Impact of Perioperative Systemic Chemotherapy on Survival for Patients Who have Diffuse Malignant Peritoneal Mesothelioma Treated with CRS-HIPEC.

BACKGROUND: The available data on the role of perioperative systemic chemotherapy (SC) for diffuse malignant peritoneal mesothelioma (DMPM) patients undergoing (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is heterogeneous and unstandardized. This study aimed to evaluate the impact of SC on the survival outcomes of DMPM patients undergoing CRS-HIPEC and to identify prognostic factors that affect the decision to administer SC. METHODS: Patients who underwent CRS-HIPEC in the National Cancer Institute Milan (1995-2020) were retrospectively analyzed using propensity score-matching of known covariates. The patients were grouped into three groups: group A (neoadjuvant chemotherapy [NACT] and no-SC), group B (no-SC and adjuvant chemotherapy [ACT]), and group C (NACT and ACT). Overall survival (OS) and progression-free survival (PFS) were calculated using the Kaplan-Meir method, and prognostic factors were calculated using the Cox-regression method. RESULTS: After a median follow-up period of 45 months (95% confidence interval [CI], 6.348-83.652 months) for group A, 115 months (95% CI, 44.379-185.621 months) for group B, and 88 months (95% CI, 3.296-172.704 months) for group C, the study analyzed 154 DMPM patients consisting of matched group A (NACT: 60 + no-SC: 52 = 112), group B (ACT: 38 + no-SC: 38 = 76), and group C (NACT: 31 + ACT: 31 = 62). The patients undergoing ACT had better 5-year OS and PFS than the patients undergoing NACT. In the multivariate analysis, ACT was significantly associated with improved OS by 48% (hazard ratio [HR], 0.52; 95% CI, 0.280-0.965, p = 0.038). For PFS, the association of ACT did not reach statistical significance (HR, 0.531; 95% CI, 0.266-1.058; p = 0.072). CONCLUSION: The optimum treatment sequence for DMPM is CRS-HIPEC followed by adjuvant chemotherapy for high-risk patients. Upfront surgery appears preferable to NACT for patients amenable to complete CRS.

Is Systemic Chemotherapy Useful in Patients Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for Colorectal Peritoneal Metastases? A Propensity-Score Analysis.

PURPOSE: Multimodal treatment of colorectal (CRC) peritoneal metastases (PM) includes systemic chemotherapy (SC) and surgical cytoreduction (CRS), eventually with hyperthermic intraperitoneal chemotherapy (HIPEC), in select patients. Considering lack of clear guidelines, this study was designed to analyze the role of chemotherapy and its timing in patients treated with CRS-HIPEC. METHODS: Data from 13 Italian centers with PM expertise were collected by a collaborative group of the Italian Society of Surgical Oncology (SICO). Clinicopathological variables, SC use, and timing of administration were correlated with overall survival (OS), disease-free survival (DFS), and local (peritoneal) DFS (LDFS) after propensity-score (PS) weighting to reduce confounding factors. RESULTS: A total of 367 patients treated with CRS-HIPEC were included in the propensity-score weighting. Of the total patients, 19.9% did not receive chemotherapy within 6 months of surgery, 32.4% received chemotherapy before surgery (pregroup), 28.9% after (post), and 18.8% received both pre- and post-CRS-HIPEC treatment (peri). SC was preferentially administered to younger (p = 0.02) and node-positive (p = 0.010) patients. Preoperative SC is associated with increased rate of major complications (26.9 vs. 11.3%, p = 0.0009). After PS weighting, there were no differences in OS, DFS, or LDFS (p = 0.56, 0.50, and 0.17) between chemotherapy-treated and untreated patients. Considering SC timing, the post CRS-HIPEC group had a longer DFS and LDFS than the pre-group (median DFS 15.4 vs. 9.8 m, p = 0.003; median LDFS 26.3 vs. 15.8 m, p = 0.026). CONCLUSIONS: In patients with CRC-PM treated with CRS-HIPEC, systemic chemotherapy was not associated with overall survival benefit. The adjuvant schedule was related to prolonged disease-free intervals. Additional, randomized studies are required to clarify the role and timing of systemic chemotherapy in this patient subset.

Correlation of Morphological Appearance of Peritoneal Lesions at Laparotomy and Disease at Pathological Assessment in Patients Undergoing Cytoreductive Surgery for Peritoneal Malignancy: Results of Phase I of the PRECINCT Study in 707 Patients.

BACKGROUND: The PRECINCT (Pattern of peritoneal dissemination and REsponse to systemic Chemotherapy IN Common and uncommon peritoneal Tumors) is a prospective, multicenter, observational study. This report from phase I of PRECINCT outlines variations in recording the surgical peritoneal cancer index (sPCI) at experienced peritoneal malignancy centers and the incidence of pathologically confirmed disease in morphologically different peritoneal lesions (PL). METHODS: The sPCI was recorded in a prespecified format that included the morphological appearance of PL. Six prespecified morphological terms were provided. The surgical and pathological findings were compared. RESULTS: From September 2020 to December 2021, 707 patients were enrolled at 10 centers. The morphological details are routinely recorded at two centers, structure bearing the largest nodule, and exact size of the largest tumor deposit in each region at four centers each. The most common morphological terms used were normal peritoneum in 3091 (45.3%), tumor nodules in 2607 (38.2%) and confluent disease in 786 (11.5%) regions. The incidence of pathologically confirmed disease was significantly higher in 'tumor nodules' with a lesion score of 2/3 compared with a lesion score of 1 (63.1% vs. 31.5%; p < 0.001). In patients receiving neoadjuvant chemotherapy, the incidence of pathologically confirmed disease did not differ significantly from those undergoing upfront surgery [751 (47.7%) and 532 (51.4%) respectively; p = 0.069]. CONCLUSIONS: The sPCI was recorded with heterogeneity at different centers. The incidence of pathologically confirmed disease was 49.2% in 'tumor nodules'. Frozen section could be used more liberally for these lesions to aid clinical decisions. A large-scale study involving pictorial depiction of different morphological appearances and correlation with pathological findings is indicated.

Impact of Previous Abdominal Surgery and Timing of Peritoneal Metastases on Accuracy of Imaging in Predicting the Surgical PCI: A Report From the PRECINCT Study.

BACKGROUND AND AIM: In this report from Phase 1 of the prospective, observational, PRECINCT (Pattern of peritoneal dissemination and REsponse to systemic Chemotherapy IN Common and uncommon peritoneal Tumours) study, a correlation was performed between the radiological PCI (peritoneal cancer index; rPCI) and surgical PCI (sPCI). The impact of timing of peritoneal malignancy (PM) and previous abdominal surgery was also studied. METHODS: The rPCI and sPCI were considered the 'same' if they differed by ≤ 3 points. The agreement was assessed using Bland-Altman analysis and the strength of the agreement was assessed using the concordance correlation coefficient (CCC). The extent of prior surgery was classified according to prior surgical score (PSS). RESULTS: In 707 (79.4%) patients, rPCI and sPCI concurred in 280 (39.6%). In the Bland-Altman analysis, < 40% patients were in the ±3 PCI points limit of acceptable difference. The average difference between the two scores was 4.5 points (95% CI- -5.16 to -3.92). The CCC- was 0.59 for the whole cohort ('moderate' concordance) and was not influenced by imaging modality, timing of PM or PSS. CONCLUSIONS: The rPCI underestimated sPCI by an average of 4.5 points. The role of peritoneal MRI in patients undergoing iterative procedures and the performance of imaging according to sites of recurrence need further evaluation.

The Significance of the Morphological Appearance of Peritoneal Lesions on Imaging in Patients With Peritoneal Malignancies-A Report From Phase 1 of the PRECINCT Study.

BACKGROUND AND AIM: This is a report from Phase 1 of the prospective, observational, PRECINCT (Pattern of peritoneal dissemination and REsponse to systemic Chemotherapy IN Common and uncommon peritoneal Tumours) study, in which we studied the incidence of disease at pathological evaluation in different morphological appearances of peritoneal malignancies (PM) on imaging. METHODS: Radiological findings were captured in a specific format that included a description of the morphological appearance of PM and a correlation performed with pathological findings. RESULTS: In 630 patients enroled at seven centres (September 2022-December 2023), 24 morphological terms were used. Among prespecified terms (N = 8 used in 6350 [92.2%] regions), scalloping was pathologically positive in 93.5%, confluent disease in 78.8%, tumour nodules in 69.6%, thickening in 66.1%, infiltration in 56.3%. Among unspecified appearances (N = 16) for 540 (7.8%) regions, 'enhancement' was positive in 41.5%, micronodules in 65.3% and nodularity in 60.2%. Hierarchal clustering placed gastric cancer and rare tumours together and colorectal cancer, ovarian cancer and peritoneal mesothelioma in one cluster. CONCLUSIONS: The incidence of disease at pathological evaluation for most morphological appearances was high (> 50%). Morphological description should be provided in routine radiology reports. A set of standardized terms with their description should be developed by a consensus among experienced radiologists.

A combinatorial culture strategy to develop pseudomyxoma peritonei organoid models.

BACKGROUND AND OBJECTIVES: Few preclinical models of pseudomyxoma peritonei (PMP) have been developed, probably due to the tumor's low incidence and its peculiar characteristics of slow growth. Therefore, there is a need to develop more refined PMP models that better reflect its characteristics. The aim of the study is to develop a culture strategy to generate organoid models derived from PMP patient samples. METHODS: We followed a strategy based on combinatorial culture conditions that include the different factors essential for PMP growth and that mimic the microenvironment present in the patients. RESULTS: We cultured PMP samples in the presence of the various factors produced by the niche environment of PMP. We obtained 12 PMP organoid models, each of which grows under specific culture conditions. PMP-derived organoids show long-term expansion capacity and reproduce the genetic landscape and histological phenotype of the tumor of origin. CONCLUSION: The organoids we developed faithfully reproduce the key features of PMP disease and will allow us to understand the biology of PMP. With them, we will be able to identify key regulatory networks that support PMP progression, providing a platform for multilevel preclinical testing, identify novel diagnostic biomarkers, and generate novel targets for patient treatments.

Relapse of Pseudomyxoma Peritonei After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: Pattern of Failure, Clinical Management and Outcomes.

INTRODUCTION: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) have dramatically improved pseudomyxoma peritonei (PMP) prognosis, but treatment failures are still a concern. We investigated the pattern of failure, treatment and outcomes of progressing disease. METHODS: A prospective database of 374 PMP patients was reviewed, and 152 patients relapsing after complete CRS/HIPEC were identified. PMP was graded according to the Peritoneal Surface Oncology Group International (PSOGI) classification. Hematogenous metastases and non-regional lymph node involvement were considered as systemic metastases. RESULTS: Median follow-up was 78.3 months (95% confidence interval [CI] 66.7-90.4). PMP relapse involved the peritoneum in 112 patients, pleural cavity in 8, both peritoneum and pleura in 8, systemic sites in 11, and both peritoneum and systemic sites in 13 patients. Systemic metastases involved the lung (n = 14), liver (n = 4), distant nodes (n = 3), bone (n = 2), and both lung and distant nodes (n = 1). Survival after diagnosis of PMP relapse was independently associated with curative versus palliative treatment (hazard ratio [HR] 0.52, 95% CI 0.36-0.75; p = 0.001) and PSOGI histology (HR 1.80, 95% CI 1.19-2.74; p = 0.005), but was not influenced by site of failure (p = 0.444). Ten-year overall survival was 77.5% for 62 patients who had curative-intent surgery for PMP relapse, compared with 83.0% for 192 patients who had no recurrences (p = 0.154) and 26.1% for 90 patients who underwent palliative treatments (p = 0.001). CONCLUSIONS: Relapse after CRS/HIPEC most commonly involves the peritoneum, but pleural recurrences and systemic metastases occur in a small but clinically relevant number of patients. In selected patients, surgical resection of recurrent disease can result in long survival, irrespective of sites of failure.

Microsatellite and RAS/RAF Mutational Status as Prognostic Factors in Colorectal Peritoneal Metastases Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC).

BACKGROUND: Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) leads to prolonged survival for selected patients with colorectal (CRC) peritoneal metastases (PM). This study aimed to analyze the prognostic role of micro-satellite (MS) status and RAS/RAF mutations for patients treated with CRS. METHODS: Data were collected from 13 Italian centers with PM expertise within a collaborative group of the Italian Society of Surgical Oncology. Clinical and pathologic variables and KRAS/NRAS/BRAF mutational and MS status were correlated with overall survival (OS) and disease-free survival (DFS). RESULTS: The study enrolled 437 patients treated with CRS-HIPEC. The median OS was 42.3 months [95% confidence interval (CI), 33.4-51.2 months], and the median DFS was 13.6 months (95% CI, 12.3-14.9 months). The local (peritoneal) DFS was 20.5 months (95% CI, 16.4-24.6 months). In addition to the known clinical factors, KRAS mutations (p = 0.005), BRAF mutations (p = 0.01), and MS status (p = 0.04) were related to survival. The KRAS- and BRAF-mutated patients had a shorter survival than the wild-type (WT) patients (5-year OS, 29.4% and 26.8% vs 51.5%, respectively). The patients with micro-satellite instability (MSI) had a longer survival than the patients with micro-satellite stability (MSS) (5-year OS, 58.3% vs 36.7%). The MSI/WT patients had the best prognosis. The MSS/WT and MSI/mutated patients had similar survivals, whereas the MSS/mutated patients showed the worst prognosis (5-year OS, 70.6%, 48.1%, 23.4%; p = 0.0001). In the multivariable analysis, OS was related to the Peritoneal Cancer Index [hazard ratio (HR), 1.05 per point], completeness of cytoreduction (CC) score (HR, 2.8), N status (HR, 1.6), signet-ring (HR, 2.4), MSI/WT (HR, 0.5), and MSS/WT-MSI/mutation (HR, 0.4). Similar results were obtained for DFS. CONCLUSION: For patients affected by CRC-PM who are eligible for CRS, clinical and pathologic criteria need to be integrated with molecular features (KRAS/BRAF mutation). Micro-satellite status should be strongly considered because MSI confers a survival advantage over MSS, even for mutated patients.

Impact of Previous Gynecologic Surgical Procedures on Outcomes of Non-Gynecologic Peritoneal Malignancies Mimicking Ovarian Cancer: Less Is More?

BACKGROUND: Non-gynecologic rare peritoneal surface malignancies (PSMs) often are misdiagnosed as disseminated ovarian cancer and initially treated by gynecologic surgeons. This study aimed to assess whether these previous maneuvers (i.e., full surgical staging and/or cytoreductive attempts) affect outcomes after the definitive surgery performed in a tertiary center. METHODS: The study reviewed 298 women affected by non-gynecologic PSM who underwent cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) after previous gynecologic surgery. Prior surgery was categorized as limited surgery (pLS: abdominal exploration with biopsy plus adnexectomy and/or appendectomy) or extended surgery (pES: full surgical staging or cytoreductive attempts including hysterectomy with bilateral salpingo-oophorectomy). RESULTS: Of the 298 patients, 143 had pLS and 153 had pES. Morbidity was similar between the groups (P = 0.143), but the pES group had more severe urinary tract injuries (19 vs. 3; P < 0.001), longer operating time (585.9 vs. 506.7; P = 0.027), and more patients needing more than two anastomoses (41 vs. 26; P = 0.033). Age older than 55 years (odds ratio [OR] 2.42; P = 0.009) and number of anastomoses (OR 3.17; P = 0.002) correlated with severe morbidity; pES correlated with urinary tract grades 3 and 4 injuries (OR 7.9; P = 0.001). The 5-year cumulative incidence of locoregional relapse was significantly higher in the pES group (0.41 vs. 0.27; P = 0.012; median follow-up period, 69 months). The multivariate analysis identified a Peritoneal Carcinomatosis Index (PCI) higher than 20 and pES as independent risk factors. CONCLUSION: For women undergoing CRS±HIPEC for non-gynecologic PSM, the risk for locoregional relapse and severe postsurgical urinary tract complications is increased by pES. Therefore, prior full surgical staging or cytoreductive attempts without definitive gynecologic histology should be avoided. Prophylactic ureteral stenting and stricter oncologic follow-up assessment must be considered in this scenario.

Prognostic Impact of Primary Side and RAS/RAF Mutations in a Surgical Series of Colorectal Cancer with Peritoneal Metastases.

BACKGROUND: Selecting patients with colorectal cancer peritoneal metastases (CRC-PMs) for surgery is still a concern. Biological features have the potential to improve prognostic stratification, but their significance in this clinical setting is still unclear. We assessed the prognostic impact of primary side and KRAS/NRAS/BRAF/PIK3CA mutations in patients treated with either cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) or CRS alone. METHODS: We reviewed a prospective database of 152 CRC-PM patients selected to undergo perioperative systemic chemotherapy and CRS with or without HIPEC. Extensive mutational analysis of KRAS, NRAS, BRAF, and PIK3CA was performed by polymerase chain reaction (PCR). In 68 patients, Ion Torrent next-generation sequencing technology was used to characterize the hotspot regions of 50 genes. RESULTS: The primary tumor was right-sided in 61 patients (40.1%) and left-sided in 91 patients (59.9%). Right-sided primaries were associated with mutated KRAS (p = 0.01) and normal carcinoembryonic antigen (CEA; p = 0.03). KRAS was mutated in 71/152 patients (46.7%), NRAS in 7/152 patients (4.6%), BRAF in 10/152 patients (6.6%), PIK3CA in 17/78 patients (25.0%), TP53 in 37/68 patients (54.4%), APC in 25/68 patients (36.7%), SMAD4 in 13/68 patients (19.1%), and FBXW7 in 5/68 patients (7.4%). Median follow-up was 54.9 months and median survival from PM diagnosis was 45.1 months. The right-sided primary (hazard ratio [HR] 1.62, 95% confidence interval [CI] 0.43-0.89; p = 0.011), BRAF mutations (HR 2.21, 95% CI 1.05-4.63; p = 0.038), and Peritoneal Cancer Index (HR 1.47, 95% CI 1.03-2.10; p = 0.036) independently correlated with poorer survival, while APC mutations univariately correlated with better survival (p = 0.03). CONCLUSIONS: BRAF mutations and right-sided primary are adverse prognostic factors that may be used to optimize therapeutic strategies. APC may be involved in CRC-PM development and progression.

Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Gastric Cancer with Synchronous Peritoneal Metastases: Multicenter Study of 'Italian Peritoneal Surface Malignancies Oncoteam-S.I.C.O.'

BACKGROUND: The development of multimodality treatment, including cytoreductive surgery (CRS) with heated intraperitoneal chemotherapy (HIPEC), has led to promising results in selected patients with peritoneal disease of gastric origin. The aim of this study was to investigate the short- and long-term outcomes of CRS/HIPEC in the treatment of synchronous peritoneal metastasis in gastric cancer. METHODS: The Italian Peritoneal Surface Malignancies Oncoteam-S.I.C.O. retrospective registry included patients with synchronous peritoneal malignancy from gastric cancer submitted to gastrectomy with CRS and HIPEC between 2005 and 2018 from 11 high-volume, specialized centers. RESULTS: A total of 91 patients with a median age of 58 years (range 26-75) were enrolled. The median overall survival (OS) time for the whole group of patients was 20.2 months (95% confidence interval [CI] 11.8-28.5] and the median recurrence-free survival (RFS) was 7.3 months (95% CI 4-10.6). The completeness of cytoreduction score (CCS) of 0 and Peritoneal Cancer Index (PCI) score of ≤ 6 groups showed a significantly better long-term survival (median OS 40.7 and 44.3 months, respectively) compared with the incomplete resected groups (median OS 10.7 months, p = 0.003) and PCI score of > 6 group (median OS 13.4 months, p = 0.005). A significant difference was observed in the survival rate according to neoadjuvant treatment (untreated patients: 10.7 months, 95% CI 5.1-16.2; treated patients: 35.3 months, 95% CI 2.8-67.8; p = 0.022). CONCLUSIONS: In referral centers, CRS and HIPEC after neoadjuvant treatment significantly improved survival in selected patients. Patients with a PCI score ≤ 6, complete cytoreduction, negative nodal involvements, and negative cytology had encouraging results, showing a clinically meaningful survival.

Colorectal Peritoneal Metastases Treated by Perioperative Systemic Chemotherapy and Cytoreductive Surgery With or Without Mitomycin C-Based HIPEC: A Comparative Study Using the Peritoneal Surface Disease Severity Score (PSDSS).

BACKGROUND: The Prodige-7 trial has questioned the role of hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of peritoneal metastases from colorectal cancer (CRC-PM). PATIENTS AND METHODS: We compared a prospectively collected group of 48 patients undergoing oxaliplatin/irinotecan-based perioperative systemic chemotherapy (s-CT) with targeted agents, and cytoreductive surgery (CRS) (no-HIPEC group) with 48 controls undergoing the same perioperative s-CT and CRS/HIPEC (HIPEC group). Patients were matched (1:1) according to the Peritoneal Surface Disease Severity Score, completeness of cytoreduction, history of extraperitoneal disease (EPD), and Peritoneal Cancer Index. RESULTS: The groups were comparable, except for a higher number of patients in the HIPEC group with World Health Organization performance status 0, pN2 stage primary tumor, and treated with preoperative s-CT. Forty-one patients in the no-HIPEC group and 43 patients in the HIPEC group had optimal comprehensive treatment (P = 0.759), defined as complete cytoreduction of PM and margin-negative EPD resection. Median follow-up was 31.6 months in the no-HIPEC group and 39.9 months in the HIPEC group. Median overall survival was 39.3 months in the no-HIPEC group and 34.8 months in the HIPEC group (P = 0.702). In the two groups, severe morbidity occurred in 14 (29.2%) and 13 (27.1%) patients, respectively (P = 1.000), with no operative deaths. On multivariate analysis, left-sided primary and curative treatment independently correlated with better survival while HIPEC did not (hazard ratio 0.73; 95% confidence interval 0.47-1.15; P = 0.178). CONCLUSIONS: Our results confirmed that, in selected patients, perioperative s-CT and surgical treatment of CRC-PM resulted in unexpectedly high survival rates. Mitomycin C-based HIPEC did not increase morbidity but did not impact prognosis.

Iterative cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy for colorectal peritoneal metastases: A multi-institutional experience.

BACKGROUND AND OBJECTIVES: The aims of this multi-institutional study were to assess the feasibility of iterative cytoreductive surgery (iCRS)/hyperthermic intraperitoneal chemotherapy, iCRS in colorectal peritoneal carcinomatosis (CRPC), evaluate survival, recurrence, morbidity and mortality outcomes, and identify prognostic factors for overall survival. METHODS: Patients with CRPC that underwent an iCRS, with or without intraperitoneal chemotherapy, from June 1993 to July 2016 at 13 institutions were retrospectively analyzed from prospectively maintained databases. RESULTS: The study comprised of 231 patients, including 126 females (54.5%) with a mean age at iCRS of 51.3 years. The iterative high-grade (3/4) morbidity and mortality rates were 23.4% and 1.7%, respectively. The median recurrence-free survival was 15.0 and 10.1 months after initial and iCRS, respectively. The median and 5-year survivals were 49.1 months and 43% and 26.4 months and 26% from the initial and iCRS, respectively. Independent negative predictors of survival from the initial CRS included peritoneal carcinomatosis index (PCI) > 20 ( P = 0.02) and lymph node positivity ( P = 0.04), and from iCRS, PCI > 10 ( P = 0.03 for PCI 11-20; P < 0.001 for PCI > 20), high-grade complications ( P = 0.012), and incomplete cytoreduction ( P < 0.001). CONCLUSION: iCRS can provide long-term survival benefits to highly selected colorectal peritoneal carcinomatosis patients with comparable mortality and morbidity rates to the initial CRS procedure. Careful patient selection is necessary to improve overall outcomes.

Molecular Signatures for Combined Targeted Treatments in Diffuse Malignant Peritoneal Mesothelioma.

Background-There are currently no effective therapies for diffuse malignant peritoneal mesothelioma (DMPM) patients with disease recurrence. In this study, we investigated the biology of DMPM by analyzing the EGFR family, Axl, and MET, in order to assess the presence of cross-talk between these receptors, suggesting the effectiveness of combined targeted treatments in DMPM. Method-We analyzed a series of 22 naïve epithelioid DMPM samples from a single institute, two of which showed higher-grade malignancy ("progressed"). EGFR, HER2, HER3, Axl, and MET activation and expression were investigated by biochemical analysis, real-time PCR immunofluorescence, immunohistochemistry, next-generation sequencing, miRNA, and mRNA in situ hybridization. Results-In most DMPMs, a strong EGFR activation was associated with HER2, HER3, Axl, and MET co-activation, mediated mainly by receptor heterodimerization and autocrine-paracrine loops induced by the expression of their cognate ligands. Axl expression was downregulated by miRNA34a. Mutations in MET Sema domain were exclusively found in two "progressed" DMPMs, and the combined Axl and MET inhibition reduced cellular motility in a DMPM cell line obtained from a "progressed" DMPM. Conclusion-The results indicate that the coordinated activity of multiple cross-talks between RTKs is directly involved in the biology of DMPM, suggesting the combined inhibition of PIK3 and mTOR as an effective strategy that may be easily implemented in clinical practice, and indicating that the combined inhibition of EGFR/HER2 and HER3 and of Axl and MET deserves further investigation.

Dose-Dependent Effect of Red Blood Cells Transfusion on Perioperative and Long-Term Outcomes in Peritoneal Surface Malignancies Treated with Cytoreduction and HIPEC.

BACKGROUND: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are associated with increased red blood cell transfusion (RBT) demand. Although the deleterious effects of RBT are documented in various settings, its effect in this setting is obscure. In this study, we evaluated the effects of different-grade RBT on the short- and long-term outcomes of CRS and HIPEC. METHODS: We analyzed 231 patients with diffuse malignant peritoneal mesothelioma (DMPM) and 273 patients with pseudomyxoma peritonei (PMP) operated in our unit. RBT was categorized according to the amount of packed red blood cell units (PRBCs) administered (0, 1-2, 3-5, > 6). The effects of RBT on long-term oncological outcomes [progression-free survival (PFS) and overall survival (OS)] were assessed by using multivariate analysis. RESULTS: Overall, 74% of the patients were transfused with a median of 2 PRBCs (range 0-37). Transfusion level correlated with operative time, surgical extent (as measured by the peritoneal carcinomatosis index), and age. Postoperatively, patients with major transfusion (> 6 PRBCs) had increased mortality rate (11.1%, p = 0.01) and length of hospital stay (31.2 ± 16.8 days, p = 0.01) compared with other levels of RBT. RBT was dose-dependently associated with oncological outcomes in both DMPM and PMP for both PFS [hazard ratio (HR) = 1.40, 95% confidence interval (CI) 1.12-1.74, p = 0.003; HR = 1.44, 95% CI 1.15-1.81, p = 0.001, respectively] and OS (HR = 1.57, 95% CI 1.21-2.03, p = 0.001; HR = 1.43, 95% CI 1.15-1.90, p = 0.01, respectively). CONCLUSIONS: Our data show a dose-dependent relationship between RBT and oncological outcomes. Further research to develop transfusion sparing protocols is needed in this extensive surgical procedure.

Validation of the Recent PSOGI Pathological Classification of Pseudomyxoma Peritonei in a Single-Center Series of 265 Patients Treated by Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

BACKGROUND: Controversies still persist regarding the terminology and pathologic classification of appendiceal mucinous neoplasms and associated pseudomyxoma peritonei (PMP). We assessed reproducibility and prognostic significance of the classification recently proposed by the Peritoneal Surface Oncology Group International (PSOGI). METHODS: A prospective database of 265 PMP patients uniformly treated by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) from 1995 to 2017 was reviewed. According to the PSOGI, peritoneal disease was retrospectively classified into three categories: low-grade (LG-PMP), high-grade (HG-PMP), and signet-ring cells (SRC-PMP). Acellular mucin (AC) was classified separately. The extent of peritoneal involvement was quantified by the peritoneal cancer index (PCI). RESULTS: Twenty-six patients were diagnosed with AC (9.8%), 197 with LG-PMP (74.4%), 38 with HG-PMP (14.3%), and 4 with SRC-PMP (1.5%). In the overall series, median follow-up was 65.5 months (95% confidence interval 53.7-78.8) and 10-year overall survival was 62.9% (median 148.7 months). Operative death occurred in 10 patients (3.8%) and major complications occurred in 89 patients (33.6%). Ten-year survival was 89.6% for AC, 63.2% for LG-PMP, 40.1% for HG-PMP, and 0 for SRC-PMP. In a multivariate model, the World Health Organization (WHO) pathological classification independently correlated with survival (p = 0.028). In a separate model, the PSOGI classification did not reach statistical significance (p = 0.149). Completeness of cytoreduction and PCI > 22 correlated with prognosis in both models. CONCLUSIONS: AC and SRC-PMP pathological categories of the PSOGI classification identified two subsets of patients with favorable and exceedingly dismal prognosis, respectively. It remains unclear whether the PSOGI classification might provide better prognostic stratification than the current WHO classification. Further studies in larger prospective series are needed.

Clinical Surveillance After Macroscopically Complete Surgery for Low-Grade Appendiceal Mucinous Neoplasms (LAMN) with or Without Limited Peritoneal Spread: Long-Term Results in a Prospective Series.

BACKGROUND: Low-grade appendiceal mucinous neoplasm (LAMN) is the most common primary lesion of pseudomyxoma peritonei, a disease whose standard treatment is cytoreduction and hyperthermic intraperitoneal chemotherapy. The optimal management of LAMN is not well defined. This study prospectively assessed a clinical surveillance strategy for LAMN with or without limited peritoneal spread. METHODS: During 2003-2017, the study prospectively enrolled 41 patients treated by macroscopically complete surgery for LAMN with or without limited peritoneal spread (pelvis and right lower quadrant). Follow-up assessment included thoracic-abdomino-pelvic computed tomography scan and serum tumor markers scheduled after surgery, then every 6 months for 5 years, and yearly thereafter. All specimens were reviewed by a dedicated pathologist. RESULTS: Appendectomy and five right colectomies were performed for 36 patients. Nine patients also underwent macroscopically complete cytoreduction of mucinous peritoneal disease, and four patients had hysterectomy plus bilateral salphingo-oophorectomy. Appendiceal rupture was evaluable in 38 of the 41 patients, being present in 21 patients (51.2%). Mucin, cells, or both outside the appendix were observed in 24 patients (58.5%). The median follow-up period was 58 months (range 9.3-162 months). The 5-year recurrence-free survival rate was 95.1%. Only two patients experienced peritoneal recurrences (4.9%), respectively 18 and 22 months after appendectomy. Their primary lesions were LAMNs with and without appendix wall rupture or extra-appendiceal mucin, respectively. No death occurred. CONCLUSION: These findings strongly suggest that radically resected LAMN, even with limited peritoneal spread, carries a low recurrence risk. Furthermore, appendix wall perforation and the presence of mucin, cells, or both outside the appendix were not associated with a higher risk of metachronous peritoneal dissemination. In this setting, clinical and radiologic surveillance is a viable choice.