Platinum-Based Treatment for Well- and Poorly Differentiated Pancreatic Neuroendocrine Neoplasms.

OBJECTIVES: Pancreatic neuroendocrine neoplasms include well-differentiated tumors (PanNETs) and poorly differentiated carcinomas (PanNECs). Previous reports suggested a role for platinum-based therapy largely in PanNEC. We sought to investigate the role of platinum-based therapy in pancreatic neuroendocrine neoplasms regardless of tumor grade and differentiation. METHODS: Patients with pancreatic neuroendocrine neoplasms treated with platinum-based therapy at Memorial Sloan Kettering (1994-2016) and Verona University Hospital (2008-2016) were retrospectively identified. Response to treatment by RECIST v1.1, overall survival, and progression-free survival were defined. Among patients with available tissue, DAXX, ATRX, Rb, and p53 expression was evaluated to support the histologic grade of differentiation. RESULTS: Fifty PanNETs, 29 PanNECs, and 22 high-grade tumors with undeterminable differentiation were included. No patients achieved complete response. Overall rate of partial response was 31%, 41% for PanNEC, and 20% for PanNETs. Among PanNETs, partial response was achieved in 33% of G1 (2/6), 10% of G2 (2/19), and 24% of G3 (6/25) tumors. Median overall survival was 29.3 months for PanNETs and 10.9 months for PanNEC (P < 0.001). There was no significant difference in median progression-free survival (P = 0.2). CONCLUSIONS: Platinum-based therapies demonstrated increased activity in PanNEC; however, promising efficacy was also observed in PanNETs, irrespective of grade.

Myositis and myasthenia during nivolumab administration for advanced lung cancer: a case report and review of the literature.

The immunotherapy significantly improved survival of non-small cell lung cancer patients, but it may cause immune-related adverse events, which are severe in less than 10% of cases. We report the case of one patient who developed myositis and myasthenia during nivolumab treatment for metastatic lung squamous carcinoma. Moreover, we reviewed literature data in order to identify similar cases in cancer patients treated with immune-checkpoints inhibitors. A 65-year-old patient, who had previously received a first-line platinum-based therapy, developed diplopia and ptosis 4 weeks after the start of nivolumab. Although antibodies associated with myositis, myasthenia gravis and paraneoplastic syndromes were absent, immune-related myositis and myasthenia were diagnosed. Corticosteroids, immunoglobulin and pyridostigmine showed poor efficacy and the patient died 7 weeks after the appearance of the first symptoms. Fifteen similar cases were found in the literature. A close collaboration between different specialists is essential to rapidly identify and treat severe immune-related adverse events.

Adjuvant chemotherapy in resected bile duct cancer: A systematic review and meta-analysis of randomized trials.

BACKGROUND: The role of adjuvant chemotherapy (ACT) for resected biliary tract cancer (BTC) is still unclear and there is no specific recommendation by international guidelines. AIM: To perform a meta-analysis of randomized clinical trials (RCTs) to better define the clinical benefit and risks of ACT or observation in resected BTC. METHOD: A systematic literature search of Pubmed, Embase, and the Cochrane Library was performed up to April 2019. A meta-analysis was carried out using the random effects model. RESULTS: ACT provided a mild improvement in recurrence free survival (RFS) (HR:0.83, 95%CI 0.69-0.99) and no effect on overall survival (OS) (HR:0.91, 95%CI 0.75-1.09). Similarly, ACT showed no effect on OS in lymph-node positive subgroup (HR:0.84, 95% CI 0.65-1.08) and surgical margin positive subgroup (HR:0.95, 95%CI 0.69-1.31). Moreover, ACT led to a substantial increase of chemotherapy-associated adverse events (RR:3.03, 95%CI 2.22-4.15). CONCLUSION: ACT for resected BTC patients modestly improved RFS with no effect on OS and a substantial increase in chemotherapy associated AEs.

The development of PARP as a successful target for cancer therapy.

INTRODUCTION: PARP1 and BRCA genes are essential genome caretakers and their interaction has been the first example of synthetic lethality, a genetic concept proposed in the early 20th century, but deeply explored in cancer patients only in the last decade. Areas covered: This review describes PARP1 and BRCA main functions and different roles in genome protection. Furthermore, an overview of the principle mechanisms of action and resistance to PARP inhibitors (PARPi) is presented. This review illustrates the concept of BRCAness, and how this discovery has broadened the routes of PARPi to several different malignancies such as ovarian, breast and prostate cancer. Finally, an insight is provided into the key data of PARPi in these distinctive clinical settings. Expert commentary: PARP inhibition could be a new therapeutic option for a number of tumors in the near future. However, several aspects will be of paramount interest for future investigations, including the molecular bases for PARPi synthetic lethality, the DNA repair independent functions of PARP and BRCA genes, the resistance and biomarkers of response to PARP inhibition, and the mechanisms of interaction between PARPi and antiangiogenic or immunotherapeutic agents.

Pathogenesis, clinical manifestations and management of immune checkpoint inhibitors toxicity.

Immune checkpoint inhibitors have emerged as an effective treatment for several tumor types and their use in clinical practice is expected to further increase in the immediate future. Although these agents are well tolerated, they are associated with a peculiar spectrum of toxicity, which is immune mediated and may potentially affect every organ. However, immune-related adverse events are mostly reversible if promptly diagnosed and adequately treated. Therefore, it is crucial that medical oncologists know how to diagnose and treat immune-related adverse events. This review focuses on the pathogenesis, clinical manifestations and management of immune-related toxicity of anti-CTLA-4 and anti-PD-1 antibodies.

Perfusion CT Changes in Liver Metastases from Pancreatic Neuroendocrine Tumors During Everolimus Treatment.

AIM: To evaluate modifications of perfusional parameters assessed by perfusion computed tomography (P-CT) of liver metastases (LM) from pancreatic neuroendocrine tumors (PanNETs) during everolimus treatment. PATIENTS AND METHODS: All patients with LMs from G1-2 PanNETs undergoing everolimus treatment between January 2013 and January 2015 were prospectively evaluated with P-CT at baseline, and after 2 and 4 months of therapy. Size, perfusion, blood volume (BV), peak enhancement intensity (PEI) and time to peak for each lesion were calculated. RESULTS: A total of 33 LMs in nine patients with G1-2 PanNETs were prospectively evaluated: 23/33 (69.7%) were responders, 10/33 (30.3%) were non-responders. Among perfusional parameters, only numerical peak enhancement intensity values significantly differed between the two groups at baseline (p=0.043). BV increase was the most significant perfusional modification identifying responding lesions, even at an early stage of treatment, with a high positive predictive value (89.47%). CONCLUSION: P-CT seems to be useful for prediction of response to everolimus of LMs from PanNETs.

Role of Combined 68Ga-DOTATOC and 18F-FDG Positron Emission Tomography/Computed Tomography in the Diagnostic Workup of Pancreas Neuroendocrine Tumors: Implications for Managing Surgical Decisions.

OBJECTIVES: Ga-DOTATOC (Ga) positron emission tomography (PET)/computed tomography (CT) is recommended in the workup of pancreas neuroendocrine tumors (PanNETs); evidence suggests that F-FDG (F) PET/CT can also provide prognostic information. Aims of this study were to assess the role of combined Ga- and F-PET/CT in the evaluation of grade (G) 1-2 PanNETs and to test the correlation between F-PET/CT positivity and tumor grade. METHODS: Preoperative Ga- and F-PET/CT of 35 patients with surgically resected G1-2 PanNETs were evaluated. For grading, the 2010 World Health Organization Classification was used; an ancillary analysis with Ki67 cutoffs at 5% to 20% was conducted. Correlation between F-PET/CT positivity (SUVmax > 3.5) and grade was assessed. RESULTS: Of 35 PanNETs, 28.6% and 71.4% were G1 and G2 as per World Health Organization. Ga-PET/CT showed high sensitivity (94.3%) in detecting G1-2 PanNETs. F-PET/CT was positive in 20% and 76% G1 and G2 tumors (P = 0.002). F-PET/CT identified G2 PanNETs with high positive predictive value (PPV, 90.5%). F-PET/CT correlated with tumor grade also in the ancillary analysis (P = 0.009). CONCLUSIONS: The high sensitivity of Ga-PET/CT in NET detection is known. The high PPV of F-PET/CT in the identification of G2 forms suggests its potential role in PanNETs prognostication and risk stratification.

Acquired hemophagocytic syndrome in a patient with synovial sarcoma: a case report.

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome characterized by severe hyperinflammation due to an overwhelming ineffective immune response to different triggers. Most important symptoms are fever, hepatosplenomegaly and cytopenias. Biochemical signs include elevated ferritin, hypertriglyceridemia and low fibrinogen. Hemophagocytosis in the bone marrow is a hallmark of this syndrome. Based on the pathogenetic mechanism, it can be classified into primary (inherited) or secondary (acquired) HLH. We report, to our knowledge, the first case of acquired hemophagocytic syndrome that arose in a 20-year-old man affected by synovial sarcoma as a complication during chemotherapy.