Remotely sensed environmental measurements detect decoupled processes driving population dynamics at contrasting scales.

The increasing availability of satellite imagery has supported a rapid expansion in forward-looking studies seeking to track and predict how climate change will influence wild population dynamics. However, these data can also be used in retrospect to provide additional context for historical data in the absence of contemporaneous environmental measurements. We used 167 Landsat-5 Thematic Mapper (TM) images spanning 13 years to identify environmental drivers of fitness and population size in a well-characterized population of banner-tailed kangaroo rats (Dipodomys spectabilis) in the southwestern United States. We found evidence of two decoupled processes that may be driving population dynamics in opposing directions over distinct time frames. Specifically, increasing mean surface temperature corresponded to increased individual fitness, where fitness is defined as the number of offspring produced by a single individual. This result contrasts with our findings for population size, where increasing surface temperature led to decreased numbers of active mounds. These relationships between surface temperature and (i) individual fitness and (ii) population size would not have been identified in the absence of remotely sensed data, indicating that such information can be used to test existing hypotheses and generate new ecological predictions regarding fitness at multiple spatial scales and degrees of sampling effort. To our knowledge, this study is the first to directly link remotely sensed environmental data to individual fitness in a nearly exhaustively sampled population, opening a new avenue for incorporating remote sensing data into eco-evolutionary studies.

High-Quality Reference Genome for an Arid-Adapted Mammal, the Banner-Tailed Kangaroo Rat (Dipodomys spectabilis).

Kangaroo rats in the genus Dipodomys are found in a variety of habitat types in western North America, including deserts, arid and semiarid grasslands, and scrublands. Many Dipodomys species are experiencing strong population declines due to increasing habitat fragmentation, with two species listed as federally endangered in the United States. The precarious state of many Dipodomys populations, including those occupying extreme environments, make species of this genus valuable subjects for studying the impacts of habitat degradation and fragmentation on population genomic patterns and for characterizing the genomic bases of adaptation to harsh conditions. To facilitate exploration of such questions, we assembled and annotated a reference genome for the banner-tailed kangaroo rat (Dipodomys spectabilis) using PacBio HiFi sequencing reads, providing a more contiguous genomic resource than two previously assembled Dipodomys genomes. Using the HiFi data for D. spectabilis and publicly available sequencing data for two other Dipodomys species (Dipodomys ordii and Dipodomys stephensi), we demonstrate the utility of this new assembly for studies of congeners by conducting inference of historic effective population sizes (Ne) and linking these patterns to the species' current extinction risk statuses. The genome assembly presented here will serve as a valuable resource for population and conservation genomic studies of Dipodomys species, comparative genomic research within mammals and rodents, and investigations into genomic adaptation to extreme environments and changing landscapes.

The long-standing significance of genetic diversity in conservation.

Since allozymes were first used to assess genetic diversity in the 1960s and 1970s, biologists have attempted to characterize gene pools and conserve the diversity observed in domestic crops, livestock, zoos and (more recently) natural populations. Recently, some authors have claimed that the importance of genetic diversity in conservation biology has been greatly overstated. Here, we argue that a voluminous literature indicates otherwise. We address four main points made by detractors of genetic diversity's role in conservation by using published literature to firmly establish that genetic diversity is intimately tied to evolutionary fitness, and that the associated demographic consequences are of paramount importance to many conservation efforts. We think that responsible management in the Anthropocene should, whenever possible, include the conservation of ecosystems, communities, populations and individuals, and their underlying genetic diversity.

Incipient resistance to an effective pesticide results from genetic adaptation and the canalization of gene expression.

The resistance of pest species to chemical controls has vast ecological, economic, and societal costs. In most cases, resistance is only detected after spreading throughout an entire population. Detecting resistance in its incipient stages, by comparison, provides time to implement preventative strategies. Incipient resistance can be detected by coupling standard toxicology assays with large-scale gene expression experiments. We apply this approach to a system where an invasive parasite, sea lamprey (Petromyzon marinus), has been treated with the highly effective pesticide 3-trifluoromethyl-4-nitrophenol (TFM) for 60 years. Toxicological experiments revealed that lamprey from treated populations did not have higher survival to TFM exposure than lamprey from untreated populations, demonstrating that full-fledged resistance has not yet evolved. In contrast, we find hundreds of genes differentially expressed in response to TFM in the population with the longest history of exposure, many of which relate to TFM's primary mode of action, the uncoupling of oxidative phosphorylation, and subsequent depletion of ATP. Three genes critical to oxidative phosphorylation, ATP5PB, PLCB1, and NDUFA9, were nearly fixed for alternative alleles in comparisons of SNPs between treated and untreated populations (FST  > 5 SD from the mean). ATP5PB encodes subunit b of ATP synthase and an additional subunit, ATP5F1B, was canalized for high expression in treated populations, but remained plastic in response to TFM treatment in individuals from the untreated population. These combined genomic and transcriptomic results demonstrate that an adaptive, genetic response to TFM is likely driving incipient resistance in a damaging pest species.

Increased peripheral inflammation in schizophrenia is associated with worse cognitive performance and related cortical thickness reductions.

While the biological substrates of brain and behavioural changes in persons with schizophrenia remain unclear, increasing evidence implicates that inflammation is involved. In schizophrenia, including first-episode psychosis and anti-psychotic naïve patients, there are numerous reports of increased peripheral inflammation, cognitive deficits and neuropathologies such as cortical thinning. Research defining the relationship between inflammation and schizophrenia symptomatology and neuropathology is needed. Therefore, we analysed the level of C-reactive protein (CRP), a peripheral inflammation marker, and its relationship with cognitive functioning in a cohort of 644 controls and 499 schizophrenia patients. In a subset of individuals who underwent MRI scanning (99 controls and 194 schizophrenia cases), we tested if serum CRP was associated with cortical thickness. CRP was significantly increased in schizophrenia patients compared to controls, co-varying for age, sex, overweight/obesity and diabetes (p < 0.006E-10). In schizophrenia, increased CRP was mildly associated with worse performance in attention, controlling for age, sex and education (R =- 0.15, p = 0.001). Further, increased CRP was associated with reduced cortical thickness in three regions related to attention: the caudal middle frontal, the pars opercularis and the posterior cingulate cortices, which remained significant after controlling for multiple comparisons (all p < 0.05). Together, these findings indicate that increased peripheral inflammation is associated with deficits in cognitive function and brain structure in schizophrenia, especially reduced attention and reduced cortical thickness in associated brain regions. Using CRP as a biomarker of peripheral inflammation in persons with schizophrenia may help to identify vulnerable patients and those that may benefit from adjunctive anti-inflammatory treatments.

[Rieger-Marchac flaps: Complications and patient satisfaction]. / Le lambeau de Rieger-Marchac : complications et satisfaction des patients.

PURPOSE: Like all surgical procedures, dorsal nasal flaps may be followed by both early and late complications. The aim of this study was to evaluate the surgical complications and cosmetic outcome of dorsal nasal flaps over a 7-year period in an academic dermatologic surgery unit. PATIENTS AND METHODS: Data were collected retrospectively for all patients undergoing dorsal nasal flap between 1 January 2006 and 31 December 2013. Early and late complications were recorded. Patients were contacted by phone to assess long-term outcomes. RESULTS: A total of 35 patients were included. Early complications included bleeding (n=2), local infection (n=2) and focal flap necrosis (n=1). Late complications comprised flap thickening (n=7), restriction of the medial canthus (n=2), opening of the labionasal angle (n=1), stitch granuloma (n=1) and telangiectasia on the flap (n=1). Regarding the aesthetic result, seven patients were very satisfied with the flap. Four patients underwent corrective surgery and one patient had laser treatment for telangiectasia on the flap. CONCLUSION: Two thirds of patients were satisfied with the aesthetic results and one third had late complications of the flap. Consequently, patients undergoing Rieger-Marchac procedures must be informed of the potential need for further corrective measures following nasal dorsal flap repair.

Among-family variation in survival and gene expression uncovers adaptive genetic variation in a threatened fish.

Variation in among-family transcriptional responses to different environmental conditions can help to identify adaptive genetic variation, even prior to a selective event. Coupling differential gene expression with formal survival analyses allows for the disentanglement of treatment effects, required for understanding how individuals plastically respond to environmental stressors, from the adaptive genetic variation responsible for differential survival. We combined these two approaches to investigate responses to an emerging conservation issue, thiamine (vitamin B1 ) deficiency, in a threatened population of Atlantic salmon (Salmo salar). Thiamine is an essential vitamin that is increasingly limited in many ecosystems. In Lake Champlain, Atlantic salmon cannot acquire thiamine in sufficient quantities to support natural reproduction; fertilized eggs must be reared in hatcheries and treated with supplemental thiamine. We evaluated transcriptional responses (via RNA sequencing) to thiamine treatment across families and found 3,616 genes differentially expressed between control (no supplemental thiamine) and treatment individuals. Fewer genes changed expression equally across families (i.e., additively) than exhibited genotype × environment interactions in response to thiamine. Differentially expressed genes were related to known physiological effects of thiamine deficiency, including oxidative stress, cardiovascular irregularities and neurological abnormalities. We also identified 1,446 putatively adaptive genes that were strongly associated with among-family survival in the absence of thiamine treatment, many of which related to neurogenesis and visual perception. Our results highlight the utility of coupling RNA sequencing with formal survival analyses to identify candidate genes that underlie the among-family variation in survival required for an adaptive response to natural selection.

The Impact of Childhood Adversity on Cognitive Development in Schizophrenia.

Childhood adversity, such as physical, sexual, and verbal abuse, as well as neglect and family conflict, is a risk factor for schizophrenia. Such adversity can lead to disruptions of cognitive function during development, undermining intellectual capabilities and academic achievement. Schizophrenia is a neurodevelopmental disorder that is associated with cognitive impairments that may become evident during childhood. The Australian Schizophrenia Research Bank database comprises a large community cohort (N = 1169) in which we previously identified 3 distinct cognitive groups among people with schizophrenia: (1) Compromised, current, and estimated premorbid cognitive impairment; (2) Deteriorated, substantial decline from estimated premorbid function; and (3) Preserved, performing in the normal cognitive range without decline. The compromised group displayed the worst functional and symptom outcomes. Here, we extend our previous work by assessing the relationship among these categories of cognitive abilities and reported childhood adversity in 836 patients and healthy controls. Exploratory factor analysis of the Childhood Adversity Questionnaire revealed 3 factors (lack of parental involvement; overt abuse; family breakdown and hardship). People with schizophrenia reported significantly more childhood adversity than healthy controls on all items and factors. People with schizophrenia in the compromised group reported significantly more lack of parental involvement and family breakdown and hardship and lower socioeconomic status than those in the deteriorated group. The cognitive groups were not related to family history of psychosis. These findings identify specific social and family factors that impact cognition, highlighting the important role of these factors in the development of cognitive and functional abilities in schizophrenia.

Rapid genetic adaptation to a novel environment despite a genome-wide reduction in genetic diversity.

Introduced species often colonize regions that have vastly different ecological and environmental conditions than those found in their native range. As such, species introductions can provide a deeper understanding into the process of adaptive evolution. In the 1880s, steelhead trout (Oncorhynchus mykiss) from California were introduced into Lake Michigan (Laurentian Great Lakes, North America) where they established naturally reproducing populations. In their native range, steelhead hatch in rivers, migrate to the ocean and return to freshwater to spawn. Steelhead in Lake Michigan continue to swim up rivers to spawn, but now treat the freshwater environment of the Great Lakes as a surrogate ocean. To examine the effects of this introduction, we sequenced the genomes of 264 fish. By comparing steelhead from Lake Michigan to steelhead from their ancestral range, we determined that the introduction led to consistent reductions in genetic diversity across all 29 chromosomes. Despite this reduction in genetic diversity, three chromosomal regions were associated with rapid genetic adaptation to the novel environment. The first region contained functional changes to ceramide kinase, which likely altered metabolic and wound-healing rates in Lake Michigan steelhead. The second and third regions encoded carbonic anhydrases and a solute carrier protein, both of which are critical for osmoregulation, and demonstrate how steelhead physiologically adapted to freshwater. Furthermore, the contemporary release of diverse hatchery strains into the lake increased genetic diversity but reduced the signature of genetic adaptation. This study illustrates that species can rapidly adapt to novel environments despite genome-wide reductions in genetic diversity.

Comparison of auscultatory and oscillometric BP measurements in children with obesity and their effect on the diagnosis of arterial hypertension / Comparación de la medición de PA auscultatoria y oscilométrica en niños con obesidad y su efecto en el diagnóstico de hipertensión arterial

Abstract: Objective: The level of agreement between two blood pressure (BP) reading methods, auscultatory vs oscillometric, was examined using a mercury sphygmomanometer and an electronic device in children and adolescents with different levels of obesity. The readings were compared to determine their impact on the diagnosis of pre-hypertension/hypertension. Methods: Blood pressure readings were taken in children with obesity (body mass index ≥ 95th percentile) and severe obesity (≥120% 95th percentile). Bland-Altman analysis and Intraclass Correlation Coefficient were used to determine the agreement between measurements. Results: The mercury sphygmomanometer readings were lower than those obtained with the electronic device for both systolic and diastolic BP (P = .01 and P = .001, respectively). The mean systolic and diastolic BP differences between the oscillometric vs first mercury reading were 4.2/10.2 mm Hg, respectively. A large difference was observed between the BP measurement methods. The ICC showed regular to moderate reliability for the systolic BP (.595), but poor for the diastolic BP (.330). Screening using the first of three mercury measurements showed that 10.4% of the children and adolescents had BPs within the pre-hypertension/hypertension range. This was reduced to 5.2% when the mean of three mercury readings was used. Conclusions: Large discrepancies were observed in both the systolic and diastolic BP. These differences are not clinically acceptable as to consider the two instruments interchangeable. The electronic device readings were higher, and they overestimated the diagnosis of hypertension. © 2017 Instituto Nacional de Cardiología Ignacio Chávez. Published by Masson Doyma Mèxico S.A. This is an open access article under the CC BY-NC-ND license (https://creativecommons.org/licenses/by-nc-nd/4.0/).

Resumen: Objetivo: Para conocer el grado de concordancia entre 2 métodos de medición de presión arterial (PA), auscultatorio vs oscilométrico se utilizó un esfigmomanómetro de mercurio y un dispositivo electrónico en niños y adolescentes con diferentes grados de obesidad. Las lecturas fueron comparadas para conocer su impacto en el diagnóstico de prehipertensión/hipertensión. Método: Se midió la PA a niños con obesidad (percentil 95 del índice masa corporal) y obesidad severa (120% del percentil 95). Utilizamos análisis de Bland-Altman y Coeficiente de Correlación Intraclase (CCI) para conocer acuerdo entre mediciones. Resultados: Las lecturas con esfigmomanómetro de mercurio fueron más bajas que con el electrónico para la PA sistólica y diastólica (p = 0.01 y 0.001, respectivamente). El promedio de las diferencias en sistólica y diastólica entre oscilométrico vs. primera medición con mercurio fue de 4.2/10.2 mm Hg respectivamente. Se observó una gran diferencia de las mediciones entre los métodos de medición de PA. El CCI mostró una confiabilidad regular a moderada para la sistólica (0.595) pero pobre para la diastólica (0.330). El tamizaje con una medición mediante mercurio mostró que el 10.4% de los niños y adolescentes tenían PA en el rango de prehipertensión/hipertensión, pero se redujo a un 5.2% con el promedio de 3 mediciones. Conclusiones: Se observaron grandes discrepancias en la PA sistólica y diastólica. Tales diferencias no son clínicamente aceptables como para considerar equivalentes los 2 instrumentos. Las mediciones realizadas en este estudio con dispositivo electrónico fueron más altas y sobre estimaron el diagnóstico de hipertensión. © 2017 Instituto Nacional de Cardiología Ignacio Chávez. Publicado por Masson Doyma México S.A. Este es un artículo Open Access bajo la licencia CC BY-NC-ND (https://creativecommons.org/licenses/by-nc-nd/4.0/).

Anaplastic Kaposi's sarcoma: 5 cases of a rare and aggressive type of Kaposi's sarcoma.

BACKGROUND: Anaplastic Kaposi's sarcoma (KS) is a rare form of KS characterized clinically by the development of a tumour mass with unusual local aggressiveness and histologically by a specific architecture and cytological morphology. A very small number of limited series in endemic countries have established characteristics common to these anaplastic forms of KS. We present five patients with an anaplastic form in a context of KS ongoing for several years in a non-endemic country. MATERIALS AND METHODS: We collected 5 cases of anaplastic KS followed in our department over a period of 20years. We describe the main developmental, clinical, virological and histological features. RESULTS: The cases involved 4 men and 1 woman whose mean age at diagnosis of anaplastic KD was 70years, with an average time of 25years between initial diagnosis of KD and anaplastic transformation. Our patients were all treated with chemotherapy and/or radiotherapy (RT) prior to diagnosis of anaplastic transformation. All patients had a tumour mass of the lower limbs developing in classically indolent KS with associated chronic lymphoedema. Progression was very aggressive locally with deep invasion of the soft tissues as well as osteoarticular involvement, without visceral dissemination. At present, three patients are dead, one patient is showing partial response, and one patient is in locoregional progression. Diagnosis of the disease was based on histopathological findings. The tumour cells were undifferentiated, pseudo-cohesive, and chiefly organized in sheets. The mitotic count was high (27 mitoses per 10 fields at high magnification). Necrosis was constant. DISCUSSION: To our knowledge, this is the first series describing anaplastic Kaposi's sarcoma in a non-endemic country. The severity of the prognosis, despite the absence of visceral dissemination, is related to the local aggressiveness of anaplastic KS and to its resistance to radiotherapy and chemotherapy, with amputation being required in certain cases.

A fifth subtype of Kaposi's sarcoma, classic Kaposi's sarcoma in men who have sex with men: a cohort study in Paris.

BACKGROUND: Classic Kaposi's sarcoma (CKS) occurs predominantly among elderly men and is associated with Kaposi's sarcoma-associated herpesvirus (KSHV). In low-endemic countries, KSHV infects predominantly men having sex with men (MSM). OBJECTIVES: To describe a cohort of classic Kaposi sarcoma in a low-endemic area for KSHV, to highlight the features of CKS in MSM and identify prognostic factors. METHODS: Retrospective single-centre study of CKS cases. We compared MSM to heterosexual patients. Then, we divided the patients into two subgroups, those requiring a systemic treatment and the others, and we performed univariate and multivariate analyses to determine aggressiveness of CKS. RESULTS: Between 2006 and 2015, seventy-four patients were included. Mean age at diagnosis was 68.9 years; sex ratio (M/F) was 6.4, and 28% were MSM; MSM patients were younger (P = 0.02), less often originated from endemic areas (P < 0.0001). KS was less severe (P = 0.04), required more often a local treatment than a systemic one (P = 0.03). On multivariate analysis, CD4 T-cell count > 500/mm3 at baseline was associated with a reduced risk of severe evolution. CONCLUSION: First CKS cohort in low-endemic zone. We describe a fifth subtype of KS: KS in MSM. The CD4 T-cell count was found to correlate with prognosis.

Comparison of auscultatory and oscillometric BP measurements in children with obesity and their effect on the diagnosis of arterial hypertension.

OBJECTIVE: The level of agreement between two blood pressure (BP) reading methods, auscultatory vs oscillometric, was examined using a mercury sphygmomanometer and an electronic device in children and adolescents with different levels of obesity. The readings were compared to determine their impact on the diagnosis of pre-hypertension/hypertension. METHODS: Blood pressure readings were taken in children with obesity (body mass index ≥ 95th percentile) and severe obesity (≥120% 95th percentile). Bland-Altman analysis and Intraclass Correlation Coefficient were used to determine the agreement between measurements. RESULTS: The mercury sphygmomanometer readings were lower than those obtained with the electronic device for both systolic and diastolic BP (P=.01 and P=.001, respectively). The mean systolic and diastolic BP differences between the oscillometric vs first mercury reading were 4.2/10.2mmHg, respectively. A large difference was observed between the BP measurement methods. The ICC showed regular to moderate reliability for the systolic BP (.595), but poor for the diastolic BP (.330). Screening using the first of three mercury measurements showed that 10.4% of the children and adolescents had BPs within the pre-hypertension/hypertension range. This was reduced to 5.2% when the mean of three mercury readings was used. CONCLUSIONS: Large discrepancies were observed in both the systolic and diastolic BP. These differences are not clinically acceptable as to consider the two instruments interchangeable. The electronic device readings were higher, and they overestimated the diagnosis of hypertension.

[Dermatologic surgery, hemophilia and Von Willebrand disease]. / Risques en dermatologie interventionnelle chez les patients hémophiles ou atteints de la maladie de Willebrand.

BACKGROUND: Von Willebrand disease (VWD) and hemophilia A and B are the most common types of hereditary coagulation-factor deficiencies. The frequency and type of complications of skin surgery in these patients are unknown. The increasing incidence of skin cancer prompted us to reflect upon this issue. While the incidence of skin cancer is increasing, the complications of skin surgery or ablative laser treatment remain unknown in this population. AIM: The aim of this study was to determine the frequency of bleeding complications during and after skin surgery in patients with a hereditary coagulation-factor deficiency (hemophilia or VWD). PATIENTS AND METHODS: We conducted a retrospective study in patients with hemophilia A or B or VWD undergoing skin surgery or ablative laser treatment at the Dermatology Department of the Cochin Hospital in Paris, France. RESULTS: Fourteen procedures were performed in 8 patients. Three episodes of bleeding occurred (n=3/14, 21.4%): one hematoma, one delayed bleed and one immediate bleed. None of these complications required surgical revision or resuscitation. DISCUSSION: The rate of hemorrhagic complications was higher than in the general population. However, these complications can be considered non-serious and the risk-benefit ratio remains favorable. Multidisciplinary management and coordination with the reference hemophilia center are mandatory in this population to establish a coagulation-factor (CF) substitution protocol suited to the disease characteristics and the surgical procedure.

[Dermatoses and herpes superinfection: A retrospective study of 34 cases]. / Dermatoses et surinfection herpétique : étude rétrospective de 34 cas.

BACKGROUND: Although varicelliform Kaposi eruption is a well-known complication of dermatoses, it has not been widely investigated. AIM: To investigate features of dermatoses and herpes superinfection in patients hospitalized in a dermatology department. PATIENTS AND METHODS: We performed a single-centre, retrospective study between 2008 and 2014 that included cases of Kaposi varicelliform eruptions defined by positive PCR of an unconventional site of herpetic recurrence in a setting of active dermatitis. A record was compiled of each case giving details of the history, clinical and laboratory findings, therapeutic data and outcome. RESULTS: Thirty-four cases of Kaposi varicelliform eruptions in 30 subjects were studied. Mean age at diagnosis was 63.3±24.2 years. The underlying dermatoses were as follows: 7 pemphigus, 6 bullous pemphigoid, 3 cicatricial pemphigoid, 3 atopic dermatitis, 1 Darier disease, and 14 other dermatoses. Patients presented with skin (94.1 %) or mucous membrane lesions (62 %), mostly erosive (79 %), vesicular (27 %) or bullous (41 %), often painful (56 %) or pruritic (29 %). At diagnosis, 41.2 % were undergoing systemic immunotherapy and 24 % were on topical corticosteroids. PCR was positive for HSV1 in 20 cases and for HSV2 in 4 cases, and indeterminate in 10 cases. Lymphocytopenia was seen in 59 % of cases. The majority of patients received treatment. Nine patients experienced at least one relapse. CONCLUSION: Our study confirms the over-representation not only of the expected dermatoses (pemphigus and atopic dermatitis), but also of others such as pemphigoid and acute dermatoses; these results should be investigated in a more systematic prospective study.

Reassessing the clinical spectrum associated with hereditary leiomyomatosis and renal cell carcinoma syndrome in French FH mutation carriers.

We addressed uncertainties regarding hereditary leiomyomatosis and renal cell carcinoma (HLRCC) by exploring all French cases, representing the largest series to date. Fumarate hydratase (FH) germline testing was performed with Sanger sequencing and qPCR/MLPA. Enzyme activity was measured when necessary. We carried out whenever possible a pathology review of RCC and S-(2-succino)-cysteine (2SC)/fumarate hydratase immunohistochemistry. We estimated survival using non-parametric Kaplan-Meier. There were 182 cases from 114 families. Thirty-seven RCC were diagnosed in 34 carriers (19%) at a median age of 40. Among the 23 RCC with pathology review, 13 were papillary type 2. There were 4 papillary RCC of unspecified type, 3 unclassified, 2 tubulocystic, and 1 collecting duct (CD) RCC, all 2SC+ and most (8/10) FH-. Of the remaining 14, papillary type 2, papillary unspecified, CD, and clear cell histologies were reported. The vast majority of RCC (82%) were metastatic at diagnosis or rapidly became metastatic. Median survival for metastatic disease was 18 months (95%CI: 11-29). 133 cases (73%) had a history of cutaneous leiomyomas, 3 developed skin leiomyosarcoma. Uterine leiomyomas were frequent in women (77%), but no sarcomas were observed. Only 2 cases had pheochromocytomas/paraganglioma. CONCLUSION: Our findings have direct implications regarding the identification and management of HLRCC patients.

Neutrophilic eccrine hidradenitis in two patients treated with BRAF inhibitors: a new cutaneous adverse event.

Neutrophilic eccrine hidradenitis (NEH) is a rare neutrophilic dermatosis, first described in patients undergoing chemotherapy for a malignant haemopathy. It has polymorphous clinical features and the association of both clinical and histological features is necessary to make a diagnosis. We report the first two cases of NEH in patients treated with a BRAF inhibitor (BRAFi), either dabrafenib or vemurafenib, for a stage IV metastatic melanoma. Disseminated erythematous plaques associated with fever and polyarthralgia occurred early after the initiation of treatment and were badly tolerated. Histological analyses confirmed the diagnosis of NEH. Symptoms disappeared a few days after the cessation of treatment and introduction of topical steroids. The replacement of one BRAFi with another is a therapeutic alternative as it is not necessarily associated with a relapse of NEH. NEH can be added to the spectrum of neutrophilic dermatoses induced by BRAFis. It occurs earlier (3-4 days) than previously described drug-induced NEH (9-12 days) and may be an earlier stage of eccrine squamous syringometaplasia, which has already been reported in the context of BRAFi-treated patients.

Vemurafenib in metastatic melanoma patients with brain metastases: an open-label, single-arm, phase 2, multicentre study.

Background: Vemurafenib has shown activity in patients with BRAFV600 mutated melanoma with brain metastases (BM). This phase 2 study evaluated vemurafenib in patients with/without prior treatment for BM. Methods: Patients with BRAFV600 mutated melanoma with BM were enrolled into cohort 1 (previously untreated BM) and cohort 2 (previously treated BM) and received vemurafenib (960 mg BID) until disease progression (PD) or intolerance. Primary endpoint was best overall response rate (BORR) in the brain in cohort 1 that was evaluated using modified RECIST 1.1 criteria using lesions ≥0.5 cm to assess response. Results: 146 patients were treated (cohort 1 n = 90; cohort 2 n = 56), 62% of whom were male. Median (range) time since diagnosis of BM: 1.0 (0-9) month in cohort 1 and 4.2 (1-68) months in cohort 2. Median duration of treatment was 4.1 months (range 0.3-34.5) in cohort 1 and 4.1 months (range 0.2-27.6) in cohort 2. Intracranial BORR in cohort 1 by an independent review committee (IRC) was 18% (2 CRs, 14 PRs). Extracranial BORR by IRC was 33% in cohort 1 and 23% in cohort 2. Median PFS (brain only, investigator-assessed) was 3.7 months (range 0.03-33.4; IQR 1.9-5.6) in cohort 1 and 4.0 months (range 0.3-27.4; IQR 2.2-7.4) in cohort 2. Median OS was 8.9 months (range 0.6-34.5; IQR 4.9-17.0) in cohort 1 and 9.6 months (range 0.7-34.3; IQR 4.5-18.4) in cohort 2. Adverse events (AEs) were similar in type, grade and frequency to other studies of single-agent vemurafenib. Grade 3/4 AEs occurred in 59 (66%) patients in cohort 1 and 36 (64%) in cohort 2. Overall, 84% of patients died during the study (86% in cohort 1 and 80% in cohort 2), mainly due to disease progression. Conclusions: The study demonstrates clinically meaningful response rates of melanoma BM to vemurafenib, which was well tolerated and without significant CNS toxicity.