Molecular and clinical diversity in primary central nervous system lymphoma.

BACKGROUND: Primary central nervous system lymphoma (PCNSL) is a rare and distinct entity within diffuse large B-cell lymphoma presenting with variable response rates probably to underlying molecular heterogeneity. PATIENTS AND METHODS: To identify and characterize PCNSL heterogeneity and facilitate clinical translation, we carried out a comprehensive multi-omic analysis [whole-exome sequencing, RNA sequencing (RNA-seq), methylation sequencing, and clinical features] in a discovery cohort of 147 fresh-frozen (FF) immunocompetent PCNSLs and a validation cohort of formalin-fixed, paraffin-embedded (FFPE) 93 PCNSLs with RNA-seq and clinico-radiological data. RESULTS: Consensus clustering of multi-omic data uncovered concordant classification of four robust, non-overlapping, prognostically significant clusters (CS). The CS1 and CS2 groups presented an immune-cold hypermethylated profile but a distinct clinical behavior. The 'immune-hot' CS4 group, enriched with mutations increasing the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) and nuclear factor-κB activity, had the most favorable clinical outcome, while the heterogeneous-immune CS3 group had the worse prognosis probably due to its association with meningeal infiltration and enriched HIST1H1E mutations. CS1 was characterized by high Polycomb repressive complex 2 activity and CDKN2A/B loss leading to higher proliferation activity. Integrated analysis on proposed targets suggests potential use of immune checkpoint inhibitors/JAK1 inhibitors for CS4, cyclin D-Cdk4,6 plus phosphoinositide 3-kinase (PI3K) inhibitors for CS1, lenalidomide/demethylating drugs for CS2, and enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) inhibitors for CS3. We developed an algorithm to identify the PCNSL subtypes using RNA-seq data from either FFPE or FF tissue. CONCLUSIONS: The integration of genome-wide data from multi-omic data revealed four molecular patterns in PCNSL with a distinctive prognostic impact that provides a basis for future clinical stratification and subtype-based targeted interventions.

Systemic relapses of primary CNS lymphomas (PCNSL): a LOC network study.

Primary central nervous system lymphomas (PCNSLs) classically remain confined within the CNS throughout their evolution for unknown reasons. Our objective was to analyse the rare extracerebral relapses of PCNSL in a nationwide population-based study. We retrospectively selected PCNSL patients who experienced extracerebral relapse during their follow-up from the French LOC database. Of the 1968 PCNSL included in the database from 2011, 30 (1.5%, median age 71 years, median KPS 70) presented an extracerebral relapse, either pure (n = 20) or mixed (both extracerebral and in the CNS) (n = 10), with a histological confirmation in 20 cases. The median delay between initial diagnosis and systemic relapse was 15.5 months [2-121 months]. We found visceral (n = 23, 77%), including testis in 5 (28%) men and breast in 3 (27%) women, lymph node (n = 12, 40%), and peripheral nervous system (PNS) (n = 7, 23%) involvement. Twenty-seven patients were treated with chemotherapy, either with only systemic targets (n = 7) or mixed systemic and CNS targets (n = 20), 4 were consolidated by HCT-ASCT. After systemic relapse, the median progression-free survival and overall survival (OS) were 7 and 12 months, respectively. KPS > 70 and pure systemic relapses were significantly associated with higher OS. Extracerebral PCNSL relapses are rare, mainly extranodal, and frequently involve the testis, breast, and PNS. The prognosis was worse in mixed relapses. Early relapses raise the question of misdiagnosed occult extracerebral lymphoma at diagnostic workup that should systematically include a PET-CT. Paired tumour analysis at diagnosis/relapse would provide a better understanding of the underlying molecular mechanisms.

[Contribution of electronic cigarettes in smoking patients with psychotic disorders. A literature review]. / Cigarette électronique chez les patients fumeurs présentant une pathologie psychotique. Revue de la littérature.

OBJECTIVES: This systematic literature review focused on patients suffering from schizophrenia (SZ), psychotic disorders or mental illness (MI) including SZ. It was interested in data on prevalence of electronic cigarette (EC) use, patient perceptions and expectations, as well as caregivers' attitudes towards the EC and its benefit in helping to stop or reduce smoking. METHOD: The research was carried out on Medline for the period 2000-2020. Cross-sectional, case-control, prospective, randomized controlled studies and preliminary studies were included in this review. RESULTS: EC is widely used by MI patients with current and lifetime use from 7.4% to 28.6%. More specifically, patients with SZ and schizoaffective disorders observe current and lifetime use from 7% to 36%, respectively. Many reasons are given by patients for its use including the possibility of using it in places where smoking is prohibited, its lower toxicity compared to cigarettes for oneself and those around, its lower cost, and the help provided to reduce consumption. CONCLUSION: EC is used by smokers with MI; several studies confirm the possibility for these smokers to reduce tobacco consumption through EC and without disturbing their mental state. However, its value in helping to quit smoking remains uncertain.

Multimode Hydrodynamic Instability Growth of Preimposed Isolated Defects in Ablatively Driven Foils.

The Nike KrF laser facility was used to study the evolution of isolated defects with characteristic sizes of <1 to 10s of µm in laser-accelerated plastic foils. The experimental platform permitted, for the first time, the systematic study of localized perturbation growth, which is inherently multimode, through ablative Richtmyer-Meshkov and Rayleigh-Taylor stages and into the strongly nonlinear regime. Initial target defects were relatively large amplitude, but spatially localized, and emulated tent, fill-tube, and other nonuniformities that are present in inertial confinement fusion capsules. Face-on x-ray radiography indicated initial growth of the perturbation in both depth and width, followed by its apparent closure due to oblique spike growth. Hollow jetlike profiles of laterally expanding, rising, Rayleigh-Taylor bubbles were observed on the rear surface of the target from each isolated defect. Radiation hydrodynamic simulations provided insight into the mechanism of the closure and other features of the bubble and spike evolution specific to isolated defects.

A standard set of person-centred outcomes for diabetes mellitus: results of an international and unified approach.

AIMS: To select a core list of standard outcomes for diabetes to be routinely applied internationally, including patient-reported outcomes. METHODS: We conducted a structured systematic review of outcome measures, focusing on adults with either type 1 or type 2 diabetes. This process was followed by a consensus-driven modified Delphi panel, including a multidisciplinary group of academics, health professionals and people with diabetes. External feedback to validate the set of outcome measures was sought from people with diabetes and health professionals. RESULTS: The panel identified an essential set of clinical outcomes related to diabetes control, acute events, chronic complications, health service utilisation, and survival that can be measured using routine administrative data and/or clinical records. Three instruments were recommended for annual measurement of patient-reported outcome measures: the WHO Well-Being Index for psychological well-being; the depression module of the Patient Health Questionnaire for depression; and the Problem Areas in Diabetes scale for diabetes distress. A range of factors related to demographic, diagnostic profile, lifestyle, social support and treatment of diabetes were also identified for case-mix adjustment. CONCLUSIONS: We recommend the standard set identified in this study for use in routine practice to monitor, benchmark and improve diabetes care. The inclusion of patient-reported outcomes enables people living with diabetes to report directly on their condition in a structured way.

Erdheim-Chester disease: expanding the spectrum of cutaneous manifestations.

BACKGROUND: Erdheim-Chester disease (ECD) is a rare condition and there is limited information available regarding its cutaneous manifestations. OBJECTIVES: To describe the clinical and histopathological features of cutaneous involvement in ECD. METHODS: This study is a single-centre retrospective analysis of patients 18 years old and older with biopsy-proven diagnosis of ECD between 1 January 1990 and 1 April 2017. Patients from this cohort were screened for cutaneous manifestations, and BRAF c.1799T>A (p.V600E) mutational analysis was conducted in novel skin manifestations. Primary outcomes included cutaneous manifestations (morphology and topography of lesions) and BRAF mutation status in novel cutaneous findings. RESULTS: Of 71 patients with ECD, 15 patients (21%; median age 52 years) presented with cutaneous manifestations. The most common finding was the presence of xanthelasma-like lesions (n = 8). Two patients had nonfacial cutaneous xanthomas. Seven patients presented with nonxanthomatous cutaneous involvement, with the most common finding being subcutaneous nodules (n = 5). A single patient presented with granuloma annulare-like lesions. Another patient with mixed ECD and Langerhans cell histiocytosis presented with lightly scaling, pink-red macules. In three patients, the appearance of skin lesions was the first manifestation of the disease. Most patients presented with bone/extremity pain, weight loss and other constitutional symptoms at the time of diagnosis. The BRAF V600E mutation was not found in patients with panniculitis-like and granuloma annulare-like lesions. CONCLUSIONS: The most common presentation in ECD is the presence of periorbital xanthelasma-like lesions. Other presentations include nonfacial cutaneous xanthomas, panniculitis-like lesions and granuloma annulare-like lesions. Associated symptoms at presentation include bone/extremity pain and weight loss. What's already known about this topic? Erdheim-Chester disease is a rare form of non-Langerhans cell histiocytosis characterized by lipid-laden macrophage infiltration of tissue and subsequent fibrosis. Cutaneous involvement is found in approximately 25% of patients, with the majority presenting with periorbital xanthelasma-like lesions. What does this study add? We report two novel cutaneous findings: panniculitis-like lesions and granuloma annulare-like lesions. Associated bone/extremity pain and weight loss should raise suspicion for Erdheim-Chester disease.

Direct drive with the argon fluoride laser as a path to high fusion gain with sub-megajoule laser energy.

Argon fluoride (ArF) is currently the shortest wavelength laser that can credibly scale to the energy and power required for high gain inertial fusion. ArF's deep ultraviolet light and capability to provide much wider bandwidth than other contemporary inertial confinement fusion (ICF) laser drivers would drastically improve the laser target coupling efficiency and enable substantially higher pressures to drive an implosion. Our radiation hydrodynamics simulations indicate gains greater than 100 are feasible with a sub-megajoule ArF driver. Our laser kinetics simulations indicate that the electron beam-pumped ArF laser can have intrinsic efficiencies of more than 16%, versus about 12% for the next most efficient krypton fluoride excimer laser. We expect at least 10% 'wall plug' efficiency for delivering ArF light to target should be achievable using solid-state pulsed power and efficient electron beam transport to the laser gas that was demonstrated with the U.S. Naval Research Laboratory's Electra facility. These advantages could enable the development of modest size and lower cost fusion power plant modules. This would drastically change the present view on inertial fusion energy as being too expensive and the power plant size too large. This article is part of a discussion meeting issue 'Prospects for high gain inertial fusion energy (part 1)'.

Modeling reticular and ventral ruminal pH of lactating dairy cows using ingestion and rumination behavior.

The prevention and control of metabolic and digestive diseases is an enormous challenge in dairy farming. Subacute ruminal acidosis (SARA) is assumed to be the most severe feed-related disorder and it impairs both animal health and economic efficiency. Currently, ruminal pH as well as variables derived from the daily pH curve are the main indicators for SARA. The objective of this study was to explain the daily pH course in the ventral rumen and reticulum of dairy cows using ingestion pattern and rumination behavior data gathered by automated data recording systems. The data of 13 ruminally fistulated lactating cows were collected at the experimental station of the Friedrich-Loeffler-Institut (Brunswick, Germany). The data included continuous pH measurements, which were recorded simultaneously in the reticulum by pH-measuring boluses and in the ventral rumen by a separate data logger. In addition, rumination behavior was measured using jaw movement sensors, and feed and water intakes were recorded by transponder-assisted systems. Milk yield and body weight were determined during and after each milking, respectively. For statistical evaluation, the data were analyzed using time-series modeling with multiple linear mixed regressions. Before applying the developed mathematical statistical modeling, we performed a plausibility assessment to ensure data quality. The major part of the mathematical statistical modeling consisted of data preparation, where all variables were transformed into a uniform 1-min resolution. Signal transformations were used to model individual feed and water intakes as well as rumination behavior events over time. Our results indicated that diurnal pH curves of both the reticulum and ventral rumen could be predicted by the transformed feed and water intake rates. Rumination events were associated with a marginal temporal increase in pH. We observed that the pH of the ventral rumen was delayed by approximately 37 min compared with that of the reticulum, which was therefore considered in the modeling. With the models developed in this study, 67.0% of the variance of the reticular pH curves and 37.8% of the variance of the ruminal pH curves could be explained by fixed effects. We deduced that the diurnal pH course is, to a large extent, associated with the animal's individual feed intake and rumination behavior.

Poorly differentiated thyroid carcinoma : An underdiagnosed entity.

Poorly differentiated thyroid carcinomas (PDTCs) are a rare subtype of thyroid carcinomas that are biologically situated between well-differentiated papillary/follicular thyroid carcinomas and anaplastic thyroid carcinomas (ATCs).The diagnosis of conventional as well as oncocytic poorly differentiated thyroid carcinoma is difficult and often missed in daily routine. The current WHO criteria to allow the diagnosis of PDTCs are based on the results of a consensus meeting held in Turin in 2006. Even a minor poorly differentiated component of only 10%of a given carcinoma significantly affects patient prognosis and the oncocytic subtype may even have a worse outcome. Immunohistochemistry is not much help and is mostly used to exclude a medullary thyroid carcinoma with calcitonin and to establish a follicular cell of origin via thyroglobulin staining.Due to the concept of stepwise dedifferentiation, there is a vast overlap of different molecular alterations like BRAF, RAS, CTNNB1, TP53 and others between different thyroid carcinoma subtypes. A distinctive molecular tumor profile is therefore currently not available.PDTCs have a unique miRNA signature, which separates them from other thyroid carcinomas. The average relapse free survival is less than one year and about 50% of patients die of the disease. Modern tyrosine kinase inhibitors offer in conjunction with powerful molecular diagnostic new chances in these difficult to treat carcinomas.

[Diagnosis and therapy of chronic patellofemoral instability]. / Diagnostik und Therapie der chronischen patellofemoralen Instabilität.

The chronic patellofemoral instability is a multifactorial disease, which is mostly congenital. Luxation of the patella is mainly atraumatic. Sole conservative treatment is often unsuccessful. Surgical treatment is needed in most cases and requires consideration of all pathologic changes of the patella-stabilizing anatomic structures. Rupture of the medial patellofemoral ligament is almost pathognomonic. In addition, the frontal mechanical axis, rotation of femur and tibia, the trochlear shape, the distance from the tibial tuberosity to the trochlear sulcus and the patellar height play an important role. Often, in addition to soft tissue reconstruction, the bony alignment needs to be corrected. Consideration of risk factors in both adult and adolescent patients is needed to avoid recurrent instability.

Lenalidomide in combination with intravenous rituximab (REVRI) in relapsed/refractory primary CNS lymphoma or primary intraocular lymphoma: a multicenter prospective 'proof of concept' phase II study of the French Oculo-Cerebral lymphoma (LOC) Network and the Lymphoma Study Association (LYSA)†.

BACKGROUND: Primary central nervous system lymphomas (PCNSLs) are mainly diffuse large B-cell lymphomas (DLBCLs) of the non-germinal center B-cell (non-GCB) subtype. This study aimed to determine the efficacy of rituximab plus lenalidomide (R2) in DLBCL-PCNSL. PATIENTS AND METHODS: Patients with refractory/relapsed (R/R) DLBCL-PCNSL or primary vitreoretinal lymphoma (PVRL) were included in this prospective phase II study. The induction treatment consisted of eight 28-day cycles of R2 (rituximab 375/m2 i.v. D1; lenalidomide 20 mg/day, D1-21 for cycle 1; and 25 mg/day, D1-21 for the subsequent cycles); in responding patients, the induction treatment was followed by a maintenance phase comprising 12 28-day cycles of lenalidomide alone (10 mg/day, D1-21). The primary end point was the overall response rate (ORR) at the end of induction (P0 = 10%; P1 = 30%). RESULTS: Fifty patients were included. Forty-five patients (PCNSL, N = 34; PVRL, N = 11) were assessable for response. The ORR at the end of induction was 35.6% (95% CI 21.9-51.2) in assessable patients and 32.0% (95% CI 21.9-51.2) in the intent-to-treat analysis, including 13 complete responses (CR)/unconfirmed CR (uCR; 29%) and 3 partial responses (PR; 7%). The best responses were 18 CR/uCR (40%) and 12 PR (27%) during the induction phase. The maintenance phase was started and completed by 18 and 5 patients, respectively. With a median follow-up of 19.2 months (range 1.5-31), the median progression-free survival (PFS) and overall survival (OS) were 7.8 months (95% CI 3.9-11.3) and 17.7 months (95% CI 12.9 to not reached), respectively. No unexpected toxicity was observed. The peripheral baseline CD4/CD8 ratio impacted PFS [median PFS = 9.5 months (95% CI, 8.1-14.8] for CD4/CD8 ≥ 1.6; median PFS = 2.8 months, [95% CI, 1.1-7.8) for CD4/CD8 < 1.6, P = 0.03). CONCLUSIONS: The R2 regimen showed significant activity in R/R PCNSL and PVRL patients. These results support assessments of the efficacy of R2 combined with methotrexate-based chemotherapy as a first-line treatment of PCNSL. CLINICAL TRIALS NUMBER: NCT01956695.

Rarefaction Flows and Mitigation of Imprint in Direct-Drive Implosions.

Using highly resolved 3D radiation-hydrodynamic simulations, we identify a novel mechanism by which the deleterious impact of laser imprinting is mitigated in direct-drive inertial confinement fusion. Unsupported shocks and associated rarefaction flows, commonly produced with short laser bursts, are found to reduce imprint modulations prior to target acceleration. Optimization through the choice of laser pulse with picket(s) and target dimensions may improve the stability of lower-adiabat designs, thus providing the necessary margin for ignition-relevant implosions.

OCD-like behavior is caused by dysfunction of thalamo-amygdala circuits and upregulated TrkB/ERK-MAPK signaling as a result of SPRED2 deficiency.

Obsessive-compulsive disorder (OCD) is a common neuropsychiatric disease affecting about 2% of the general population. It is characterized by persistent intrusive thoughts and repetitive ritualized behaviors. While gene variations, malfunction of cortico-striato-thalamo-cortical (CSTC) circuits, and dysregulated synaptic transmission have been implicated in the pathogenesis of OCD, the underlying mechanisms remain largely unknown. Here we show that OCD-like behavior in mice is caused by deficiency of SPRED2, a protein expressed in various brain regions and a potent inhibitor of Ras/ERK-MAPK signaling. Excessive self-grooming, reflecting OCD-like behavior in rodents, resulted in facial skin lesions in SPRED2 knockout (KO) mice. This was alleviated by treatment with the selective serotonin reuptake inhibitor fluoxetine. In addition to the previously suggested involvement of cortico-striatal circuits, electrophysiological measurements revealed altered transmission at thalamo-amygdala synapses and morphological differences in lateral amygdala neurons of SPRED2 KO mice. Changes in synaptic function were accompanied by dysregulated expression of various pre- and postsynaptic proteins in the amygdala. This was a result of altered gene transcription and triggered upstream by upregulated tropomyosin receptor kinase B (TrkB)/ERK-MAPK signaling in the amygdala of SPRED2 KO mice. Pathway overactivation was mediated by increased activity of TrkB, Ras, and ERK as a specific result of SPRED2 deficiency and not elicited by elevated brain-derived neurotrophic factor levels. Using the MEK inhibitor selumetinib, we suppressed TrkB/ERK-MAPK pathway activity in vivo and reduced OCD-like grooming in SPRED2 KO mice. Altogether, this study identifies SPRED2 as a promising new regulator, TrkB/ERK-MAPK signaling as a novel mediating mechanism, and thalamo-amygdala synapses as critical circuitry involved in the pathogenesis of OCD.

(R)-GEMOX chemotherapy for unfit patients with refractory or recurrent primary central nervous system lymphoma: a LOC study.

Recurrent primary central nervous system lymphomas (PCNSL) have a very poor prognosis. For young and fit patients, intensive chemotherapy followed by autologous stem cell transplantation could be proposed at relapse. In the other cases (unfit or elderly patients), therapeutic options are limited with no consensual regimen. The poly-chemotherapy by (R)-GEMOX is associated with anti-tumor activity in systemic lymphomas and a favorable toxicity profile. Our objective was to evaluate the activity and tolerance of (R)-GEMOX in PCNSL patients enrolled in the French nation-wide LOC cohort. We retrospectively analyzed all refractory or recurrent patients included in the LOC network who benefited from (R)-GEMOX (rituximab 375 mg/m2, gemcitabine 1000 mg/m2, and oxaliplatine 100 mg/m2). Administration, tolerance, and efficacy data were analyzed. Thirteen patients, treated in five different institutions, benefited from the (R)-GEMOX regimen from February 2013 to August 2017. At the initiation of (R)-GEMOX, median age was 71.4 years old (range, 49.5-82.5) and median Karnofsky performance status (KPS) was 60 (range, 40-80). Seven patients were in second line of treatment whereas the six others were in third line or over. All patients had received methotrexate-based polychemotherapy as first-line treatment except one. Overall response rate was 38% with two complete responses and three partial responses. Median progression-free survival was 3.2 months (95%CI: 0.2-6.2), and median overall survival was 8.2 months (95%CI: 0.6-15.8). Toxicity was mainly hematological including grade ¾ neutropenia (38%), lymphopenia (23%), and thrombopenia (23%). Older age (p = 0.046) and low KPS (p = 0.054) tended to be associated with a worse prognosis. (R)-GEMOX is associated with substantial response rate and favorable toxicity profile in unfit patients with recurrent PCNSL. (R)-GEMOX could be considered to be an additional option in patients with recurrent/refractory PCNSL.

Solving the Martian meteorite age conundrum using micro-baddeleyite and launch-generated zircon.

Invaluable records of planetary dynamics and evolution can be recovered from the geochemical systematics of single meteorites. However, the interpreted ages of the ejected igneous crust of Mars differ by up to four billion years, a conundrum due in part to the difficulty of using geochemistry alone to distinguish between the ages of formation and the ages of the impact events that launched debris towards Earth. Here we solve the conundrum by combining in situ electron-beam nanostructural analyses and U-Pb (uranium-lead) isotopic measurements of the resistant micromineral baddeleyite (ZrO2) and host igneous minerals in the highly shock-metamorphosed shergottite Northwest Africa 5298 (ref. 8), which is a basaltic Martian meteorite. We establish that the micro-baddeleyite grains pre-date the launch event because they are shocked, cogenetic with host igneous minerals, and preserve primary igneous growth zoning. The grains least affected by shock disturbance, and which are rich in radiogenic Pb, date the basalt crystallization near the Martian surface to 187 ± 33 million years before present. Primitive, non-radiogenic Pb isotope compositions of the host minerals, common to most shergottites, do not help us to date the meteorite, instead indicating a magma source region that was fractionated more than four billion years ago to form a persistent reservoir so far unique to Mars. Local impact melting during ejection from Mars less than 22 ± 2 million years ago caused the growth of unshocked, launch-generated zircon and the partial disturbance of baddeleyite dates. We can thus confirm the presence of ancient, non-convecting mantle beneath young volcanic Mars, place an upper bound on the interplanetary travel time of the ejected Martian crust, and validate a new approach to the geochronology of the inner Solar System.

Chain dynamics of human dermis by Thermostimulated currents: A tool for new markers of aging.

BACKGROUND/PURPOSE: The purpose of this clinical study was to identify dielectric markers to complete a previous thermal and vibrational study on the molecular and organizational changes in human dermis during intrinsic and extrinsic aging. METHODS: Sun-exposed and non-exposed skin biopsies were collected from 28 women devised in two groups (20-30 and ≥60 years old). The dielectric relaxation modes associated with localized and delocalized dynamics in the fresh and dehydrated state were determined by the Thermostimulated currents technique (TSC). RESULTS: Intrinsic and extrinsic aging induced significant evolution of some of the dielectric parameters of localized and delocalized dynamics of human skin. With photo-aging, freezable water forms a segregated phase in dermis and its dynamics is close to free water, what evidences the major role of extrinsic aging on water organization in human skin. Moreover, TSC indicators highlight the restriction of localized mobility with intrinsic aging due to glycation, and the cumulative effect of chronological aging and photo-exposition on the molecular mobility of the main structural proteins of the dermis at the mesoscopic scale. CONCLUSION: TSC is a well-suited technique to scan the molecular mobility of human skin. It can be uses as a relevant complement of vibrational and thermal characterization to follow human skin modifications with intrinsic and extrinsic aging.

Dermatology today and tomorrow: from symptom control to targeted therapy.

For many decades and until recently, medical approach to dermatologic diseases has been based on the physician's ability to recognize and treat symptoms. Nowadays, advances in the understanding of the biology of diseases and in technologies for intervening against them have allowed physicians to diagnose and treat underlying disease processes rather than simply addressing the symptoms. This means that rather than addressing 'the disease in humans', physicians can now address the particular pathologic (biologic, molecular) disturbance as it presents in the individual patient, i.e., physicians now can practice something much closer to 'personalized medicine', leading to greater benefits for the patients and the health of society in general. The deeper understanding of ultraviolet radiation, the importance of photoprotection and increased knowledge about signalling pathways of melanoma and carcinoma have led to more complete care for the dermatologic patient. The current popularity for excessive exposure to the sun, without adequate application of the appropriate photoprotection remedies, is the origin of melanoma, but also for the weakening of the structure and functions of the skin. Indeed, fragility of the skin can affect humans around the world. In the senior population, this skin fragility is accompanied by pruritus, whereas atopic dermatitis is an inflammatory disease with highest prevalence in children and adolescents. Acne, the number one reason for dermatologic consultations worldwide, increases its prevalence in adolescents and in females. Senescent alopecia affects humans after menopause and andropause. The articles in this publication present an overview of the current advanced understanding of the diagnosis and therapeutic approaches in 6 fields of dermatology - dermatopaediatry and gerontodermatology, oncodermatology, hair loss, atopic dermatitis, photoprotection and acne - and thereby serve as a useful compendium of updated information and references for all healthcare professionals who see patients with presentations of the symptoms of these diseases.

Degenerative isolated cartilage defects of the patellofemoral joint are associated with more severe symptoms compared to trauma-related defects: results of the German Cartilage Registry (KnorpelRegister DGOU).

PURPOSE: The purpose of this study was to utilize data from the German Cartilage Registry (KnorpelRegister DGOU) to examine the hypothesis that degenerative cartilage defects of the patellofemoral joint are associated with more severe clinical symptoms compared to trauma-related defects. METHODS: All patients with isolated focal cartilage defects of the patellofemoral joint registered in the German Cartilage Registry until May 2017 were included in the study. Patients with previous surgery of the ipsilateral knee were excluded. Baseline data including etiology (traumatic, degenerative), size, location and ICRS grade of the cartilage defects as well as the duration of symptoms were analyzed. Clinical symptoms were evaluated by means of the numeric analog scale (NAS) for pain and the Knee injury and Osteoarthritis Outcome Score (KOOS). Group comparisons were performed using the Mann-Whitney-U test along with the Chi-squared test and Fisher's exact test. A bivariate correlation analysis and a multivariable linear regression analysis were performed to investigate the association between the defect characteristics and the clinical scores. RESULTS: A total of 423 patients (203 traumatic and 220 degenerative defects) were included. Isolated degenerative cartilage defects were found to have significantly more trochlear locations (28% vs. 18%; p = 0.006), significantly less ICRS grade 4 lesions (50% vs. 73%; p = 0.002) and a significantly smaller defect size [median 300 (IQR 105-400) vs. 300 (200-400) mm2] when compared to those from traumatic etiology. Traumatic defects showed significantly better KOOS-ADL [77 (60-90) vs. 69 (56-82); p = 0.005], KOOS-pain [69 (56-81) vs. 61 (47-75); p = 0.001] and NAS [2 (1-5) vs. 4 (1-6); p = 0.005] scores compared to degenerative defects. The correlation analysis revealed only weak correlations between the quantitative defect characteristics and clinical scores. CONCLUSIONS: Degenerative isolated cartilage defects in the patellofemoral joint are associated with more severe clinical symptoms in comparison to trauma-related defects. Additionally, they show a larger variance regarding their location with more trochlear defects. LEVEL OF EVIDENCE: III.

[Poorly differentiated thyroid carcinoma : An underdiagnosed entity. German version]. / Gering differenzierte Schilddrüsenkarzinome : Eine unterdiagnostizierte Entität.

Poorly differentiated thyroid carcinomas (PDTCs) are a rare subtype of thyroid carcinomas that are biologically situated between well-differentiated papillary/follicular thyroid carcinomas and anaplastic thyroid carcinomas (ATCs).The diagnosis of conventional as well as oncocytic poorly differentiated thyroid carcinoma is difficult and often missed in daily routine. The current WHO criteria to allow the diagnosis of PDTCs are based on the results of a consensus meeting held in Turin in 2006. Even a minor poorly differentiated component of only 10% of a given carcinoma significantly affects patient prognosis and the oncocytic subtype may even have a worse outcome. Immunohistochemistry is not much help and is mostly used to exclude a medullary thyroid carcinoma with calcitonin and to establish a follicular cell of origin via thyroglobulin staining.Due to the concept of stepwise dedifferentiation, there is a vast overlap of different molecular alterations like BRAF, RAS, CTNNB1, TP53 and others between different thyroid carcinoma subtypes. A distinctive molecular tumor profile is therefore currently not available.PDTCs have a unique miRNA signature, which separates them from other thyroid carcinomas.The average relapse free survival is less than one year and about 50% of patients die of the disease. Modern tyrosine kinase inhibitors offer in conjunction with powerful molecular diagnostic new chances in these difficult to treat carcinomas.

[Stopping and reducing smoking in patients with schizophrenia]. / Arrêt et réduction du tabac chez le patient souffrant de schizophrénie.

OBJECTIVES: This systematic review of the literature looked at data on pharmacological and non-pharmacological strategies of smoking cessation and reduction of consumption in patients with schizophrenia. METHOD: The research was conducted on Medline for the period 1980-2018. We included randomized controlled trials, including preliminary studies of stable schizophrenic patients with no other severe psychiatric disorder and no other substance use than tobacco, treated with antipsychotic medications. Individual or group smoking cessation programs with or without pharmacological treatment, including a validation of abstinence, were included. RESULTS: Pharmacotherapies for nicotine dependence-nicotine replacement therapy (n=3), bupropion (n=6), varenicline (n=8), association of medications (n=4)-were used in 23 studies combined with behavioral support. Compared to the placebo, bupropion and varenicline at the end of treatment were found to be the most effective pharmacotherapies to stop or reduce smoking and control craving. All the medications were well tolerated and did not lead to aggravation of psychosis or changes in symptoms. Non-pharmacological interventions: behavioral and cognitive therapies (n=5) combined with pharmacological treatment facilitated the management of smoking risk situations and improved adherence to antipsychotics; other psychosocial interventions (n=7) allowed the development of social skills; contigency management strategies with financial reinforcement can be used (n=4); the practice of physical activity and the use of an electronic cigarette allowed reduction of tobacco consumption. The results of transcranial electromagnetic stimulation studies (n=6) were discordant. Atypical antipsychotics appear to be associated with a better success of attempts to stop smoking. CONCLUSION: Smoking cessation strategies for patients with schizophrenia appear to be effective and should combine (1) smoking cessation medications with sufficient duration, (2) diversified psychosocial approaches and (3) physical activity practice.