Hydration and clinical warning signs of dengue fever in primary care: An observational prospective study.

OBJECTIVES: Dengue fever is an arbovirosis expanding worldwide, for which hydration has been reported to reduce the risk of hospitalization. Our objective was to estimate the volume of hydration in Reunionese patients with dengue. METHODS: A prospective observational study included patients presenting with a 'dengue-like' syndrome in ambulatory care. General practitioners recruited patients during consultation, and beverage consumption over the previous 24 hours was reported at two different times. Warning signs were defined according to the 2009 WHO guidelines. RESULTS: GPs included 174 patients from April to July 2019. Average oral hydration volume was 1863 mL and 1944 mL, at the 1st and 2nd medical consultations, respectively. Water was the most wide consumed liquid. Drinking at least 5 glasses of liquid was significantly associated with fewer clinical warning signs at the 1st medical consultation (p = 0.044). CONCLUSIONS: Sufficient hydration volume could prevent dengue warning signs. Further studies with standardized measurement of hydration would be needed.

MOVIE: a phase I, open-label, multicenter study to evaluate the safety and tolerability of metronomic vinorelbine combined with durvalumab plus tremelimumab in patients with advanced solid tumors.

BACKGROUND: Anti-programmed cell death protein 1 (PD1)/programmed death-ligand 1 (PD-L1) agents have only moderate antitumor activity in some advanced solid tumors (AST), including breast cancer (BC), prostate cancer (PC), cervical cancer (CC), and head and neck cancer (HNC). Combining anti-PD-L1 with anti-cytotoxic T-lymphocyte-associated protein (CTLA) and chemotherapy may significantly improve efficacy. PATIENTS AND METHODS: MOVIE is a multicohort phase I/II study examining the combination of anti-PD-L1 durvalumab (Durv; 1500 mg IV Q4W) plus anti-CTLA tremelimumab (Trem; 75 mg IV Q4W) with metronomic vinorelbine (MVino; 20-40 mg orally daily) in various AST resistant to conventional therapies. The primary objective of the phase I part was to determine the maximum tolerated dose (MTD) and recommended dose for phase II (RP2D). RESULTS: Among the 14 patients enrolled during phase I, including 13 women and 1 man, 9 had BC, 1 PC, 2 CC, and 2 miscellaneous cancers with high mutational loads. Median age was 53 years. A total of 12 patients were assessable for the dose-escalation part in which only one dose-limiting toxicity (DLT) was observed [one neutropenia without fever, grade (G) 4]. Two (14.3%), four (28.6%), and four (28.6%) patients had G ≥3 adverse events (AEs) related to MVino, Durv, and Trem, respectively. Treatment-related events included mostly clinical AEs with asthenia (eight G2; three G3), colitis (one G2, one G3), diarrhea (one G3), nausea (two G2), dry skin (two G2), maculopapular rash (one G3), and hyperthyroidism (three G2). No toxic death was reported. Preliminary data showed one patient (CC) who presented a complete response and four patients with stable disease (SD). CONCLUSIONS: MTD was not reached and dose level 2 (MVino 40 mg, Durv 1500 mg, Trem 75 mg) was selected as RP2D. The safety profile of the combination was manageable and consistent with previous reports of Trem + Durv or MVino. Phase II is currently ongoing in BC, PC, CC, HNC, and miscellaneous cohorts.

Foot ischemia related to essential thrombocytemia and atherosclerosis.

We report two cases of foot ischemia combining microvascular thrombosis related to essential thrombocytemia (ET) and a proximal ulcerating atherosclerotic plaque. This suggests that myeloproliferative neoplasms could also trigger distal embolism from an unstable atherosclerotic plaque by creating a prothrombotic status. These distal ischemic events were the first ET manifestation and therefore lead to myeloproliferative neoplasm diagnosis. In ET, thrombosis event can occur with a normal platelet count. Furthermore, hemogram should be regularly controlled among JAK2 muted patients considering the frequent evolution from isolated JAK2 mutation to ET.

Combining immunotherapy with an epidrug in squamous cell carcinomas of different locations: rationale and design of the PEVO basket trial.

Squamous cell carcinomas (SCCs) are among the most frequent solid tumors in humans. SCCs, related or not to the human papillomavirus, share common molecular features. Immunotherapies, and specifically immune checkpoint inhibitors, have been shown to improve overall survival in multiple cancer types, including SCCs. However, only a minority of patients experience a durable response with immunotherapy. Epigenetic modulation plays a major role in escaping tumor immunosurveillance and confers resistance to immune checkpoint inhibitors. Preclinical evidence suggests that modulating the epigenome might improve the efficacy of immunotherapy. We herein review the preclinical and the clinical rationale for combining immunotherapy with an epidrug, and detail the design of PEVOsq, a basket clinical trial combining pembrolizumab with vorinostat, a histone deacetylase inhibitor, in patients with SCCs of different locations. Sequential blood and tumor sampling will be collected in order to identify predictive and pharmacodynamics biomarkers of efficacy of the combination. We also present how clinical and biological data will be managed with the aim to enable the development of a prospective integrative platform to allow secure and controlled access to the project data as well as further exploitations.

[New strategies in specific care for benign prostatic hypertrophy in older men]. / Nouvelles stratégies dans la prise en charge de l'hypertrophie bénigne de la prostate chez le sujet âgé.

Beyond its scientific and ethical competencies, a good doctor is characterized by his communication skills. The ability to listen is fundamental. During an interview, the physician must keep in mind a bio-psycho-social approach while being able to hear the unspeakable and inaudible. Knowledge of patients and their relatives, which seems to be a specific knowledge for general practitioners, offers a lot of information. Among the main sensitive topics that the clinician must identify are: intrafamily violence, domestic violence, substance abuse and anxiety-depressive disorders. In order to improve, the practitioner can use tools such as the Calgary-Cambridge guide and techniques used in Motivational Maintenance.

Au-delà de ses compétences scientifiques et déontologiques, un bon médecin se caractérise par ses compétences communicationnelles. La capacité d'écoute est fondamentale. Durant un entretien, le médecin doit garder à l'esprit une approche bio-psycho-sociale tout en étant capable d'entendre l'indicible et l'inaudible. La connaissance des patients et de leurs proches, qui semble être une connaissance spécifique aux médecins généralistes, offre énormément d'informations. Parmi les principaux sujets sensibles que doit repérer le clinicien, se trouvent : la violence intrafamiliale, la violence conjugale, les abus de substances et les pathologies anxio-dépressives. Afin de s'améliorer, le praticien peut s'aider d'outils tels que le guide de Calgary-Cambridge ainsi que des techniques utilisées en Entretien Motivationnel.

Effect of whole body cryotherapy interventions on health-related quality of life in fibromyalgia patients: A randomized controlled trial.

INTRODUCTION: Although fibromyalgia syndrome (SFM) affects 2-4 percent of adults, research has not identified a preferred therapeutic option for patients worldwide yet. Based on recent findings, it can be expected that whole body cryotherapy can improve health-reported quality of life by alleviating the symptoms of musculoskeletal pain and fatigue. OBJECTIVE: Our aim was to determine whether whole body cryotherapy only can result in improved perceived health and quality of life in fibromyalgia patients. METHODS: 24 patients with fibromyalgia diagnosis were randomized into 2 groups (n=11 in the whole body cryotherapy group, n=13 in the control group). In the whole body cryotherapy group, 10 sessions of whole body cryotherapy were performed (in addition to usual care) in a standard cryotherapy room over a duration of 8days. Subjects in the control group did not change anything in their everyday activities. Quality of life was assessed just before and one month after treatment. RESULTS: Compared with the control group, patients in the whole body cryotherapy group reported significantly improved for health-reported quality of life. These effects lasted for at least one month following intervention. CONCLUSION: Based on these findings, whole body cryotherapy can be recommended as an effective clinically adjuvant approach in the improvement of health-related quality of life in fibromyalgia patients.

[Evaluation of stone size before flexible ureteroscopy: Which measurement is best?] / Évaluation de la taille des calculs urinaires avant urétéroscopie souple : quelle mesure choisir ?

PURPOSE: To retrospectively assess the clinical utility in ureteroscopy (URS) planning of radiological parameters as predictor of stone-free status after a single flexible ureteroscopy. MATERIAL: Sixty-seven patients with renal stones treated by flexible URS were retrospectively evaluated. To assess the clinical utility of radiological parameters, relationships between stone-free (SF) status and stone burden (maximal diameter, calculated area, calculated volume, cumulative diameter, and tridimentionnal volume [V3D]) were analyzed using the area under the receiver operating characteristics curve and logistic regression. RESULTS: Maximal diameter (AUC=0.75), calculated area (AUC 0.79), calculated volume (AUC=0.79), cumulative diameter (AUC=0.80) and tridimensional volume (AUC=0.82) revealed ability to predict SF status after URS. CONCLUSION: Stone burden evaluation is critical in predicting SF status after a single URS. Planar and volumetric measurements showed equal ability to predict SF status. V3D is more accurate but diameter measurement remains easier in clinical practice. LEVEL OF EVIDENCE: 4.

[Diagnosis and treatment of nephrolithiasis and prevention of recurrences]. / Mise au point et traitement des lithiases rénales et prévention des récidives.

INTRODUCTION: despite fluctuations, the prevalence of nephrolithiasis has significantly increased during the last decades in industrialized nations worldwide (1 to 15 %), which has a significant impact on the cost of healthcare. This increased prevalence is mainly explained by diet modifications. Environmental, metabolic and genetic factors may also influence the formation of kidney stones. As a consequence, the medical management of this disease is preferentially multidisciplinary and involves urologists, nephrologists, radiologists, biologists and dietitians. Urological management : may be mandatory during any acute and/or remote phase of an episode of renal colic, in case of residual stones. Several techniques are available: insertion of double J stent, extracorporeal shock wave lithotripsy, ureteroscopy (flexible or rigid), percutaneous nephrolithotomy and more occasionally, open surgery. Nephrological management: is justified in the course of the acute episode and aims to identify the causal factor(s) of kidney stones formation. The diagnostic approach involves a thorough interrogation (personal medical and surgical history, details of the kidney stone disease and family medical history) as well as a metabolic assessment. Moreover, given the high rate of recurrence (about 50 % within 5 to 10 years), individualized secondary prevention measures are necessary. The recommendations should take into account the identified risk factors and any metabolic abnormalities.

INTRODUCTION: la néphrolithiase est une affection dont la prévalence (1 à 15 %) a beaucoup augmenté ces dernières décennies dans les pays industrialisés et a, de ce fait, un impact sur les dépenses en soins de santé. Cette augmentation de prévalence s'explique essentiellement par une modification des habitudes alimentaires. La survenue d'une néphrolithiase peut en outre, être influencée par des facteurs environnementaux, métaboliques voire génétiques. La prise en charge de cette affection est le plus souvent pluridisciplinaire, impliquant urologues, néphrologues, radiologues, biologistes et diététiciens. La prise en charge urologique peut être nécessaire en phase aiguë et/ou à distance de l'épisode de colique néphrétique, pour l'élimination éventuelle de calculs résiduels. Plusieurs techniques sont disponibles : la mise en place de sondes double J, la lithotritie extracorporelle, l'urétéroscopie (souple ou rigide) voire la néphrolithotomie percutanée et plus rarement la chirurgie ouverte. La prise en charge néphrologique est justifiée au décours de l'épisode aigu et vise à identifier la ou les cause(s) ayant conduit à la formation de calculs. La démarche diagnostique comporte un interrogatoire approfondi (antécédents personnels médicaux et chirurgicaux, histoire de la maladie lithiasique et antécédents familiaux) et un bilan métabolique. Par ailleurs, compte-tenu du taux élevé de récidive (environ 50 % dans les 5 à 10 ans), la mise en place de mesures individualisées de prévention secondaire est nécessaire. Ces recommandations doivent tenir compte des facteurs de risque identifiés et des éventuelles anomalies du bilan métabolique.

Clinical impact of NK-cell reconstitution after reduced intensity conditioned unrelated cord blood transplantation in patients with acute myeloid leukemia: analysis of a prospective phase II multicenter trial on behalf of the Société Française de Greffe de Moelle Osseuse et Thérapie Cellulaire and Eurocord.

Unrelated cord blood transplantation (UCBT) after a reduced intensity conditioning regimen (RIC) has extended the use of UCB in elderly patients and those with co-morbidities without an HLA-identical donor, although post-transplant relapse remains a concern in high-risk acute myeloid leukemia (AML) patients. HLA incompatibilities between donor and recipient might enhance the alloreactivity of natural killer (NK) cells after allogeneic hematopoietic stem-cell transplantation (HSCT). We studied the reconstitution of NK cells and KIR-L mismatch in 54 patients who underwent a RIC-UCBT for AML in CR in a prospective phase II clinical trial. After RIC-UCBT, NK cells displayed phenotypic features of both activation and immaturity. Restoration of their polyfunctional capacities depended on the timing of their acquisition of phenotypic markers of maturity. The incidence of treatment-related mortality (TRM) was correlated with low CD16 expression (P=0.043) and high HLA-DR expression (P=0.0008), whereas overall survival was associated with increased frequency of NK-cell degranulation (P=0.001). These features reflect a general impairment of the NK licensing process in HLA-mismatched HSCT and may aid the development of future strategies for selecting optimal UCB units and enhancing immune recovery.

[Evaluation of adverse events caused by intravesical BCG instillations: Has the strain used a potential implication?]. / Évaluation des effets indésirables des instillations endovésicales par BCG : implication potentielle de la souche utilisée ?

INTRODUCTION: Intravesical instillations of BCG represent an established treatment of high-risk non-muscle-invasive bladder cancer but also carry considerable toxicity. The aim of this work was to identify adverse effects, their impact on the treatment and the possible involvement of the BCG strain used. MATERIAL AND METHODS: To evaluate adverse events in terms of incidence, severity and moment of occurrence, we performed a retrospective analysis of all patients treated with BCG in our institution from 1998 to 2012. RESULTS: One hundred and forty-six patients were retained for analysis, 140 (95.9%) finished their first induction cycle. Thirty patients (20.6%) had to stop the treatment because of BCG-related adverse events, 80% of which happened during the first 3 BCG cycles (12 instillations). The strain used may have had a significant impact: 16 out of 42 patients (38.1%) treated with Connaught (Immucyst®) and 14 out of 104 patients (13.5%) treated with Tice (Oncotice®) had to stop treatment because of BCG related adverse events (P=0.0019) with an odds ratio of 2.83 (IC 95%: 1.52-5.23). CONCLUSION: BCG-related adverse events generally occur at the beginning of the treatment and therefore do not limit the use of BCG maintenance therapy. Good instillation practice and, in our series, the shift from Connaught to Tice strain enabled to significantly reduce BCG-related adverse events through time. The potential implication of the BCG strain used should be evaluated in prospective trials.

[Mucositis after allogeneic stem cell transplantation: Risk factors, clinical consequences and prophylaxis]. / La mucite post-allogreffe de cellules souches hématopoïétiques: facteurs de risque, conséquences cliniques et prévention.

AIM: Oral mucositis is a very common complication of allograft. However, preventive treatments are still limited. The objective of this study is to identify risk factors for onset of oral mucositis in patients undergoing allogeneic hematopoietic stem cells transplantation (HSCT), to measure clinical consequences and to study their evolution according to type of prevention. PATIENTS AND METHODS: All patients undergoing HSCT in hematology unit of CHU Besançon between January 2009 and August 2010 were included, and received according to their choice, either the standard protocol: solution of sodium bicarbonate 1.4% associated with chlorhexidine-chlorobutanol (Eludril(®)) (n=49), or the experimental treatment by the ionic solution, Caphosol(®) (n=42). RESULTS: The overall incidence of severe mucositis and mucositis is respectively 69% and 36%. In multivariate analysis, a myeloablative conditioning (OR=11.1) and prevention of GVHD (graft-versus-host disease) including methotrexate (OR=7.5) appear such as the two significant mucositis risk factors. The presence of mucositis resulting in a significant increase in the incidence of febrile aplasia (P=0.008) and the use of opioid analgesics and parenteral nutrition (P<10(-3)). The risk of acute gastrointestinal GVHD is also increased in severe mucositis (P=0.01). The duration of post-transplant hospitalization is not changed. The type of prevention does not influence the incidence of mucositis (P=0.11). CONCLUSION: The consequences of mucositis are significant and the risk factors identified. The interest of the ionic solution Caphosol(®) seems limited, the incidence of mucositis is not decreased by this prevention.

Mucormycosis after allogeneic haematopoietic stem cell transplantation: a French Multicentre Cohort Study (2003-2008).

We conducted a nationwide retrospective study to evaluate clinical characteristics and outcome of mucormycosis among allogeneic haematopoietic stem cell transplant recipients. Twenty-nine patients were diagnosed between 2003 and 2008. Mucormycosis occurred at a median of 225 days after allogeneic haematopoietic stem cell transplant, and as a breakthrough infection in 23 cases. Twenty-six patients were receiving steroids, mainly for graft-versus-host disease treatment, while ten had experienced a prior post-transplant invasive fungal infection. Twenty-six patients received an antifungal treatment; surgery was performed in 12. Overall survival was 34% at 3 months and 17% at 1 year.

Ribosomal and mitochondrial DNA target for real-time PCR diagnosis of invasive aspergillosis.

The aim of the present study was to assess the diagnostic efficacy of a combination of two quantitative Aspergillus PCR assays, targeting a mitochondrial and a ribosomal target, in patients with risk factors for invasive aspergillosis (IA) and positive galactomannan (GM) antigen. Forty-four patients with hematological malignancies and risk factors for IA according to revised European Organization for Research on Treatment of Cancer and the Mycoses Study Group criteria (EORTC/MSG) criteria and presenting at least two sequential GM-positive sera were included in the study. Mitochondrial PCR was carried out prospectively on all GM-positive serum samples. Ribosomal PCR was carried out retrospectively on frozen stored sera. The sensitivities of mitochondrial and ribosomal PCRs were 58% and 50%, respectively. The diagnostic test performance was improved by using a combination of both PCR assays and by considering a patient PCR positive when at least two positive results were obtained. The sensitivity, specificity, and positive and negative likelihood ratios were 65%, 94%, and 11.8 and 0.37, respectively. A significant association between fatal outcome at 90 days and positive results of ribosomal PCR assays was observed (adjusted hazard ratio = 8.2; 95% confidence interval [CI] = 1.0 to 65.8; P = 0.048). Our results showed that the combination of two PCR assays targeting mitochondrial and ribosomal Aspergillus DNA improves the sensitivity of PCR in the diagnosis of IA in hematological patients with risk factors and positive GM results. This study also confirms that a positive PCR result is associated with a poor prognosis in these patients and should lead to specific antifungal therapy being introduced immediately.

Diagnosis and treatment of digestive cryptosporidiosis in allogeneic haematopoietic stem cell transplant recipients: a prospective single centre study.

Digestive cryptosporidiosis (DC) can mimic GVHD after allogeneic haematopoietic stem cell transplantation (HSCT), thus requiring a reduction of immunosuppressive drugs and a specific therapy, whereas GVHD requires an intensification of immunosuppression. We systematically searched for cryptosporidiosis by light microscopy, immunochromatography and PCR in HSCT recipients who presented with at least one episode of diarrhoea. Of 115 consecutive patients allografted between July 2006 and November 2008, we analysed stools in 52 of 56 patients meeting these criteria. We identified Cryptosporidium parvum in 5 of the 52 patients (9.6%) at a median of 503 days (range 20-790) after HSCT. In those five patients, the median CD4+ cell and B lymphocyte counts were 60/mm3 (0-234) and 0/mm3 (0-96), respectively. Two patients died of invasive fungal infections. In the other three patients, diarrhoea disappeared after a median of 5 weeks following onset of bitherapy with azithromycine and nitazoxanide; they were still alive 433, 380 and 1179 days after the DC diagnosis. DC is probably under diagnosed after HSCT because it is difficult to detect during the asymptomatic phase. Early bitherapy and reduction of immunosuppression seem efficacious. In our series, DC has a seasonal pattern and is promoted by profound T lymphopenia.

False-positive Aspergillus real-time PCR assay due to a nutritional supplement in a bone marrow transplant recipient with GVH disease.

PCR screening for circulating DNA, especially when combined with antigen testing, has shown promise for the definitive diagnosis of invasive aspergillosis. False positives for Aspergillus real-time PCR assays have been described in several reports, but no sources of fungal DNA contamination could be clearly identified. We report a false-positive case for both galactomannan (GM) antigenemia and Aspergillus PCR due to nutritional supplement intake in a bone marrow transplant recipient with digestive graft-versus-host disease. Our case report also suggests that fungal DNA can pass into the serum from the intestinal tract in the same way as fungal GM. Clinicians should be aware of this possibility, so that the administration of costly, unnecessary antifungal treatments with potential adverse side-effects can be avoided.

[Hypereosinophilic syndromes: pathogenic and therapeutic up-to-date]. / Syndromes hyperéosinophiliques : actualités physiopathologiques et thérapeutiques.

The hypereosinophilic syndromes (HES), defined by an unexplained and sustained hypereosinophilia, can be associated with heterogeneous hematological conditions. Several molecular mechanisms underlying the eosinophilia, which remained indeterminate for a long time, have been recently identified. These recent advances allowed a better classification of the various forms of HES and the development of targeted therapies. The role of tyrosine kinases, especially PDGFRA, and the efficacy of tyrosine kinases inhibitors dramatically improved the diagnosis and the treatment of myeloproliferative variant of HES. On the other side, eosinophilia can be driven by IL-5 secreting abnormal and often clonal T cell subsets (lymphocytic variant of HES). The crucial role of this cytokine in eosinophil development, activation and survival leads to the assessment of anti-IL-5 monoclonal antibodies which have recently shown to provide a significant corticosteroid sparing effect in FIP1L1-PDGFRA negative HES patients. Despite these major advances, half of HES remains unexplained (idiopathic HES). Some FIPL1-PDGFRA negative patients respond to imatinib, suggesting the role of other tyrosine kinases (or other partners than FIP1L1 in a fusion gene implicating PDGFRA). Development of new biomarkers is needed to help physicians in the diagnosis, classification of HES and in the choice of a targeted therapy.

AllergoOncology: the role of IgE-mediated allergy in cancer.

Epidemiological studies have suggested inverse associations between allergic diseases and malignancies. As a proof of concept for the capability of immunoglobulin E (IgE) to destruct tumor cells, several experimental strategies have evolved to specifically target this antibody class towards relevant tumor antigens. It could be demonstrated that IgE antibodies specific to overexpressed tumor antigens have been superior to any other immunoglobulin class with respect to antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP) reactions. In an alternative approach, IgE nonspecifically attached to tumor cells proved to be a powerful adjuvant establishing tumor-specific immune memory. Active Th2 immunity could also be achieved by applying an oral immunization regimen using mimotopes, i.e. epitope mimics of tumor antigens. The induced IgE antibodies could be cross-linked by live tumor cells leading to tumoricidic mediator release. Thus, IgE antibodies may not only act in natural tumor surveillance, but could possibly also be exploited for tumor control in active and passive immunotherapy settings. Thereby, eosinophils, mast cells and macrophages can be armed with the cytophilic IgE and become potent anti-tumor effectors, able to trace viable tumor cells in the tissues. It is strongly suggested that the evolving new field AllergoOncology will give new insights into the role of IgE-mediated allergy in malignancies, possibly opening new avenues for tumor therapy.