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BackgroundDespite the profound number of malignant pleural mesothelioma (MPM) patients now treated with PD-1 blockade, insight into the underpinnings of rational therapeutic strategies to treat resistance to checkpoint immunotherapy remain unrealized. Our objective was to develop a novel therapeutic approach to overcome primary resistance to PD-1 blockade in MPM.MethodsWe generated a transcriptome signature of resistance to PD-1 blockade in MPM patients treated with nivolumab (4 responders and 4 non-responders). We used the TCGA MPM cohort (N=73) to determine what genomic alterations were associated with the resistance signature. We tested whether regulation of identified molecules could overcome resistance to PD-1 blockade in an immunocompetent mouse malignant mesothelioma model.ResultsImmunogenomic analysis by applying our anti-PD-1 resistance signature to the TCGA cohort revealed that deletion ofCDKN2Awas highly associated with primary resistance to PD-1 blockade. Under the hypothesis that resistance to PD-1 blockade can be overcome byCDK4/6inhibition, we tested whetherCDK4/6inhibitors could overcome resistance to PD-1 blockade in subcutaneous tumors derived fromCdkn2a(−/−)AB1 malignant mesothelioma cells, which were resistant to PD-1 blockade. The combination of daily oral administration ofCDK4/6inhibitors (abemaciclib or palbociclib) and intraperitoneal anti-PD-1 treatment markedly suppressed tumor growth, compared with anti-PD-1 orCDK4/6inhibitor alone.ConclusionsWe identified a novel therapeutic target,CDK4/6, to overcome primary resistance to PD-1 blockade through comprehensive immunogenomic approaches. These data provide a rationale for undertaking clinical trials ofCDK4/6inhibitors in the more than 40% of patients with MPM who demonstrate loss ofCDKN2A.

Background Treatment selection for patients with esophageal adenocarcinoma is predicated on clinical staging information, which is inaccurate in 20% to 30% of cases and could impact the delivery of guideline-concordant treatment. We aimed to evaluate the association between staging concordance at the patient and hospital levels with the delivery of guideline-concordant treatment among esophageal adenocarcinoma patients. Methods This was a national cohort study of resected esophageal adenocarcinoma patients in the National Cancer Data Base (2006 to 2015) treated either with upfront resection or neoadjuvant therapy followed by surgery. Patient- and hospital-level clinical and pathologic staging concordance and deviations from treatment guidelines were ascertained. For neoadjuvant therapy patients, staging concordance was predicted through Bayesian analysis. Reliability adjustment was used when evaluating hospital-level concordance. Results Among 9393 esophageal adenocarcinoma patients treated at 927 hospitals, 41% had upfront surgery. Among upfront surgery patients, staging concordance was 85.1% for T1N0 and 86.9% for T3-T4N+ disease, but less than 50% for all others. Among patients treated with neoadjuvant therapy, treatment downstaging was observed in 33.9%. Deviations from treatment guidelines were identified in 38.5% of upfront surgery patients and 3.3% of neoadjuvant therapy patients. The proportion of concordantly staged patients ranged from 60.1% to 87.9%, and deviations from treatment guidelines were observed among 14.9% to 22.7% of the patients. Patient staging concordance increased, and deviations from guidelines decreased, as hospital-level concordance increased (trend test, P values less than .001 for all). Conclusions Deviations from treatment guidelines in esophageal adenocarcinoma patients appear to be a function of inaccurate clinical staging information, which should be a new focus for quality improvement efforts.

BACKGROUND AND OBJECTIVES: Chemotherapeutic options for patients with recurrent/metastatic adrenocortical carcinoma (ACC) are limited, leading to consideration for surgical management. We sought to determine characteristics associated with an unequivocal survival benefit amongst patients undergoing re-resection or metastasectomy. METHODS: Patients who underwent surgery for recurrent/metastatic ACC were identified and stratified into two groups: those with postoperative survival comparable with what has been reported with chemotherapy alone (24 months). Those who survived between 12 and 24 months were excluded, as the objective was to characterize patients who most distinctly benefited from resection. Clinicopathologic and treatment variables were evaluated for associations with survival. RESULTS: Forty-three patients survived more than 24 months and 15 patients died less than 12 months after reoperation. Tumor stage (odds ratio [OR], 0.66; 95% confidence interval [CI], 0.45–0.96) and disease-free interval (DFI; OR, 3.23; 95% CI, 1.68–6.22) were associated with prolonged survival. Tumor size, hormonal status, resection margin, and treatment with chemotherapy, radiation, and mitotane were not associated with prolonged survival. Patients who survived more than 24 months underwent more procedures for subsequent recurrences (median 4 vs 2; P < .001). CONCLUSION: Stage and DFI can help select optimal candidates for resection of recurrent/metastatic ACC. Patients selected for surgical management should be informed of the likelihood of requiring multiple interventions.

Background The standard of care for colorectal peritoneal carcinomatosis is evolving from chemotherapy to cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) for patients with disease limited to the peritoneum. Peritoneal carcinomatosis from colorectal cancer treated with chemotherapy alone results in median survival of 5 to 13 months, whereas CRS with HIPEC for early peritoneal carcinomatosis from colorectal cancer resulted in median survival of 48-63 months and 5 year survival of 51%. Completeness of cytoreduction and limited disease are associated with longer survival, yet early peritoneal carcinomatosis is undetectable by conventional imaging. Exploratory laparotomy can successfully identify early disease, but this approach can only be justified in patients with high risk of peritoneal carcinomatosis. Historical data indicates that patients presenting with synchronous peritoneal carcinomatosis, ovarian metastases, perforated primary tumor, and emergency presentation with bleeding or obstructing lesions are at high risk of peritoneal carcinomatosis. Approximately 55% of these patient populations will develop peritoneal carcinomatosis. We hypothesize that performing a mandatory second look laparotomy with CRS and HIPEC for patients who are at high risk for developing peritoneal carcinomatosis from colorectal cancer will lead to improved survival as compared to patients who receive standard of care with routine surveillance. Methods/Design This study is a prospective randomized trial designed to answer the question whether mandatory second look surgery with CRS and HIPEC will prolong overall survival compared to the standard of care in patients who are at high risk for developing peritoneal carcinomatosis from colorectal cancer (CRC). Patients with CRC at high risk for developing peritoneal carcinomatosis who underwent curative surgery and subsequently received standard of care adjuvant chemotherapy will be evaluated. The patients who remain without evidence of disease by imaging, physical examination, and tumor markers for 12 months after the primary operation will be randomized to mandatory second look surgery or standard-of-care surveillance. At laparotomy, CRS and HIPEC will be performed with intraperitoneal oxaliplatin with concurrent systemic 5-fluorouracil and leucovorin. Up to 100 patients will be enrolled to allow for 35 evaluable patients in each arm; accrual is expected to last 5 years. Trial Registration ClinicalTrials.gov ID: NCT01095523