Long-term effectiveness and safety of interleukin-1 receptor antagonist (anakinra) in Schnitzler's syndrome: A french multicenter study

The aim of this study is to assess the long-term effectiveness and safety of IL1Ra in Schnitzler syndrome (SchS). Between 2010 and 2012, we performed a nationwide survey among French internal medicine departments to identify SchS patients. We retrospectively analyzed the long-term efficacy and safety of IL1Ra and the outcome of patients that did not receive this treatment. Forty-two patients were included in the study, 29 of whom received IL1Ra. The mean age at disease onset was 59.9 years. Disease manifestations included urticaria (100%), fever (76%), bone/joint pain (86%), bone lesions (76%), anemia (67%), and weight loss (60%). The monoclonal gammopathy was overwhelmingly IgM kappa (83%). The mean follow-up was 9.5 years (range: 1.6-35). Two patients developed Waldenström's macroglobulinemia and one developed AA amyloidosis. All of the 29 patients who received IL1Ra responded dramatically. After a median follow-up of 36 months (range: 2-79), the effectiveness remained unchanged. All patients remained on anti-IL-1 therapy. Twenty-four patients (83%) went into complete remission and five (17%) into partial remission. Three patients experienced grade 3-4 neutropenia. Six patients developed severe infections. No lymphoproliferative diseases occurred while on IL1Ra. When last seen, all patients without anakinra had an active disease with variable impact on their quality of life. Their median corticosteroids dosage was 6 mg/d (range: 5-25). IL1Ra is effective in SchS, with a sharp corticosteroid-sparing effect. Treatment failures should lead to reconsider the diagnosis. Long-term follow-up revealed no loss of effectiveness and a favorable tolerance profile. The long-term effects on the risk of hemopathy remain unknown.     

Use of a Smartphone Self-assessment App for a Tobacco-Induced Disease (COPD,Cardiovascular Diseases,Cancer) Screening Strategy and to Encourage Smoking Cessation: Observational Study

BackgroundPatient self-assessment via a mobile app detects actionable symptoms and has been shown to detect lung cancer relapses early, thereby lengthening survival.ObjectiveThe purpose of this study was to assess the incidence of chief symptoms associated with the main tobacco-induced pathologies in both current and ex-smokers through a self-assessment smartphone app and to evaluate the app’s capacity to encourage users to quit smoking or reduce consumption, as well as its impact on early lung cancer stages at the time of diagnosis.MethodsCurrent and ex-smokers were recruited through an advertising campaign in Sarthe county (France) proposing the free download of a smartphone app. App users were asked to answer 13 questions related to symptoms associated with tobacco-induced diseases (chronic obstructive pulmonary disease [COPD], cardiovascular diseases, cancer). In the event of any positive answer, a message was displayed recommending the user to consult a physician. In addition, they were asked about smoking cessation intention before and after answering these 13 questions. Finally, incidence of stage 1 or 2 lung cancers diagnosed during the launch period of our application was evaluated by comparing data from various sources to those from the same period during the previous year.ResultsOf the 5671 users who were eligible for evaluation, an alert was sent to the majority (4118/5671, 72.6%), with a higher incidence for current smokers (2833/3679, 77.0% vs 1298/1992, 65.2%; P<.001). The most frequent symptoms triggering the notifications were fatigue (2023/5671, 35.7%), cough (1658/5671, 29.2%), dyspnea (1502/5671, 26.5%), and persistent chest pain (1286/5671, 22.7%). Of the current smokers, 14.0% (515/3679) showed symptoms suggesting COPD, 15.5% (571/3679) showed symptoms suggesting stable angina, 12.4% (455/3679) probably had lower extremity artery disease, and 6.8% (249/3679) had possible cancer. Of the users, 36.5% (1343/3679) claimed that they thought about quitting smoking, and 48.7% (1795/3679) had thought about reducing their consumption. Surgery-eligible stage 1 and 2 lung cancer incidence was 24% (14/58) during the study period versus 9% (5/54) during the previous year in Sarthe county (P=.04), whereas it remained unchanged in the neighboring county of Maine-et-Loire.ConclusionsA majority of current and ex-smokers showed worrying symptoms, and the use of a self-assessment smartphone app may drive a majority of smokers toward the intention of smoking cessation or decreasing consumption. A randomized study should be performed to confirm this intention and to support the potential increase of symptomatic lung cancer detection at early, surgery-accessible stages.Trial RegistrationClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT04048954","term_id":"NCT04048954"}}NCT04048954; https://www.clinicaltrials.gov/ct2/show/{"type":"clinical-trial","attrs":{"text":"NCT04048954","term_id":"NCT04048954"}}NCT04048954     

Therapeutic value of pretherapeutic extraperitoneal laparoscopic staging of locally advanced cervical carcinoma

BACKGROUND: Although cervical cancer is clinically staged, surgery has long been considered the best means to assess extrapelvic disease and remains the gold standard for the detection of both intraperitoneal spread and small volume nodal metastases. The objective of this study was to determine short- and long-term outcomes for patients with locally advanced cervical cancer who underwent pretherapeutic laparoscopic staging. METHODS: From 1997 to 2004, 184 patients with stages IB2-IVA cervical cancer underwent pretherapeutic laparoscopic staging procedure including transperitoneal abdomino-pelvic exploration and extraperitoneal bilateral infrarenal paraaortic lymph node dissection. Patients were then treated with definitive radiotherapy tailored according to the staging results. RESULTS: The median age and BMI were respectively 45.8 years old and 27.1 kg/m2. Most lesions were squamous (n=172) and clinical stage was evenly distributed. Median operative time was 155 min with an average of 20.8 lymph nodes removed. Postoperative hospital stay averaged 1.4 days. Major complications included 1 intraoperative ureteral injury and 1 postoperative bowel obstruction from an umbilical trocar site hernia. The final pathology revealed that 44 patients (24.3%) had metastatic disease within paraaortic lymph nodes. With a median follow-up of 26.8 months (average 32.9), 67 patients (36.4%) had recurrent disease. Overall 5-year survival rate was 58.3%. Successful resection of positive lymph node correlated with a survival advantage. CONCLUSIONS: Pretherapeutic laparoscopic assessment of patients with locally advanced cervical cancer offers valuable information for individualized treatment planning with minimal morbidity. This appears to be a therapeutic effect with resection of positive nodes followed by a tailored chemoradiation therapy.     

Prescription,Compliance, and Burden Associated with Salt-Restricted Diets in Heart Failure Patients: Results from the French National OFICSel Observatory

(1) Background: There is much debate about the use of salt-restricted diet for managing heart failure (HF). Dietary guidelines are inconsistent and lack evidence. (2) Method: The OFICSel observatory collected data about adults hospitalised for HF. The data, collected using study-specific surveys, were used to describe HF management, including diets, from the cardiologists’ and patients’ perspectives. Cardiologists provided the patients’ clinical, biological, echocardiography, and treatment data, while the patients provided dietary, medical history, sociodemographic, morphometric, quality of life, and burden data (burden scale in restricted diets (BIRD) questionnaire). The differences between the diet recommended by the cardiologist, understood by the patient, and the estimated salt intake (by the patient) and diet burden were assessed. (3) Results: Between March and June 2017, 300 cardiologists enrolled 2822 patients. Most patients (90%) were recommended diets with <6 g of salt/day. Mean daily salt consumption was 4.7 g (standard deviation (SD): 2.4). Only 33% of patients complied with their recommended diet, 34% over-complied, and 19% under-complied (14% unknown). Dietary restrictions in HF patients were associated with increased burden (mean BIRD score of 8.1/48 [SD: 8.8]). (4) Conclusion: Healthcare professionals do not always follow dietary recommendations, and their patients do not always understand and comply with diets recommended. Restrictive diets in HF patients are associated with increased burden. An evidence-based approach to developing and recommending HF-specific diets is required.     

Association between hereditary predisposition to common cancers and congenital multimalformations

In a previous article we reported that mutations favoring cancer at adulthood seemed to improve fertility and limit miscarriages. Because spontaneous abortion may result from anomalies in embryo, we questioned if an increased frequency of congenital malformation could be evidenced among cancer-prone families. Oncogenetics database (≈193 000 members) of the comprehensive cancer center Jean Perrin was crossed with regional registry of congenital malformations (≈10 000). Among children born between 1986 and 2011, 176 children with malformation matched in both databases. In breast/ovaries cancer-prone families, the risk for malformations was multiplied by 2.4 [1.2-4.5] in case of a BRCA1 mutation. Frequencies of malformation in BRCA2 and MMR mutated families were similar to families without a cancer syndrome. In comparison to malformations concerning a unique anatomical system, multimalformations were significantly more frequent in case of BRCA or MMR mutations: compared to families without cancer syndrome, the risk of multimalformations was multiplied by 4.1 [0.8-21.7] for cancer-prone families but with no known deleterious mutation, by 6.9 [1.2-38.6] in families with a known mutation but an unknown parental mutational status and by 10.4 [2.3-46.0] when one parent carried the familial mutation. No association with the type of anatomical system was found, nor with multiple births. These results suggest that BRCA and MMR genes play an important role in human embryogenesis and that if their function is lowered because of heterozygote mutations, congenital malformations are either more likely (BRCA1 mutations) and/or more susceptible to concern several anatomical systems.     

Transient cortico-cortical disconnection during psychogenic nonepileptic seizures (PNES)

Psychogenic nonepileptic seizures (PNES) are paroxysmal clinical events that are often misdiagnosed as epileptic seizures, but which are not associated with electrographic discharge. Brain connectivity changes occurring during PNES are not known. We studied functional connectivity (Fc) in two patients with drug-resistant epilepsy, explored by stereotactic electroencephalography (EEG), in whom we recorded both epileptic seizures (ES) and PNES. Functional connectivity using pair-wise nonlinear correlation was computed between signals from seven brain areas: amygdala, hippocampus, lateral temporal cortex, anterior insula, orbitofrontal cortex, prefrontal cortex, and lateral parietal cortex. We assessed changes in global Fc during PNES in comparison with a background period. During PNES, a global decrease of Fc occurred between the different brain regions studied, compared with the interictal period. In both patients, decreased Fc was prominent in connections involving the anterior insula and parietal cortex. In conclusion, some PNES are associated with ictal functional disconnection between brain areas, particularly involving the parietal cortices and the anterior insula.     

Neural connectivity between the hypothalamic supramammillary nucleus and appetite‐ and motivation‐related regions of the rat brain

The supramammillary nucleus (SuM) has an emerging role in appetite control. We have shown that the rat SuM is activated during hunger or food anticipation, or by ghrelin administration. In the present study, we characterised the connectivity between the SuM and key appetite‐ and motivation‐related nuclei in the rat. In adult wild‐type rats, or rats expressing Cre recombinase under the control of the tyrosine hydroxylase (TH) promoter (TH‐Cre rats), we used c‐Fos immunohistochemistry to visualise and correlate the activation of medial SuM (SuMM) with activation in the lateral hypothalamic area (LH), the dorsomedial hypothalamus (DMH) or the ventral tegmental area (VTA) after voluntary consumption of a high‐sugar, high‐fat food. To determine neuroanatomical connectivity, we used retrograde and anterograde tracing methods to specifically investigate the neuronal inputs and outputs of the SuMM. After consumption of the food there were positive correlations between c‐Fos expression in the SuMM and the LH, DMH and VTA (P = 0.0001, 0.01 and 0.004). Using Fluoro‐Ruby as a retrograde tracer, we demonstrate the existence of inputs from the LH, DMH, VTA and ventromedial hypothalamus (VMH) to the SuMM. The SuMM showed reciprocal inputs to the LH and DMH, and we identified a TH‐positive output from SuMM to DMH. We co‐labelled retrogradely‐labelled sections for TH in the VMH, or for TH, orexin and melanin‐concentrating hormone in the LH and DMH. However, we did not observe any colocalisation of immunoreactivity with any retrogradely‐labelled cells. Viral mapping in TH‐Cre rats confirms the existence of a reciprocal SuMM‐DMH connection and shows that TH‐positive cells project from the SuMM and VTA to the lateral septal area and cingulate cortex, respectively. These data provide evidence for the connectivity of the SuMM to brain regions involved in appetite control, and form the foundation for functional and behavioural studies aiming to further characterise the brain circuitry controlling eating behaviours.     

Functional bundle branch block and orthodromic reciprocating tachycardia cycle length: do not bet on accessory pathway location.

AIMS: To show 2 examples in which the analysis of the effect of bundle branch block on orthodromic reciprocating tachycardia cycle length was misleading. METHODS AND RESULTS: We performed an electrophysiological study in two patients with orthodromic reciprocating tachycardia showing a transition from wide to narrow QRS during tachycardia. Our two cases of left bundle branch block during reciprocating tachycardia using infero-septal pathways show that ventricular to atrial conduction time prolongation may be larger than 30 ms and may be concealed by a shortening of atrial to ventricular conduction time. In the 2 cases, the atrial insertion of the accessory pathway could be successfully ablated from the right atria at the ostium of the coronary sinus. CONCLUSIONS: The observation of the association between left bundle branch block and cycle length prolongation during reciprocating tachycardia may be associated with a successful ablation at the ostium of the coronary sinus.