Corticotropic insufficiency in a monocentric prospective cohort of patients with lung cancer treated with nivolumab: Prevalence and etiology.

INTRODUCTION: Cancer therapy has greatly progressed in the past few years, due to development of immune checkpoint proteins. These immunotherapies, when applied to eligible patients, have significantly reduced mortality but are prone to induce immune side-effects, including pituitary disorder and low adreno-corticotropic hormone (ACTH) and cortisol levels. We aimed to assess the prevalence and etiology of corticotropic insufficiency through a systematic screening of cortisol and ACTH levels in patients with lung cancer treated with nivolumab perfusion. MATERIAL AND METHODS: All patients from our Center with indications for nivolumab treatment for pulmonary squamous cell carcinoma or adenocarcinoma resistant to chemotherapy were successively included and underwent cortisol and ACTH assay before each nivolumab perfusion. When cortisol was below normal without ACTH elevation, we screened for pituitary metastasis, hypophysitis or corticosteroid treatment that could explain the corticotropic insufficiency. RESULTS: Data from 75 patients (80.0% men, 20.0% women) showed 10.7% asymptomatic corticotropic insufficiency, with a mean cortisol level of 2.76±1.27µg/dl. Diagnosis was made during the first 2 months of nivolumab treatment in 88% of cases. Corticosteroid treatment explained the low cortisol level in 25.0% of cases. No pituitary metastases were found. Hypophysitis was suspected in 75.0% of cases. CONCLUSION: In a 75-patient cohort with non-small cell lung cancer treated with the PD1 antibody nivolumab and systematically screened for cortisol abnormalities, 10.7% of patients showed asymptomatic corticotropic insufficiency. Excluding corticotropic insufficiency secondary to corticosteroid treatment, 8.0% of patients presented cortisol level<5µg/dl attributed to hypophysitis. Cortisol screening enables hydrocortisone replacement treatment to be prescribed if necessary, preventing risk of adrenal crisis.

Multiple endocrinological failures as a clinical presentation of a metastatic lung adenocarcinoma.

SUMMARY: Multiple endocrine metastases are a rare but possible complication of lung adenocarcinoma (LAC). Pituitary metastasis is a rare condition with poor clinical expression. Diabetes insipidus (DI) is its most common presenting symptom. Here we report an original case of a pituitary stalk (PS) metastasis from LAC presenting as central DI followed by adrenal insufficiency (AI) from bilateral adrenal metastasis, without known evidence of the primary malignancy. A 45-year-old woman whose first clinical manifestations were polyuria and polydipsia was admitted. She was completely asymptomatic with no cough, no weight loss or anorexia. Chest radiography was normal. Brain MRI showed a thick pituitary stalk (PS). DI was confirmed by water restriction test and treated with vasopressin with great clinical results. Explorations for systemic and infectious disease were negative. Few months later, an acute AI led to discovering bilateral adrenal mass on abdominal CT. A suspicious 2.3 cm apical lung nodule was found later. Histopathological adrenal biopsy revealed an LAC. The patient received systemic chemotherapy with hormonal replacement for endocrinological failures by both vasopressin and hydrocortisone. We present this rare case of metastatic PS thickness arising from LAC associated with bilateral adrenal metastasis. Screening of patients with DI and stalk thickness for lung and breast cancer must be considered. Multiple endocrine failures as a diagnostic motive of LAC is a rare but possible circumstance. LEARNING POINTS: Adrenal metastasis is a common location in lung adenocarcinoma; however, metastatic involvement of the pituitary stalk remains a rare occurrence, especially as a leading presentation to diagnose lung cancer. The posterior pituitary and the infundibulum are the preferential sites for metastases, as they receive direct arterial blood supply from hypophyseal arteries. Patients diagnosed with diabetes insipidus due to pituitary stalk thickness should be considered as a metastasis, after exclusion of the classical systemic and infectious diseases. The diagnosis of an endocrinological metastatic primary lung adenocarcinoma for patients without respiratory symptoms is often delayed due to a lack of correlation between endocrinological symptoms and lung cancer. The main originality of our case is the concomitant diagnosis of both endocrinological failures, as it was initiated with a diabetes insipidus and followed by an acute adrenal insufficiency.

Comparison of a new versus standard removable offloading device in patients with neuropathic diabetic foot ulcers: a French national, multicentre, open-label randomized, controlled trial.

INTRODUCTION: The offloading is crucial to heal neuropathic diabetic foot ulcer (DFU). Removable offloading are the most used devices. Orthèse diabète is a new customized removable knee-high offloading device immobilizing foot and ankle joints, with some specific and innovative features that may improve offloading. We aimed to evaluate the efficiency of this device in DFU healing. RESEARCH, DESIGN AND METHODS: The evaluation of Offloading using a new removable ORTHOsis in DIABetic foot study is a French multicenter (13 centers) randomized controlled trial with blinded end points evaluation. Adults with neuropathic DFU were randomly assigned to either Orthèse Diabète (experimental device), or any type of conventional (usually used in France) removable offloading devices (control group). The primary outcome was the 3-month proportion of patients with fully healed DFU. RESULTS: Among 112 randomized patients (men 78%, age 62±10 years), the primary outcome occurred in 19 (33%) participants using conventional device vs 19 (35%) Orthèse Diabète users (p=0.79). Study groups were also comparable in terms of prespecified secondary end points including occurrence of new DFU (25% vs 27% in conventional and experimental groups), ipsilateral lower-limb amputation (4% vs 10%) or infectious complications (14% vs 13%) (p>0.05 for all). Adverse events were comparable between groups, including 4 deaths unrelated to study allocation (1 sudden death, 2 ventricular arrhythmias and 1 pancreatic cancer). Adverse events believed to be related to the device were higher in the Orthèse Diabète group than in the control group (15% vs 4%). Orthèse Diabète was less frequently worn than conventional devices (46% vs 66%, p=0.04). CONCLUSIONS: Orthèse Diabète, a new removable offloading orthosis immobilizing foot and ankle joints did not show superiority compared with conventional removable devices in neuropathic DFU healing and cannot be recommended to heal DFU. TRIAL REGISTRATION NUMBER: NCT01956162.

The evaluation of off-loading using a new removable oRTHOsis in DIABetic foot (ORTHODIAB) randomized controlled trial: study design and rational.

BACKGROUND: Off-loading is essential for diabetic foot management, but remains understudied. The evaluation of Off-loading using a new removable oRTHOsis in DIABetic foot (ORTHODIAB) trial aims to evaluate the efficacy of a new removable device "Orthèse Diabète" in the healing of diabetic foot. METHODS/DESIGN: ORTHODIAB is a French multi-centre randomized, open label trial, with a blinded end points evaluation by an adjudication committee according to the Prospective Randomized Open Blinded End-point. Main endpoints are adjudicated based on the analysis of diabetic foot photographs. Orthèse Diabète is a new removable off-loading orthosis (PROTEOR, France) allowing innovative functions including real-time evaluation of off-loading and estimation of patients' adherence. Diabetic patients with neuropathic plantar ulcer or amputation wounds (toes or transmetatarsal) are assigned to one of 2 parallel-groups: Orthèse Diabète or control group (any removable device) according to a central computer-based randomization. Study visits are scheduled for 6 months (days D7 and D14, and months M1, M2, M3, and M6). The primary endpoint is the proportion of patients whose principal ulcer is healed at M3. Secondary endpoints are: the proportion of patients whose principal ulcer is healed at M1, M2 and M6; the proportion of patients whose initial ulcers are all healed at M1, M2, M3, and M6; principal ulcer area reduction; time-related ulcer-free survival; development of new ulcers; new lower-extremity amputation; infectious complications; off-loading adherence; and patient satisfaction. The study protocol was approved by the French National Agency for Medicines and Health Products Safety, and by the ethics committee of Saint-Louis Hospital (Paris). Comprehensive study information including a Patient Information Sheet has been provided to each patient who must give written informed consent before enrolment. Monitoring, data management, and statistical analyses are providing by UMANIS Life Science (Paris), independently to the sponsor. Since 27/10/2013, 13 centres have agreed to participate in this study, 117 participants were included, and 70 have achieved the study schedules. The study completion is expected for the end of 2016, and the main results will be published in 2017. CONCLUSION: ORTHODIAB trial evaluates an innovating removable off-loading device, seeking to improve diabetic foot healing (ClinicalTrials.gov identifier: NCT01956162).

[Emergencies in diabetic foot ulcers management] / Pied du diabétique: les situations d'urgence

Emergencies in diabetic foot ulcers management. Treatment of diabetic foot ulcers must be organized in specialized care centers to improve healing rates and reduce amputation rates. Some frequent and especially urgent situations will be described: infection, ischemia, Charcot joint. Other less common pathologies will be mentioned: bacterial arthritis, tenosynovitis, necrotizing fasciitis, gas gangrene. French diabetic foot clinics are easily found online.

Pied du diabétique : les situations d'urgence. Toute plaie du pied diabétique doit bénéficier rapidement d'une prise en charge spécialisée et multidisciplinaire, afin d'augmenter les chances de cicatrisation et de diminuer le risque d'amputation. Certaines situations urgentes seront abordées, en commençant par les plus fréquentes : dermo-hypodermite, ischémie critique, pied de Charcot aigu. D'autres situations plus rares seront également évoquées : arthrite bactérienne, ténosynovite, fasciite nécrosante, gangrène gazeuse. Un accès facilité aux centres français de cicatrisation du pied diabétique est disponible en ligne.

High vitamin D deficiency rate in metabolic inpatients: is bariatric surgery planning found guilty?

BACKGROUND: High rates of vitamin D insufficiency are usually found in obese patients, even before any malabsorptive bariatric surgery. It is not clear whether they lack vitamin D because of different food intake, different solar exposure, or different storage pathways or bioavailability in adipose tissue. To better understand vitamin D deficiency, we studied different categories of inpatients. METHODS: We collected clinical and biological data from 457 consecutive inpatients during a year: 217 nonobese diabetic patients, 159 obese nonsurgical diabetic patients, 46 obese surgical nondiabetic patients, and 35 obese surgical diabetic patients. Statistically significant differences between two mean 25-hydroxyvitamin D (25(OH)D) levels were defined at the 5 % level using a Z-test. RESULTS: Vitamin D deficiency was found in 69 % of the patients, while 24 % had a normal level and 7 % an optimal level. A significant difference was found between obese (25(OH)D = 40.3 nmol/l) and nonobese patients (25(OH)D = 46.8 nmol/l). Patients undergoing bariatric surgery were not different from the other obese patients. CONCLUSION: No significant difference in 25(OH) vitamin D level could be demonstrated between obese patients before bariatric surgery and obese patients with no obesity surgery project. No difference was found between our Parisian obese population and a Spanish obese population, which benefits from a better solar exposure. Both findings suggest that obesity itself is the link with vitamin D deficiency, independently from behavioral differences.

Cross-sectional assessment of the roles of comorbidities in resting and activity-related dyspnea in severely obese women.

OBJECTIVES: Obesity has been associated with a lesser degree of asthma control that may be biased by other comorbidities. The objectives of this cross-sectional study were to describe resting and activity-related dyspnea complaints according to the presence of obesity-related comorbidities (asymptomatic airway hyperresponsiveness (AHR), asthma, gastroesophageal reflux disease (GERD) and sleep-disordered breathing (SDB)). We hypothesized that obese women can exhibit both resting and activity-related dyspnea, independently of the presence of asthma. METHODS: Severely obese (body mass index (BMI) > 35 kg m(-2)) women prospectively underwent description of resting and activity-related dyspnea (verbal descriptors and Medical Research Council (MRC) scale), pulmonary function testing (spirometry, absolute lung volumes, and methacholine challenge test), oesogastro-duodenal fibroscopy, and overnight polygraphy. Thirty healthy lean women without airway hyperresponsiveness were enrolled. RESULTS: Resting dyspnea complaints were significantly more prevalent in obesity (prevalence 41%) than in healthy lean women (prevalence 3%). Chest tightness and the need for deep inspirations were independently associated with both asthma and GERD while wheezing and cough were related to asthma only in obese women. Activity-related dyspnea was very prevalent (MRC score > 1, 75%), associated with obesity, with the exception of wheezing on exertion due to asthma. Asymptomatic AHR and SDB did not affect dyspneic complaints. CONCLUSIONS: In severely obese women referred for bariatric surgery, resting dyspnea complaints are observed in association with asthma or GERD, while activity-related dyspnea was mainly related to obesity only. Consequently, asthma does not explain all respiratory complaints of obese women.

Risk factors for airway hyperresponsiveness in severely obese women.

Obesity affects airway diameter and tidal ventilation pattern, which could perturb smooth muscle function. The objective was to assess the pathophysiology of airway hyperresponsiveness in obesity while controlling for gastro-oesophageal reflux disease. Obese women (n=118, mean±SD BMI 46.1±6.8kg/m(-2)) underwent pulmonary function testing (including tidal ventilation monitoring and methacholine challenge) and oesogastro-duodenal fibroscopy. Fifty-seven women (48%, 95% CI: 39-57%) exhibited hyperresponsiveness (dose-response slope ≥2.39% decrease/µmol) that was independently and positively correlated with predicted % FRC, Raw0.5 and negatively correlated with sigh frequency during tidal ventilation. Obese women had an increased breathing frequency but a similar sigh frequency than healthy lean women (n=30). Twenty-two obese women (19%, 95% CI: 12-26%) were classified as asthmatics (hyperresponsiveness and suggestive symptoms) without confounding effect of gastro-oesophageal reflux disease. In conclusion, in women referred for bariatric surgery, unloading of bronchial smooth muscle (reduced airway calibre and sigh frequency) is associated with hyperresponsiveness.

Vitamin D deficiency before bariatric surgery: should supplement intake be routinely prescribed?

BACKGROUND: Before bariatric surgery, we demonstrate a 96% rate of vitamin D deficiency in morbidly obese French patients: should supplement intake be routinely prescribed? We conducted a prospective observational study to demonstrate the prevalence of vitamin D deficiency in morbidly obese patients awaiting bariatric surgery. METHODS: Clinical and biological data were collected on 50 successive patients. RESULTS: Data showed vitamin D deficiency in 96% (25-OH vitamin D = 31 ± 13 nmol/l), with a cut-point of 50 nmol/l. Secondary hyperparathyroidism was found in 44% of patients with hypovitaminosis D (parathyroid hormone (PTH), 59 ± 24 pg/ml). Impaired PTH level concerned 89% of this group, considering the cut-point at 30 pg/ml. No significant correlation appeared between vitamin D and calcium or phosphate levels. CONCLUSIONS: Before surgery, we demonstrated a higher incidence of vitamin D deficiency in morbidly obese French patients as compared to the general population. The incidence was also higher than previous American studies. Screening for hypovitaminosis D may routinely be considered in morbid obesity. Long-term observation is, however, needed to assess the advantages and potential side effects of systematic vitamin D supplements.