Small Cell Neuroendocrine Carcinoma of the Paranasal Sinuses with Unexpected Location and Clinical Presentation and Occupational Exposure: A Case Report.

BACKGROUND Small cell carcinoma (SCC) is usually aggressive and associated with a poor prognosis. This type of cancer is rarely found in extra-pulmonary or digestive-tract locations. This report describes an unusual presentation in terms of clinical symptoms and primary location (even among head and neck presentations), and unexpected occupational exposure. CASE REPORT This case report is a novel observation of SCC in the paranasal sinuses and is to the best of our knowledge the first case associated with occupational exposure to sawdust, with almost no ear, nose, and throat (ENT) symptoms related to the primary tumor location. Our patient had no past medical history and none of the usual risk factors, apart from a smoking history of 32 pack-years. He was not taking any regular treatment. The inaugural clinical presentation was mainly digestive, with neither ENT nor neurological symptoms. Diagnostic wavering ensued and numerous paraclinical tests were performed. This is one of the very few cases of an ethmoidal location ever reported for SCC. This cancer type is unusual in neck and head locations, but has occasionally been reported in the larynx and hypopharynx. To the best of our knowledge, this is only the second report of an ethmoidal location. In addition, this patient was a carpenter, implying exposure to sawdust, which is usually associated with adenocarcinoma of the ethmoid. We illustrate here that SCC, which has been described elsewhere without sawdust exposure, is also possible. CONCLUSIONS Exposure to sawdust should suggest a possible ethmoidal cancer location, even if there are few ENT symptoms. Adenocarcinoma is the most prevalent but clearly not the only possible histological pattern.

Optimization of G-CSF dosing schedule in patients treated with eribulin: a modeling approach.

BACKGROUND: Granulocyte colony-stimulating factors (G-CSF) are commonly given to limit chemotherapy-induced neutropenia, but, in case of weekly chemotherapy such as eribulin, their administration schedules remain empirical. OBJECTIVES: This pharmacokinetic/pharmacodynamic (PK/PD) study was conducted to establish the effect of different G-CSF regimens on neutropenia's incidence for patients treated by eribulin, to propose an optimal G-CSF dosing schedule. METHODS: A population PK/PD model was developed to describe absolute neutrophil counts' (ANC) time course in 87 cancer patients receiving eribulin. The structural model considered ANC dynamics, neutropenic effect of eribulin and stimulating effect of G-CSF. Final model estimates were used to calculate neutropenia's incidence following different G-CSF dosing schedules for 1000 virtual subjects. RESULTS: The final model successfully described most of the ANC time course for all patients. Simulations showed that a single G-CSF administration 48 h after each eribulin injection reduced the risk of severe neutropenia from 29.7 to 5.2%. Five days of G-CSF only after the second eribulin injection or no G-CSF administration induces similar incidence of neutropenia. CONCLUSION: Simulations showed a single G-CSF administration 48 h after the end of each eribulin injection seems to be the optimal schedule to reduce eribulin-induced neutropenia. However, the new administration scheme should be tested in real life to evaluate its pertinence. TRIAL REGISTRATION: Eudract 2015-001753-32, 2015/01/26.

Phase I Dose-Escalation Trial of an Innovative Chemotherapy Regimen Combining a Fractionated Dose of Irinotecan Plus Bevacizumab, Oxaliplatin, 5-Fluorouracil, and Folinic Acid (bFOLFIRINOX-3) in Chemorefractory Metastatic Colorectal Cancer.

The care of metastatic colorectal cancers is based on combination chemotherapies including 5-fluorouracil, oxaliplatin, irinotecan, and monoclonal antibodies targeting the epidermal growth factor receptor or vascular endothelial growth factor. The regimen is determined based on the patient's molecular biology and general condition. Irinotecan bifractionation showed efficacy in chemorefractory patients in a previous study, FOLFIRI-3, but a desynchronized triplet has never been tested. The aim of bFOLFIRINOX-3 is to determine the safety, tolerance, and efficacy of a new regimen (FOLFIRINOX-3 bevacizumab) in chemorefractory patients. The aim of this study was to evaluate the safety and efficacy of FOLFIRINOX-3 bevacizumab in chemorefractory metastatic colorectal cancer (mCRC). A standard phase I, "3 + 3" design study was performed. The standard protocol comprised simplified FOLFOX 4 (folinic acid 400 mg/m2), 5-fluorouracil (a 400 mg/m2 bolus followed by 2400 mg/m2 for 46 h), oxaliplatin (85 mg/m2) and irinotecan (administered before and after 5-fluorouracil infusion), plus bevacizumab (5 mg/kg). In a "3 + 3" design, three different doses of irinotecan were tested: 60, 70 and 90 mg/m2. The primary endpoint was the maximum tolerable dose (MTD) of irinotecan. The secondary endpoints included the objective response (at 8 and 16 weeks) according to the RECIST 1.1 criteria and progression free survival. Thirteen patients were enrolled, and twelve patients were finally evaluated for dose-limiting toxicity (DLT). The dose level defined was 70 mg/m2 irinotecan. A total of three DLTs were observed (grade 3 diarrhea): two DLTs at the 90 mg/m2 dose level and one at the 70 mg/m2 dose level. The most frequently described adverse events were asthenia (93%), diarrhea (77%), nausea (62%) and peripheral sensory neuropathy (46%). The most frequent biological event was thrombopenia (54%). Regarding efficacy, among the 11 evaluable patients, no progression was observed at 8 weeks, and the partial response rate was 18.2%. At 16 weeks, a partial response rate of 27.3% was observed, and five patients had a stable disease. The new regimen of bFOLFIRINOX-3 with irinotecan at 70 mg/m2 was well tolerated. In chemorefractory patients, this protocol shows a high response rate.

Targeting BRAF and RAS in Colorectal Cancer.

Colorectal cancer (CRC) is still one of the most frequent forms of cancer in the world in terms of incidence. Around 40% of CRC patients carry a mutation of the Kirsten rat sarcoma (KRAS) gene, while 10% have a mutation in the B-Raf proto-oncogene serine/threonine kinase (BRAF) gene. These mutations are responsible for dysregulation of the mitogen-associated protein kinase (MAPK) pathway, leading to the proliferation, differentiation, angiogenesis, and resistance to apoptosis of cells. Activation of the MAPK pathway results in adaptive therapeutic resistance, rendering EGFR inhibitors ineffective. This review aims to highlight the recent findings that have improved our understanding of KRAS and BRAF mutations in colorectal cancer and to describe new targeted therapies, used alone or in combination.