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.

2022 Peritoneal Surface Oncology Group International Consensus on HIPEC Regimens for Peritoneal Malignancies: Colorectal Cancer.

BACKGROUND: Selected patients with peritoneal metastases of colorectal cancer (PM-CRC) can benefit from potentially curative cytoreductive surgery (CRS) ± hyperthermic intraperitoneal chemotherapy (HIPEC), with a median overall survival (OS) of more than 40 months. OBJECTIVE: The aims of this evidence-based consensus were to define the indications for HIPEC, to select the preferred HIPEC regimens, and to define research priorities regarding the use of HIPEC for PM-CRC. METHODS: The consensus steering committee elaborated and formulated pertinent clinical questions according to the PICO (patient, intervention, comparator, outcome) method and assessed the evidence according to the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) framework. Standardized evidence tables were presented to an international expert panel to reach a consensus (4-point, weak and strong positive/negative) on HIPEC regimens and research priorities through a two-round Delphi process. The consensus was defined as ≥ 50% agreement for the 4-point consensus grading or ≥ 70% for either of the two combinations. RESULTS: Evidence was weak or very weak for 9/10 clinical questions. In total, 70/90 eligible panelists replied to both Delphi rounds (78%), with a consensus for 10/10 questions on HIPEC regimens. There was strong negative consensus concerning the short duration, high-dose oxaliplatin (OX) protocol (55.7%), and a weak positive vote (53.8-64.3%) in favor of mitomycin-C (MMC)-based HIPEC (preferred choice: Dutch protocol: 35 mg/m2, 90 min, three fractions), both for primary cytoreduction and recurrence. Determining the role of HIPEC after CRS was considered the most important research question, regarded as essential by 85.7% of the panelists. Furthermore, over 90% of experts suggest performing HIPEC after primary and secondary CRS for recurrence > 1 year after the index surgery. CONCLUSIONS: Based on the available evidence, despite the negative results of PRODIGE 7, HIPEC could be conditionally recommended to patients with PM-CRC after CRS. While more preclinical and clinical data are eagerly awaited to harmonize the procedure further, the MMC-based Dutch protocol remains the preferred regimen after primary and secondary CRS.

2022 PSOGI Consensus on HIPEC Regimens for Peritoneal Malignancies: Diffuse Malignant Peritoneal Mesothelioma.

BACKGROUND: Diffuse malignant peritoneal mesothelioma (DMPM) is a rare and aggressive primary peritoneal disease, with recommended treatment, in eligible patients, of a combination of complete cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). As treatment is multimodal, there is a wide heterogeneity of HIPEC protocols precluding clear comparisons. Standardization at an international level is required. METHODS: The Peritoneal Surface Oncology Group International (PSOGI) designated a steering committee to produce consensus recommendations for HIPEC regimens, adapted to each etiology. The Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) methodology was used, based on a systematic review focused on main outcomes related to HIPEC regimens in DMPM patients and on the patient, intervention, comparator, and outcome (PICO) method to elaborate main questions. An opinion survey was added. Furthermore, a Delphi process was performed with voting from a panel of international experts. RESULTS: Eleven questions were elaborated, including two for future research requirements and three to assess the HIPEC regimen preference of the panel. The level of evidence underlying questions was globally low. Overall, 75 (86%) and 67 (77%) of the 87 invited experts completed the vote at the first and second round, respectively. HIPEC following complete CRS was strongly supported by 88% of voters with no need to plan comparative studies with CRS alone for 61.2% of voters. Bi-drug regimens appeared to be preferred to mono-drug ones and cisplatin was globally favored. The opinion survey confirmed the combination of cisplatin and doxorubicin as the recommended regimen. CONCLUSION: International consensus confirmed the indication of HIPEC following complete CRS in DMPM patients and recommended cisplatin-doxorubicin as the first-line HIPEC regimen.

The 2022 PSOGI International Consensus on HIPEC Regimens for Peritoneal Malignancies: Methodology.

BACKGROUND: A group of experts from the Peritoneal Surface Oncology Group International (PSOGI) and the BIG-RENAPE group carried out a consensus among surgeons experienced in treating peritoneal malignancies from around the world to derive recommendations on indications of hyperthermic intraperitoneal chemotherapy (HIPEC), choice and details of HIPEC regimens, and areas for future research. This manuscript describes the methodology of achieving this consensus and the degree of participation of experts. METHODS: The Delphi technique was used and the questionnaire comprised three categories: evidence-based recommendations using the GRADE (Grades of Recommendation, Assessment, Development, and Evaluation) system with the PICO (patient, intervention, comparison, and outcome) method, an opinion survey, and research recommendations. A consensus was achieved if any one option had >50% of votes, or positive or negative recommendations combined had > 70% of votes. RESULTS: Of the 145 experts solicited, 71.1% in round I and 72.2% in round II took the survey. Participation was highest among surgeons treating both gastrointestinal and gynecological malignancies. Of 113 questions, after round I, a consensus was achieved for 72 (63.7%) questions, and after the second round, consensus was achieved for another 22 (19.4%) questions, making a total of 94 (83.1%) questions for which a consensus was achieved. CONCLUSION: This consensus was carried out using a thorough review of literature and robust rating of evidence, and included key experts and opinion leaders from across the world. The results could guide clinicians on the use of HIPEC, both in their day-to-day clinical practice and in designing clinical trials.

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.

HIPEC Methodology and Regimens: The Need for an Expert Consensus.

BACKGROUND: Hyperthermic intraperitoneal chemotherapy (HIPEC) is performed with a wide variation in methodology, drugs, and other elements vital to the procedure. Adoption of a limited number of regimens could increase the collective experience of peritoneal oncologists, make comparison between studies more meaningful, and lead to a greater acceptance of results from randomized trials. This study aimed to determine the possibility of standardizing HIPEC methodology and regimens and to identify the best method of performing such a standardization. METHODS: A critical review of preclinical and clinical studies evaluating the pharmacokinetic aspects of different HIPEC drugs and drug regimens, the impact of hyperthermia, and the efficacy of various HIPEC regimens as well as studies comparing different regimens was performed. RESULTS: The preclinical and clinical data were limited, and studies comparing different regimens were scarce. Many of the regimens were neither supported by preclinical rationale or data nor validated by a dose-escalating formal phase 1 trial. All the regimens were based on pharmacokinetic data and did not take chemosensitivity of peritoneal metastases into account. Personalized medicine approaches such as patient-derived tumor organoids could offer a solution to this problem, although clinical validation is likely to be challenging. CONCLUSIONS: Apart from randomized trials, more translational research and phases 1 and 2 studies are needed. While waiting for better preclinical and clinical evidence, the best way to minimize heterogeneity is by an expert consensus that aims to identify and define a limited number of regimens for each indication and primary site. The choice of regimen then can be tailored to the patient profile and its expected toxicity and the methodology according regional factors.

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.

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.

A Pilot Study of the Predictive Potential of Chemosensitivity and Gene Expression Assays Using Circulating Tumour Cells from Patients with Recurrent Ovarian Cancer.

Circulating tumour cells (CTCs) from liquid biopsies are under current investigation in several cancers, including epithelial ovarian cancer (EOC) but face significant drawbacks in terms of non-standardised methodology, low viable cell numbers and accuracy of CTC identification. In this pilot study, we report that chemosensitivity assays using liquid biopsy-derived metastatic EOC CTCs, from 10 patients, nine with stage IIIC and one with stage IV disease, in progression after systemic chemotherapy, submitted for hypoxic isolated abdominal perfusion (HAP), are both feasible and useful in predicting response to therapy. Viable metastatic EOC CTCs (>5 cells/mL for all 10 blood samples), enriched by transient culture and identified by reverse transcription polymerase chain reaction (RT-PCR) and indirect immunofluorescence (IF), were subjected to flow cytometry-based Annexin V-PE assays for chemosensitivity to several chemotherapeutic agents and by RT-PCR for tumour gene expression profiling. Using a cut-off value of >80% cell death, CTC chemosensitivity tests were predictive of patient RECIST 1.1 responses to HAP therapy associated with 100% sensitivity, 50% specificity, 33% positive predictive, 100% negative predictive and 60% accuracy values. We propose that the methodology employed in this study is feasible and has the potential to predict response to therapy, setting the stage for a larger study.

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.

Correction to: 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.

In the original article Massimo Milione's last name was spelled incorrectly. It is correct as reflected here. The original article has also been updated.

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.

Is Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy Justified for Biphasic Variants of Peritoneal Mesothelioma? Outcomes from the Peritoneal Surface Oncology Group International Registry.

BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) has dramatically improved the survival of patients with epithelioid peritoneal mesothelioma. It is unknown if CRS/HIPEC is indicated for the more aggressive biphasic mesothelioma variant. METHODS: A retrospective analysis of the Peritoneal Surface Oncology Group International (PSOGI) registry including data from 33 centers was performed. Survival was reviewed based on mesothelioma type, completion of cytoreduction, and volume of disease. RESULTS: Overall, 484 of 1165 (41.5%) CRS/HIPEC procedures with complete CC0 and CC1 cytoreductions were analyzed; 450 (93%) procedures were performed for epithelioid mesotheliomas, while 34 (7%) were performed for biphasic mesotheliomas. For patients with CC0 resection, 5-year survival was 64.5 and 50.2% (median 7.8 and 6.8 years; p = 0.015) for epithelioid and biphasic mesotheliomas, respectively, while inclusion of CC1 resections in the analysis resulted in inferior 5-year survival of 62.9% and 41.6% (median 7.8 and 2.8 years; p = 0.0012), respectively. Incomplete CC2 resections for biphasic primaries resulted in a median survival of 4.3 months. Univariate analysis of the biphasic cohort indicated Peritoneal Cancer Index (PCI; p = 0.015), CC status of resection (p < 0.0001), and Ki67 (p = 0.04) as predictors of survival. Systemic chemotherapy before (p = 0.55) or after (p = 0.7) CRS/HIPEC did not influence survival. In multivariate analysis, only PCI (p = 0.03) and CC (p = 0.04) remained significant. CONCLUSIONS: Long-term survival is achievable in patients with low-volume biphasic mesothelioma after complete macroscopic cytoreduction. Biphasic peritoneal mesotheliomas should not be considered as an absolute contraindication for CRS/HIPEC if there is low-volume disease and if complete cytoreduction can be achieved.