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Objective: First-line chemotherapy in metastatic neuroendocrine carcinomas (NECs) is based on etoposide and platinum. However, there is no standard concerning second-line treatment. The objective of this study was to evaluate efficacy and tolerance of dacarbazine or temozolomide in metastatic digestive NEC as post first-line treatment., Material and Methods: This study included patients with a metastatic NEC of digestive or unknown primary site. All patients received platinum-etoposide as first-line chemotherapy. Primary endpoint was progression-free survival (PFS). Secondary endpoints were clinical/morphological responses, toxicity, and overall survival (OS)., Results: Twenty-seven patients were included: 17 received dacarbazine and 10 temozolomide as post-first line treatments. Median PFS was 3.0 (95%CI (2.2;3.7)) months. There was no significant difference between dacarbazine and temozolomide on PFS. Clinical and morphological responses were found in 12 and 9 patients, respectively. Median OS was 7.2 (95%CI (2.2;12.2)) months. The toxicity profile was that expected with such treatments., Conclusion: LV5FU2-dacarbazine or temozolomide-capecitabine chemotherapies allow a temporary clinical response for almost half of patients and/or a morphological response for a third of patients.

Purpose: KEYNOTE-158 (ClinicalTrials.gov identifier: NCT02628067) investigated the efficacy and safety of pembrolizumab across multiple cancers. We present results from patients with previously treated advanced well-differentiated neuroendocrine tumors (NET)., Patients and Methods: Pembrolizumab 200 mg was administered every 3 weeks for 2 years or until progression, intolerable toxicity, or physician/patient decision. Tumor imaging was performed every 9 weeks for the first year and then every 12 weeks. Endpoints included objective response rate (ORR) per RECIST v1.1 by independent central radiologic review (primary) and duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety (secondary)., Results: A total of 107 patients with NETs of the lung, appendix, small intestine, colon, rectum, or pancreas were treated. Median age was 59.0 years (range, 29-80), 44.9% had ECOG performance status 1, 40.2% had received ≥3 prior therapies for advanced disease, and 15.9% had PD-L1-positive tumors (combined positive score ≥1). Median follow-up was 24.2 months (range, 0.6-33.4). ORR was 3.7% (95% CI, 1.0-9.3), with zero complete responses and four partial responses (three pancreatic and one rectal) all in patients with PD-L1-negative tumors. Median DOR was not reached, with one of four responses ongoing after ≥21 months follow-up. Median PFS was 4.1 months (95% CI, 3.5-5.4); the 6-month PFS rate was 39.3%. Median OS was 24.2 months (95% CI, 15.8-32.5). Treatment-related adverse events (AE) occurred in 75.7% of patients, 21.5% of whom had grade 3-5 AEs., Conclusions: Pembrolizumab monotherapy showed limited antitumor activity and manageable safety in patients with previously treated advanced well-differentiated NETs., (©2020 American Association for Cancer Research.)

Kinase inhibitors (KI) for advanced and aggressive forms of differentiated, medullary and anaplastic thyroid carcinoma have been shown to provide significant tumor response, locally and in distant metastases. Their use, however, may also increase the risk for local complications such as fistula formation and bleeding, and head and neck surgeons may be solicited to palliatively remove potentially dangerous lesions before initiating these systemic treatments. During KI therapy for progressive metastatic and/or locally invasive disease, surgery may be urgently necessary to secure the airway or for symptomatic neck lesions. Finally, there are more and more reports of surgery following KI therapy that suggest a new neoadjuvant paradigm for extensive lesions. In this review, we aim to discuss the literature regarding surgery before, during and after KI therapy in the context of progressive metastatic and/or locally invasive thyroid cancer., Competing Interests: Declaration of competing interest The authors of Surgery in the context of Kinase Inhibitor therapy for Locally Invasive Thyroid Cancer declare to have no conflict of interest with regards to the content of the manuscript and to have received no funding concerning this report., (Copyright © 2019 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: Cancer-related thrombotic microangiopathy (CR-TMA) is a rare entity associated with a dismal prognosis. Usually, CR-TMA is associated with mucin-producing carcinomas among which stomach, breast, prostate, lung and pancreas tumours are the most frequent., Cases Presentation: We describe for the first time three cases of CR-TMA due to adrenocortical carcinoma (ACC). All of them had mechanical hemolytic anemia and thrombocytopenia without any other identifiable cause. Bicytopenia was diagnosed either simultaneously with ACC or at the time of metastatic evolution. Two patients had acute kidney injury (AKI) with severe pathological findings on kidney biopsy. Despite total adrenalectomy, chemotherapy, and specific treatment of TMA with plasma-exchanges, renal failure and hemolytic anemia remained. The only manifestation of CR-TMA in the third patient was hemolytic anemia, which resolved after surgical removal of ACC. The evolutions in these patients suggests ACC-related TMA may be related to a circulating factor., Conclusions: CR-TMAs are rare. Here we describe the first case series of ACC-related TMA, among which two had renal involvement. This entity is associated with dismal renal prognosis despite specific treatment of TMA. According to patients' evolution, the persistence of TMA may reflect an uncontrolled malignancy.

Background: Elevated postoperative serum calcitonin (Ctn) level indicates persistent/recurrent disease in patients with medullary thyroid carcinoma (MTC). Its location is a challenge. The aim of our study was to compare the disease detection rates of F-18-Dopa (fluoro dihydroxyphenylalanine) positron emission tomography (PET)/computed tomography (CT), whole-body (WB) magnetic resonance imaging (MRI), F-18-FDG (fluorodeoxyglucose) PET/CT, WB CT scanning, neck ultrasonography, and bone scintigraphy in MTC patients with increased Ctn levels and unknown localization of the source. Methods: We compared the independent reading of each imaging procedure with a reference assessment for structural disease defined by pathology or concordance between two imagings or with subsequent follow-up. The detection rate of each imaging modality was determined in per patient, per organ, and per lesion analysis. Results: Thirty-six consecutive patients (21 females, mean age: 57 years, sporadic MTC in 26 cases, median serum Ctn level: 760 pg/mL; range: 21-10,121) were analyzed. The reference assessment localized disease in 24 (64%) patients with 74 lesions detected in the thyroid bed (8), in neck lymph nodes (15), mediastinal lymph nodes (6), lungs (1), liver (2), bones (3), and other site (1). At the patient level, the detection rates were 64% (CI 0.48-0.80) for F-18-Dopa PET/CT with early acquisitions, 40% (CI 0.24-0.56) for F-18-FDG PET/CT, 40% (CI 0.24-0.56) for WB MRI, and 48% (CI 0.31-0.66) for WB CT scan. Conclusions: In MTC patients with increased Ctn and no known distant metastases, F-18-Dopa PET/CT is more sensitive to detect structural disease than any other imaging modality, including WB MRI.

Adapting treatment and follow-up according to the risk of recurrence and/or death from thyroid cancer is a relatively recent concept of "personnalized" medicine, developed particularly to avoid overtreatment of low-risk thyroid cancer which represents the majority of thyroid cancers diagnosed in the world today. For low-risk thyroid cancer, this decrease in extent of treatment involves the extent of surgery-total thyroidectomy, lobectomy or no surgery with active surveillance-but also the indications, doses and methods of stimulation when or if administering radioactive iodine (RAI), the indication for suppressive thyroxin therapy and the extent and modalities for follow-up that should be adapted to the risk of recurrence. The aim is to optimize medical resources and quality of life, particularly for low-risk patients whose life expectancy is that of the general population., (Copyright © 2019. Published by Elsevier Ltd.)

Introduction: Metastatic lung carcinoids (MLCs) remain poorly characterized and no prognostic stratification exists., Methods: We conducted a retrospective study including patients with MLCs in two European expert centers. The aims were to characterize these cases and to identify prognostic factors of survival and effectiveness of their treatments., Results: A total of 162 patients with MLC were included: 50% were women, and the median age was 61 years. Half of the patients had synchronous metastases, mainly located in the liver (75%), bone (42%), and lung (25%). According to WHO classification, MLCs were typical (28%), atypical (60%), or unspecified (12%). A functioning syndrome was observed in 43% of cases and an uptake at somatostatin receptor scintigraphy in 76% of cases. The 5-year overall survival rate was 60% and at 10 years this was 25%. In multivariate analysis, Eastern Cooperative Oncology Group performance status of 0-1 (hazard ratio [HR]: 5.81, 95% confidence interval [CI]: 2.10-16.11), uptake on SRS (HR: 0.38, 95% CI: 0.22-0.66), low serum chromogranin A (HR: 2.27, 95% CI: 1.36-3.81), and typical carcinoid (HR: 1.87, 95% CI: 1.26-2.78) were associated with better survival. According to Response Evaluation Criteria in Solid Tumors version 1.0, the highest objective response rates were obtained after radiofrequency ablation of metastases (86%), liver embolization (56%), peptide receptor radionuclide therapy (27%), and oxaliplatin-based chemotherapy (18%)., Conclusions: MLCs are characterized by a high frequency of atypical carcinoids, functioning syndrome, and liver/bone metastases. WHO classification, performance status, somatostatin receptor scintigraphy, and chromogranin A were associated with longer survival. Partial response was more frequent with locoregional therapies, peptide receptor radionuclide therapy, or oxaliplatin-based chemotherapy., (Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

A 59-year-old woman with locally invasive poorly differentiated thyroid cancer with synchronous lung, mediastinal, and bone metastases and a somatic BRAF K601E mutation with contraindication for antiangiogenic drugs was treated with dabrafenib and trametinib. During treatment, serum levels of thyroglobulin increased as early as day 7 up to 10-fold over baseline at week 4. Concurrently, clinical hyperthyroidism occurred, with free triiodothyronine and free thyroxine levels increasing to 6.6 and 4.4 times their upper reference limit. Fludeoxyglucose positron emission tomography/computed tomography at one and two months after treatment initiation showed a PERCIST metabolic response with a 82% decrease in fludeoxyglucose uptake, whereas disease remained morphologically stable according to RECIST criteria. A diagnostic radioactive iodine whole-body scan performed when the patient was thyrotoxic with an undetectable serum thyrotropin level, in the absence of any exogenous thyrotropin stimulation, showed high radioactive iodine uptake in the lung, mediastinum, and skull metastases. A biopsy performed two months after treatment initiation showed a more differentiated growth pattern and a decrease in the mitotic activity compared to baseline. An increase of thyroglobulin and thyroid peroxidase was observed at both the protein and mRNA levels. Sodium-iodide symporter mRNA expression increased by >750 times over its initial level, and sodium-iodide symporter protein expression became detectable under treatment. A decrease in general status due to thyrotoxicosis led to treatment discontinuation. Thyrotoxicosis resolved rapidly and radioactive iodine uptake decreased by >90%. This clinical case shows that redifferentiation itself is not necessarily associated with an antitumor effect.

Vacuolar H+-ATPase-dependent (V-ATPase-dependent) functions are critical for neural proteostasis and are involved in neurodegeneration and brain tumorigenesis. We identified a patient with fulminant neurodegeneration of the developing brain carrying a de novo splice site variant in ATP6AP2 encoding an accessory protein of the V-ATPase. Functional studies of induced pluripotent stem cell-derived (iPSC-derived) neurons from this patient revealed reduced spontaneous activity and severe deficiency in lysosomal acidification and protein degradation leading to neuronal cell death. These deficiencies could be rescued by expression of full-length ATP6AP2. Conditional deletion of Atp6ap2 in developing mouse brain impaired V-ATPase-dependent functions, causing impaired neural stem cell self-renewal, premature neuronal differentiation, and apoptosis resulting in degeneration of nearly the entire cortex. In vitro studies revealed that ATP6AP2 deficiency decreases V-ATPase membrane assembly and increases endosomal-lysosomal fusion. We conclude that ATP6AP2 is a key mediator of V-ATPase-dependent signaling and protein degradation in the developing human central nervous system.

Context: Pheochromocytomas and paragangliomas (PPGLs) are characterized by a strong genetic component, with up to 40% of patients carrying a germline mutation in a PPGL susceptibility gene. International guidelines recommend that genetic screening be proposed to all patients with PPGL., Objective: Our objective was to evaluate how a positive genetic test impacts the management and outcome of patients with SDHx or VHL-related PPGL., Design: We performed a multicentric retrospective study involving 221 propositi carrying an SDHB, SDHD, SDHC, or VHL germline mutation. Patients were divided into two groups: genetic patients, who were informed of their genetic status within the year following the first PPGL diagnosis, and historic patients, who only benefited from the genetic test several years after initial PPGL diagnosis., Results: Genetic patients had better follow-up than historic patients, with a greater number of examinations and a reduced number of patients lost to follow-up (9.6% vs 72%, respectively). During follow-up, smaller (18.7 vs 27.6 mm; P = 0.0128) new PPGLs and metastases as well as lower metastatic spread were observed in genetic patients. Of note, these differences were reversed in the historic cohort after genetic testing. Genetic patients who developed metachronous metastases had a better 5-year survival rate than historic patients (P = 0.0127)., Conclusion: Altogether, our data suggest that early knowledge of genetic status had a positive impact on the management and clinical outcome of patients with a germline SDHx or VHL mutation., (Copyright © 2019 Endocrine Society.)

Objective: Therapeutic lateral neck dissection (ND) is recommended for N1b papillary thyroid carcinoma (PTC), while prophylactic contralateral lateral ND is not. Given the paucity of data, we investigated the frequency of and risk factors for occult lymph node metastases (LNM) in the contralateral lateral neck for N1b patients., Patients and Methods: This is a retrospective study conducted at a cancer center. Inclusion criteria were: unilateral PTC and ipsilateral lateral LNM confirmed by fine-needle aspiration biopsy. Patients with contralateral lateral LNM or bilateral tumor on ultrasound were excluded. All patients were treated with total thyroidectomy, bilateral central ND, ipsilateral therapeutic lateral ND and prophylactic contralateral ND of levels III-IV, followed by radioactive iodine., Results: Sixty-three patients met the inclusion criteria. Occult contralateral lateral LNM were found in 23/63 patients (36.5%) who had more LNM in ispilateral (p = .01) and contralateral level VI (p < .0001), more frequent microscopic tumor in the contralateral lobe (p = .017) and a trend toward being at high risk (p = .06). Using receiver operating characteristic analysis, a cutoff of >4 LNM in ipsilateral level VI optimized sensitivity and specificity for predicting contralateral lateral LNM, with a sensitivity of 74%, specificity of 65%, positive predictive value of 55% and negative predictive value of 81%. Neck recurrence occurred in 14%, with only 1 patient recurring only in the contralateral lateral neck (1.5%)., Conclusion: Occult LNM in the contralateral lateral neck was found in 36.5% of patients. Five or more ipsilateral central LNM may aid in predicting contralateral lateral LNM, and high-risk patients may be more at risk. The clinical benefit of prophylactic contralateral lateral ND remains doubtful, however.

Purpose: To evaluate the added value of 18 F-Fluorocholine ( 18 F-FCH) PET/CT in presurgical imaging of patients with primary hyperparathyroidism (HPT) and challenging localization of the hyper-functioning parathyroid glands., Methods: We included 27 consecutive patients with primary HPT (19 F; median age: 58 years), with either (i) non-conclusive pre-surgical localization with 99 mTc-sestaMIBI scintigraphy and neck ultrasonography (US), (ii) recurrence of previously operated HPT, or (iii) familiar HPT with a suspicion of multiple gland disease. Histological findings and resolution of HPT were considered as the gold standard., Results: 18 F-FCH PET/CT was positive in 24/27 patients. Twenty-one patients underwent surgery with 27 resected lesions (14 adenomas, 11 hyperplastic glands, two hyper-functioning histologically normal glands), with resolution of HPT in 19/21 patients (90%). 18 F-FCH PET/CT localized 22 lesions in 17/21 patients (per patient: sensitivity 81%, positive predictive value (PPV) 94%; per gland: sensitivity 76%, PPV 85%, specificity 91%, negative predictive value (NPV) 86%). 18 F-FCH PET/CT found eight lesions which were undetectable on both 99 mTc-sestaMIBI scintigraphy and US. In patients with a familial HPT and/or a multiple gland disease, sensitivity was 100 and 79% on a per-patient and a per-gland analysis respectively, while NPV was 63%. In six patients with a persistence or recurrence of previously treated HPT, 18 F-FCH PET/CT localized all lesions, both in sporadic and familiar disease., Conclusions: 18 F-FCH PET/CT is a promising modality in challenging pre-surgical localization of hyper-functioning parathyroid glands, such as inconclusive standard imaging, recurrence after surgery, or suspected multiple gland disease.

Purpose: Bone metastases (BM) and skeletal-related events (SRE) are frequent in patients with malignant pheochromocytoma and paraganglioma (PPM) and the best modality of prevention unknown. The role of interventional radiology (IR) techniques for the prevention of SRE in the multidisciplinary management of malignant PPM has not been evaluated in that setting., Methods: Single referral center retrospective review of all patients with malignant PPM with BM from 2000 to 2016. The primary endpoint was the time to first serious SRE (TTSRE). At time of inclusion, patients with high bone tumor burden disease were defined as those having more than five BM with the biggest exceeding 2 cm (Group A) and patients with moderate bone tumor burden disease were defined as those having five or less BM or no BM exceeding 2 cm (Group B)., Results: A total of 28 patients were included in this study. Thirteen were treated by IR techniques for prevention of first serious SRE. After a median follow-up of 48.2 months, the median TTSRE was not reached in patients treated by IR techniques and was 26.0 months in patients without IR procedures (p = .058). When comparing patients in group B, TTSRE was significantly higher in patients treated by IR (10 patients) when compared to patients without IR procedures (12 patients) (p = .021)., Conclusions: IR techniques may help to delay the occurrence of first serious SRE in patients with malignant PPM with moderate bone tumor burden disease. Prospective studies are expected to confirm these results.

MEN2A is a hereditary cancer-predisposing syndrome that affects patients with germline RET mutations. The effects of this oncogenic tyrosine kinase in the context of primitive stem cells are not known. In order to study these events, we generated a MEN2A induced Pluripotent Stem Cell (iPSC) line from a patient with RET mutation and an isogenic counterpart by CRISPR-Cas9 correction of the mutation. Whole exome sequencing of iPSC before and after CRISPR-Cas9 genome edition revealed no major exonic off target effect of the CRISPR correction. However, an integrative differential gene expression analysis of iPSC with oncogenic RET C634Y and its gene-corrected iPSC with RET Y634C as well as RET wt iPSCs revealed activation of the Early Growth Response 1 (EGR1) transcriptional program in RET-mutated iPSC, a pathway shown to be involved in RET-induced oncogenesis. These data constitute the first proof of concept of the feasibility of the use of an iPSC and its genome-corrected counterpart to unravel the molecular mechanisms underlying the development of the hereditary MEN2A cancer predisposing syndrome., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Interferon-alpha (IFN-alpha) is recommended in neuroendocrine tumors (NET). Malignant pheochromocytoma and paragangliomas (MPPGLs) constitute a rare subgroup of NET with few treatment options. IFN-alpha efficacy in patients with MPPGLs was evaluated in a single-center retrospective study. Progression-free survival (PFS) was the primary endpoint according to RECIST 1.1 and/or PERCIST 1.0, and response rate, safety, and symptomatic efficacy were secondary endpoints. Fourteen patients received peginterferon alfa-2a (90 to 180 μg/week) or interferon alfa-2b (1.5 to 3 million units × 3/week) at our institution between December 2005 and February 2014 as the first (n = 7), second (n = 3), or subsequent line (n = 4) of treatment. Most of the patients had a slowly progressive disease before IFN-alpha initiation. Eight patients were men (57%); the median age was 44. At the beginning of treatment, 12 patients had progressive disease demonstrated by FDG-PET (n = 9), MIBG (n = 1), or CT scan (n = 2). Most of the patients treated (64%) had metastatic disease limited to or predominantly located in the bones. During IFN-alpha therapy, bone-directed loco-regional treatments were performed in 9 patients (range 1-4). Median PFS was 17.2 months (95% CI [12.1-58.3]). We observed 3 partial metabolic responses, 9 stable diseases, and 2 progressive diseases. No partial response according to RECIST 1.1 was observed. Symptomatic relief of pain, headaches, diarrhea, or sweating occurred in 6 out of 10 symptomatic pts. Most frequent all grade IFN-α-related toxicities were asthenia (n = 10), lymphopenia (n = 7), thrombopenia (n = 6), and anemia (n = 5). Median overall survival was 7.5 years (95% CI [4-NR]). This study suggests symptomatic response and tumor control effect with interferon-alpha in progressive MPPGLs.

Medullary thyroid cancer (MTC) represents 3% of all clinical thyroid cancers and arises from thyroid C cells that produce calcitonin. Locally advanced or metastatic MTC requires a careful work-up including measurement of serum calcitonin and carcinoembryonic antigen, determination of their doubling time and comprehensive imaging to determine the extent of the disease, its aggressiveness, and the need for treatment. Cytotoxic chemotherapy can control tumor burden in some patients with response rates of around 20% in old series. For the last 10 years, systemic therapy for MTC patients with large tumor burden and documented progression of the disease has involved the use of tyrosine kinase inhibitors targeting VEGFR and ret. Progression-free survival benefits have been demonstrated for both vandetanib and cabozantinib, as compared to placebo. Although these molecules are effective, they also have specific toxicity profiles which require a thorough clinical management in specialized centers. In the present review, we describe the work-up and treatment modalities of patients with advanced or metastatic medullary thyroid cancer with a focus on chemotherapy and targeted therapy results., (Copyright © 2017. Published by Elsevier Ltd.)

Competing Interests: M. Schlumberger déclare des liens ponctuels (aide à la recherche et honoraires) avec AstraZeneca, Bayer, Eisai, Exelixis-Ipsen et SanofiGenzyme. S. Leboulleux déclare des liens ponctuels (interventions, prise en charge lors de congrès) avec Sanofi et Genzyme. J. Hadoux déclare n'avoir aucun lien d'intérêts.

Competing Interests: M. Schlumberger déclare des liens ponctuels (aide à la recherche et honoraires) avec AstraZeneca, Bayer, Eisai, Exelixis-Ipsen et Sanofi Genzyme. S. Leboulleux déclare des liens ponctuels (interventions, prise en charge lors de congrès) avec Sanofi et Genzyme. J. Hadoux déclare n’avoir aucun lien d’intérêts.

Purpose: Antiproliferative activity of somatostatin analogues (SSAs) has been demonstrated in digestive neuroendocrine tumours but few data have been published on pulmonary carcinoids (PC). The aim of this retrospective study was to report the antitumour activity of SSAs in patients with progressive, metastatic PC., Methods: Patients with PC and treated with SSA monotherapy were reviewed. Disease was classified according to the tumour slope prior to SSA initiation as rapidly progressive (at least 20% increase in the sum of the longest diameter of target lesions or the appearance of one or more new lesions within 6 months) or slowly progressive (if progression occurred over 6 months). Survival outcomes were progression-free survival (PFS) and overall survival (OS). We additionally examined the overall response rate and safety. Prognostic factors associated with PFS and OS were sought. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using the Cox model., Results: Among 67 patients reviewed, 61 were included in the study. Forty-one (67%) of them exhibited slowly progressive disease prior to SSAs, 41 (67%) had atypical carcinoids and 29 (48%) had functioning tumours. Forty-six (76%) patients had received SSAs as first-line therapy. The best overall response was stable disease in 47 (77%) patients. The median duration of SSAs was 13.7 months. With a median follow-up of 5.8 years, median PFS and OS were 17.4 (95% CI: 8.7-26.0) and 58.4 (95% CI: 44.2-102.7) months, respectively. Functioning tumours and slowly progressive disease were significantly associated with longer PFS: HR = 0.48 ([95% CI: 0.24-0.95], p = 0.03) and HR = 7.43 ([95% CI: 3.02-18.25], p < 0.0001), respectively. Only functioning tumours remained significantly associated with OS: HR = 0.33 ([95% CI: 0.14-0.79], p = 0.01). Treatment had been discontinued in two patients due to side-effects., Conclusions: Median PFS observed in our study is encouraging for PC patients. Patients with functioning tumours and slowly progressive disease treated with SSAs have better prognosis., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Medullary thyroid cancer arises from calcitonin-producing C-cells and accounts for 3-5% of all thyroid cancers. The discovery of a locally advanced medullary thyroid cancer that is not amenable to surgery or of distant metastases needs careful work-up, including measurement of serum calcitonin and carcinoembryonic antigen (and their doubling times), in addition to comprehensive imaging to determine the extent of the disease, its aggressiveness, and the need for any treatment. In the past, cytotoxic chemotherapy was used for treatment but produced little benefit. For the past 10 years, tyrosine kinase inhibitors targeting vascular endothelial growth factor receptors and RET (rearranged during transfection) have been used when a systemic therapy is indicated for large tumour burden and documented disease progression. Vandetanib and cabozantinib have shown benefits on progression-free survival compared with placebo in this setting, but their toxic effect profiles need thorough clinical management in specialised centres. This Review describes the management and treatment of patients with advanced medullary thyroid cancer with emphasis on current targeted therapies and perspectives to improve patient care. Most treatment responses are transient, emphasising that mechanisms of resistance need to be better understood and that the efficacy of treatment approaches should be improved with combination therapies or other drugs that might be more potent or target other pathways, including immunotherapy., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objective: Uterine leiomyosarcoma (ULMS) is a rare gynecologic malignancy characterized by a poor prognosis due to a high rate of local and metastatic recurrences. Chemotherapy with doxorubicin or ifosfamide or both is associated with a 10% to 30% objective response rate. We report a monocentric experience with doxorubicin, cisplatin, and ifosfamide (API) combination in the setting of multimodal treatment of advanced or metastatic ULMS., Patients and Methods: This monocentric retrospective study included patients with metastatic or locally advanced ULMS with a physiological age younger than 65 years treated in first line with a multimodal aggressive approach with API chemotherapy. Treatment consisted of doxorubicin 50 mg/m2 d1, ifosfamide 3 g/m2 per day d1d2 plus mesna, cisplatin 75 mg/m2 d3, plus G-CSF; every 3 weeks up to 6 cycles. Surgery, radiation therapy, or radiofrequency ablation therapy of metastatic sites was associated whenever possible., Results: Thirty-eight patients received API for metastatic or locally advanced ULMS. Median age was 51 years (40-64 years); 4 (11%) patients were treated for a locally advanced disease and 34 (89%) for metastatic disease. Sixteen patients responded (4 complete responses+12 partial responses) among 33 evaluable patients (objective response rate, 48%); 8 and 9 patients had, respectively, stable and progressive disease. Twelve patients had surgeries with 9 surgical complete responses and 3 surgical partial responses. Median progression-free and overall survival in the whole population were 9.8 and 27 months, respectively. Main grade 3-4 toxicities in 38 patients were neutropenia (74%), thrombocytopenia (60%), anemia (55%), fatigue (18%), and vomiting (13%). Febrile neutropenia was observed in 37% of patients., Conclusions: Despite the toxicity observed, API is an effective treatment which compares favorably with other first-line therapies for patients with metastatic or advanced ULMS.

Cyclophosphamide-dacarbazine-vincristine regimen is recommended for the treatment of malignant pheochromocytoma and paraganglioma (MPP); however, dacarbazine is the only recognized active drug in neuroendocrine tumours. We investigated the therapeutic benefit of temozolomide (TMZ), an oral alternative to dacarbazine, in patients with MPP. This is a retrospective study of consecutive patients with documented progressive MPP. We examined the correlation between Succinate dehydrogenase B (SDHB) mutation and O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation and MGMT expression in the French nation-wide independent cohort of 190 pheochromocytomas or paragangliomas (PP). Progression-free survival (PFS) according to RECIST 1.1 and PERCIST 1.0 criteria was the primary end point. Fifteen consecutive patients with MPP were enrolled; ten (67%) carried a mutation in SDHB. The mean dose intensity of TMZ was 172 mg/m(2) /d for 5 days every 28 days. Median PFS was 13.3 months after a median follow-up of 35 months. There were five partial responses (33%), seven stable (47%) and three progressive diseases (20%). Grade 3 toxicities were lymphopenia in two patients and hypertension in one. Partial responses were observed only in patients with mutation in SDHB. MGMT immunohistochemistry was negative in tumour samples from four patients who responded to treatment. SDHB germline mutation was associated with hypermethylation of the MGMT promoter and low expression of MGMT in 190 samples of the French nation-wide independent cohort. This study demonstrates that TMZ is an effective antitumour agent in patients with SDHB-related MPP. The silencing of MGMT expression as a consequence of MGMT promoter hypermethylation in SDHB-mutated tumours may explain this finding., (© 2014 UICC.)

Background: The combination of paclitaxel and bevacizumab was EMA-approved as first-line therapy in metastatic breast cancer. Moreover, in vitro studies showed a potential antiangiogenic synergistic effect of paclitaxel and bevacizumab., Methods: Between November 2008 and March 2010, this case series study included 15 patients with metastatic non squamous-cell lung carcinoma (NSCLC). Those were bevacizumab eligible and received the same regimen used in metastatic breast cancer with weekly paclitaxel (80 mg/m(2), days 1, 8 and 15) and bevacizumab (10 mg/kg at days 1 and 15) after at least one prior line of chemotherapy. Efficacy was evaluated by CT-scan and PET-FDG every two months. Circulating endothelial progenitor cells (CEP) and circulating endothelial cells (CEC) levels were explored in a subset of patients., Results: Median age 56 (36-75), female: 47%, never smokers: 27%, adenocarcinoma: 100%, PS 0-1: 87% and PS 3: 13%. All patients were treated with a first-line platinum-based doublet with or without bevacizumab and 70% of them with erlotinib in the second-line. No major toxicity was observed. Partial response (PR) rate was 44% (31-63%) using RECIST criteria on CT-scan, and 65% (29-88%) with PET FDG. PS improved in 33% of the cases. Median progression free survival was 4.6 months. An increase of CEC and CEP was observed in patients with NSCLC treated with paclitaxel and bevacizumab., Conclusion: In this retrospective series, our results suggest efficacy signal in pre-treated metastatic NSCLC and warrant further assessment in a randomized clinical trial.

Uterine leiomyosarcoma is a rare disease with a poor prognosis. The rarity of this tumor needs a specialized management in tertiary reference centers in order to provide patients with optimal diagnostic, prognostic and therapeutic care. The pathological diagnosis relies on the presence of three characteristics in proliferating smooth muscle cells: necrosis, cytologic atypia and mitosis. Despite progress in the knowledge of the biology of these tumors, no oncogenic driver has been found. Prognosis depends mainly on the age of the patient, race, FIGO stage, mitotic index and hormonal receptor expression in the tumor. Surgery is one of the cornerstones of management and cytotoxic chemotherapy is the mainstay of treatment in metastatic disease with a potential role in the adjuvant setting. In locally advanced or metastatic disease, prognosis is poor with a median overall survival of about 12 to 14 months despite a 30% response rate to polychemotherapy regimens. Anti-angiogenics and hormonal therapy have a role to play in the setting of metastatic disease. It is mandatory to include such patients in clinical trials aiming to improve the therapeutic management of these patients. Multimodal therapy can improve the prognosis of selected patients too.

The new WHO classification of gastroenteropancreatic (GEP) neuroendocrine tumors (NET) implies that G3 neoplasms with mitotic index >20 and/or Ki67 index >20% are neuroendocrine carcinomas (NEC), described as poorly differentiated, small or large cell types, by analogy with lung NEC. To characterize the subgroup of non-small-cell-type GEP and thoracic NET with mitotic index >20 and/or Ki67 >20% according to their pathological features, response to cisplatin and overall survival (OS). We reviewed pathological and clinical presentation of G3 non-small-cell-type NET referred to our institution for 5 years. Data from 166 patients with metastatic thoracic and GEP-NET were collected. Twenty-eight patients (17%) fulfill the inclusion criteria. Tumors were classified as well-differentiated NET (G3-WDNET) in 42.8% of cases and poorly differentiated, large-cell NEC (G3-LCNEC) in 57.2% of cases. Plasma chromogranin A or neuron-specific enolase were elevated in 42 and 25% respectively of G3-WDNET and 31 and 50% of G3-LCNEC. Somatostatin receptor scintigraphy was positive in 88 and 50% of G3-WDNET or G3-LCNEC respectively. Complete or partial response to cisplatin was observed in 31% of cases, all classified as G3-LCNEC. The median OS was 41 months for G3-WDNET but 17 months for G3-LCNEC (P=0.34). Short survival was observed in 25% of G3-WDNET but 62.5% of G3-LCNEC patients (P=0.049). G3 ENETS GEP and thoracic neuroendocrine neoplasms (NEN) could constitute a heterogeneous subgroup of NEN as regards diagnosis, prognosis, and treatment. If confirmed, future classifications may consider splitting them into two groups according to their morphological differentiation.

Neuroendocrine tumours require dedicated interventions to control their capacity to secrete hormones but also, antitumour growth strategies. Recommendations for early interventions in NET include the management of hormone-related symptoms and poorly differentiated neuroendocrine carcinomas. In contrast, prognostic heterogeneity is a key feature of well differentiated NET that complexified the antitumour strategy whatever the stage in this subgroup of tumour. In this review, timely therapeutic interventions to control hormone-related symptoms and tumour growth in GEP NET patients are discussed. The necessity of controlling hormone-related symptoms as the first step of any strategy affects also the tumour growth control strategy. In the absence of cure at the metastatic stage, progresses are expected in the recognition of well differentiated NET subgroups that display either excellent or poor prognosis., (Copyright © 2013. Published by Elsevier Ltd.)

Thymic epithelial neoplasms are rare malignancies with about 250 new incident cases in France every year. The WHO histologic classification distinguishes thymoma and thymic carcinoma which are tumors with different biological and clinical behaviors and outcomes. The Masaoka-Koga staging system is considered as a reference and is also of prognosis value. Diagnosis, multimodal treatment and follow-up of thymic epithelial neoplasms require a multidisciplinary approach where surgery is the cornerstone treatment. A national expert center coordinates thymic epithelial neoplasms management with 12 other regional expert centers through the French organization named RYTHMIC (www.rythmic.org). Patient's files have to be discussed at regional or national multidisciplinary staff. A group of expert pathologists will centrally review tumors when the diagnosis or classification is a matter of controversy. Among its objectives, RYHTMIC has to promote medical education, patient's information and research. This review focuses on RYTHMIC guidelines and data regarding multimodal management and targeted therapies in epithelial thymic neoplasms.

Smoking status is essential to know when taking care of a lung cancer patient. Never-smoking patients account for 15% of lung cancer patients, more often women and adenocarcinoma. Environmental tobacco smoke and occupational exposure could be important risk factors. Lung cancer in never-smoker appears to be a distinct entity from lung cancer in smoker, with specific molecular characteristics such as frequent EGFR mutations. New molecular targets are on investigation, such as EML4-ALK translocation. Treatment of lung cancer in never-smoker is getting different from that of smoker with more efficacy of molecular targeted therapies., (Copyright © 2011. Published by Elsevier Masson SAS.)

Metastatic renal cell carcinoma has harboured a poor prognosis for decades with immunotherapy being the only available therapy with high toxicity and modest effect. Dependance of renal cell carcinoma oncogenesis on the mTOR pathway has led to clinical development of temsirolimus in this setting. This sirolimus derivative has shown clinical efficacy in monotherapy for poor-risk renal cell carcinoma leading to an overall survival of 10.8 months in the pivotal phase III trial of this agent. Its specific adverse events consist of metabolic dysregulation (hyperlipemia, hyperglycemia), mucositis, rash and pneumonitis which can be severe and need careful monitoring and management. In this review, we will discuss of the clinical development of this molecule, its efficacy, its safety profile and future perspectives.