Activity and safety of oral etoposide in pretreated patients with metastatic or recurrent thymic epithelial tumors (TET): A single-institution experience.

OBJECTIVES: Standard regimens in pretreated advanced TETs are lacking. Single agent responses have been reported with pemetrexed, gemcitabine and targeted therapies. Oral etoposide monotherapy has a favorable safety and efficacy profile in other tumor types. We assessed its activity and safety in advanced or recurrent pretreated TETs. PATIENTS AND METHODS: We conducted a retrospective analysis of patients with advance or recurrent TET treated with single agent oral etoposide at Gustave Roussy (GR) between 1992 and 2015. Efficacy analyses was made by treating physician according to RECIST and retrospectively collected from medical records. Kaplan-Meier method was used to estimate progression-free survival (PFS) and overall survival (OS). RESULTS: Twenty patients were included. Median age was 62 years [range 34-88], 60% were male, 25% had thymoma (T) and 75% had thymic carcinoma (TC). Myasthenia gravis was reported in 15% of them. A median of 2 [range 0-7] prior chemotherapy regimens had been administered, with 60% exposed to etoposide (VIP 40%, carboplatin-etoposide 15%, BEP 5%). Median follow-up since etoposide was 7 years [range 0.5-8.9]. Three patients achieved partial response and nine had stable disease, giving an overall response rate of 15% [T: 20%, TC: 13%] and a 60% disease control rate [T: 100%, TC: 46%]. Median PFS was 4 months [95%CI 3-14] and median OS was 41 months [95%CI 6-86]. Median PFS for T and TC were 21 months [95%CI 9-42] and 4 months [95%CI 2-4]; median OS were 99 months [95%CI 43-not reached] and 13 months [95%CI 4-41], respectively. The most common grade 3-4 related events occurred in 9 patients (45%) and were neutropenia followed by anemia and thrombocytopenia. CONCLUSION: Oral etoposide monotherapy is an active option for pretreated TET patients, with manageable toxicity profile.

Regional CAR-T cell infusions for peritoneal carcinomatosis are superior to systemic delivery.

Metastatic spread of colorectal cancer (CRC) to the peritoneal cavity is common and difficult to treat, with many patients dying from malignant bowel obstruction. Chimeric antigen receptor T cell (CAR-T) immunotherapy has shown great promise, and we previously reported murine and phase I clinical studies on regional intrahepatic CAR-T infusion for CRC liver metastases. We are now studying intraperitoneal (IP) delivery of CAR-Ts for peritoneal carcinomatosis. Regional IP infusion of CAR-T resulted in superior protection against carcinoembryonic antigen (CEA+) peritoneal tumors, when compared with systemically infused CAR-Ts. IP CAR-Ts also provided prolonged protection against IP tumor re-challenges and demonstrated an increase in effector memory phenotype over time. IP CAR-Ts provided protection against tumor growth at distant subcutaneous (SC) sites in association with increases in serum IFNγ levels. Given the challenges posed by immunoinhibitory pathways in solid tumors, we combined IP CAR-T treatment with suppressor cell targeting. High frequencies of myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) were found within the IP tumors, with MDSC expressing high levels of immunosuppressive PD-L1. Combinatorial IP CAR-T treatment with depleting antibodies against MDSC and Treg further improved efficacy against peritoneal metastases. Our data support further development of combinatorial IP CAR-T immunotherapy for peritoneal malignancies.

Immune-related adverse events with immune checkpoint blockade: a comprehensive review.

Cancer immunotherapy is coming of age; it has prompted a paradigm shift in oncology, in which therapeutic agents are used to target immune cells rather than cancer cells. The first generation of new immunotherapies corresponds to antagonistic antibodies that block specific immune checkpoint molecules cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein (PD-1) and its ligand PD-L1. Targeting these checkpoints in patients living with cancer had led to long-lasting tumour responses. By unbalancing the immune system, these new immunotherapies also generate dysimmune toxicities, called immune-related adverse events (IRAEs) that mainly involve the gut, skin, endocrine glands, liver, and lung but can potentially affect any tissue. In view of their undisputed clinical efficacy, anti-CTLA-4 and anti-PD-1 antibodies are entering in the routine oncological practice, and the number of patients exposed to these drugs will increase dramatically in the near future. Although steroids can be used to treat these IRAEs, the associated immunosuppression may compromise the antitumour response. Oncologists must be ready to detect and manage these new types of adverse events. This review focuses on the mechanisms of IRAE generation, putative relationship between dysimmune toxicity and antitumour efficacy, as a basis for management guidelines.

Antitumor activity in advanced cancer patients with thymic malignancies enrolled in early clinical drug development programs (Phase I trials) at Gustave Roussy.

OBJECTIVES: Thymic epithelial neoplasms (TENs) represent a rare entity with poor prognosis and limited systemic treatment options. The aim of this study was to assess the clinical benefit, the efficacy and toxicities of agents for patients with TEN enrolled in Phase I trials. MATERIALS AND METHODS: We reviewed retrospectively patients with advanced TEN enrolled in Phase I trials at Gustave Roussy (DITEP) between 1994 and 2012. Efficacy was assessed using RECIST version 1.1. RESULTS: Twenty-two treated patients were enrolled (15 with thymic carcinoma, 7 with thymoma). The median number of prior systemic therapies was 2 (0-8). The median age was 50 years (range 23-72), and 4 females were treated. Treatments received encompassed mTOR inhibitor (mTORi) in 4 of patients, antiangiogenic agents (AA) in 11 patients, and other targeted therapies in 7 patients. 18% had grade 3-4 toxicity, 85% all grade toxicity and no toxic death was reported. One patient experienced a complete response (CR) and 3 a partial response (PR); 16 patients had stable disease (median 6.6 months; range 1.0-30.7) and 2 had a progressive disease. The median overall survival was 54.5 months (95% CI 25-75.50). The median progression free survival (PFS) was 6.6 months (95% CI 1.35-11.59). Median PFS was 11.6 months for mTORi, 6.9 for AA, and 6.6 for other targeted therapies. CONCLUSION: Phase I trials appear as a sound therapeutic option in TENs pts progressing after standard treatments. Use of AA and mTORi seem to yield a good clinical response and warrant further investigation.

A preoperative nomogram to predict the risk of synchronous distant metastases at diagnosis of primary breast cancer.

BACKGROUND: The detection of synchronous metastases at primary diagnosis of breast cancer (BC) affects its initial management. A risk calculator that incorporates many factors to evaluate an individual's risk of harbouring synchronous metastases would be useful to adapt cancer management. PATIENTS AND METHODS: Patients with primary diagnosis of BC were identified from three institutional databases sharing homogeneous work-up recommendations. A risk score for synchronous metastases was estimated and a nomogram was constructed using the first database. Its performance was assessed by receiver characteristic (ROC) analysis. The nomogram was externally validated in the two independent cohorts. RESULTS: A preoperative nomogram based on the clinical tumour size (P<0.001), clinical nodal status (P<0.001), oestrogen (P=0.17) and progesterone receptors (P=0.04) was developed. The nomogram accuracy was 87.3% (95% confidence interval (CI), 84.45-90.2%). Overall, the area under the ROC curve (AUC) was 86.1% for the validation set from the Institut Curie-René Huguenin, and 63.8% for the MD Anderson validation set. The negative predictive value (NPV) was high in the three cohorts (97-99%). CONCLUSIONS: We developed and validated a strong metastasis risk calculator that can evaluate with high accuracy an individual's risk of harbouring synchronous metastases at diagnosis of primary BC. CONDENSED ABSTRACT: A nomogram to predict synchronous metastases at diagnosis of breast cancer was developed and externally validated. This tool allows avoiding unnecessary expensive work-up.

Gallbladder cancer: past, present and an uncertain future.

Although gallbladder cancer (GBC) is the most common malignancy of the biliary tract, its relatively low incidence and confounding symptomatology result in advanced disease at the time presentation, contributing to the poor prognosis and decreased survival associated with this disease. It is therefore increasingly important to understand its pathogenesis and risk factors to allow for the earliest possible diagnosis. To date, gallbladder cancer is poorly understood compared to other malignancies, and is still most commonly discovered incidentally after cholecystectomy. Moreover, while much is known about biliary neoplasms as a whole, understanding the clinical and molecular nuances of GBC as a separate disease process will prove a cornerstone in the development of early intervention, potential screening and overall more effective treatment strategies. The present work reviews the most current understanding of the pathogenesis, diagnosis, staging and natural history of GBC, with additional focus on surgical treatment. Further, review of current adjuvant therapies for unresectable and advanced disease as well as prognostic factors provide fertile ground for the development of future studies which will hopefully improve treatment outcomes and affect overall survival for this highly morbid, poorly understood malignancy.

Microwave coagulation therapy for hepatic tumors: review of the literature and critical analysis.

BACKGROUND: Surgical resection of malignant hepatic tumors has been demonstrated to increase overall survival; however, the majority of patients are not candidates for resection. For patients with unresectable tumors, various chemical and thermal ablation modalities have been developed. microwave coagulation therapy (MCT) is one such thermal ablation modality and the purpose of this review is to evaluate the presently available data for MCT and assess the level of evidence to support its clinical use. METHODS: This review is limited to published studies in the English literature including at least 30 patients per study with MCT for hepatocellular cancer (HCC) or colorectal hepatic metastasis (CRHM). Patterns of local recurrence, complications and survival outcome of MCT ablation are presented and discussed including assessment of Asian experience using the 2.4GHZ device and American experience using the 914MHZ device. CONCLUSIONS: Although randomized controlled trials comparing RFA and MCT for hepatic ablation are lacking, our review (based on level 2 data) supports that MCT may be optimal when larger necrosis zones and/or ablation of multiple lesions are the objectives. The data support that the potential procedural advantage(s) noted for ablation of CRHM and HCC >3cm, is not supported for HCC <3cm; moreover MCT shares with all other ablation modalities a high rate of locoregional recurrence in HCC; likely due to the multicentricity of this disease process.

Low common bile duct bifurcation incidentally discovered during pancreaticoduodenectomy.

INTRODUCTION: Bile duct injury due to failure to recognize anatomical variations can have considerable consequences. DISCUSSION: We report an incidental discovery of a low common bile duct bifurcation below the level of the cystic duct, incidentally discovered during pancreaticoduodenectomy.

A combined frontal and maxillary sinus approach for repulsion of the third maxillary molar in a horse.

The 3rd maxillary molar is a difficult tooth to remove by extraction or repulsion. A combined frontal and maxillary approach provides good exposure for repulsion of this tooth, debridement of the sinuses, and placement of an alveolar seal. The improved exposure should minimize operative difficulties and postoperative complications.