Ten Years of HIV Diagnosis in a Dermatology and Venereology Department: A Retrospective Study on Demographic, Clinical, and Laboratory Characteristics.

Human immunodeficiency virus (HIV) transmission remains an important health issue, with a high burden that is felt across the world. This work aims to analyze the demographic, clinical, and laboratory characteristics of newly diagnosed patients with HIV in a Department of Dermatology and Venereology. A retrospective observational study was conducted from all health records of newly diagnosed patients with HIV from a Dermatology unit from January 2011 to December 2020. A total of 134 patients with new HIV diagnoses were included in the analysis. Concurrent dermatological or venereal diseases were diagnosed in 91.0% of the patients (n=122), being the most common conditions syphilis (22.4%, n=30) and urethritis (14.9%, n=20). Out of all the patients with diagnoses of concurrent sexually transmitted infection (STI) (41.0%, n=55), syphilis was reported in 81.8% of the patients (n=45), gonorrhea in 9.1% (n=5), and chlamydia in 5.5% (n=3). We present a large patient database on the clinical conditions associated with newly diagnosed HIV, concluding that infectious diseases were the most common conditions associated with newly diagnosed HIV.

Osimertinib treatment based on plasma T790M monitoring in patients with EGFR-mutant non-small-cell lung cancer (NSCLC): EORTC Lung Cancer Group 1613 APPLE phase II randomized clinical trial.

BACKGROUND: The APPLE trial aimed to evaluate the feasibility of longitudinal plasma epidermal growth factor receptor (EGFR) T790M monitoring for the best sequencing strategy of gefitinib and osimertinib. METHODS: APPLE is a randomized, non-comparative, phase II study in patients with common EGFR-mutant, treatment-naive non-small-cell lung cancer including three arms: arm A (osimertinib upfront until RECIST progression, PD), arm B [gefitinib until emergence of circulating tumor DNA (ctDNA) EGFR T790M mutation by cobas EGFR test v2 or RECIST PD], and arm C (gefitinib until RECIST PD), and then switch to osimertinib in both arms. The primary endpoint is the progression-free survival (PFS) rate 'on osimertinib' at 18 months (PFSR-OSI-18) after randomization in arm B (H0: PFSR-OSI-18 of ≤40%). Secondary endpoints include response rate, overall survival (OS), and brain PFS. We report the results of arms B and C. RESULTS: From November 2017 to February 2020, 52 and 51 patients were randomized into arms B and C, respectively. Most patients were females (70%) and had EGFR Del19 (65%); one-third had baseline brain metastases. In arm B, 17% of patients (8/47) switched to osimertinib based on the emergence of ctDNA T790M mutation before RECIST PD, with a median time to molecular PD of 266 days. The study met its primary endpoint of PFSR-OSI-18 of 67.2% (84% confidence interval 56.4% to 75.9%) in arm B versus 53.5% (84% confidence interval 42.3% to 63.5%) in arm C, with a median PFS of 22.0 months versus 20.2 months, respectively. The median OS was not reached in arm B versus 42.8 months in arm C. Median brain PFS in arms B and C was 24.4 and 21.4 months, respectively. CONCLUSIONS: The serial monitoring of ctDNA T790M status in advanced EGFR-mutant non-small-cell lung cancer during treatment with first-generation EGFR inhibitors was feasible, and a molecular progression before RECIST PD led to an earlier switch to osimertinib in 17% of patients with satisfactory PFS and OS outcomes.

Association of Peripheral Blood and Cutaneous Eosinophils With Bullous Pemphigoid Disease Severity and Treatment Outcomes.

BACKGROUND AND AIMS: A dermal inflammatory infiltrate rich in eosinophils is a prominent histological feature of bullous pemphigoid (BP) and peripheral blood eosinophilia has been documented in 50-60% of BP patients. Nevertheless, the impact of circulating and dermal infiltrate eosinophil levels on BP remains poorly understood. The main objective of this work was to investigate the association of peripheral blood and dermal infiltrate eosinophil levels with clinical and immunological characteristics of the disease. MATERIAL AND METHODS: Retrospective cohort study including all patients diagnosed with BP between 2011 and 2020. RESULTS: The study cohort included 233 patients with BP. The mean baseline peripheral blood eosinophil count was 956.3±408.6×106/L and the mean number of tissue eosinophils at the dermal hot spot area was 30.5±19.0. Patients with disseminated presentation (i.e. BSA>50%) had significantly higher peripheral blood eosinophil counts (P=0.028). Mucosal involvement was significantly associated with lower dermal eosinophil count (P=0.001). Requiring inpatient care and relapsing were significantly associated with high peripheral blood eosinophil count (P=0.025; P=0.020, respectively). Among the 68 patients who experienced a relapse, 31 had peripheral blood eosinophilia (i.e. >500×106/L) at relapse (44.2%). Peripheral blood eosinophil counts at baseline and at relapse were significantly correlated (r=0.82, P<0.001). CONCLUSIONS: Peripheral blood and cutaneous eosinophils levels may be useful biomarkers for disease activity and treatment outcomes in BP. Monitoring peripheral blood eosinophil counts may allow early detection of relapse.

Managing cancer patients during the COVID-19 pandemic: an ESMO multidisciplinary expert consensus.

We established an international consortium to review and discuss relevant clinical evidence in order to develop expert consensus statements related to cancer management during the severe acute respiratory syndrome coronavirus 2-related disease (COVID-19) pandemic. The steering committee prepared 10 working packages addressing significant clinical questions from diagnosis to surgery. During a virtual consensus meeting of 62 global experts and one patient advocate, led by the European Society for Medical Oncology, statements were discussed, amended and voted upon. When consensus could not be reached, the panel revised statements until a consensus was reached. Overall, the expert panel agreed on 28 consensus statements that can be used to overcome many of the clinical and technical areas of uncertainty ranging from diagnosis to therapeutic planning and treatment during the COVID-19 pandemic.

Clinical utility of plasma-based digital next-generation sequencing in patients with advance-stage lung adenocarcinomas with insufficient tumor samples for tissue genotyping.

BACKGROUND: Approximately 30% of tumor biopsies from patients with advanced-stage lung adenocarcinomas yield insufficient tissue for successful molecular subtyping. We have analyzed the clinical utility of next-generation sequencing (NGS) of cell-free circulating tumor DNA (ctDNA) in patients with inadequate tumor samples for tissue genotyping. PATIENTS AND METHODS: We conducted the study in a multi-institutional prospective cohort of clinically unselected patients with advanced-stage lung adenocarcinomas with insufficient tissue for EGFR, ALK or ROS1 genotyping across 12 Spanish institutions (n = 93). ctDNA NGS was carried out by Guardant Health (Guardant360, Redwood City, CA), using a hybrid-capture-based 73-gene panel. Variants were deemed actionable if they were part of the OncoKB precision oncology knowledge database and classified in four levels of actionability based on their clinical or preclinical evidence for drug response. RESULTS: Eighty-three out of 93 patients (89%) had detectable levels of ctDNA. Potentially actionable level 1-4 genomic alterations were detected in 53 cases (57%), of which 13 (14%) had level 1-2A alterations (Food and Drug Administration-approved and standard-care biomarkers according to lung cancer guidelines). Frequencies of each genomic alteration in ctDNA were consistent with those observed in unselected pulmonary adenocarcinomas. The majority of the patients (62%), particularly those with actionable alterations (87%), had more than one pathogenic variant in ctDNA. The median turnaround time to genomic results was 13 days. Twelve patients (13%) received genotype-matched therapies based on ctDNA results, deriving the expected clinical benefit. Patients with co-occurring pathogenic alterations had a significantly shorter median overall survival as compared with patients without co-occurring pathogenic alteration (multivariate hazard ratio = 5.35, P = 0.01). CONCLUSION: Digital NGS of ctDNA in lung cancers with insufficient tumor samples for tissue sequencing detects actionable variants that frequently co-occur with other potentially clinically relevant genomic alterations, allowing timely initiation of genotype-matched therapies.

Targeted next-generation sequencing of circulating-tumor DNA for tracking minimal residual disease in localized colon cancer.

BACKGROUND: A high percentage of patients diagnosed with localized colon cancer (CC) will relapse after curative treatment. Although pathological staging currently guides our treatment decisions, there are no biomarkers determining minimal residual disease (MRD) and patients are at risk of being undertreated or even overtreated with chemotherapy in this setting. Circulating-tumor DNA (ctDNA) can to be a useful tool to better detect risk of relapse. PATIENTS AND METHODS: One hundred and fifty patients diagnosed with localized CC were prospectively enrolled in our study. Tumor tissue from those patients was sequenced by a custom-targeted next-generation sequencing (NGS) panel to characterize somatic mutations. A minimum variant allele frequency (VAF) of 5% was applied for variant filtering. Orthogonal droplet digital PCR (ddPCR) validation was carried out. We selected known variants with higher VAF to track ctDNA in the plasma samples by ddPCR. RESULTS: NGS found known pathological mutations in 132 (88%) primary tumors. ddPCR showed high concordance with NGS (r = 0.77) for VAF in primary tumors. Detection of ctDNA after surgery and in serial plasma samples during follow-up were associated with poorer disease-free survival (DFS) [hazard ratio (HR), 17.56; log-rank P = 0.0014 and HR, 11.33; log-rank P = 0.0001, respectively]. Tracking at least two variants in plasma increased the ability to identify MRD to 87.5%. ctDNA was the only significantly independent predictor of DFS in multivariable analysis. In patients treated with adjuvant chemotherapy, presence of ctDNA after therapy was associated with early relapse (HR 10.02; log-rank P < 0.0001). Detection of ctDNA at follow-up preceded radiological recurrence with a median lead time of 11.5 months. CONCLUSIONS: Plasma postoperative ctDNA detected MRD and identified patients at high risk of relapse in localized CC. Mutation tracking with more than one variant in serial plasma samples improved our accuracy in predicting MRD.

Differential effects of FXR or TGR5 activation in cholangiocarcinoma progression.

BACKGROUND AND AIMS: Cholangiocarcinoma (CCA) is an aggressive tumor type affecting cholangiocytes. CCAs frequently arise under certain cholestatic liver conditions. Intrahepatic accumulation of bile acids may facilitate cocarcinogenic effects by triggering an inflammatory response and cholangiocyte proliferation. Here, the role of bile acid receptors FXR and TGR5 in CCA progression was evaluated. METHODS: FXR and TGR5 expression was determined in human CCA tissues and cell lines. An orthotopic model of CCA was established in immunodeficient mice and tumor volume was monitored by magnetic resonance imaging under chronic administration of the specific FXR or TGR5 agonists, obeticholic acid (OCA) or INT-777 (0,03% in chow; Intercept Pharmaceuticals), respectively. Functional effects of FXR or TGR5 activation were evaluated on CCA cells in vitro. RESULTS: FXR was downregulated whereas TGR5 was upregulated in human CCA tissues compared to surrounding normal liver tissue. FXR expression correlated with tumor differentiation and TGR5 correlated with perineural invasion. TGR5 expression was higher in perihilar than in intrahepatic CCAs. In vitro, FXR was downregulated and TGR5 was upregulated in human CCA cells compared to normal human cholangiocytes. OCA halted CCA growth in vivo, whereas INT-777 showed no effect. In vitro, OCA inhibited CCA cell proliferation and migration which was associated with decreased mitochondrial energy metabolism. INT-777, by contrast, stimulated CCA cell proliferation and migration, linked to increased mitochondrial energy metabolism. CONCLUSION: Activation of FXR inhibits, whereas TGR5 activation may promote, CCA progression by regulating proliferation, migration and mitochondrial energy metabolism. Modulation of FXR or TGR5 activities may represent potential therapeutic strategies for CCA.

Modified SureSelectQXT Target Enrichment Protocol for Illumina Multiplexed Sequencing of FFPE Samples.

BACKGROUND: Personalised medicine is nowadays a major objective in oncology. Molecular characterization of tumours through NGS offers the possibility to find possible therapeutic targets in a time- and cost-effective way. However, the low quality and complexity of FFPE DNA samples bring a series of disadvantages for massive parallel sequencing techniques compared to high-quality DNA samples (from blood cells, cell cultures, etc.). RESULTS: We performed several experiments to understand the behaviour of FFPE DNA samples during the construction of SureSelectQXT libraries. First, we designed a quality checkpoint for FFPE DNA samples based on the quantification of their amplification capability (qcPCR). We observed that FFPE DNA samples can be classified according to DIN value and qcPCR concentration into unusable, or low-quality (LQ) and good-quality (GQ) DNA. For GQ samples, we increased the amount of input DNA to 150 ng and the digestion time to 30 min, whereas for LQ samples, we used 50 ng of DNA as input but we decreased the digestion time to 1 min. In all cases, we increased the cycles of the pre-hyb PCR to 10 but decreased the cycles of the post-hyb PCR to 8. In addition, we confirmed that using half of the volume of reagents can be beneficial. Finally, in order to obtain better results, we designed a decision flow-chart to achieve a seeding concentration of 12-14 pM for MiSeq Reagent Kit v2. CONCLUSIONS: Our experiments allowed us to unveil the behaviour of low-quality FFPE DNA samples during the construction of SureSelectQXT libraries. Sequencing results showed that, using our modified SureSelectQXT protocol, the final percentage of usable reads for low-quality samples was increased more than three times allowing to reach median depth/million reads values of 76.35. This value is equivalent to ~ 0.9 and ~ 0.7 of the values obtained for good-quality FFPE and high-quality DNA respectively.

Heat shock proteins in Varroa destructor exposed to heat stress and in-hive acaricides.

Varroa destructor is one of the major pests that affect honeybees around the world. Chemical treatments are common to control varroosis, but mites possess biochemical adaptive mechanisms to resist these treatments, enabling them to survive. So far, no information is available regarding whether these pesticides can induce the expression of heat shock protein (Hsp) as a common protective mechanism against tissue damage. The aims of this study were to determine differences in heat shock tolerance between mites collected from brood combs and phoretic ones, and to examine patterns of protein expression of Hsp70 that occur in various populations of V. destructor after exposure to acaricides commonly employed in beekeeping, such as flumethrin, tau-fluvalinate and coumaphos. Curiously, mites obtained from brood cells were alive at 40 °C, unlike phoretic mites that reached 100% mortality, demonstrating differential thermo-tolerance. Heat treatment induced Hsp70 in mites 4 × more than in control mites and no differences in response were observed in phoretic versus cell-brood-obtained mites. Dose-response assays were carried out at increasing acaricide concentrations. Each population showed a different stress response to acaricides despite belonging to the same geographic region. In one of them, coumaphos acted as a hormetic stressor. Pyrethroids also induced Hsp70, but mite population seemed sensitive to this treatment. We concluded that Hsp70 could represent a robust biomarker for measuring exposure of V. destructor to thermal and chemical stress, depending on the acaricide class and interpopulation variability. This is relevant because it is the first time that stress response is analyzed in this biological model, providing new insight in host-parasite-xenobiotic interaction.

Eruptive melanocytic nevi in HIV infected patients: report of three cases.

The abrupt development of multiple melanocytic nevi has been described in association with many conditions, including human immunodeficiency virus infection. We report three cases of eruptive nevi in men with human immunodeficiency virus type 1 infection. One patient developed this phenomenon during the stage of acquired immunodeficiency syndrome. The other two patients had human immunodeficiency virus infection recently diagnosed and presented to our clinic reporting the development of multiple melanocytic nevi after starting highly active antiretroviral treatment, with improvement of their immunity. To our knowledge, this is the first report of eruptive melanocytic nevi as a possible consequence of the immune reconstitution inflammatory syndrome.

Order and Symmetry Breaking in the Fluctuations of Driven Systems.

Dynamical phase transitions (DPTs) in the space of trajectories are one of the most intriguing phenomena of nonequilibrium physics, but their nature in realistic high-dimensional systems remains puzzling. Here we observe for the first time a DPT in the current vector statistics of an archetypal two-dimensional (2D) driven diffusive system and characterize its properties using the macroscopic fluctuation theory. The complex interplay among the external field, anisotropy, and vector currents in 2D leads to a rich phase diagram, with different symmetry-broken fluctuation phases separated by lines of first- and second-order DPTs. Remarkably, different types of 1D order in the form of jammed density waves emerge to hinder transport for low-current fluctuations, revealing a connection between rare events and self-organized structures which enhance their probability.

Incidence, surgical procedures, and outcomes of hip fracture among elderly type 2 diabetic and non-diabetic patients in Spain (2004-2013).

UNLABELLED: Hip fracture is a serious public health problem. We used Spanish hospital discharge data to examine trends in 2004-2013 in the incidence of hip fracture among elderly patients. We found that hip fracture incidence is higher in subjects with than without diabetes and is much higher among women than men. INTRODUCTION: This study aimed to describe trends in the incidence of hip fracture hospitalizations, use of surgical procedures, and hospital outcomes among elderly patients with and without type 2 diabetes mellitus (T2DM) in Spain, 2004-2013. METHODS: We selected all patients with a discharge primary diagnosis of hip fracture using the Spanish national hospital discharge database. Discharges were grouped by diabetes status: Incidences were calculated overall and stratified by diabetes status and year. We analyzed surgical procedures, length of hospital stay (LOHS), and in-hospital mortality (IHM). Multivariate analysis was adjusted by age, year, comorbidity, and in-hospital complications (IHC). RESULTS: From 2004 to 2013, 432,760 discharges with hip fracture were identified (21.3 % suffered T2DM). Incidence among diabetic men and women increased until year 2010 and then remained stable. Diabetic women have three times higher incidence than diabetic men. Incidences and IHC were higher among patients with diabetes beside sex. The proportion of patients that underwent internal fixation increased for all groups of patients and the arthroplasty repair decreased. After multivariate analysis, IHM has improved over the study period for all patients. Suffering diabetes was associated to higher IHM in women (odds ratio (OR) 1.12; 95 % confidence interval (CI) 1.07-1.17). CONCLUSIONS: Hip fracture incidence is higher in subjects with than without diabetes and is much higher among women than men. In diabetic patients, incidence rates increased initially but have leveled from 2010 onwards. For all groups, the use of internal fixation has increased overtime and IHM and LOHS have decreased from 2004 to 2013.

Predictors of medication use in the Roma population in Spain: a population-based national study.

OBJECTIVES: To describe the prevalence of prescribed and self-medicated use of medication in the Spanish Roma population, and identify the associated factors. STUDY DESIGN: Descriptive cross-sectional study. METHODS: Data from the first National Health Survey conducted on the Roma population in Spain were used. The sample comprised 1000 Spanish Roma adults of both sexes aged ≥16 years. Answers (yes/no) to the question, 'In the last two weeks have you taken the following medicines [in reference to a list of medicines that might be used by the population] and were they prescribed for you by a doctor?' were used to ascertain 'medication use'. 'Self-medication' referred to use of these medicines without medical prescription. Using multivariate logistic regression models, odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to identify associated factors. RESULTS: The overall prevalence of medication use in the Roma population for both sexes was 69.1%, and 38.7% was self-medicated. Females reported higher use of medication than males (75.1% vs 62.3%); however, self-medication was higher among males. Analgesics and antipyretics were used most often (35.8%). Among males, the variables that were independently and significantly associated with a higher probability of medication use were: age; negative perception of health; presence of chronic disease (OR 2.81; 95% CI 1.67-4.73); and medical visits (OR 4.51; 95% CI 2.54-8.01). The variables were the same among females, except for age. CONCLUSION: A high percentage of the Spanish Roma population use medication, and a significant proportion of them self-medicate. The presence of chronic diseases, a negative perception of health and medical consultations were associated with increased use of medication in the study population.

Social disparities in access to breast and cervical cancer screening by women living in Spain.

OBJECTIVES: To describe uptake of breast and cervical cancer screening by women living in Spain, analyse the possible associated social and health factors, and compare uptake rates with those obtained in previous surveys. STUDY DESIGN: Cross-sectional study using data from the 2011 Spanish national health survey. METHODS: Uptake of breast cancer screening was analysed by asking women aged 40-69 years whether they had undergone mammography in the previous two years. Uptake of cervical cancer screening was analysed by asking women aged 25-65 years whether they had undergone cervical cytology in the previous three years. Independent variables included sociodemographic characteristics, and variables related to health status and lifestyle. RESULTS: Seventy-two percent of women had undergone mammography in the previous two years. Having private health insurance increased the probability of breast screening uptake four-fold [odds ratio (OR) 3.96, 95% confidence interval (CI) 2.71-5.79], and being an immigrant was a negative predictor for breast screening uptake. Seventy percent of women had undergone cervical cytology in the previous three years. Higher-educated women were more likely to have undergone cervical cancer screening (OR 2.59, 95% CI 1.97-3.40), and obese women and women living in rural areas were less likely to have undergone cervical cancer screening. There have been no relevant improvements in uptake rates of either breast or cervical cancer screening since 2006. CONCLUSION: Uptake of breast and cervical cancer screening could be improved in Spain, and uptake rates have stagnated over recent years. Social disparities have been detected with regard to access to these screening tests, indicating that it is necessary to continue researching and optimizing prevention programmes in order to improve uptake and reduce these disparities.

Health Belief Model applied to non-compliance with HPV vaccine among female university students.

OBJECTIVES: To investigate the reasons for refusal of human papillomavirus (HPV) vaccination, and to explore participants' perceptions and attitudes about Health Belief Model (HBM) constructs (perceived susceptibility, perceived severity, perceived benefits, perceived barriers, cues to action and self-efficacy) among a sample of female university students. STUDY DESIGN: Cross-sectional. A self-administered questionnaire based on the HBM was used. METHODS: Confirmatory factor analysis was applied to the data to examine the construct validity of the six factor models extracted from the HBM. The predictors of non-HPV vaccination were determined by logistic regression models, using non-HPV vaccination as the dependent variable. RESULTS: The sample included 2007 students. The participation rate was 88.9% and the percentage of non-vaccination was 71.65%. Participants who had high scores for 'general perceived barriers', 'perceived barriers to vaccination', 'no perceived general benefits', 'no perceived specific benefits' and 'no general benefits' were more likely to report being unvaccinated. CONCLUSIONS: The findings demonstrated the utility of HBM constructs in understanding vaccination intention and uptake. There is an urgent need to improve health promotion and information campaigns to enhance the benefits and reduce the barriers to HPV vaccination.