Recommendations on the Clinical Management of Androgenetic Alopecia: A Consensus Statement From the Spanish Trichology Group of the Spanish Academy of Dermatology and Venererology (AEDV). / Recomendaciones sobre el manejo clínico de la alopecia androgénica: un documento de consenso del Grupo Español de Tricología de la Academia Española de Dermatología y Venereología.

Androgenetic alopecia can be challenging to treat due to the wide range of available treatments, most of which are not based on evidence from clinical trials. In addition many of the options do not include androgenetic alopecia among the approved indications according to their summaries of product characteristics. A panel of 34 dermatologists from the Spanish Trichology Society of the Spanish Academy of Dermatology and Venereology (AEDV) used the Delphi method to develop a consensus statement on the management of androgenetic alopecia. Over a 2-round process the experts agreed on 138 (86%) of the 160 proposed items, which were structured into 4 blocks of recommendations: general considerations, pharmacologic treatment, procedures and hair transplant, and special cases. The resulting consensus statement based on expert opinion of the scientific evidence can guide professionals in the routine management of androgenetic alopecia.

APOBEC mutagenesis, kataegis, chromothripsis in EGFR-mutant osimertinib-resistant lung adenocarcinomas.

BACKGROUND: Studies of targeted therapy resistance in lung cancer have primarily focused on single-gene alterations. Based on prior work implicating apolipoprotein b mRNA-editing enzyme, catalytic polypeptide-like (APOBEC) mutagenesis in histological transformation of epidermal growth factor receptor (EGFR)-mutant lung cancers, we hypothesized that mutational signature analysis may help elucidate acquired resistance to targeted therapies. PATIENTS AND METHODS: APOBEC mutational signatures derived from an Food and Drug Administration-cleared multigene panel [Memorial Sloan Kettering Cancer Center Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT)] using the Signature Multivariate Analysis (SigMA) algorithm were validated against the gold standard of mutational signatures derived from whole-exome sequencing. Mutational signatures were decomposed in 3276 unique lung adenocarcinomas (LUADs), including 93 paired osimertinib-naïve and -resistant EGFR-mutant tumors. Associations between APOBEC and mechanisms of resistance to osimertinib were investigated. Whole-genome sequencing was carried out on available EGFR-mutant lung cancer samples (10 paired, 17 unpaired) to investigate large-scale genomic alterations potentially contributing to osimertinib resistance. RESULTS: APOBEC mutational signatures were more frequent in receptor tyrosine kinase (RTK)-driven lung cancers (EGFR, ALK, RET, and ROS1; 25%) compared to LUADs at large (20%, P < 0.001); across all subtypes, APOBEC mutational signatures were enriched in subclonal mutations (P < 0.001). In EGFR-mutant lung cancers, osimertinib-resistant samples more frequently displayed an APOBEC-dominant mutational signature compared to osimertinib-naïve samples (28% versus 14%, P = 0.03). Specifically, mutations detected in osimertinib-resistant tumors but not in pre-treatment samples significantly more frequently displayed an APOBEC-dominant mutational signature (44% versus 23%, P < 0.001). EGFR-mutant samples with APOBEC-dominant signatures had enrichment of large-scale genomic rearrangements (P = 0.01) and kataegis (P = 0.03) in areas of APOBEC mutagenesis. CONCLUSIONS: APOBEC mutational signatures are frequent in RTK-driven LUADs and increase under the selective pressure of osimertinib in EGFR-mutant lung cancer. APOBEC mutational signature enrichment in subclonal mutations, private mutations acquired after osimertinib treatment, and areas of large-scale genomic rearrangements highlights a potentially fundamental role for APOBEC mutagenesis in the development of resistance to targeted therapies, which may be potentially exploited to overcome such resistance.

Characterization of on-target adverse events caused by TRK inhibitor therapy.

BACKGROUND: The tropomyosin receptor kinase (TRK) pathway controls appetite, balance, and pain sensitivity. While these functions are reflected in the on-target adverse events (AEs) observed with TRK inhibition, these AEs remain under-recognized, and pain upon drug withdrawal has not previously been reported. As TRK inhibitors are approved by multiple regulatory agencies for TRK or ROS1 fusion-positive cancers, characterizing these AEs and corresponding management strategies is crucial. PATIENTS AND METHODS: Patients with advanced or unresectable solid tumors treated with a TRK inhibitor were retrospectively identified in a search of clinical databases. Among these patients, the frequency, severity, duration, and management outcomes of AEs including weight gain, dizziness or ataxia, and withdrawal pain were characterized. RESULTS: Ninety-six patients with 15 unique cancer histologies treated with a TRK inhibitor were identified. Weight gain was observed in 53% [95% confidence interval (CI), 43%-62%] of patients and increased with time on TRK inhibition. Pharmacologic intervention, most commonly with glucagon-like peptide 1 analogs or metformin, appeared to result in stabilization or loss of weight. Dizziness, with or without ataxia, was observed in 41% (95% CI, 31%-51%) of patients with a median time to onset of 2 weeks (range, 3 days to 16 months). TRK inhibitor dose reduction was the most effective intervention for dizziness. Pain upon temporary or permanent TRK inhibitor discontinuation was observed in 35% (95% CI, 24%-46%) of patients; this was more common with longer TRK inhibitor use. TRK inhibitor reinitiation was the most effective intervention for withdrawal pain. CONCLUSIONS: TRK inhibition-related AEs including weight gain, dizziness, and withdrawal pain occur in a substantial proportion of patients receiving TRK inhibitors. This safety profile is unique relative to other anticancer therapies and warrants careful monitoring. These on-target toxicities are manageable with pharmacologic intervention and dose modification.

COVID-19 in patients with lung cancer.

BACKGROUND: Patients with lung cancers may have disproportionately severe coronavirus disease 2019 (COVID-19) outcomes. Understanding the patient-specific and cancer-specific features that impact the severity of COVID-19 may inform optimal cancer care during this pandemic. PATIENTS AND METHODS: We examined consecutive patients with lung cancer and confirmed diagnosis of COVID-19 (n = 102) at a single center from 12 March 2020 to 6 May 2020. Thresholds of severity were defined a priori as hospitalization, intensive care unit/intubation/do not intubate ([ICU/intubation/DNI] a composite metric of severe disease), or death. Recovery was defined as >14 days from COVID-19 test and >3 days since symptom resolution. Human leukocyte antigen (HLA) alleles were inferred from MSK-IMPACT (n = 46) and compared with controls with lung cancer and no known non-COVID-19 (n = 5166). RESULTS: COVID-19 was severe in patients with lung cancer (62% hospitalized, 25% died). Although severe, COVID-19 accounted for a minority of overall lung cancer deaths during the pandemic (11% overall). Determinants of COVID-19 severity were largely patient-specific features, including smoking status and chronic obstructive pulmonary disease [odds ratio for severe COVID-19 2.9, 95% confidence interval 1.07-9.44 comparing the median (23.5 pack-years) to never-smoker and 3.87, 95% confidence interval 1.35-9.68, respectively]. Cancer-specific features, including prior thoracic surgery/radiation and recent systemic therapies did not impact severity. Human leukocyte antigen supertypes were generally similar in mild or severe cases of COVID-19 compared with non-COVID-19 controls. Most patients recovered from COVID-19, including 25% patients initially requiring intubation. Among hospitalized patients, hydroxychloroquine did not improve COVID-19 outcomes. CONCLUSION: COVID-19 is associated with high burden of severity in patients with lung cancer. Patient-specific features, rather than cancer-specific features or treatments, are the greatest determinants of severity.

Alopecia areata totalis and universalis: a multicenter review of 132 patients in Spain.

BACKGROUND: Alopecia areata totalis (AAT) and universalis (AAU) pose a therapeutic challenge. OBJECTIVE: To describe the clinical and epidemiological features, therapeutic response and prognostic factors in a large series of patients diagnosed with AAT and AAU. METHODS: This retrospective multicenter study included patients diagnosed with AAT/AAU with a minimum follow-up of 12 months. Response was assessed based on the regrowth of scalp hair. RESULTS: In all, 132 patients (92 women and 40 men) - 80 (61%) diagnosed with AAU and 52 (39%) diagnosed with AAT - were included. The median time between the presentation of alopecia areata (AA) and the development of extensive AA was 1 year and it was less than 4 years in 121 patients (91%). There was an initial response to treatment in 64% of patients, although only 14% presented a persistent response. Adverse side effects from the medications used were detected in 33% of patients. The prognostic factors associated with poor response were the presence of AAU and a positive family history of AA. CONCLUSIONS: Treatment of AAT and AAU is challenging. Although an initial regrowth may be achieved, the duration of response is usually short. There were no significant differences on the effectiveness or duration of response between the various systemic therapies.

Folliculitis decalvans: a multicentre review of 82 patients.

BACKGROUND: Folliculitis decalvans (FD) is a rare neutrophilic scarring alopecia that represents a therapeutic challenge for dermatologists. OBJECTIVE: To describe the epidemiology, comorbidities, clinical presentation, diagnostic findings and therapeutic options in a large series of patients with FD. METHODS: This retrospective multicentre review includes patients diagnosed with FD based on clinical and histopathologic findings. The clinical severity was determined by the maximum diameter of the largest alopecic patch (slight: <2 cm, moderate: 2-4.99 cm, severe: 5 cm or more). Response to therapy was assessed as improvement, worsening or stabilization depending on the clinical symptoms (pruritus and trichodynia), inflammatory signs (erythema, pustules and crusts) and the extension of the alopecic patch. RESULTS: Overall, 82 patients (52 males and 30 females) with a mean age of 35 years were included. No significant comorbidities were present. A family history was present in three males. Severe FD was observed in 17 patients (21%). The independent factors associated with severe FD after multivariate analysis were: onset of FD before 25 years of age and presence of pustules. Oral antibiotics (tetracyclines and the combination of clindamycin and rifampicin) improved 90% and 100% of the patients, with a mean duration of response of 4.6 and 7.2 months respectively. CONCLUSIONS: The onset of FD before 25 years of age and the presence of pustules within the alopecic patch were associated with severe FD. Tetracyclines and the combination of clindamycin and rifampicin were the most useful treatments.

Diagnostic imaging in dermatology: utility of PET-CT in cutaneous melanoma.

Malignant melanoma accounts for 5% of all malignant skin tumors and its incidence is increasing. In the natural course of melanoma, tumors grow locally and can spread via the lymph system or the blood. Because survival is directly related to the stage of the disease at diagnosis, early detection (secondary prevention) has an impact on prognosis. Positron emission tomography (PET) is a nuclear medicine technique that generates images using molecules labeled with positron-emitting isotopes. The most widely used molecule is fluorodeoxyglucose (FDG). Because of the elevated glycolytic rate in tumor cells, which results in increased FDG uptake, greater quantities of FDG become trapped in tumor cells, enabling external detection. Today, most PET scanners are multimodal PET-computed tomography (CT) scanners, which provide more detailed information by combining morphological information with functional PET findings. The possible utility of PET-CT in patients with malignant melanoma is a subject of debate. Various questions have been raised: when the scan should be performed, whether PET-CT has advantages over conventional diagnostic methods, and whether PET-CT provides a real benefit to patients. In this review of the literature, we will analyze each of these questions.

Photo-isomerization fronts in dye-doped nematic liquid crystals.

An experimental study of the photo-isomerization dynamics in dye-doped nematic crystals is reported, which shows that, when the sample is illuminated by a Gaussian beam, and for high enough input power, a transition from the nematic to the isotropic phase takes place in the illuminated area. The two phases are spatially connected via a front propagating outward from the center of the beam and following the local intensity profile and thus inducing a photo-controlled optical aperture. The optical intensity and temperature fields on the sample follow the same dynamical profile. The front dynamics is described by a phenomenological bi-stable model with an inhomogeneous control parameter, directly related to the beam intensity profile.

Emergence of spatiotemporal dislocation chains in drifting patterns.

One-dimensional patterns subjected to counter-propagative flows or speed jumps exhibit a rich and complex spatiotemporal dynamics, which is characterized by the perpetual emergence of spatiotemporal dislocation chains. Using a universal amplitude equation of drifting patterns, we show that this behavior is a result of a combination of a phase instability and an advection process caused by an inhomogeneous drift force. The emergence of spatiotemporal dislocation chains is verified in numerical simulations on an optical feedback system with a non-uniform intensity pump. Experimentally this phenomenon is also observed in a tilted quasi-one-dimensional fluidized shallow granular bed mechanically driven by a harmonic vertical vibration.

Hair and scalp evaluation: the trichogram.

Hair and scalp evaluation techniques can be classified into 3 categories: noninvasive methods (clinical history, general examination, inspection and palpation of the hair and scalp, photography, dermoscopy, etc.); semi-invasive methods (the trichogram); and invasive methods (biopsy). In this article, we provide a practical guide on how to evaluate hair and scalp conditions in the dermatology office.

fMRI of the sensorimotor cortex in patients with traumatic brain injury after intensive rehabilitation.

For evaluating the patterns of brain activation in sensorimotor areas following motor rehabilitation, seven male patients diagnosed with TBI underwent an fMRI study before and after being subjected to motor rehabilitation. Six patients showed a reduction in the BOLD signal of their motor cortical areas during the second fMRI evaluation. A decrease in cerebellum activation was also observed in two patients. Newly activated areas, were observed in four patients after treatment. In addition, an increase in the activation of the supplementary motor area (SMA) following rehabilitation was observed in only one test subject. The findings show that motor rehabilitation in TBI patients produces a decrease in the BOLD signal for the sensorimotor areas that were activated prior to treatment. In addition, we observed the recruitment of different brain areas to compensate for functional loss due to TBI in line with the cortical reorganisation mechanism.

5α-Reductase isozymes and aromatase mRNA levels in plucked hair from young women with female pattern hair loss.

Female pattern hair loss (FPHL) is an important hair disorder, especially when young women are affected. However, pharmacological treatments are not successful in all women. Androgens, especially dihydrotestosterone (DHT), may play a role in FPHL, but many women with this disorder have normal serum androgen levels. It therefore appears that hair follicle levels of DHT depend on in situ testosterone (T) metabolism. Because T can be converted to DHT or estradiol (E2) by 5α-reductase (5α-R) and aromatase, respectively, these enzymes would determine DHT and E2 concentrations and their ratio. We propose and apply a low-invasive, sensitive and precise method for the absolute quantification of mRNA levels of aromatase and 5α-R isozymes (type 1, type 2 and type 3) in plucked hair from young women with FPHL. Normoandrogenic women with FPHL and controls were studied. Plucked hair samples were obtained by trichogram from vertex scalp and mRNA levels quantified by real-time RT-PCR. We revealed for the first time the presence of 5α-R3 mRNA in human hair. Interestingly, one, two, or even three 5α-R isozymes were increased in some women with FPHL but not in others, which may explain the lack of response to 5α-R inhibitors in some FPHL cases. Aromatase mRNA levels were significantly lower in women with FPHL than in controls. It may therefore produce a reduction in oestrogen levels and an increase in the androgen/oestrogen ratio in hair. The proposed low-invasive technique offers a molecular aetiologic diagnosis of FPHL for the selection of more appropriate pharmacological treatments with early predicted effectiveness.

Phospholipid molecular species, beta-oxidation, desaturation and elongation of fatty acids in Atlantic salmon hepatocytes: effects of temperature and 3-thia fatty acids.

We have investigated the effects of a 3-thia fatty acid (TTA) and of temperature on the fatty acid (FA) metabolism of Atlantic salmon (Salmo salar). One experiment investigated the activity of the peroxisomal beta-oxidation enzyme, acyl-CoA oxidase (ACO), and the incorporation of TTA into phospholipid (PL) molecular species. Salmon hepatocytes in culture were incubated either without TTA (control(spades)) or with 0.8 mM TTA (TTA(spades)) in a short term (48 h) temperature study at 5 degrees C and at 12 degrees C. TTA was incorporated into the four PL classes studied: phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI) and phosphatidylserine (PS). TTA was preferentially esterified with 18:1, 16:1, 20:4 and 22:6 in the PLs. Hepatocytes incubated with TTA had higher ACO activity at 5 degrees C than at 12 degrees C. In a second experiment salmon were fed a diet based on fish meal-fish oil without any TTA added (control) or a fish meal-fish oil diet supplemented with 0.6% TTA for 8 weeks at 12 degrees C and 20 weeks at 5 degrees C. At the end of the feeding trial, hepatocytes from fish acclimated to high or low temperatures were isolated from both dietary groups and incubated with either [1-(14)C]18:1 n-9 or [1-(14)C]20:4 n-3 at 5 degrees C or 12 degrees C. Radiolabelled 18:1 n-9 was mainly esterified into neutral lipids (NL), whereas [1-(14)C]20:4 n-3 was mainly esterified into PL at both temperatures. The rate of elongation of [1-(14)C]18:1 n-9 to 20:1 n-9 was twice as high in hepatocytes from fish fed the control diet than it was in hepatocytes from fish fed the TTA diet, at both temperatures. The amount of [1-(14)C]20:4 n-3 converted to 22:6 n-3 was approximately the same in hepatocytes from the two dietary groups, but there was a tendency to higher production of 22:6 n-3 at the lower temperature. Oxidation of [1-(14)C]18:1 n-9 to acid soluble products (ASP) and CO(2) was approximately 10-fold greater in hepatocytes kept at 5 degrees C than in those kept at 12 degrees C and the main oxidation products formed were acetate, oxaloacetate and malate.

Front propagation sustained by additive noise.

The effect of noise in a motionless front between a periodic spatial state and an homogeneous one is studied. Numerical simulations show that noise induces front propagation. From the subcritical Swift-Hohenberg equation with noise, we deduce an adequate equation for the envelope and the core of the front. The equation of the core of the front is characterized by an asymmetrical periodic potential plus additive noise. The conversion of random fluctuations into direct motion of the core of the front is responsible of the propagation. We obtain an analytical expression for the velocity of the front, which is in good agreement with numerical simulations.

[Safety of the automated microkeratome for Sub-Bowman's Keratomileusis on the flat cornea]. / Sécurité du microkératome automatisé pour le Kératomileusis sous-Bowman sur la cornée plate.

INTRODUCTION: Use of the One Use-Plus SBK (Sub-Bowman's Keratomileusis) automated microkeratome (Moria, Antony, France) has been shown to be safe, predictable and comfortable for the creation of thin corneal flaps with a smooth and regular stromal bed. PURPOSE: To evaluate the use of the Moria One Use-Plus SBK (Moria, Antony, France) automated microkeratome on corneas with 180°-keratometry under 40 diopters (D). METHODS: We retrospectively studied cases that underwent SBK whose 180°-keratometry was under 40 D. We separated the cases between 39 and 40 D and those less than 39 D. The preoperative data, the procedure and the postoperative outcomes were analyzed. The Moria One Use-Plus SBK microkeratome with the 90-micron head was used for all cases. RESULTS: Among the 2883 eyes that underwent SBK LASIK over the past six years, 80 eyes (2.77%) had a preoperative topographical 180°-keratometry of less than 40 D: 63 eyes (2.19%) between 39 and 40 D and 17 eyes (0.59%) between 38 and 39 D (38.13-38.97 D). The spherical equivalent was between -3.50 D (-2.25 sph -2.50 cyl. at 175°) and+6.00 D (+5.50 sph +1.00 cyl. at 85°). Fifty-eight eyes (72.5%) had hyperopia and/or hyperopic astigmatism; 18 eyes (22.5%) had mixed astigmatism; and 4 eyes (5%) had myopia and/or myopic astigmatism. Twenty-six eyes (32%) had a history of strabismus. Thirteen patients (27.66%) had a history of amblyopia. The "-1" ring was used in all cases, with a 7.5 stop (14%) or 8 stop (86%). The procedure went uneventfully in all cases with a stable vacuum between 117 and 123 mm Hg. The nasal hinge and the stromal bed were normal in size in all cases and sufficient to perform the photoablation laser safely with an optical zone between 6.00 and 7.00 millimeters. There were no intraoperative nor immediate postoperative complications: free cap 0%; incomplete flap 0%; button hole 0%; epithelial erosion 0%; bleeding 0%; irregular stromal bed 0%. Postoperative complications: flap displacement 0%; punctate keratitis: 8%; LASIK retreatments: 12%; safety: 100% (no loss of lines of visual acuity). DISCUSSION: Corneas with a topographical 180°-keratometry under 40 D are a very small percentage of the total eyes that undergo LASIK (SBK). Those with a 180°-keratometry under 39 D are even more infrequent. Due to the characteristics of the flat cornea, the percentage of hyperopia is much larger in than in the general LASIK group. In addition, the percentage with a history of strabismus and amblyopia is higher. CONCLUSION: The Moria One Use-Plus SBK microkeratome is an excellent device that allows the easy creation of thin corneal flaps and regular and smooth corneal beds, safely and predictably even in extremely flat corneas without complications. The safety, efficacy and predictability are quite comparable to the general LASIK group.

Effects of dietary supplementation of rapeseed oil on metabolism of [1-14C]18:1n-9, [1-14C]20:3n-6, and [1-14C]20:4n-3 in Atlantic salmon hepatocytes.

Atlantic salmon were fed fish meal-based diets supplemented with either 100% fish oil (FO) or 100% rapeseed oil (RO) from an initial weight of 85 g to a final average weight of 280 g. The effects of these diets on the capacity of Atlantic salmon hepatocytes to elongate, desaturate, and esterify [1-14C] 18:1n-9 and the immediate substrates for the delta5 desaturase, [1-14C] 20:3 n-6 and [1-14C] 20:4n-3, were investigated. Radiolabeled 18:1n-9 was mainly esterified into cellular TAG, whereas the more polyunsaturated FA, [1-14C] 20:3n-6 and [1-14C] 20:4n-3, were primarily esterified into cellular PL. More of the elongation product, [1-14C] 20:1n-9, was produced from 18:1n-9 and more of the desaturation and elongation products, 22:5n-6 and 22:6n-3, were produced from [1-14C]20:3n-6 and [1-14C] 20:4n-3, respectively, in RO hepatocytes than in FO hepatocytes. Further, we studied whether increased addition of [1-14C]18:1n-9 to the hepatocyte culture media would affect the capacity of hepatocytes to oxidize 18:1n-9 to acid-soluble products and CO2. An increase in exogenous concentration of 18:1 n-9 from 7 to 100 microM resulted in a nearly twofold increase in the amount of 18:1n-9 that was oxidized. The conversion of 20:4n-3 and 20:3n-6 to the longer-chain 22:6n-3 and 22:5n-6 was enhanced by RO feeding in Atlantic salmon hepatocytes. The increased capacity of RO hepatocytes to produce 22:6n-3 was, however, not enough to achieve the levels found in FO hepatocytes. Our data further showed that there were no differences in the hepatocyte FA oxidation capacity and the lipid deposition of carcass and liver between the two groups.

[Influence of photon scattering on the quantification of relative changes in longitudinal brain PET studies with 18F-FDG]. / Influencia de la dispersión de fotones en la cuantificación de cambios relativos en estudios longitudinales de PET cerebral con 18F-FDG.

AIM: To study the effect of photon scattering on the quantification of relative changes of 18F-FDG uptake in longitudinal brain PET studies. MATERIALS AND METHODS: Two studies from a numerical Zubal phantom were simulated. One of these was a basal reference study and the other was an activated study showing an increase or decrease in the uptake in a region of the anterior cingulated cortex. SimSET Monte Carlo code was used to simulate PET sinograms. Primary photons, which did not undergo interactions, and scattered photons, which underwent one or more interactions, were stored in separate files to assess the effect of scattering. Reconstruction was carried out using an iterative algorithm based on ordered subsets of projections (OSEM-2D). The relative changes in uptake were calculated from images reconstructed with all the photons (primary and scattered) and from images reconstructed with only primary photons. RESULTS: A linear relationship between the calculated and theoretical values was obtained both for the images reconstructed with all the photons and for those reconstructed with primary photons. Our findings show a relative change recovery of 79% +/- 0.4% for all photons and 91% +/- 0.5% for primary photons only. CONCLUSIONS: Our results highlight subestimation of relative changes of 12% +/- 0.7% when scattered photons are used. Thus the importance of correcting this degradation in order to improve quantification is shown.