A combined analysis of two prospective randomised studies exploring the impact of extended post-radiation temozolomide on survival outcomes in newly diagnosed glioblastoma.

PURPOSE: The optimal duration of post-radiation temozolomide in newly diagnosed glioblastoma remains unclear, with no published phase III randomised trials. Standard-of-care stipulates 6 months. However, in routine care, it is often extended to 12 months, despite lacking robust supporting data. METHODS: GEINO14-01 (Spain) and EX-TEM (Australia) studies enrolled glioblastoma patients without progression at the end of 6 months post-radiation temozolomide. Participants were randomised 1:1 to six additional months of temozolomide or observation. Primary endpoint was 6-month progression free survival from date of randomisation (6mPFS). Secondary endpoints included overall survival (OS) and toxicity. 204 patients were required to detect an improvement in 6mPFS from 50 to 60% (80% power). Neither study recruited sufficient patients. We performed a combined analysis of individual patient data. RESULTS: 205 patients were recruited: 159 in GEINO14-01 (2014-2018) and 46 in EX-TEM (2019-2022). Median follow-up was 20.0 and 14.5 months. Baseline characteristics were balanced. There was no significant improvement in 6mPFS (57.2% vs 64.0%, OR0.75, p = 0.4), nor across any subgroups, including MGMT methylated; PFS (HR0.92, p = 0.59, median 7.8 vs 9.7 months); or OS (HR1.03, p = 0.87, median 20.1 vs 19.4 months). During treatment extension, 64% experienced any grade adverse event, mainly fatigue and gastrointestinal (both 54%). Only a minority required treatment changes: 4.5% dose delay, 7.5% dose reduction, 1.5% temozolomide discontinuation. CONCLUSION: For glioblastoma patients, extending post-radiation temozolomide from 6 to 12 months is well tolerated but does not improve 6mPFS. We could not identify any subset that benefitted from extended treatment. Six months should remain standard-of-care.

Exploring management and outcomes of elderly patients with glioblastoma using data from two randomised trials (GEINO1401/EX-TEM).

PURPOSE: The impact of age on optimal management of glioblastoma remains unclear. A recent combined analysis of two randomised trials, GEINO14-01 and EX-TEM, found no benefit from extending post-radiation temozolomide in newly diagnosed glioblastoma. Here, we explore the impact of age. METHODS: Relevant intergroup statistics were used to identify differences in tumour, treatment and outcome characteristics based on age with elderly patients (EP) defined as age 65 years and over. Survival was estimated using the Kaplan Meier method. RESULTS: Of the combined 205 patients, 57 (28%) were EP. Of these, 95% were ECOG 0-1 and 65% underwent macroscopic resection compared with 97% and 61% of younger patients (YP) respectively. There were numerically less MGMT-methylated (56% vs. 63%, p = 0.4) and IDH-mutated (4% vs. 13%, p = 0.1) tumours in EP vs. YP. Following surgery, EP were more likely to receive short course chemoradiation (17.5% vs. 6%, p = 0.017). At recurrence, EP tended to receive or best supportive care (28.3% vs. 15.4%, p = 0.09) or non-surgical options (96.2% vs. 84.6%, p = 0.06), but were less likely to receive bevacizumab (23.1% vs. 49.5%, p < 0.01). Median PFS was similar at 9.3months in EP and 8.5months in YP, with similar median OS at 20months. CONCLUSION: In this trial population of predominantly fit EP, survival was similar to YP despite a proportion receiving less aggressive therapy at diagnosis and recurrence. Advancing age does not appear to be an adverse prognostic factor for glioblastoma when patients are fit for treatment, and a less aggressive approach in selected patients may not compromise outcomes.

[Atypical hand, foot and mouth disease in adults: A note on 6 cases]. / Syndrome main-pied-bouche atypique de l'adulte : à propos de 6 observations.

INTRODUCTION: Hand, foot and mouth disease (HFMD) is form of viral dermatosis well known among the pediatric population, in whom it has a typical presentation. However, it is less common in adults, with a more heterogeneous presentation, potentially making diagnosis extremely challenging for the clinician. PATIENTS AND METHODS: This was a retrospective case series from 2013 to 2018 of HFMD in adults, with all cases being confirmed by cutaneous polymerase chain reaction (PCR). We studied the clinical, epidemiological and viral characteristics of each patient. RESULTS: This series of 6 cases comprised 4 men and 2 women, with a mean age of 42.5 years. Five patients presented extended purpuric lesions, four had bullous lesions, and three showed cutaneous signs without any mucosal lesions. Extended lesions on the trunk were found in four patients. One patient presented rosette-shaped pustular lesions on the limbs, one had eczema-like lesions on the scalp, and one presented extended purpuric lesions on the soles. DISCUSSION: These different cases of adult HFMD raise questions about differential diagnosis in relation to other acute cutaneous and mucous diseases. It is essential to be aware of these different types of presentation of the disease in order to determine the diagnosis and discuss preventive measures.

[Eruptive disseminated superficial porokeratosis associated with acute hepatitis E]. / Porokératose éruptive superficielle disséminée associée à une hépatite virale E aiguë.

BACKGROUND: Porokeratosis (PK) is a rare form of dermatosis characterized by a keratinization disorder of unknown etiology. Herein we describe the first case associated with hepatitis E virus infection. PATIENTS AND METHODS: A 69-year-old patient with colorectal cancer treated with radiation and chemotherapy followed by surgery in April 2017 presented two months later with jaundice associated with annular keratotic lesions of the skin with a raised border. Blood tests revealed elevated liver enzymes and hyperbilirubinemia. Viral hepatitis E was diagnosed based on serology and viral PCR after other aetiologies such as obstruction, auto-immune disease and other viruses (HAV, HBV, HCV, HSV, HIV, EBV and CMV) had been ruled out. A skin biopsy showed a cornoid lamella. Disseminated superficial porokeratosis associated with hepatitis E infection was then diagnosed. DISCUSSION: The mechanism of PK is unknown and probably involves a combination of different factors. PK has been described in patients with treatment-induced immunosuppression, solid cancer or AIDS, sometimes promoted by HCV viral infection, but never with concomitant HEV infection. A combination of immunosuppression induced by radio-chemotherapy and HEV infection could have prompted the development of PK in our patient. CONCLUSION: We report the first case of eruptive disseminated superficial porokeratosis associated with hepatitis E infection. The exact role of hepatitis E infection in the development of PK is still unclear.

[Amoxicillin-induced skin rash sparing a plaque of erythema migrans: Renbök phenomenon: Case report and literature review]. / Toxidermie à l'amoxicilline épargnant une plaque d'érythème migrant : phénomène de Renbök et revue de la littérature.

INTRODUCTION: Renbök phenomenon describes the inhibition of a lesion when a different one appears. We describe the first case of Renbök phenomenon occurring in a context of erythema migrans (EM) spared by an amoxicillin-induced skin rash and we also present a literature review. CASE REPORT: A 60-year-old patient was treated with amoxicillin for EM on the right knee and subsequently developed generalized erythema as a result of an antibiotic-induced skin rash, with sparing of the area previously affected by EM. Renbök phenomenon was diagnosed. DISCUSSION: In 1981, Cochran et al. first described a maculopapular drug reaction, which spared the sites of previous X irradiation for a tumor. Since then, nearly 40 cases have been reported, mostly describing patient with alopecia areata of the scalp with hair growth within plaques of psoriasis. One of the mechanisms suggested is a role played by cytokine cross-regulation in competition among distinct immune responses. CONCLUSION: We report the first case of Renbök phenomenon involving EM spared by a drug reaction. This phenomenon provides an insight into inflammatory response competition within a single patient.

TRPV4 channels mediate the infrared laser-evoked response in sensory neurons.

Infrared laser irradiation has been established as an appropriate stimulus for primary sensory neurons under conditions where sensory receptor cells are impaired or lost. Yet, development of clinical applications has been impeded by lack of information about the molecular mechanisms underlying the laser-induced neural response. Here, we directly address this question through pharmacological characterization of the biological response evoked by midinfrared irradiation of isolated retinal and vestibular ganglion cells from rodents. Whole cell patch-clamp recordings reveal that both voltage-gated calcium and sodium channels contribute to the laser-evoked neuronal voltage variations (LEVV). In addition, selective blockade of the LEVV by micromolar concentrations of ruthenium red and RN 1734 identifies thermosensitive transient receptor potential vanilloid channels as the primary effectors of the chain reaction triggered by midinfrared laser irradiation. These results have the potential to facilitate greatly the design of future prosthetic devices aimed at restoring neurosensory capacities in disabled patients.

Surveillance of female patients with inherited bleeding disorders in United States Haemophilia Treatment Centres.

Inherited bleeding disorders are especially problematic for affected girls and women due to the monthly occurrence of menstrual periods and the effects on reproductive health. Although heavy menstrual bleeding (HMB) is the most common manifestation, females with inherited bleeding disorders (FBD) experience other bleeding symptoms throughout the lifespan that can lead to increased morbidity and impairment of daily activities. The purpose of this article is to describe the utility of a female-focused surveillance effort [female Universal Data Collection (UDC) project] in the United States Haemophilia Treatment Centres (HTCs) and to describe the baseline frequency and spectrum of diagnoses and outcomes. All FBD aged 2 years and older receiving care at selected HTCs were eligible for enrollment. Demographic data, diagnoses and historical data regarding bleeding symptoms, treatments, gynaecological abnormalities and obstetrical outcomes were analysed. Analyses represent data collected from 2009 to 2010. The most frequent diagnoses were type 1 von Willebrand's disease (VWD) (195/319; 61.1%), VWD type unknown (49/319; 15.4%) and factor VIII deficiency (40/319; 12.5%). HMB was the most common bleeding symptom (198/253; 78.3%); however, 157 (49.2%) participants reported greater than four symptoms. Oral contraceptives were used most frequently to treat HMB (90/165; 54.5%), followed by desmopressin [1-8 deamino-D-arginine vasopressin (DDAVP)] (56/165; 33.9%). Various pregnancy and childbirth complications were reported, including bleeding during miscarriage (33/43; 76.7%) and postpartum haemorrhage (PPH) (41/109; 37.6%). FBD experience multiple bleeding symptoms and obstetrical-gynaecological morbidity. The female UDC is the first prospective, longitudinal surveillance in the US focusing on FBD and has the potential to further identify complications and reduce adverse outcomes in this population.

Multiple sclerosis and solar exposure before the age of 15 years: case-control study in Cuba, Martinique and Sicily.

Few studies report a protective role of childhood solar exposure to multiple sclerosis. Our objective was to confirm the protective role of childhood solar exposure in multiple sclerosis in Cuba, Martinique and Sicily. This was a matched case- control study, and cases met Poser criteria for clinically, laboratory (definite, probable) multiple sclerosis. Controls were resident population, without neurological disorder, living close to cases (within 100 km), matched for sex, age (+/-5 years), residence before age 15. We recruited 551 subjects during a 1-year period (193 cases, Cuba n = 95, Sicily n = 50, Martinique n = 48; 358 controls). Some (89%) met definite clinical multiple sclerosis criteria (relapsing remitting form (with and without sequel) (74%), secondary progressive (21%), primary progressive (5%)). Odds ratios in a uni-variate analysis were: family history of multiple sclerosis (5.1) and autoimmune disorder (4.0); wearing shirt (3.5), hat (2.7), pants (2.4); sun exposure causing sunburn (1.8); sun exposure duration (1 h more/day; weekends 0.91, weekdays 0.86); bare-chested (0.6); water sports (0.2). Independent factors in the multivariate analysis were family history of multiple sclerosis (4.8 (1.50-15.10)), wearing pants under sunlight (1.9 (1.10-3.20)), sun exposure duration (1 h more/ day, weekdays 0.90 (0.85-0.98), weekends 0.93 (0.87-0.99)), water sports (0.23 (0.13-0.40)). We conclude that outdoor leisure activities in addition to sun exposure reports are associated with a reduced multiple sclerosis risk, with evidence of dose response.

[Cholesterol crystal embolism mimicking a DRESS]. / Des embolies de cristaux de cholestérol mimant un DRESS.

INTRODUCTION: Clinical presentation of cholesterol crystal embolism (CCE) can be dermatologic when cholesterol crystals become lodged in small cutaneous arteries resulting in ischemia. We report a case of CCE with erythroderma misleading to a diagnostic of drug reaction with eosinophilia and systemic symptoms (DRESS). CASE REPORT: A 66 year-old woman presented with erythroderma few months after initiation of allopurinol. Acute renal failure was present with elevation in plasma creatinine concentration (523µmol/L) and hypereosinophilia (HE) (5666/mm3). Finally, the REGISCAR score helped to rule out DRESS diagnostic. Past blood-count tests were analyzed revealing chronic HE present before allopurinol initiation. Renal biopsy identified CCE. CONCLUSION: This case is the first to report a DRESS like presentation of CCE. Clinical findings are secondary to HE and not to occlusion of cutaneous arteries.

[Exercise capacity in children with mild sleep-disordered breathing]. / Capacité physique de l'enfant présentant un syndrome d'apnée du sommeil léger.

INTRODUCTION: While the association between sleep-disordered breathing (SDB) and low physical activity has been reported in children, little information is available on the impact of SDB on exercise capacity. The aim of this study was to assess exercise capacity in children with SDB in order to estimate the relevance of exercise training intervention. METHODS: Twelve young patients with suspected SDB matched with 11 presumably healthy subjects of same age range (aged 13±0.5yr) were investigated. Both groups underwent physical activity assessment, full night polysomnography, incremental and all-out exercise tests. RESULTS: The respiratory disturbance index was higher in the patient group (4.6±4.7 vs 0.8±0.6; P=0.02). Children with SDB had lower VO2max (32.0±9.9 vs 42.3±5.7mL.kg-1.min-1, P=0.007) and lower peak power (8.6±3.4 vs 11.8±1.9W.kg-1, P=0.009). A significant correlation between VO2max and weekly physical activity only was found in the SDB group (P=0.005). CONCLUSION: Mild SDB may be associated with impairment of both aerobic and anaerobic exercise capacity in children, related to poor physical activity. Exercise training could bring clinical benefit in this population.

Expression and function of aquaporins in human skin: Is aquaporin-3 just a glycerol transporter?

The aquaporins (AQPs) are a family of transmembrane proteins forming water channels. In mammals, water transport through AQPs is important in kidney and other tissues involved in water transport. Some AQPs (aquaglyceroporins) also exhibit glycerol and urea permeability. Skin is the limiting tissue of the body and within skin, the stratum corneum (SC) of the epidermis is the limiting barrier to water loss by evaporation. The aquaglyceroporin AQP3 is abundantly expressed in keratinocytes of mammalian skin epidermis. Mice lacking AQP3 have dry skin and reduced SC hydration. Interestingly, however, results suggested that impaired glycerol, rather than water transport was responsible for this phenotype. In the present work, we examined the overall expression of AQPs in cells from human skin and we reviewed data on the functional role of AQPs in skin, particularly in the epidermis. By RT-PCR on primary cell cultures, we found that up to 6 different AQPs (AQP1, 3, 5, 7, 9 and 10) may be selectively expressed in various cells from human skin. AQP1, 5 are strictly water channels. But in keratinocytes, the major cell type of the epidermis, only the aquaglyceroporins AQP3, 10 were found. To understand the role of aquaglyceroporins in skin, we examined the relevance to human skin of the conclusion, from studies on mice, that skin AQP3 is only important for glycerol transport. In particular, we find a correlation between the absence of AQP3 and intercellular edema in the epidermis in two different experimental models: eczema and hyperplastic epidermis. In conclusion, we suggest that in addition to glycerol, AQP3 may be important for water transport and hydration in human skin epidermis.

An epidemiological study of familial neurocysticercosis in an endemic Mexican community.

Neurocysticercosis (NC) caused by Taenia solium is a frequent parasitic disease of the central nervous system. It is highly endemic in many developing countries, where many people are exposed but few become infected. Here, the relevance of age, gender, and genetic and exposure factors on NC susceptibility was studied in 649 inhabitants of a rural community of Mexico. Endemicity was confirmed by the high prevalence of pig cysticercosis (32.8%) and human seroprevalence (43.8%). Human NC cases were diagnosed by computerised tomography scans. A questionnaire to evaluate risk factors was applied and familial relationships between participants were registered. An overall NC frequency of 9.1% (59/649) was found. NC frequency increased with age but did not associate with gender. Most NC cases were asymptomatic. None of the evaluated risk factors were associated with NC. No familial aggregation was detected when studying all cases, although a significant relationship between mother and child in cases with multiple parasites was found. These findings point to the fact that human NC in high exposure conditions is not simply related to exposure factors and they do not support the participation of a major gene in single-cyst NC. Rather, our results point to a complex interaction of genetic and environmental factors involved in NC.

Expression and function of neurotrophins and their receptors in human melanocytes.

Melanocytes and cells of the nervous system are of common ectodermal origin and neurotrophins (NT) have been shown to be released by human keratinocytes. We investigated the expression and function of NT [nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), NT-3, NT-4/-5] and their receptors in human melanocytes. Human melanocytes produce all NT in different amounts, whereas they only release NT-4. NT-4 release is downregulated, whereas NT-3 is upregulated by ultraviolet (UVB) irradiation. Melanocytes treated with phorbol 12-myristate 13-acetate (PMA) express TrkA and TrkB, but not TrkC. NT fail to stimulate melanocyte proliferation, whereas they stimulate the synthesis of tyrosinase and tyrosinase-related protein-1 (TRP-1). Finally, NT-3, NT-4 and NGF increase melanin production. Taken together, these results demonstrate an intriguing interaction between melanocytes and the nervous system. We speculate that NT could be considered the target of therapy for disorders of skin pigmentation.

Multicenter phase II trial of interleukin-2, interferon-alpha, and 13-cis-retinoic acid in patients with metastatic renal-cell carcinoma.

PURPOSE: To determine the response rate and toxicity of oral 13-cis-retinoic acid (CRA) added to an outpatient regimen of subcutaneous interleukin-2 (IL2) and interferon-alpha (IFNA) in previously untreated patients with metastatic renal-cell carcinoma (RCC). PATIENTS AND METHODS: Eligibility included a performance status of 2 or better, no significant end-organ dysfunction, and written informed consent. Characteristics of 47 of 48 assessable patients included a median performance status of 0, prior nephrectomy in 68% of patients, one metastatic site in 30% of patients, and lung-only metastatic disease in 21% of patients. Therapy consisted of IL2 11 x 10(6) IU 4 days per week for 4 weeks, IFNA 9 x 10(6) IU 2 days per week for 4 weeks, and CRA 1 mg/kg daily on a 6-week cycle. RESULTS: Eight of 47 patients (17%) responded (one complete response, seven partial responses). Three partial responders were rendered disease free by subsequent surgical resection. Four additional patients experienced a minor response in lung or soft tissue metastases. The median duration of response, which included minor responses, was 42 weeks, and median survival was 74 weeks (17 months). Grades 3 or greater toxicities during the first cycle included flu-like symptoms (21% of patients), fatigue (6% of patients), and nausea and vomiting (15% of patients). Significant cumulative toxicities were hyperlipidemia (four of 18 patients), and cardiomyopathy (one of 18 patients). There was one therapy-related death. CONCLUSION: Outpatient CRA plus IL2 and IFNA is feasible and modestly effective in metastatic RCC. The prolonged median survival is encouraging, but randomized trials are required to show that the combination represents an improvement over single-agent immunotherapy.

Feasibility of using quinine, a potential multidrug resistance-reversing agent, in combination with mitoxantrone and cytarabine for the treatment of acute leukemia.

PURPOSE: We demonstrated previously that sera from quinine-treated patients reversed the multidrug resistance (MDR) of a human leukemic cell line. We now report a phase I and II clinical study that examined the toxicity of the combination of quinine with mitoxantrone and cytarabine (Ara-C). PATIENTS AND METHODS: Fifteen adult patients with relapsed or refractory acute leukemia were treated with quinine formiate (30 mg/kg/d in continuous intravenous (IV) infusion from day 1 through day 5 or 6) associated with Ara-C (1 g/m2 in 3-hour IV infusion twice a day for 5 days) and five increasing doses of mitoxantrone (from 8 mg/m2/d for 4 days to 12 mg/m2/d for 5 days). RESULTS: The main toxicity was severe myelosuppression: the mean times to leukocyte recovery (> 500/microL), granulocytes recovery (> 500/microL), and platelet count recovery (> 50,000/microL) were 23 days (range, 17 to 29 days), 30.6 days (range, 17 to 48 days), and 35.4 days (range, 14 to 75 days), respectively. The nonhematopoietic toxicity of this regimen was acceptable. Nausea and vomiting were common, but severe mucositis was observed in only two patients. Cardiotoxicity was limited to transient episodes of moderate supraventricular tachycardia and a clinically well-tolerated bradycardia. Tinnitus and vertigo were observed in 10 cases (67%), and mild hearing loss and transient increase of serum bilirubin were observed in six patients (40%). Total quinine serum levels reached a steady-state concentration between 6.4 and 18 mg/L in 24 hours. Complete remission (CR) was achieved in eight of 14 (57%) assessable patients, and partial response (PR) was achieved in two additional patients (14%). P-glycoprotein expression was detected on blast cells from five of 13 studied patients before treatment. A response was observed in all P-glycoprotein-positive cases. CONCLUSION: Quinine can be used safely as a potential reversing agent of MDR for the treatment of clinically resistant acute leukemias.

Improved management of invasive pulmonary aspergillosis in neutropenic patients using early thoracic computed tomographic scan and surgery.

PURPOSE: The prognosis of invasive pulmonary aspergillosis (IPA) occurring in neutropenic patients remains poor. We studied whether new strategies for early diagnosis could improve outcome in these patients. PATIENTS AND METHODS: Twenty-three histologically proven and 14 highly probable IPAs in 37 hematologic patients (neutropenic in 36) were analyzed retrospectively. RESULTS: The most frequent clinical signs associated with IPA were cough (92%), chest pain (76%), and hemoptysis (54%). Bronchoalveolar lavage (BAL) was positive in 22 of 32 cases. Aspergillus antigen test was positive in 83% of cases when tested on BAL fluid. Since October 1991, early thoracic computed tomographic (CT) scans were systematically performed in febrile neutropenic patients with pulmonary x-ray infiltrates. This approach allowed us to recognize suggestive CT halo signs in 92% of patients, compared with 13% before this date, and the mean time to IPA diagnosis was reduced dramatically from 7 to 1.9 days. Among 36 assessable patients, 10 failed to respond (amphotericin B [AmB] plus fluorocytosyne, n = 2; itraconazole + AmB, n = 8) and died of aspergillosis. Twenty-six patients were cured or improved by antifungal treatment (itraconazole with or without AmB, n = 22; voriconazole, n = 4). In 15 of 16 cases, surgical resection was combined successfully with medical treatment. Achievement of hematologic response, early diagnosis, unilateral pulmonary involvement, and highest level of fibrinogen value < 9 g/L were associated with better outcome. CONCLUSION: In febrile neutropenic patients, systematic CT scan allows earlier diagnosis of IPA. Early antifungal treatment, combined with surgical resection if necessary, improves IPA prognosis dramatically in these patients.