Origin.

INTRODUCTION: The Peritoneal Regression Grading Score (PRGS) is a 4-tied histologic regression grading score for determining the response of peritoneal metastasis to chemotherapy. Peritoneal biopsies in every abdominal quadrant are recommended. A positive therapy response is defined as a decreasing or stable mean PRGS between 2 therapy cycles. The added value of periodic acid satin (PAS) and Ber-EP4 staining over HE staining for diagnosing PRGS1 (the absence of vital tumor cells) is unclear. MATERIALS AND METHODS: A total of 339 biopsies obtained during 76 laparoscopies in 33 patients with peritoneal metastasis of gastric cancer were analyzed. Biopsies classified as PRGS 1 (no residual tumor, n=95) or indefinite (n=50) were stained with PAS, and remaining indefinite or PRGS1 cases additionally stained with BerEP4. RESULTS: After PAS-staining tumor cells were detected in 28 out of 145 biopsies (19%), the remaining 117 biopsies were immunostained with Ber-EP4. Tumor cells were detected in 22 biopsies (19%). In total, additional staining allowed the detection of residual tumor cells in 50 out of 339 biopsies (15%) and changed the therapy response assessment in 7 out of 33 (21%) patients. CONCLUSIONS: In summary, 25% (24 out of 95) of initially tumor-free samples (PRGS1) showed residual tumor cells after additional staining with PAS and/or BerEp4. Immunohistochemistry provided important additional information (the presence of tumor cells) in 22 of all 339 biopsies (11.2%). Further staining reduced the instances of unclear diagnosis from 50 to 0 and changed the therapy response assessment in 7 out of 33 patients (21%). We recommend additional staining in PRGS1 or unclear cases.

Peritoneal regression grading score (PRGS): first evidence for independent predictive and prognostic significance.

Objectives: The peritoneal regression grading score (PRGS) is a four-tied pathologic score measuring tumor regression in biopsies from patients with peritoneal metastasis (PM) receiving chemotherapy. Methods: This retrospective analysis of a prospective registry (NCT03210298) analyses 97 patients with isolated PM under palliative chemotherapy. We examined the predictive value of the initial PRGS for overall survival (OS) and the prognostic value of PRGS in repeated peritoneal biopsies. Results: The 36 (37.1 %) patients with an initial mean PRGS≤2 had a longer median OS (12.1 months, CI 95 % 7.8-16.4) vs. 8.0 months (CI 95 % 5.1-10.8 months) in 61 (62.9 %) patients with PRGS≥3 (p=0.02) After stratification, the initial PRGS was an independent predictor of OS (Cox-regression, p<0.05). Out of 62 patients receiving≥two chemotherapy cycles, 42 (67.7 %) had a histological response (defined as a lower or stable mean PRGS in successive therapy cycles), and 20 (32.3 %) progressed (defined as an increasing mean PRGS). PRGS response was associated with a longer median OS (14.6 months, CI 5-95 % 6.0-23.2) vs. 6.9 (CI 5-95 % 0.0-15.9) months. PRGS response was prognostic in the univariate analysis (p=0.017). Thus, PRGS had both a predictive and prognostic significance in patients with isolated PM receiving palliative chemotherapy in this patient cohort. Conclusions: This is the first evidence for the independent predictive and prognostic significance of PRGS in PM. These encouraging results need validation in an adequately powered, prospective study.