The contemporary management of peritoneal metastasis: A journey from the cold past of treatment futility to a warm present and a bright future.

Peritoneal metastasis (PM) is often regarded as a less frequent pattern of spread; however, collectively across all spectra of primary tumors, the consequences of PM impact a large population of patients annually. Unlike other modes of metastasis, symptoms at presentation or during the treatment course are common, representing an additional challenge in the management of PM. Early efforts with chemotherapy and incomplete surgical interventions transiently improved symptoms, but durable symptom control and survival extension were rare, which established a perspective of treatment futility for PM through most of the 20th century. Notably, the continued development of better systemic therapy combinations, optimization of cytoreductive surgery (CRS), and rigorous investigation of combining regional therapy-specifically hyperthermic intraperitoneal chemotherapy-with CRS, have resulted in more effective multimodal treatment options for patients with PM. In this article, the authors provide a comprehensive review of the data establishing the contemporary approach for tumors with a high frequency of PM, including appendix, colorectal, mesothelioma, and gastric cancers. The authors also explore the emerging role of adding hyperthermic intraperitoneal chemotherapy to the well established paradigm of CRS and systemic therapy for advanced ovarian cancer, as well as the recent clinical trials identifying the efficacy of poly(adenosine diphosphate ribose) polymerase maintenance therapy. Finally, recent data are included that explore the role of precision medicine technology in PM management that, in the future, may help further improve patient selection, identify the best systemic therapy regimens, detect actionable mutations, and identify new targets for drug development.

Mesothelioma: Scientific clues for prevention, diagnosis, and therapy.

Mesothelioma affects mostly older individuals who have been occupationally exposed to asbestos. The global mesothelioma incidence and mortality rates are unknown, because data are not available from developing countries that continue to use large amounts of asbestos. The incidence rate of mesothelioma has decreased in Australia, the United States, and Western Europe, where the use of asbestos was banned or strictly regulated in the 1970s and 1980s, demonstrating the value of these preventive measures. However, in these same countries, the overall number of deaths from mesothelioma has not decreased as the size of the population and the percentage of old people have increased. Moreover, hotspots of mesothelioma may occur when carcinogenic fibers that are present in the environment are disturbed as rural areas are being developed. Novel immunohistochemical and molecular markers have improved the accuracy of diagnosis; however, about 14% (high-resource countries) to 50% (developing countries) of mesothelioma diagnoses are incorrect, resulting in inadequate treatment and complicating epidemiological studies. The discovery that germline BRCA1-asssociated protein 1 (BAP1) mutations cause mesothelioma and other cancers (BAP1 cancer syndrome) elucidated some of the key pathogenic mechanisms, and treatments targeting these molecular mechanisms and/or modulating the immune response are being tested. The role of surgery in pleural mesothelioma is controversial as it is difficult to predict who will benefit from aggressive management, even when local therapies are added to existing or novel systemic treatments. Treatment outcomes are improving, however, for peritoneal mesothelioma. Multidisciplinary international collaboration will be necessary to improve prevention, early detection, and treatment.

Extent of Resection and Long-Term Outcomes for Appendiceal Adenocarcinoma: a SEER Database Analysis of Mucinous and non-Mucinous Histologies.

BACKGROUND: Mucinous appendiceal adenocarcinomas (MAA) and non-mucinous appendiceal adenocarcinomas (NMAA) demonstrate differences in rates and patterns of recurrence, which may inform the appropriate extent of surgical resection (i.e., appendectomy versus colectomy). The impact of extent of resection on disease-specific survival (DSS) for each histologic subtype was assessed. PATIENTS AND METHODS: Patients with resected, non-metastatic MAA and NMAA were identified in the Surveillance, Epidemiology, and End Results database (2000-2020). Multivariable models were created to examine predictors of colectomy for each histologic subtype. DSS was calculated using Kaplan-Meier estimates and examined using Cox proportional hazards modeling. RESULTS: Among 4674 patients (MAA: n = 1990, 42.6%; NMAA: n = 2684, 57.4%), the majority (67.8%) underwent colectomy. Among colectomy patients, the rate of nodal positivity increased with higher T-stage (MAA: T1: 4.6%, T2: 4.0%, T3: 17.1%, T4: 21.6%, p < 0.001; NMAA: T1: 6.8%, T2: 11.4%, T3: 25.6%, T4: 43.8%, p < 0.001) and higher tumor grade (MAA: well differentiated: 7.7%, moderately differentiated: 19.2%, and poorly differentiated: 31.3%; NMAA: well differentiated: 9.0%, moderately differentiated: 20.5%, and 44.4%; p < 0.001). Nodal positivity was more frequently observed in NMAA (27.6% versus 16.4%, p < 0.001). Utilization of colectomy was associated with improved DSS for NMAA patients with T2 (log rank p = 0.095) and T3 (log rank p = 0.018) tumors as well as moderately differentiated histology (log rank p = 0.006). Utilization of colectomy was not associated with improved DSS for MAA patients, which was confirmed in a multivariable model for T-stage, grade, and use of adjuvant chemotherapy [hazard ratio (HR) 1.00, 95% confidence interval (CI) 0.81-1.22]. CONCLUSIONS: Colectomy was associated with improved DSS for patients with NMAA but not MAA. Colectomy for MAA may not be required.

Pancreatectomy for intraductal papillary mucinous neoplasm: has anything changed in North America?

BACKGROUND: Multiple guidelines on the management of intraductal papillary mucinous neoplasm (IPMN) have been published over the past decade. However, practice data are lacking. This study aims to determine whether pancreatectomy procedures, IPMN pathology, or outcomes have changed. METHODS: ACS-NSQIP Procedure Targeted Pancreatectomy database was queried for patients with IPMN from 2014 to 2019. Cases were stratified by pathology, tumor stage/cyst size and procedure. Pancreatectomies for IPMN by year, 30-day morbidity, and clinically relevant postoperative pancreatic fistula (CR-POPF) were quantified. Mann-Kendall trend tests were performed to assess surgical trends and associated outcomes over time. RESULTS: 3912 patients underwent pancreatectomy for IPMN. 21% demonstrated malignancy and 79% were benign. Morbidity and mortality occurred in 29.7% and 1.5% of cases, respectively. Over time, no change was observed in use of pancreatectomy for IPMN (10%) or in benign/malignant pathology, or cyst size. Robotic approach increased from 9.1% to 16.5% with decreases in laparoscopic (19.5%-15.0%) and open interventions (71.5%-68.1%, p = 0.016). No change was observed over time in morbidity or mortality; however, rates of CR-POPF decreased (18.8%-13.8%, p < 0.001). CONCLUSIONS: Practice patterns in treatment of IPMN have not changed significantly in North America. More patients are undergoing robotic pancreatectomy, and postoperative pancreatic fistula rates are improving.

Robotic pancreatoduodenectomy: trends in technique and training challenges.

BACKGROUND: More complex cases are being performed robotically. This study aims to characterize trends in robotic pancreatoduodenectomy (RPD) over time and assess opportunities for advanced trainees. METHODS: Using the ACS-NSQIP database from 2014 to 2019, PD cases were characterized by operative approach (open-OPN, laparoscopic-LAP, robotic-ROB). Proficiency and postoperative outcomes were described by approach over time. RESULTS: 24,268 PDs were identified, with the ROB approach increasing from 2.8% to 7.5%. Unplanned conversion increased over time for LAP (27.7-39.0%, p = 0.003) but was unchanged for ROB cases (14.8-14.7%, p = 0.257). Morbidity increased for OPN PD (35.5-36.8%, p = 0.041) and decreased for ROB PD (38.7-30.3%, p = 0.010). Mean LOS was lower in ROB than LAP/OPN (9.5 vs. 10.9 vs. 10.9 days, p < 0.00001). Approximately, 100 AHPBA, SSO, and ASTS fellows are being trained each year in North America; however, only about 5 RPDs are available per trainee per year which is far below that recommended to achieve proficiency. CONCLUSION: Over a 6-year period, a significant increase was observed in the use of RPD without a concomitant increase in conversion rates. RPD was associated with decreased morbidity and length of stay. Despite this shift, the number of cases being performed is not adequate for all fellows to achieve proficiency before graduation.

Expression of PD-L1 in Patients With Malignant Peritoneal Mesothelioma: A Pilot Study.

INTRODUCTION: Frequency of PD-L1 expression and the role of immunotherapy in malignant peritoneal mesothelioma (MPM) have not been well characterized. The purpose of this study was to determine PD-L1 expression in patients with MPM and perform an exploratory analysis for associations between PD-L1 and its biological behavior in MPM. METHODS: Tumor samples were collected from patients undergoing surgical interventions between January 2018 and June 2020. Specimens were stained with anti-PD-L1 antibodies (Dako 22c3) and positivity was determined by tumor proportion score (TPS) or combined positive score (CPS) being ≥1%. RESULTS: Twenty one samples were obtained from 21 patients. Sixteen of 21 (76%) samples were CPS positive and 9 of 21 (43%) were TPS positive. Three samples had more aggressive biphasic/sarcomatoid histology and a high CPS and TPS (CPS: 3, 75, 95%; TPS: 2, 60, 90%). On an exploratory analysis, as the CPS or TPS threshold increased, there was a trend towards worse survival. CONCLUSIONS: MPM has a high frequency of PD-L1 expression, which may be associated with more aggressive tumor biology. These data provide the foundation for continued evaluation of checkpoint inhibition in patients with MPM.

Desmoid-type fibromatosis in the setting of malignant peritoneal mesothelioma: a case report of two rare diseases.

BACKGROUND: Desmoid-type fibromatosis (DTF) is a rare benign lesion that usually arises from the abdominal wall or extremities and rarely from the mesentery or intrabdominal organs. Malignant peritoneal mesothelioma is also a rare, yet aggressive disease. To our knowledge, this is the first case report of desmoid-type fibromatosis in the setting of malignant peritoneal mesothelioma. CASE PRESENTATION: An early 30-year-old female was referred to our center for large intra-abdominal mass concerning for recurrent malignant peritoneal mesothelioma after previous cytoreductive surgery with hyperthermic intraperitoneal chemotherapy and adjuvant chemotherapy. Further investigation revealed a large mesenteric mass, which was resected en bloc with the cecum and terminal ileum. Pathologic findings confirmed a surprising diagnosis of desmoid-type fibromatosis. CONCLUSIONS: No adjuvant therapy was offered to this patient due to negative tumor margins; however, close follow-up will be provided for recurrence of both malignant peritoneal mesothelioma and desmoid-type fibromatosis, which can be differentiated in the future via biopsy in this patient.

NO• /RUNX3/kynurenine metabolic signaling enhances disease aggressiveness in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy and is refractory to available treatments. Delineating the regulatory mechanisms of metabolic reprogramming, a key event in pancreatic cancer progression, may identify candidate targets with potential therapeutic significance. We hypothesized that inflammatory signaling pathways regulate metabolic adaptations in pancreatic cancer. Metabolic profiling of tumors from PDAC patients with a high- (>median, n = 31) and low-NOS2 (inducible nitric oxide synthase;

Outcomes Following Major Oncologic Operations for Non-AIDS-Defining Cancers in the HIV Population: A Matched Comparison to the General Population.

INTRODUCTION: Human immunodeficiency virus (HIV) patients are living longer due to the availability of antiretroviral therapies, and non-AIDS-defining cancers are becoming more prevalent in this patient population. A paucity of data remains on post-operative outcomes following resection of non-AIDS-defining cancers in the HIV population. METHODS: The National Inpatient Sample was utilized to identify patients who underwent surgical resection for malignancy from 2005 to 2015 (HIV, N = 52,742; non-HIV, N = 11,885,184). Complications were categorized by international classification of disease (ICD)-9 diagnosis codes. Cohorts were matched on insurance, household income, zip code and urban/rural setting. Logistic regression assessed whether HIV was an independent predictor of post-operative complications. RESULTS: Descriptive statistics found HIV patients to have an increased rate of complications following select oncologic surgical resections. Univariate and multivariate logistic regression found HIV to only be an independent predictor of complications following pulmonary lobectomy (p = 0.011; OR 2.93, 95% CI 1.29-6.73). Length of stay was statistically longer following colectomy (2.61 days, 95% CI 1.98-3.44) in those with HIV. CONCLUSIONS: Our findings are hypothesis generating and highlight the potential safety of major cancer surgery in the HIV population. However, care providers need be cognizant of the potential increased risk of post-operative complications following pulmonary lobectomy and the potential for increased length of stay. These findings are an initial insight into quality of care and outcomes metrics on HIV patients undergoing major cancer operations.

Prospective Evaluation of Results of Reoperation in Zollinger-Ellison Syndrome.

OBJECTIVE: To determine the role of reoperation in patients with persistent or recurrent Zollinger-Ellison Syndrome (ZES). BACKGROUND: Approximately, 0% to 60% of ZES patients are disease-free (DF) after an initial operation, but the tumor may recur. METHODS: A prospective database was queried. RESULTS: A total of 223 patients had an initial operation for possible cure of ZES and then were subsequently evaluated serially with cross sectional imaging-computed tomography, magnetic resonance imaging, ultrasound, more recently octreoscan-and functional studies for ZES activity. The mean age at first surgery was 49 years and with an 11-year mean follow-up 52 patients (23%) underwent reoperation when ZES recurred with imageable disease. Results in this group are analyzed in the current report. Reoperation occurred on a mean of 6 years after the initial surgery with a mean number of reoperations of 1 (range 1-5). After reoperation 18/52 patients were initially DF (35%); and after a mean follow-up of 8 years, 13/52 remained DF (25%). During follow-up, 9/52 reoperated patients (17%) died, of whom 7 patients died a disease-related death (13%). The overall survival from first surgery was 84% at 20 years and 68% at 30 years. Multiple endocrine neoplasia type 1 status did not affect survival, but DF interval and liver metastases did. CONCLUSIONS: These results demonstrate that a significant proportion of patients with ZES will develop resectable persistent or recurrent disease after an initial operation. These patients generally have prolonged survival after reoperation and 25% can be cured with repeat surgery, suggesting all ZES patients postresection should have systematic imaging, and if tumor recurs, advise repeat operation.

Current Management and Future Opportunities for Peritoneal Metastases: Peritoneal Mesothelioma.

PURPOSE: Diffuse malignant peritoneal mesothelioma (MPM) is a rare and ultimately fatal cancer that was first described just over a century ago. It is a diffuse malignancy arising from the mesothelial lining of the peritoneum; morbidity and mortality from MPM is due to its propensity to progress locoregionally within the abdominal cavity. METHODS: The purpose of this article is to review the current state-of-the-science related to the diagnosis, staging, and treatment of MPM. RESULTS: The condition afflicts men and women equally and the peak incidence is between 55 and 60 years of age although it can arise in the young and elderly. Patients afflicted with MPM most commonly present with nonspecific abdominal symptoms that usually lead to diagnosis when the condition is relatively advanced. Historically, median overall survival for MPM patients without treatment is < 1 year. The couplet of systemic pemetrexed and cisplatin has an overall response rate of approximately 25% and a median overall survival of approximately 1 year. CONCLUSION: The available data, almost all retrospective in nature, have shown that in selected patients, operative cytoreduction (CRS) and regional chemotherapy administered as hyperthermic intraoperative peritoneal chemotherapy (HIPEC) or early postoperative intraperitoneal chemotherapy (EPIC) is associated with long-term survival. Studies on the molecular biology of MPM have yielded new insights relating to the potentially important role of the phosphoinsitide-3-kinase/mammalian target of rapamycin (PI3 K/mTOR) pathways and immune checkpoint inhibitors that may translate into new therapeutic options for patients with diffuse MPM.

Current management strategies for peritoneal mesothelioma.

Mesothelioma of the peritoneum is a distinct entity that requires multidisciplinary care to improve oncological outcomes. In this article, we review the current management strategies discussed at the PSOGI meeting in Washington DC 2016 and provide evidence based recommendations for diagnosis and management of this disease.

Results of a Randomized Controlled Multicenter Phase III Trial of Percutaneous Hepatic Perfusion Compared with Best Available Care for Patients with Melanoma Liver Metastases.

PURPOSE: There is no consensus for the treatment of melanoma metastatic to the liver. Percutaneous hepatic perfusion with melphalan (PHP-Mel) is a method of delivering regional chemotherapy selectively to the liver. In this study, we report the results of a multicenter, randomized controlled trial comparing PHP-Mel with best alternative care (BAC) for patients with ocular or cutaneous melanoma metastatic to the liver. PATIENTS AND METHODS: A total of 93 patients were randomized to PHP-Mel (n = 44) or BAC (n = 49). On the PHP-Mel arm, melphalan was delivered via the hepatic artery, and the hepatic effluent captured and filtered extracorporeally prior to return to the systemic circulation via a venovenous bypass circuit. PHP-Mel was repeatable every 4-8 weeks. The primary endpoint was hepatic progression-free survival (hPFS), and secondary endpoints included overall PFS (oPFS), overall survival (OS), hepatic objective response (hOR), and safety. RESULTS: hPFS was 7.0 months for PHP-Mel and 1.6 months for BAC (p < 0.0001), while oPFS was 5.4 months for PHP-Mel and 1.6 months for BAC (p < 0.0001). Median OS was not significantly different (PHP-Mel 10.6 months vs. BAC 10.0 months), likely due to crossover to PHP-Mel treatment (57.1 %) from the BAC arm, and the hOR was 36.4 % for PHP-Mel and 2.0 % for BAC (p < 0.001). The majority of adverse events were related to bone marrow suppression. Four deaths were attributed to PHP-Mel, three in the primary PHP-Mel group, and one post-crossover to PHP-Mel from BAC. CONCLUSION: This randomized, phase III study demonstrated the efficacy of the PHP-Mel procedure. hPFS, oPFS, and hOR were significantly improved with PHP-Mel. PHP with melphalan should provide a new treatment option for unresectable metastatic melanoma in the liver.

Low neighborhood socioeconomic status is associated with poor outcomes in young adults with colorectal cancer.

BACKGROUND: The incidence of early-onset colorectal cancer has increased markedly over the past decade. Although established for older adults, there are limited data on socioeconomic and racial disparities in screening, treatment, and outcomes in this distinct group. METHODS: Adults with primary colorectal cancer diagnosed at age <50 were identified from the Surveillance, Epidemiology, and End Results database. The exposure of interest was neighborhood socioeconomic status based on the Yost Index, a census-tract level composite score of neighborhood economic health. Univariate analysis was performed with χ2 analyses. Logistic regression models were created to evaluate the association of neighborhood socioeconomic status (Yost Index quintile) with metastasis at presentation and surgical intervention. Kaplan-Meier and Cox proportional hazards models were created. RESULTS: In total, 45,660 early-onset colorectal cancer patients were identified; 16.8% (7,679) were in the lowest quintile of neighborhood socioeconomic status. Patients with the lowest neighborhood socioeconomic status were 1.13 times (95% confidence interval 1.06-1.21) more likely to present with metastases and had lower survival (hazard ratio 1.45, 95% confidence interval 1.37-1.53) compared to those with the highest neighborhood socioeconomic status. Non-Hispanic Black patients were more likely to present with metastatic disease (odds ratio 1.11, 95% confidence interval 1.05-1.19), less likely to undergo surgery for localized or regional disease (odds ratio 0.48, 95% confidence interval 0.43-0.53), and had lower survival (hazard ratio 1.21, 95% confidence interval 1.15-1.27) than non-Hispanic White patients. CONCLUSION: Socioeconomic and racial disparities in early-onset colorectal cancer span diagnosis, treatment, and survival. As the disease burden of early-age onset colorectal cancer increases, interventions to boost early diagnosis and access to surgery are necessary to improve survival among minorities and patients with low neighborhood socioeconomic status.