Efficacy of subsequent chemotherapy for patients with BRCA1/2-mutated recurrent epithelial ovarian cancer progressing on olaparib versus placebo maintenance: post-hoc analyses of the SOLO2/ENGOT Ov-21 trial.

BACKGROUND: In the SOLO2 trial (ENGOT Ov-21; NCT01874353), maintenance olaparib in patients with platinum-sensitive relapsed ovarian cancer (PSROC) and BRCA mutation significantly improved progression-free survival (PFS) and prolonged overall survival (OS). Following disease progression on olaparib, efficacy of subsequent chemotherapy remains unknown. PATIENTS AND METHODS: We conducted a post-hoc hypothesis-generating analysis of SOLO2 data to determine the efficacy of different chemotherapy regimens following RECIST disease progression in patients who received olaparib or placebo. We evaluated time to second progression (TTSP) calculated from the date of RECIST progression to the next progression/death. RESULTS: The study population comprised 147 patients who received chemotherapy as their first subsequent treatment after RECIST progression. Of these, 69 (47%) and 78 (53%) were originally randomized to placebo and olaparib arms, respectively. In the placebo-treated cohort, 27/69 and 42/69 received non-platinum and platinum-based chemotherapy, respectively, compared with 24/78 and 54/78, respectively, in the olaparib-treated cohort. Among patients treated with chemotherapy (N = 147), TTSP was significantly longer in the placebo than in the olaparib arm: 12.1 versus 6.9 months [hazard ratio (HR) 2.17, 95% confidence interval (CI) 1.47-3.19]. Similar result was obtained on multivariable analysis adjusting for prognostic factors at RECIST progression (HR 2.13, 95% CI 1.41-3.22). Among patients treated with platinum-based chemotherapy (n = 96), TTSP was significantly longer in the placebo arm: 14.3 versus 7.0 months (HR 2.89, 95% CI 1.73-4.82). Conversely, among patients treated with non-platinum-based chemotherapy (n = 51), the TTSP was comparable in the placebo and olaparib arms: 8.3 versus 6.0 months (HR 1.58, 95% CI 0.86-2.90). CONCLUSIONS: Following progression from maintenance olaparib in the recurrent setting, the efficacy of platinum-based subsequent chemotherapy seems to be reduced in BRCA1/2-mutated patients with PSROC compared to patients not previously receiving poly (ADP-ribose) polymerase inhibitors (PARPi). The optimal strategy for patients who relapse after PARPi is an area of ongoing research.

The Effect of Lipofilling and Platelet-Rich Plasma on Patients with Moderate-Severe Vulvar Lichen Sclerosus who were Non-Responders to Topical Clobetasol Propionate: A Randomized Pilot Study.

BACKGROUND: The first-line treatment for vulvar lichen sclerosus (VLS) is 3 months of topical corticosteroid therapy. However, limited evidence is available concerning the use of fat grafting and platelet-rich plasma as a second-line treatment for patients who do not respond to first-line treatment. METHODS: This prospective single-center randomized pilot trial included 20 patients with a clinical and histological diagnosis of moderate to severe VLS. The patients in the treatment group (TG) received two infiltrations (at 3-month intervals) of nanofat mixed with platelet-rich plasma (PRP) into the vulvar area, while the control group (CG) received standard topical corticosteroid therapy. Fat was aspirated from the medial thigh or lower abdomen regions. Microfat was obtained after centrifugation and was emulsified to obtain a nanofat suspension. Treatment efficacy was determined by measuring changes in the vulvar skin elasticity, histopathology, and clinical signs, symptoms, and patient quality of life at after 1 year. RESULTS: A total of 19 patients were finally assessed (9 TG and 10 CG). At the end of the study (1 year), there had been no significant improvement in vulvar skin elasticity. However, patients in the TG showed a significant improvement in their symptoms (itching, pain, burning, and dyspareunia) and clinical signs (cervical erosions, fissures, stenosis, and leukoderma). Analysis of skin biopsies revealed a significant decrease in all inflammatory cell types in the TG. No adverse events related to the autologous treatment were recorded. CONCLUSIONS: Compared with topical corticosteroids, two infiltrations delivered 3 months apart decreased the inflammation of the vulva and improved most of the clinical signs and symptoms associated with VLS. Nonetheless, no improvement in vulvar skin elasticity was derived from the autologous treatment. LEVEL OF EVIDENCE I: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Predictors and Outcomes for COVID-19 Re-Admissions in the Anticipate Cohort.

Aims To describe readmissions of hospitalised patients with COVID-19, define predictors of readmission and explore the long term outcomes using the SF-12 score compared to patients who were not readmitted and those not hospitalised. Methods A single centre retrospective in North Inner-City Dublin. Recruitment was done through a COVID follow up clinic. Predictors of readmission and SF-12 scores at two timepoints post follow up at median 3 months and 12 months. Results Seventy (45%) participants were admitted, with a median age of 49.5 years (IQR 41.3-56.9), 36(51%) of whom were female. Unscheduled readmissions at ≤30 days in COVID-19 patients were 9(12.9%) and length of stay was four days (IQR 2-5). Readmissions were due to ongoing symptoms(n=9(64.3%)) or new complications(n=5(35.7%)). Mechanical ventilation and having symptoms of nausea and vomiting on index admission were predictive of readmission. (p=0.002). SF-12 scores at one year of readmitted patients were not different to patients who were never admitted at median one year follow up, p=.089. Conclusions Most readmissions were of short duration. Early follow up of patients post MV or who had nausea and vomiting on index admission should be prioritised. Wellbeing of readmitted patients was not different to those never hospitalised, at one year.

Supportive care in the acute phase of Stevens-Johnson syndrome and toxic epidermal necrolysis: an international, multidisciplinary Delphi-based consensus.

BACKGROUND: Supportive care is the cornerstone of management of adult and paediatric Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). However, consensus on the modalities of supportive care is lacking. OBJECTIVES: Our aim in this international multicentric Delphi exercise was to establish a multidisciplinary expert consensus to standardize recommendations regarding supportive care in the acute phase of SJS/TEN. METHODS: Participants were sent a survey via the online tool SurveyMonkey, consisting of 103 statements organized into 11 topics: multidisciplinary team composition, suspect drug management, infection prevention, fluid resuscitation and prevention of hypothermia, nutritional support, pain and psychological distress management, management of acute respiratory failure, local skincare, ophthalmological management, management of other mucosa, and additional measures. Participants evaluated the level of appropriateness of each statement on a scale of 1 (extremely inappropriate) to 9 (extremely appropriate). The results were analysed according to the RAND/UCLA Appropriateness Method. RESULTS: Forty-five participants from 13 countries (on three continents) participated. After the first round, a consensus was obtained for 82.5% of the 103 initially proposed statements. After the second round, a final consensus was obtained for 102 statements. CONCLUSIONS: We have reached an international Delphi-based consensus on best supportive care practice for SJS/TEN. Our expert consensus should help guide physicians in treating patients with SJS/TEN and thereby improve short-term prognosis and the risk of sequelae.

Heterogeneity of virological suppression in the national antiretroviral programme of Cameroon (ANRS 12288 EVOLCAM).

OBJECTIVES: In terms of HIV infection, western and central Africa is the second most affected region world-wide, and the gap between the regional figures for the testing and treatment cascade and the Joint United Nations Programme on HIV/AIDS (UNAIDS) 90-90-90 targets is particularly worrying. We assessed the prevalence of virological suppression in patients routinely treated in 19 hospitals in Cameroon. METHODS: A cross-sectional survey was performed in adult patients receiving antiretroviral therapy (ART) in the Centre and Littoral regions. The prevalences of virological suppression (<1000 HIV-1 RNA copies/mL) were compared among all 19 hospitals using the χ2 test. Potential individual and health care-related determinants of virological suppression were assessed using multivariate logistic regression models. RESULTS: A total of 1700 patients (74% women; median age 41 years; median time on ART 3.7 years) were included in the study. The prevalence of virological suppression was 82.4% overall (95% confidence interval 80.5-84.2%). It ranged from 57.1 to 97.4% according to the individual hospital (P < 0.001). After adjustment, virological suppression was associated with age, CD4 cell count at ART initiation, disclosure of HIV status to family members, interruption of ART for more than two consecutive days, and location of patient's residence and hospital (rural/urban). These factors did not explain the heterogeneity of virological suppression between the study hospitals (P < 0.001). CONCLUSIONS: The overall prevalence of virological suppression was reassuring. Nevertheless, the heterogeneity of virological suppression among hospitals highlights that, in addition to programme-level data, health facility-level data are crucial in order to tailor the national AIDS programme's interventions with a view to achieving the third UNAIDS 90 target.

Implementation of a pharmaceutical care programme for patients receiving new molecular-targeted agents in a clinical trial unit.

A pharmaceutical care programme was implemented at our hospital in early 2013. The main objectives were to analyse and describe the pharmaceutical interventions made, to calculate adherence, interventions and to evaluate patient satisfaction with the care programme. We performed a single-centre descriptive and prospective intervention in cancer patients who received oral chemotherapy as part of a clinical trial in 2013. Eighty-three patients were included. Median age was 58 years (range, 31-80) and 42 patients (50.6%) were men. We recorded 23 interventions, 13 of which were associated with drug interactions. The mean percentage of adherence was 98.9%. The interview with the pharmacist was considered to be very important by 84.6% of the respondents. A total of 92.3% said that they would like to speak to the pharmacist at subsequent visits. The doubts detected during the visits enable us to conclude that the information patients receive with respect to their study medication is usually incomplete. An integrated pharmaceutical care programme for cancer patients participating in clinical trials with oral cytostatic drugs was successful in terms of adherence and patient satisfaction and makes it possible to guarantee the safety and effectiveness of treatment on an individual basis.

Cytotoxic and genotoxic actions of Casiopeina III-Ea (Cas III-Ea) in somatic and germ cells of Drosophila melanogaster.

Casiopeinas® are a group of newly synthesized drugs designed to treat cancer. These copper (Cu) complexes exhibit cytostatic, cytotoxic, genotoxic, and antineoplastic activities through different mechanisms of action. To evaluate the influence of these compounds, some in vivo studies were performed using predominantly somatic cells. The aim of the present study was to examine the cytotoxic and genotoxic actions of Casiopeina III-Ea (Cas III-Ea) in somatic as well as germ cells of Drosophila melanogaster. For cytotoxicity, the productivity and some morphometric parameters were measured and genotoxicity was assessed by means of the somatic mutation and recombination test assay in the wing. For this purpose, second-instar larvae of the Canton-S strain were treated with different concentrations of Cas III-Ea. The emerged adults were weighed, the area of the wings determined, and the number of trichomes of the region C' counted. The productivity of treated males was measured by a brood method to monitor the influence of Cas III-Ea on spermatozoa, meiotic stage cells, and spermatogonia. For genotoxicity, mwh + /+ flr3 larvae 48 hr age were chronically treated within the same concentration range. Results indicated that Cas III-Ea at all concentrations tested significantly increased the productivity per couple in Brood III (spermatids) while at 1 mM a marked elevation was noted in the three broods tested. In contrast, the weight and size of individuals as well as the size and number of cells in the wing were decreased significantly. Data suggest that Cas III-Ea is a weak genotoxic but selective mutagen. Failure to obtain a dose-related genotoxic response suggests that one of the preferred mechanisms of action of Cas III-Ea is to induce apoptosis.

NS3 protease polymorphisms and genetic barrier to drug resistance of distinct hepatitis C virus genotypes from worldwide treatment-naïve subjects.

Hepatitis C virus (HCV) NS3 protease inhibitors have been primarily designed against genotype 1, the one with the lowest response to dual therapy. However, less evidence of their efficacy on non-1 genotypes is available, and any such information is mostly concentrated on genotypes 2-4. This study evaluated HCV protease resistance profiles in the major six HCV genotypes and identified genetic barrier (GB) profiles to each available protease inhibitor across HCV strains from different locations worldwide. We obtained 15 099 HCV sequences from treatment-naïve subjects retrieved at the Los Alamos HCV Sequence Database. The wild-type codons of different HCV genotypes were used to analyse the smallest number of nucleotide substitution steps required for changing that codon to the closest one associated with drug resistance. The 36L and 175L RAVs were found as genetic signatures of genotypes 2-5, while the 80K RAV was found in all genotype 5 sequences. Genotypes 4 and 6 showed a higher GB to RAV mutations conferring resistance to telaprevir, while genotypes 2-5 presented baseline resistance to that drug, carrying the 36L mutation. Genotype 4 had a higher GB to simeprevir resistance, requiring three substitutions to acquire the 155K mutation. Subtype 1b showed a higher GB than subtype 1a to resistance for most PIs, with RAVs at codons 36 and 155. Geographic disparities were also found in frequencies of certain RAVs in genotypes 2 and 3. Under a scenario of unprecedented evolution of anti-HCV direct-acting agents, the genetic composition of the circulating HCV sequences should be evaluated worldwide to choose the most appropriate/feasible therapeutic schemes with the highest genetic barriers to resistance.

[Fournier's gangrene: Cervical and facial extension. A very rare case]. / Gangrène gazeuse périnéo-fessière à extension cervico-faciale. À propos d'un cas exceptionnel.

Fournier's gangrene is a fearsome disease with a bad prognosis and a mortality rate ranging between 10 and 80% according to the literature. It is extensive in 13 to 54% of cases. Up to date, cervico-facial extension has never been reported. We describe the case of a 51-year-old overweighed woman with a history of type 2 diabetes and a narrow lumbar canal who was referred to our institution for significant fatigue and increasingly painful legs. A diagnosis of Fournier's gangrene was made after correlating the physical findings with the results of a full body scan. Diffuse subcutaneous emphysema involving the face, neck, mediastinum, abdominal wall, right buttock, perineum and the right thigh was identified. Treatment included multiple surgical debridements, admission to intensive care unit, and an efficient antibiotic therapy that enabled preservation of the patient's life. To our knowledge, this is the first case of cervical and mediastinal extension of Fournier's gangrene to be reported. No clear guidelines exit on the management of this complication (cervico-facial and mediastinal drainage). We share our experience of this unusual case.

[18F]DPA-714 PET imaging of translocator protein TSPO (18 kDa) in the normal and excitotoxically-lesioned nonhuman primate brain.

PURPOSE: We aimed to characterize pharmacologically the TSPO- radioligand [(18)F]DPA-714 in the brain of healthy cynomolgus monkeys and evaluate the cellular origin of its binding in a model of neurodegeneration induced by intrastriatal injection of quinolinic acid (QA). METHODS: [(18)F]DPA-714 PET images were acquired before and at 2, 7, 14, 21, 49, 70, 91 days after putaminal lesioning. Blocking and displacement studies were carried out (PK11195). Different modelling approaches estimated rate constants and V T (total distribution volume) which was used to measure longitudinal changes in the lesioned putamen. Sections for immunohistochemical labelling were prepared at the same time-points to evaluate correlations between in vivo [(18)F]DPA-714 binding and microglial/astrocytic activation. RESULTS: [(18)F]DPA-714 showed a widespread distribution with a higher signal in the thalamus and occipital cortex and lower binding in the cerebellum. TSPO was expressed throughout the whole brain and about 73 % of [(18)F]DPA-714 binding was specific for TSPO in vivo. The one-tissue compartment model (1-TCM) provided good and reproducible estimates of V T and rate constants, and V T values from the 1-TCM and the Logan approach were highly correlated (r (2) = 0.85). QA lesioning induced an increase in V T, which was +17 %, +54 %, +157 % and +39 % higher than baseline on days 7, 14, 21 and 91 after QA injection, respectively. Immunohistochemistry revealed an early microglial and a delayed astrocytic activation after QA injection. [(18)F]DPA-714 binding matched TSPO immunopositive areas and showed a stronger colocalization with CD68 microglia than with GFAP-activated astrocytes. CONCLUSION: [(18)F]DPA-714 binds to TSPO with high specificity in the primate brain under normal conditions and in the QA model. This tracer provides a sensitive tool for assessing neuroinflammation in the human brain.

A case report and literature overview: Abiotrophia defectiva aortic valve endocarditis in developing countries.

A fatal case of aortic valve endocarditis due to Abiotrophia defectiva was reported in Brazil. An overview of cases of endocarditis and other human infections related to A. defectiva in developing countries was also accomplished.

Efficacy of enthomopathogenic fungus Metarhizium anisopliae against Tuta absoluta (Lepidoptera: Gelechiidae).

The tomato borer Tuta absoluta Meyrick is a serious tomato pest that has lately undergone a rapid expansion, causing severe crop losses. An integrated management is required to control this insect, within which biological control is now beginning to play a key role. In this regard, the effectiveness of a liquid formulation based on strains of the fungus Metarhizium anisopliae variety anisopliae (Metschnikoff) Sorokin (4.46 x 10(9) viable conidia per milliliter), applied together with irrigation water, has been evaluated by laboratory tests on different populations of T. absoluta. A bioassay method has been developed to test the efficacy of the product. The technique chosen has been validated and the different studied populations have been typified according to their susceptibility, determining the baseline susceptibility of the pest to the fungus. The results revealed a complete efficacy of M. anisopliae against pupae of T. absoluta at the recommended label rate (5.58 x 10(9) viable conidia per liter) for the populations assayed. Moreover, a notably lower dose was also sufficiently effective to control the tomato borer populations because values of LC90 lower than 3 x 10(9) viable conidia per liter were obtained unfailingly. The most sensitive populations were those collected in Almeria and Nijar, Spain, with LC50 values of 0.21 and 0.22 x 10(9) viable conidia per liter(-1), respectively. The average value obtained for LC50 was 0.34 x 10(9) viable conidia per liter(-1) and 2 x 10(9) for LC90. These results show the potential of M. anisopliae to control pupae of the tomato borer in integrated pest management programs.

Window of opportunity trials with immune checkpoint inhibitors in triple-negative breast cancer.

Patients with triple-negative breast cancer (TNBC) have a relatively poor clinical outcome. The immune checkpoint inhibitor (ICI) pembrolizumab combined with chemotherapy is the current standard of care in TNBC patients with stage II and III. Monotherapy with ICIs has not been comprehensively assessed in the neoadjuvant setting in TNBC patients, given unfavorable results in metastatic trials. ICIs, however, have been tested in the window of opportunity (WOO) before surgery or standard chemotherapy-based neoadjuvant treatment. The WOO design is well suited to assess an ICI alone or in combination with other ICIs, targeted therapy, radiotherapy or cryotherapy, and measure their pharmacodynamic and clinical effect in this treatment-naive population. Some patients show a good response to ICIs in WOO studies. Biomarkers like tumor-infiltrating lymphocytes, programmed death ligand-1, and interferon-γ signature may predict activity and may identify patients likely to benefit from ICIs. Moreover, an increase in tumor-infiltrating lymphocytes, programmed death ligand-1 expression or T cell receptor expansion following administration of ICIs in the WOO setting could potentially inform of immunotherapy benefit, which would allow tailoring further treatment. This article reviews WOO trials that assessed immunotherapy in the early-stage TNBC population, and how these results could be translated to test de-escalation strategies of neoadjuvant chemotherapy and immunotherapy without compromising a patient's prognosis.

Influenza A infections: predictors of disease severity.

Influenza affects approximately 10% of the world's population annually. It is associated with high morbidity and mortality rates due to its propensity to progress to severe acute respiratory infection, leading to 10-40% of hospitalized patients needing intensive care. Characterizing the multifactorial predictors of poor prognosis is essential for developing strategies against this disease. This study aimed to identify predictors of disease severity in influenza A-infected (IFA-infected) patients and to propose a prognostic score. A retrospective cross-sectional study was conducted with 142 IFA-infected out- and inpatients treated at a tertiary hospital between 2010 and 2018. The viral subtypes, hemagglutinin mutations, viral load, IL-28B SNPs, and clinical risk factors were evaluated according to the patient's ICU admission. Multivariate analysis identified the following risk factors for disease severity: neuromuscular diseases (OR = 7.02; 95% CI = 1.18-41.75; p = 0.032), cardiovascular diseases (OR = 5.47; 95% CI = 1.96-15.27; p = 0.001), subtype (H1N1) pdm09 infection (OR = 2.29; 95% CI = 1.02-5.15; p = 0.046), and viral load (OR = 1.43; 95% CI = 1.09-1.88; p = 0.009). The prognosis score for ICU admission is based on these predictors of severity presented and ROC curve AUC = 0.812 (p < 0.0001). Our results identified viral and host predictors of disease severity in IFA-infected patients, yielding a prognostic score that had a high performance in predicting the IFA patients' ICU admission and better results than a viral load value alone. However, its implementation in health services needs to be validated in a broader population.

Back on top: Resuspended by dredging and other environmental disturbances, organochlorine compounds may affect the health of a dolphin population in a tropical estuary, Sepetiba Bay.

Organochlorine compounds (OCs) are persistent organic pollutants linked to damaging the immune and endocrine systems, leading to a greater susceptibility to infectious diseases at high concentrations. Sepetiba Bay, in the Southeastern Brazilian coast, historically presents anthropogenic activities and environmental contamination that could negatively impact resident populations. In this context, this study aimed to investigate the temporal trends in the accumulation of organochlorine compounds over a 12-year database in the Guiana dolphins' (Sotalia guianensis) resident population from Sepetiba Bay, including individuals collected before, during, and after an unusual mortality event triggered by morbillivirus (n = 85). The influence of biological parameters was also evaluated. The OCs concentrations in the blubber ranged from 0.98 to 739 µg/g of ΣPCB; 0.08-130 µg/g of ΣDDT; <0.002-4.56 µg/g of mirex; <0.002-1.84 µg/g of ΣHCH and <0.001-0.16 µg/g of HCB in lipid weight. Increased temporal trends were found for OCs in Guiana dolphins coinciding with periods of large events of dredging in the region. In this way, our findings suggest that the constant high OCs concentrations throughout the years in this Guiana dolphin population are a result of the constant environmental disturbance in the area, such as dredging. These elevated OCs levels, e.g., ΣPCB concentrations found above the known thresholds, may impair the response of the immune system during outbreak periods, which could lead the population to a progressive decline.

Equitable inclusion of diverse populations in oncology clinical trials: deterrents and drivers.

The burden of cancer exerts a disproportionate impact across different regions and population subsets. Disease-specific attributes, coupled with genetic and socioeconomic factors, significantly influence cancer treatment outcomes. Precision oncology promises the development of safe and effective options for specific ethnic phenotypes and clinicodemographic profiles. Currently, clinical trials are concentrated in resource-rich geographies with younger, healthier, white, educated, and empowered populations. Vulnerable and marginalized people are often deprived of opportunities to participate in clinical trials. Despite consistent endeavors by regulators, industry, and other stakeholders, factors including diversity in trial regulations and patient and provider-related cultural, logistic, and operational barriers limit the inclusiveness of clinical trials. Understanding and addressing these constraints by collaborative actions involving regulatory initiatives, industry, patient advocacy groups, community engagement in a culturally sensitive manner, and designing and promoting decentralized clinical trials are vital to establishing a clinical research ecosystem that promotes equity in the representation of population subgroups.

Novel nanostructured lipid carriers loading Apigenin for anterior segment ocular pathologies.

Dry eye disease (DED) is a chronic multifactorial disorder of the ocular surface caused by tear film dysfunction and constitutes one of the most common ocular conditions worldwide. However, its treatment remains unsatisfactory. While artificial tears are commonly used to moisturize the ocular surface, they do not address the underlying causes of DED. Apigenin (APG) is a natural product with anti-inflammatory properties, but its low solubility and bioavailability limit its efficacy. Therefore, a novel formulation of APG loaded into biodegradable and biocompatible nanoparticles (APG-NLC) was developed to overcome the restricted APG stability, improve its therapeutic efficacy, and prolong its retention time on the ocular surface by extending its release. APG-NLC optimization, characterization, biopharmaceutical properties and therapeutic efficacy were evaluated. The optimized APG-NLC exhibited an average particle size below 200 nm, a positive surface charge, and an encapsulation efficiency over 99 %. APG-NLC exhibited sustained release of APG, and stability studies demonstrated that the formulation retained its integrity for over 25 months. In vitro and in vivo ocular tolerance studies indicated that APG-NLC did not cause any irritation, rendering them suitable for ocular topical administration. Furthermore, APG-NLC showed non-toxicity in an epithelial corneal cell line and exhibited fast cell internalization. Therapeutic benefits were demonstrated using an in vivo model of DED, where APG-NLC effectively reversed DED by reducing ocular surface cellular damage and increasing tear volume. Anti-inflammatory assays in vivo also showcased its potential to treat and prevent ocular inflammation, particularly relevant in DED patients. Hence, APG-NLC represent a promising system for the treatment and prevention of DED and its associated inflammation.