Impact of Referral Center Pathology Review on Diagnosis and Management of Patients With Appendiceal Neoplasms.

CONTEXT.­: Data regarding the clinical impact of subspecialist pathology review of appendiceal neoplasms are limited. OBJECTIVE.­: To determine whether pathology review by gastrointestinal pathologists at a tertiary-care referral center resulted in significant changes in the diagnosis and clinical management of appendiceal neoplastic lesions. DESIGN.­: We conducted a retrospective review of all patients with an initial diagnosis of appendiceal neoplasm referred to a tertiary-care referral center in Ontario, Canada, from 2010-2016. The discordance rate between original and review pathology reports, the nature of discordances, and the impact of any discordance on patient management were recorded. RESULTS.­: A total of 145 patients with appendiceal lesions were identified (low-grade mucinous appendiceal neoplasm [n = 79], invasive mucinous adenocarcinoma [n = 12], "colorectal type" adenocarcinoma [n = 12], goblet cell carcinoid and adenocarcinomas ex goblet cell carcinoid [n = 24], and other lesions/neoplasms [n = 20]). One or more changes in diagnoses were found in 36 of 145 cases (24.8%), with changes within the same category of interpretation (n = 10), stage (n = 7), grade (n = 6), and categoric interpretation (n = 5) being the most common. In 10 of 36 patients (28%), the diagnostic change led to a significant change in management, including recommendation for additional surveillance, systemic chemotherapy, additional surgery, or discontinuation of surveillance. CONCLUSIONS.­: Subspecialist pathology review of appendiceal neoplastic lesions led to a change in diagnosis in 36 of 145 cases (24.8%), of which nearly 30% (10 of 36 cases) led to a change in clinical management. The overall rate of clinically significant discordances was 7% (10 of 145). Our findings suggest that subspecialist pathology review of appendiceal neoplasms referred to specialized centers is justified.

Evidence-Based Strategies for the Treatment of Peritoneal Malignancies during Health Care Resource Restriction: The COVID-19 Pandemic.

Background: The COVID-19 pandemic has put enormous pressure on hospital resources, and has affected all aspects of patient care. As operative volumes decrease, cancer surgeries must be triaged and prioritized with careful thought and attention to ensure maximal benefit for the maximum number of patients. Peritoneal malignancies present a unique challenge, as surgical management can be resource intensive, but patients have limited non-surgical treatment options. This review summarizes current data on outcomes and resource utilization to help inform decision-making and case prioritization in times of constrained health care resources. Methods: A rapid literature review was performed, examining surgical and non-surgical outcomes data for peritoneal malignancies. Narrative data synthesis was cross-referenced with relevant societal guidelines. Peritoneal malignancy surgeons and medical oncologists reviewed recommendations to establish a national perspective on case triage and mitigating treatment strategies. Results and Conclusions: Triage of peritoneal malignancies during this time of restricted health care resource is nuanced and requires multidisciplinary discussion with consideration of individual patient factors. Prioritization should be given to patients where delay may compromise resectability of disease, and where alternative treatment options are lacking. Mitigating strategies such as systemic chemotherapy and/or surgical deferral may be utilized with close surveillance for disease stability or progression, which may affect surgical urgency. Unique hospital capacity, and ability to manage the complex post-operative course for these patients must also be considered to ensure patient and system needs are aligned.

BAP1 haploinsufficiency predicts a distinct immunogenic class of malignant peritoneal mesothelioma.

BACKGROUND: Malignant peritoneal mesothelioma (PeM) is a rare and fatal cancer that originates from the peritoneal lining of the abdomen. Standard treatment of PeM is limited to cytoreductive surgery and/or chemotherapy, and no effective targeted therapies for PeM exist. Some immune checkpoint inhibitor studies of mesothelioma have found positivity to be associated with a worse prognosis. METHODS: To search for novel therapeutic targets for PeM, we performed a comprehensive integrative multi-omics analysis of the genome, transcriptome, and proteome of 19 treatment-naïve PeM, and in particular, we examined BAP1 mutation and copy number status and its relationship to immune checkpoint inhibitor activation. RESULTS: We found that PeM could be divided into tumors with an inflammatory tumor microenvironment and those without and that this distinction correlated with haploinsufficiency of BAP1. To further investigate the role of BAP1, we used our recently developed cancer driver gene prioritization algorithm, HIT'nDRIVE, and observed that PeM with BAP1 haploinsufficiency form a distinct molecular subtype characterized by distinct gene expression patterns of chromatin remodeling, DNA repair pathways, and immune checkpoint receptor activation. We demonstrate that this subtype is correlated with an inflammatory tumor microenvironment and thus is a candidate for immune checkpoint blockade therapies. CONCLUSIONS: Our findings reveal BAP1 to be a potential, easily trackable prognostic and predictive biomarker for PeM immunotherapy that refines PeM disease classification. BAP1 stratification may improve drug response rates in ongoing phases I and II clinical trials exploring the use of immune checkpoint blockade therapies in PeM in which BAP1 status is not considered. This integrated molecular characterization provides a comprehensive foundation for improved management of a subset of PeM patients.

In Situ Vaccination after Accelerated Hypofractionated Radiation and Surgery in a Mesothelioma Mouse Model.

Purpose: How best to sequence and integrate immunotherapy into standard of care is currently unknown. Clinical protocols with accelerated nonablative hypofractionated radiation followed by surgery could provide an opportunity to implement immune checkpoint blockade.Experimental Design: We therefore assessed the impact of nonablative hypofractionated radiation on the immune system in combination with surgery in a mouse mesothelioma model. Blunt surgery (R1 resection) was used to analyze the short-term effect, and radical surgery (R0 resection) was used to analyze the long-term effect of this radiation protocol before surgery.Results: Nonablative hypofractionated radiation led to a specific immune activation against the tumor associated with significant upregulation of CD8+ T cells, limiting the negative effect of an incomplete resection. The same radiation protocol performed 7 days before radical surgery led to a long-term antitumor immune protection that was primarily driven by CD4+ T cells. Radical surgery alone or with a short course of nonablative radiation completed 24 hours before radical surgery did not provide this vaccination effect. Combining this radiation protocol with CTLA-4 blockade provided better results than radiation alone. The effect of PD-1 or PD-L1 blockade with this radiation protocol was less effective than the combination with CTLA-4 blockade.Conclusions: A specific activation of the immune system against the tumor contributes to the benefit of accelerated, hypofractionated radiation before surgery. Nonablative hypofractionated radiation combined with surgery provides an opportunity to introduce immune checkpoint blockades in the clinical setting. Clin Cancer Res; 23(18); 5502-13. ©2017 AACR.

Mucinous tumor of the appendix with limited peritoneal spread: is there a role for expectant observation?

BACKGROUND: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is now the standard management for mucinous tumors of appendiceal origin at many centers. We examined the role of expectant observation (EO) in patients who had undergone an initial resection at the time of referral to our center and who had limited residual disease. METHODS: We performed a retrospective review of patients referred to Mount Sinai/Princess Margaret Hospitals, Toronto, for consideration of surgical management of peritoneal malignancy between January 1998 and December 2009. One hundred and three patients with primary mucinous appendiceal malignancy were identified. EO, consisting of regularly scheduled imaging and clinical review, was selected for asymptomatic patients with low-grade tumor and no/limited disease on imaging. Overall survival (OS) and progression-free survival (PFS) were determined. RESULTS: Management consisted of supportive care in 7 patients, systemic chemotherapy in 7, referral for CRS with HIPEC in 8, CRS without HIPEC at our center in 51, and EO in 30. In the CRS group, 5-year OS was 74 % and PFS was 56 %; both OS and PFS were predicted by extent of residual disease after cytoreduction (p = 0.014 and p = 0.011, respectively). In the EO group, 5-year OS and PFS were 95 and 82 %, respectively. Two patients in the EO group subsequently underwent CRS for progression on imaging. CONCLUSIONS: In well-selected patients who have undergone initial resection for low-grade mucinous tumor of the appendix with limited peritoneal spread, a formal program of observation can result in excellent 5-year OS and PFS. Longer-term follow-up will help define the benefits and risks of this approach.