The role of GnRH metabolite, GnRH-(1-5), in endometrial cancer.

From the time of its discovery and isolation in the mammalian hypothalamus, the decapeptide, gonadotropin-releasing hormone (GnRH), has also been found to be expressed in non-hypothalamic tissues and can elicit a diverse array of functions both in the brain and periphery. In cancer, past studies have targeted the gonadotropin-releasing hormone receptors (GnRHR) as a way to treat reproductive cancers due to its anti-tumorigenic effects. On the contrary, its metabolite, GnRH-(1-5), behaves divergently from its parental peptide through putative orphan G-protein coupled receptor (oGPCR), GPR101. In this review, we will focus on the potential roles of GnRH-(1-5) in the periphery with an emphasis on its effects on endometrial cancer progression.

Consolidation nivolumab and ipilimumab versus observation in limited-disease small-cell lung cancer after chemo-radiotherapy - results from the randomised phase II ETOP/IFCT 4-12 STIMULI trial.

BACKGROUND: Concurrent chemotherapy and thoracic radiotherapy followed by prophylactic cranial irradiation (PCI) is the standard treatment in limited-disease small-cell lung cancer (LD-SCLC), with 5-year overall survival (OS) of only 25% to 33%. PATIENTS AND METHODS: STIMULI is a 1:1 randomised phase II trial aiming to demonstrate superiority of consolidation combination immunotherapy versus observation after chemo-radiotherapy plus PCI (protocol amendment-1). Consolidation immunotherapy consisted of four cycles of nivolumab [1 mg/kg, every three weeks (Q3W)] plus ipilimumab (3 mg/kg, Q3W), followed by nivolumab monotherapy (240 mg, Q2W) for up to 12 months. Patient recruitment closed prematurely due to slow accrual and the statistical analyses plan was updated to address progression-free survival (PFS) as the only primary endpoint. RESULTS: Of the 222 patients enrolled, 153 were randomised (78: experimental; 75: observation). Among the randomised patients, median age was 62 years, 60% males, 34%/65% current/former smokers, 31%/66% performance status (PS) 0/1. Up to 25 May 2020 (median follow-up 22.4 months), 40 PFS events were observed in the experimental arm, with median PFS 10.7 months [95% confidence interval (CI) 7.0-not estimable (NE)] versus 42 events and median 14.5 months (8.2-NE) in the observation, hazard ratio (HR) = 1.02 (0.66-1.58), two-sided P = 0.93. With updated follow-up (03 June 2021; median: 35 months), median OS was not reached in the experimental arm, while it was 32.1 months (26.1-NE) in observation, with HR = 0.95 (0.59-1.52), P = 0.82. In the experimental arm, median time-to-treatment-discontinuation was only 1.7 months. CTCAE v4 grade ≥3 adverse events were experienced by 62% of patients in the experimental and 25% in the observation arm, with 4 and 1 fatal, respectively. CONCLUSIONS: The STIMULI trial did not meet its primary endpoint of improving PFS with nivolumab-ipilimumab consolidation after chemo-radiotherapy in LD-SCLC. A short period on active treatment related to toxicity and treatment discontinuation likely affected the efficacy results.

Comparative transcriptome analysis between patient and endometrial cancer cell lines to determine common signaling pathways and markers linked to cancer progression.

The rising incidence and mortality of endometrial cancer (EC) in the United States calls for an improved understanding of the disease's progression. Current methodologies for diagnosis and treatment rely on the use of cell lines as models for tumor biology. However, due to inherent heterogeneity and differential growing environments between cell lines and tumors, these comparative studies have found little parallels in molecular signatures. As a consequence, the development and discovery of preclinical models and reliable drug targets are delayed. In this study, we established transcriptome parallels between cell lines and tumors from The Cancer Genome Atlas (TCGA) with the use of optimized normalization methods. We identified genes and signaling pathways associated with regulating the transformation and progression of EC. Specifically, the LXR/RXR activation, neuroprotective role for THOP1 in Alzheimer's disease, and glutamate receptor signaling pathways were observed to be mostly downregulated in advanced cancer stage. While some of these highlighted markers and signaling pathways are commonly found in the central nervous system (CNS), our results suggest a novel function of these genes in the periphery. Finally, our study underscores the value of implementing appropriate normalization methods in comparative studies to improve the identification of accurate and reliable markers.

[D-CBP study: Evaluation of lung cancer management times]. / Étude D-CBP : Évaluation des délais de prise en charge du cancer broncho- pulmonaire au sein du service de Pneumologie et d'Oncologie Thoracique du CHU de Caen.

INTRODUCTION: Lung cancer is the leading cause of cancer-related death. Delays may have an impact on patient survival. The objective of this study was to evaluate the diagnostic and therapeutic management times for patients admitted for lung cancer treatment in the Respiratory Department of CHU de Caen Normandie. MATERIALS AND METHODS: This is a retrospective, single-center and observational study, conducted on all patients treated for lung cancer from June 2017 to January 2018 in our department of pneumology in the Caen Normandie CHU. The main median times were investigated were: Global Time (abnormal imaging-treatment), Diagnosis time (abnormal imaging-diagnosis) and Treatment Time (diagnosis-treatment). RESULTS: One hundred and twenty-seven (127) patients were included. Median global time was 55.5 days [31,25; 393], median diagnosis time was 22 days [13; 49], and median treatment time was 24.5 days [12,25; 45]. DISCUSSION: Our treatment times are consistent with those previously published. Areas for improvement are being developed in accordance with the 2014-2019 cancer plan, in particularly the creation in our institution of a specific care pathway for patients with lung cancer.

[Lung involvement of pyoderma gangrenosum: Diagnostic and therapeutic discussion based on a case report and a targeted literature review]. / Atteinte pulmonaire de pyoderma gangrenosum : discussion diagnostique et thérapeutique à partir d'un cas et d'une revue ciblée de la littérature.

INTRODUCTION: Pyoderma gangrenosum (PG) is a rare, mainly dermatological condition, whose unusual and little-known lung involvement presents a diagnostic and therapeutic challenge. CASE REPORT: A 66-year-old man, followed for 6 years for an IgA monoclonal gammopathy of undetermined significance and an initially cutaneous corticosteroid-dependent PG, received a pneumonectomy for a mass suspected of neoplasia, that turns out to be a PG pulmonary localisation. During successive pneumopathies, sometimes dyspneic and excavated, several hypotheses are discussed. Various infectious and immunological explorations, and various antibacterial/fungal or immunosuppressive therapies are conducted, to finally conclude to pulmonary and/or cutaneous recurrences of PG. The outcome at 14 months seems finally favourable with tofacitinib. CONCLUSION: The recognition of cutaneous involvement of PG, which is essential for the diagnosis of its lung involvement, is probably the mirror of its evolution under treatment. Only multidisciplinary confrontation of reported cases will allow the elaboration of diagnostic and therapeutic recommendations.

Cost-effectiveness of three strategies for second-line erlotinib initiation in nonsmall-cell lung cancer: the ERMETIC study part 3.

Several clinical and biological parameters are known to influence the efficacy of second-line erlotinib therapy for nonsmall cell lung cancer (NSCLC), but their medico-economic impact has not been evaluated. The objective of this study was to compare the incremental cost-effectiveness ratios of strategies for second-line erlotinib initiation in NSCLC: clinically guided initiation (nonsmoking females with adenocarcinoma received erlotinib; all other patients received docetaxel) and biologically guided selection (patients with epidermal growth factor receptor (EGFR) mutation received erlotinib; patients with wild-type EGFR or unknown status received docetaxel), compared with initiation with no patient selection (strategy reference). A Markov model was constructed. Outcomes (overall and progression-free survival), transition probabilities and direct medical costs (from the French third-party payer's perspective) were prospectively collected for individual patients treated with either erlotinib or docetaxel, from treatment initiation to disease progression. Published data were used to estimate utilities and post-progression costs. Sensitivity analyses were performed. The biologically and clinically guided strategies were both more efficient (incremental quality-adjusted life-yrs equal to 0.080 and 0.081, respectively) and less expensive (cost decrease equal to €5,020 and €5,815, respectively) than the no-selection strategy, and the biologically guided strategy was slightly less expensive than the clinically guided strategy. Sensitivity analyses confirmed the robustness of the results. The cost-effectiveness of second-line NSCLC treatment is improved when patients are selected on either clinical or biological grounds.

[Primitive metastasizing bronchial carcinoid with long survival]. / Carcinoïde bronchique d'emblée multimétastatique et survie prolongée. Une entité anatomo-clinique peu connue: place de l'imagerie fonctionnelle.

BACKGROUND: Metastatic bronchial carcinoid tumours are rare but some patients have a prolonged survival. A new functional imagery now makes it possible to supplement the assessment of the extent of disease. OBSERVATION: A 57 year old patient was referred for dyspnoea on exertion revealing an upper left lobar tumour, with carcinoid syndrome. The assessment enabled to find out a bronchial carcinoid tumour with liver and bone metastases, highlighted by positron-emission tomography and pentetreotide SPECT. A chemotherapy proved to be ineffective and upper left lobectomy was carried out because of the risk of pulmonary atelectasis. The patient was treated by somatostatin analogues then underwent liver transcatheter arterial chemo-embolization. The patient was alive 44 months after diagnosis (56 months after first computed tomography). CONCLUSION: Metastatic bronchial carcinoid tumours are rare. They keep a metastatic potential, the histological type remaining the major prognosis factor. Carcinoid syndrome is suggestive. The assessment of extra-thoracic disease extent benefits by contribution of new functional imagery techniques such as the pentetreotide SPECT and positron-emission tomography. The management is essentially symptomatic since there is no effective chemotherapy. However survival can be prolonged, even in multimetastatic patients.

[Epidemiology, molecular biology, diagnostic and therapeutic strategy of malignant pleural mesothelioma in 2007 - an update]. / Prise en charge dignostique et thérapeutique du mésothéliome pleural malin en 2007.

Malignant pleural mesothelioma (MPM) is a rare tumour due to occupational asbestos exposure. The incidence of MPM will continue to increase until 2020-2030. The incidence reaches 100 cases/million/year in occupationally exposed populations as opposed to 1 case/million/year in the general population, leading to 800 to 1,000 cases per year in France. The molecular carcinogenesis of MPM is incompletely understood but alterations to genes NF2, c-met, WT1 RASSF and p16 have been described. These genes are involved in cell invasion and motility, cell division and apoptosis control. Histological diagnosis remains difficult and depends on immunohistochemical analysis as described by the French Mesopath group. Clinical diagnosis relies on thoracoscopy and large pleural biopsies, with increasing use of CT-PET for the evaluation of disease extent. Therapeutic strategy includes prophylactic irradiation following drainage or thoracoscopy to prevent tumour nodule development along drainage channels and puncture sites. In selected patients, extensive extra-pleural pneumonectomy can be performed with curative intent. First line chemotherapy is based on a combination of pemetrexed and cisplatin that has demonstrated an improvement in overall survival and quality of life in phase 3 trials. Antiangiogenic agents such as bevacizumab (Avastatin) may be of interest but need to be tested in phase 3 trials. The Mesothelioma Avastatin Pemetrexed Study (MAPS) is ongoing, coordinated by the French Thoracic Cancer Intergroup (IFCT).

[The place of targeted therapies in the management of non-small cell bronchial carcinoma. Biological mechanisms of bronchial carcinogenesis: towards a better understanding and the development of new therapies]. / La place des thérapeutiques ciblées dans la prise en charge des CBNPC. Mécanismes biologiques de la carcinogenèse bronchique: d'une meilleure compréhension naissent les nouvelles thérapeutiques.

An increasing knowledge of cell signal transduction pathways has led to a better understanding of multi-step bronchial carcinogenesis. This new data has been used to design new drugs targeting specific proteins involved in epithelial cell transformation. New biotherapies are a major part of the evolving strategies to fight lung cancer and actually represent a true revolution for subsets of patients. Future treatments in lung cancer patients will be tailored on the basis of routine molecular analysis of surgical and bronchoscopic biopsy specimens. Tyrosine-kinase EGFR inhibitors and VEGF inhibitors are the first molecules in this new class of therapies for lung cancer. Their mechanism of action and the resistance mechanisms that occur with these new drugs continue to be analysed, and this knowledge will help to improve the targeting of therapeutic regimes. In the same way, a better knowledge of the molecular resistance mechanisms to classical chemotherapy agents (platinum compounds, anti-metabolite agents or tubulin-interacting agents) will lead to a tailored use of these drugs, based again on the molecular characteristics of tumor specimens. The surprisingly long survivals observed among subsets of 'molecular-selected' patients, treated with frontline EGFR tyrosine-kinase inhibitors (TKIs) in still limited prospective clinical trials, could herald significant improvement in the global efficacy of lung cancer therapeutics.

[Diagnosis, treatment, and prognosis of lung cancer in the Manche (France) (1997-1999) according to patients socioeconomic characteristics]. / Diagnostic, traitement et pronostic des cancers bronchiques dans le département de la Manche (1997-1999) en fonction du statut socio-économique des malades.

BACKGROUND: In France, data on social environment influence on cancer management and prognosis are rare and no study has been conducted on lung cancer. This study was designed to investigate the associations between place of residence and occupation class, and diagnosis, treatment and prognosis of lung cancer. METHODS: The study population consisted of the 585 cases of lung cancer collected by the cancer registry of the Manche department (France) over a three-year period (1997-1999). Distribution of qualitative variables was tested using chi(2) test. Multivariate analysis were conducted using logistic regressions. Differences in actuarial survival were tested using log-rank test. RESULTS: Difference in diagnostic conditions did not demonstrate any prominence by social characteristics. People living in rural areas did however have a higher probability of therapeutic abstention than people living in urban areas (adjusted odds ratio=2.20 [1.18-4.10]). Similarly, people without any occupational activity had a probability of therapeutic abstention higher than people with an occupational activity (adjusted odds ratio=3.40 [1.99-5.80]). Moreover, occupational class and place of residence had a significant influence on the place of diagnosis and treatment, lower class and rural people being less often managed in university hospitals. Regarding prognosis, our results do not give prominence to difference in survival according to social characteristics. CONCLUSION: This study suggests that the type of center providing patient care and the nature of treatment given could be associated with the socioeconomic status of the patient. Nevertheless, due to the small sample size, further studies in a larger series would be required to make any formal conclusion.

[Characteristics of patients with domiciliary equipment for chronic respiratory diseases in Martinique]. / Particularités des patients appareillés au domicile pour pathologie respiratoire chronique en Martinique.

The incidence of chronic respiratory failure is underestimated in Martinique. The aim of our retrospective study was to determine local particularities. Between December 1991 and December 1995, 128 patients (55% men, mean age 60 years, range 18-89 years) were hospitalized in our pneumology unit to receive a respiratory device (oxygen concentrator, respirator, continuous positive pressure generator). The high percentage of continuous positive pressure generators contrasted with the low number of oxygen concentrators prescribed indicating that obstructive disease is relatively less common due to the absence of widespread smoking habits. Sleep apnea syndrome (SAS) was particularly frequent in women (44% of the SAS patients). 10% of the SAS patients had perturbed blood gases unexplained by an associated bronchopathy. SAS in obese, hypertensive, diabetic women in Martinique is a public health problem and should be assessed by a prospective study. We observed that home care was particularly difficult for the most severely diseased patients, especially those with a tracheotomy, due to the lack of a management structure.

[Small-cell carcinoma of the trachea in a 27-year-old patient]. / Carcinome à petites cellules de la trachée chez un jeune homme de 27 ans.

A rare small-cell carcinoma of the trachea was observed in a 27 year-old man. Treatment included chemotherapy and radiotherapy as for bronchogenic small cell carcinomas. This treatment regimen led to complete but temporary remission. The patient died 4 months after the end of the treatment due to multiple cerebral metastases.