Longitudinal profiling identifies co-occurring BRCA1/2 reversions, TP53BP1, RIF1 and PAXIP1 mutations in PARP inhibitor-resistant advanced breast cancer.

BACKGROUND: Resistance to therapies that target homologous recombination deficiency (HRD) in breast cancer limits their overall effectiveness. Multiple, preclinically validated, mechanisms of resistance have been proposed, but their existence and relative frequency in clinical disease are unclear, as is how to target resistance. PATIENTS AND METHODS: Longitudinal mutation and methylation profiling of circulating tumour (ct)DNA was carried out in 47 patients with metastatic BRCA1-, BRCA2- or PALB2-mutant breast cancer treated with HRD-targeted therapy who developed progressive disease-18 patients had primary resistance and 29 exhibited response followed by resistance. ctDNA isolated at multiple time points in the patient treatment course (before, on-treatment and at progression) was sequenced using a novel >750-gene intron/exon targeted sequencing panel. Where available, matched tumour biopsies were whole exome and RNA sequenced and also used to assess nuclear RAD51. RESULTS: BRCA1/2 reversion mutations were present in 60% of patients and were the most prevalent form of resistance. In 10 cases, reversions were detected in ctDNA before clinical progression. Two new reversion-based mechanisms were identified: (i) intragenic BRCA1/2 deletions with intronic breakpoints; and (ii) intragenic BRCA1/2 secondary mutations that formed novel splice acceptor sites, the latter being confirmed by in vitro minigene reporter assays. When seen before commencing subsequent treatment, reversions were associated with significantly shorter time to progression. Tumours with reversions retained HRD mutational signatures but had functional homologous recombination based on RAD51 status. Although less frequent than reversions, nonreversion mechanisms [loss-of-function (LoF) mutations in TP53BP1, RIF1 or PAXIP1] were evident in patients with acquired resistance and occasionally coexisted with reversions, challenging the notion that singular resistance mechanisms emerge in each patient. CONCLUSIONS: These observations map the prevalence of candidate drivers of resistance across time in a clinical setting, information with implications for clinical management and trial design in HRD breast cancers.

Obstructive sleep apnea and periodic limb movement in children: is there really an association?

PURPOSE: Periodic limb movements (PLMs) can be found isolated or related to other sleep disorders, as Obstructive Sleep Apnea (OSA). Nevertheless, this association was described before the proposal for modification of the World Association of Sleep Medicine (WASM), which incorporated major changes modifying the definition of respiratory-related leg movements (RRLM) so that the relationship between OSA and PLM could be affected. METHODS: A total of 131 PSG were studied (children with ages from 5 to 12 years old), all referred because of a suspicion of sleep-disordered breathing (65 children were diagnosed of OSA, and 66 presented snoring but no sleep apnea). Leg movements were manually scored according to both 2006 and 2016 WASM/IRLSSG criteria. RESULTS: According to 2006 WASM rules, statistical differences were found, not only for PLM index (p 0.002), but all indexes. Nevertheless, according to new 2016 WASM rules, no statistical differences were found for PLM index (p 0.677), non-REM PLM index (p 0.299), REM PLM index (P 0.511) or PLM with arousal index (p 0.180), between OSA and non-OSA group. Positive correlation between PLM and RRLM have been found with both set of rules. The percentage of children with PLM>5/h is higher when using the prior PLM scoring criteria developed in 2006 (38.93%) versus the updated PLM scoring criteria (19.08%). CONCLUSION: The lack of association when using the new WASM/IRLSSG scoring rules together with the absence of a previous clear etiopathology explanation may suggest that the association between OSA and PLM might be indeed overestimated and that, perhaps, it really did not exist.

Musical and psychomotor interventions for cognitive, sensorimotor, and cerebral decline in patients with Mild Cognitive Impairment (COPE): a study protocol for a multicentric randomized controlled study.

BACKGROUND: Regular cognitive training can boost or maintain cognitive and brain functions known to decline with age. Most studies administered such cognitive training on a computer and in a lab setting. However, everyday life activities, like musical practice or physical exercise that are complex and variable, might be more successful at inducing transfer effects to different cognitive domains and maintaining motivation. "Body-mind exercises", like Tai Chi or psychomotor exercise, may also positively affect cognitive functioning in the elderly. We will compare the influence of active music practice and psychomotor training over 6 months in Mild Cognitive Impairment patients from university hospital memory clinics on cognitive and sensorimotor performance and brain plasticity. The acronym of the study is COPE (Countervail cOgnitive imPairmEnt), illustrating the aim of the study: learning to better "cope" with cognitive decline. METHODS: We aim to conduct a randomized controlled multicenter intervention study on 32 Mild Cognitive Impairment (MCI) patients (60-80 years), divided over 2 experimental groups: 1) Music practice; 2) Psychomotor treatment. Controls will consist of a passive test-retest group of 16 age, gender and education level matched healthy volunteers. The training regimens take place twice a week for 45 min over 6 months in small groups, provided by professionals, and patients should exercise daily at home. Data collection takes place at baseline (before the interventions), 3, and 6 months after training onset, on cognitive and sensorimotor capacities, subjective well-being, daily living activities, and via functional and structural neuroimaging. Considering the current constraints of the COVID-19 pandemic, recruitment and data collection takes place in 3 waves. DISCUSSION: We will investigate whether musical practice contrasted to psychomotor exercise in small groups can improve cognitive, sensorimotor and brain functioning in MCI patients, and therefore provoke specific benefits for their daily life functioning and well-being. TRIAL REGISTRATION: The full protocol was approved by the Commission cantonale d'éthique de la recherche sur l'être humain de Genève (CCER, no. 2020-00510) on 04.05.2020, and an amendment by the CCER and the Commission cantonale d'éthique de la recherche sur l'être humain de Vaud (CER-VD) on 03.08.2021. The protocol was registered at clinicaltrials.gov (20.09.2020, no. NCT04546451).

Alternative academic approaches for testing homologous recombination deficiency in ovarian cancer in the MITO16A/MaNGO-OV2 trial.

BACKGROUND: The detection of homologous recombination deficiency (HRD) can identify patients who are more responsive to platinum and poly ADP ribose polymerase inhibitors (PARPi). MyChoice CDx (Myriad) is the most used HRD test in ovarian cancer (OC). However, some limitations of commercial tests exist, because of the high rate of inconclusive results, costs, and the impossibility of evaluating functional resistance mechanisms. PATIENTS AND METHODS: Two academic genomic tests and a functional assay, the RAD51 foci, were evaluated to detect HRD. One hundred patients with high-grade OC enrolled in the MITO16A/MaNGO-OV2 trial and treated with first-line therapy with carboplatin, paclitaxel, and bevacizumab were analyzed. RESULTS: The failure rate of the two genomic assays was 2%. The sensitivity in detecting HRD when compared with Myriad was 98.1% and 90.6%, respectively. The agreement rate with Myriad was 0.92 and 0.87, with a Cohen's κ coefficient corresponding to 0.84 and 0.74, respectively. For the RAD51 foci assay, the failure rate was 30%. When the test was successful, discordant results for deficient and proficient tumors were observed, and additional HRD patients were identified compared to Myriad; sensitivity was 82.9%, agreement rate was 0.65, and Cohen's κ coefficient was 0.18. The HRD detected by genomic assays and residual tumor at primary surgery and stage was correlated with progression-free survival at multivariate analysis. CONCLUSIONS: Results suggest the feasibility of academic tests for assessing HRD status that show robust concordance with Myriad and correlation with clinical outcome. The contribution of the functional information related to the RAD51 foci test to the genomic data needs further investigation.

Basal expression of RAD51 foci predicts olaparib response in patient-derived ovarian cancer xenografts.

BACKGROUND: The search for biomarkers to evaluate ovarian cancer (OC) homologous recombination (HR) function and predict the response to therapy is an urgent clinical need to improve the selection of patients who could benefit from platinum- and olaparib (poly-ADP ribose polymerase inhibitors, PARPi)-based therapies. METHODS: We used a large collection of OC patient-derived xenografts (PDXs) (n = 47) and evaluated their HR status based on BRCA1/2 mutations, BRCA1 promoter methylation and the HRDetect score. RAD51 foci were quantified in formalin-fixed, paraffin-embedded untreated tumour specimens by immunofluorescence and the messenger RNA expression of 21 DNA repair genes by real-time PCR. RESULTS: Tumour HR deficiency predicted both platinum and olaparib responses. The basal level of RAD51 foci evaluated in geminin-positive/replicating cells strongly inversely correlated with olaparib response (p = 0.011); in particular, the lower the foci score, the greater the sensitivity to olaparib, while low RAD51 foci score seems to associate with platinum activity. CONCLUSIONS: The basal RAD51 foci score is a candidate predictive biomarker of olaparib response in OC patients as it can be easily translatable in a clinical setting. Moreover, the findings corroborate the importance of OC-PDXs as a reliable tool to identify and validate biomarkers of response to therapy.

Association of RAD51 with homologous recombination deficiency (HRD) and clinical outcomes in untreated triple-negative breast cancer (TNBC): analysis of the GeparSixto randomized clinical trial.

BACKGROUND: Current genetic and genomic tests measuring homologous recombination deficiency (HRD) show limited predictive value. This study compares the performance of an immunohistology-based RAD51 test with genetic/genomic tests to identify patients with HRD primary triple-negative breast cancer (TNBC) and evaluates its accuracy to select patients sensitive to platinum-based neoadjuvant chemotherapy (NACT). PATIENTS AND METHODS: This is a retrospective, blinded, biomarker analysis from the GeparSixto randomized clinical trial. TNBC patients received neoadjuvant paclitaxel plus Myocet®-nonpegylated liposomal doxorubicin (PM) or PM plus carboplatin (PMCb), both arms including bevacizumab. Formalin-fixed paraffin-embedded (FFPE) tumor samples were laid on tissue microarrays. RAD51, BRCA1 and γH2AX were quantified using an immunofluorescence assay. The predictive value of RAD51 was assessed by regression models. Concordance analyses were carried out between RAD51 score and tumor BRCA (tBRCA) status or genomic HRD score (Myriad myChoice®). Associations with pathological complete response (pCR) and survival were studied. Functional HRD was predefined as a RAD51 score ≤10% (RAD51-low). RESULTS: Functional HRD by RAD51-low was evidenced in 81/133 tumors (61%). RAD51 identified 93% tBRCA-mutated tumors and 45% non-tBRCA mutant cases as functional HRD. The concordance between RAD51 and genomic HRD was 87% [95% confidence interval (CI) 79% to 93%]. In patients with RAD51-high tumors, pCR was similar between treatment arms [PMCb 31% versus PM 39%, odds ratio (OR) 0.71, 0.23-2.24, P = 0.56]. Patients with RAD51-low tumors benefited from PMCb (pCR 66% versus 33%, OR 3.96, 1.56-10.05, P = 0.004; interaction test P = 0.02). This benefit maintained statistical significance in the multivariate analysis. Carboplatin addition showed similar disease-free survival in the RAD51-high [hazard ratio (HR) 0.40, log-rank P = 0.11] and RAD51-low (0.45, P = 0.11) groups. CONCLUSIONS: The RAD51 test identifies tumors with functional HRD and is highly concordant with tBRCA mutation and genomic HRD. RAD51 independently predicts clinical benefit from adding Cb to NACT in TNBC. Our results support further development to incorporate RAD51 testing in clinical decision-making.

Mechanoethology: The Physical Mechanisms of Behavior.

Research that integrates animal behavior theory with mechanics-including biomechanics, physiology, and functional morphology-can reveal how organisms accomplish tasks crucial to their fitness. Despite the insights that can be gained from this interdisciplinary approach, biomechanics commonly neglects a behavioral context and behavioral research generally does not consider mechanics. Here, we aim to encourage the study of "mechanoethology," an area of investigation intended to encompass integrative studies of mechanics and behavior. Using examples from the literature, including papers in this issue, we show how these fields can influence each other in three ways: (1) the energy required to execute behaviors is driven by the kinematics of movement, and mechanistic studies of movement can benefit from consideration of its behavioral context; (2) mechanics sets physical limits on what behaviors organisms execute, while behavior influences ecological and evolutionary limits on mechanical systems; and (3) sensory behavior is underlain by the mechanics of sensory structures, and sensory systems guide whole-organism movement. These core concepts offer a foundation for mechanoethology research. However, future studies focused on merging behavior and mechanics may reveal other ways by which these fields are linked, leading to further insights in integrative organismal biology.

Locomotion and Energetics of Divergent Foraging Strategies in Hummingbirds: A Review.

Hummingbirds have two main foraging strategies: territoriality (defending a patch of flowers) and traplining (foraging over routine circuits of isolated patches). Species are often classified as employing one or the other. Not only have these strategies been inconsistently defined within the behavioral literature, but this simple framework also neglects the substantial evidence for flexible foraging behavior displayed by hummingbirds. Despite these limitations, research on hummingbird foraging has explored the distinct avenues of selection that proponents of either strategy presumably face: trapliners maximizing foraging efficiency, and territorialists favoring speed and maneuverability for resource defense. In earlier studies, these functions were primarily examined through wing disc loading (ratio of body weight to the circular area swept out by the wings, WDL) and predicted hovering costs, with trapliners expected to exhibit lower WDL than territorialists and thus lower hovering costs. While these pioneering models continue to play a role in current research, early studies were constrained by modest technology, and the original expectations regarding WDL have not held up when applied across complex hummingbird assemblages. Current technological advances have allowed for innovative research on the biomechanics/energetics of hummingbird flight, such as allometric scaling relationships (e.g., wing area-flight performance) and the link between high burst lifting performance and territoriality. Providing a predictive framework based on these relationships will allow us to reexamine previous hypotheses, and explore the biomechanical trade-offs to different foraging strategies, which may yield divergent routes of selection for quintessential territoriality and traplining. With a biomechanical and morphofunctional lens, here we examine the locomotor and energetic facets that dictate hummingbird foraging, and provide (a) predictions regarding the behavioral, biomechanical, and morphofunctional associations with territoriality and traplining; and (b) proposed methods of testing them. By pursuing these knowledge gaps, future research could use a variety of traits to help clarify the operational definitions of territoriality and traplining, to better apply them in the field.

Olaparib monotherapy as primary treatment in unselected triple negative breast cancer.

BACKGROUND: The antitumor efficacy of PARP inhibitors (PARPi) for breast cancer patients harboring germline BRCA1/2 (gBRCA1/2) mutations is well established. While PARPi monotherapy was ineffective in patients with metastatic triple negative breast cancer (TNBC) wild type for BRCA1/2, we hypothesized that PARPi may be effective in primary TNBCs without previous chemotherapy exposure. PATIENTS AND METHODS: In the phase II PETREMAC trial, patients with primary TNBC >2 cm received olaparib for up to 10 weeks before chemotherapy. Tumor biopsies collected before and after olaparib underwent targeted DNA sequencing (360 genes) and BRCA1 methylation analyses. In addition, BRCAness (multiplex ligation-dependent probe amplification), PAM50 gene expression, RAD51 foci, tumor-infiltrating lymphocytes (TILs) and PD-L1 analyses were performed on pretreatment samples. RESULTS: The median pretreatment tumor diameter was 60 mm (range 25-112 mm). Eighteen out of 32 patients obtained an objective response (OR) to olaparib (56.3%). Somatic or germline mutations affecting homologous recombination (HR) were observed in 10/18 responders [OR 55.6%, 95% confidence interval (CI) 33.7-75.4] contrasting 1/14 non-responders (OR 7.1%; CI 1.3-31.5, P = 0.008). Among tumors without HR mutations, 6/8 responders versus 3/13 non-responders revealed BRCA1 hypermethylation (P = 0.03). Thus, 16/18 responders (88.9%, CI 67.2-96.9), in contrast to 4/14 non-responders (28.6%, CI 11.7-54.7, P = 0.0008), carried HR mutations and/or BRCA1 methylation. Excluding one gPALB2 and four gBRCA1/2 mutation carriers, 12/14 responders (85.7%, CI 60.1-96.0) versus 3/13 non-responders (23.1%, CI 8.2-50.3, P = 0.002) carried somatic HR mutations and/or BRCA1 methylation. In contrast to BRCAness signature or basal-like subtype, low RAD51 scores, high TIL or high PD-L1 expression all correlated to olaparib response. CONCLUSION: Olaparib yielded a high clinical response rate in treatment-naïve TNBCs revealing HR deficiency, beyond germline HR mutations. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02624973.

Homologous Recombination Repair Deficiency and the Immune Response in Breast Cancer: A Literature Review.

The success of cancer immunotherapy with immune checkpoint blockade (ICB) has demonstrated the importance of targeting a preexisting immune response in a broad spectrum of tumors. This is particularly novel and relevant for less immunogenic tumors, such as breast cancer (BC), where the efficacy of ICB was more evident in the triple-negative (TNBC) subtype, in earlier stages, and in association with chemotherapy. Tumors harboring homologous recombination DNA repair (HRR) deficiency (HRD) are supposed to have a higher number of mutations, hence a higher tumor mutational burden, which could potentially make them more sensitive to immunotherapy. However, the mechanisms involved in ICB sensitivity and patient selection are still yet to be defined in BC: whether the innate system could play a role and how the adaptive immunity could be linked with HRR pathways are the two key points of debate that we will discuss in this article. The aim of this review was to close the loop between what was found in clinical trial results so far, go back to laboratory theory and preclinical results and point out what needs to be clarified from now on.

Shifting Paradigms in the Mechanics of Nectar Extraction and Hummingbird Bill Morphology.

As functional morphologists, we aim to connect structures, mechanisms, and emergent higher-scale phenomena (e.g., behavior), with the ulterior motive of addressing evolutionary patterns. The fit between flowers and hummingbird bills has long been used as an example of impressive co-evolution, and hence hummingbirds' foraging behavior and ecological associations have been the subject of intense study. To date, models of hummingbird foraging have been based on the almost two-centuries-old assumption that capillary rise loads nectar into hummingbird tongue grooves. Furthermore, the role of the bill in the drinking process has been overlooked, instead considering it as the mere vehicle with which to traverse the corolla and access the nectar chamber. As a scientific community, we have been making incorrect assumptions about the basic aspects of how hummingbirds extract nectar from flowers. In this article, we summarize recent advances on drinking biomechanics, morphological and ecological patterns, and selective forces involved in the shaping of the hummingbird feeding apparatus, and also address its modifications in a previously unexpected context, namely conspecific and heterospecific fighting. We explore questions such as: how do the mechanics of feeding define the limits and adaptive consequences of foraging behaviors? Which are the selective forces that drive bill and tongue shape, and associated sexually dimorphic traits? And finally, what are the proximate and ultimate causes of their foraging strategies, including exploitative and interference competition? Increasing our knowledge of morphology, mechanics, and diversity of hummingbird feeding structures will have implications for understanding the ecology and evolution of these remarkable animals.

RAD51 foci as a functional biomarker of homologous recombination repair and PARP inhibitor resistance in germline BRCA-mutated breast cancer.

Background: BRCA1 and BRCA2 (BRCA1/2)-deficient tumors display impaired homologous recombination repair (HRR) and enhanced sensitivity to DNA damaging agents or to poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi). Their efficacy in germline BRCA1/2 (gBRCA1/2)-mutated metastatic breast cancers has been recently confirmed in clinical trials. Numerous mechanisms of PARPi resistance have been described, whose clinical relevance in gBRCA-mutated breast cancer is unknown. This highlights the need to identify functional biomarkers to better predict PARPi sensitivity. Patients and methods: We investigated the in vivo mechanisms of PARPi resistance in gBRCA1 patient-derived tumor xenografts (PDXs) exhibiting differential response to PARPi. Analysis included exome sequencing and immunostaining of DNA damage response proteins to functionally evaluate HRR. Findings were validated in a retrospective sample set from gBRCA1/2-cancer patients treated with PARPi. Results: RAD51 nuclear foci, a surrogate marker of HRR functionality, were the only common feature in PDX and patient samples with primary or acquired PARPi resistance. Consistently, low RAD51 was associated with objective response to PARPi. Evaluation of the RAD51 biomarker in untreated tumors was feasible due to endogenous DNA damage. In PARPi-resistant gBRCA1 PDXs, genetic analysis found no in-frame secondary mutations, but BRCA1 hypomorphic proteins in 60% of the models, TP53BP1-loss in 20% and RAD51-amplification in one sample, none mutually exclusive. Conversely, one of three PARPi-resistant gBRCA2 tumors displayed BRCA2 restoration by exome sequencing. In PDXs, PARPi resistance could be reverted upon combination of a PARPi with an ataxia-telangiectasia mutated (ATM) inhibitor. Conclusion: Detection of RAD51 foci in gBRCA tumors correlates with PARPi resistance regardless of the underlying mechanism restoring HRR function. This is a promising biomarker to be used in the clinic to better select patients for PARPi therapy. Our study also supports the clinical development of PARPi combinations such as those with ATM inhibitors.

Miocardiopatía de Tako-Tsubo: una manifestación inusual de feocromocitoma / Takotsubo cardiomyopathy: rare manifestation of pheochromocytoma

Takotsubo cardiomyopathy (MTT) is an acute ventricular dysfunction and reversible in absence of coronary disease. It is a rare presentation of pheochromocytoma and paraganglioma (FPGL). It was described for the first time in 1990 by Sato et al, the physiopathology is not clear yet. It is associated with high levels of catecholamines, vasospasm in the micro vascularization, rupture of atheromatous plaque and myiocarditis. The clinical presentation is similar to an acute myocardial infarction because of that the FPGL must be considered in patients without obstructive coronary lesions. We present a case of a 50 years old women with history of Arterial Hypertension, active smoking and Neurofibromatosis, who is admitted to emergency room with an acute myocardial pain.

Effects of zinc supplementation in the prevention of respiratory tract infections and diarrheal disease in Colombian children: A 12-month randomised controlled trial.

BACKGROUND: Among the preventive strategies for lowering the incidence of upper respiratory tract infections (URTI) and acute diarrhoea episodes, two of the most common diseases in children, zinc supplementation has received special interest. However, there is a need for additional studies that determine the preventive effects of different doses of zinc on URTI and diarrhoeal disease episodes in children. METHODS: In a randomised, triple-blind clinical trial, we evaluated the efficacy of 12 months of daily zinc supplementation in the incidence of URTI and acute diarrhoea in a population of healthy children aged between 6 and 12 months living in Bogota, Colombia. The outcomes analysed were incidence of URTI, acute diarrhoeal disease episodes, and side effects of the interventions. RESULTS: Between 2010 and 2013, a total of 355 children underwent randomisation, with 174 assigned to the zinc supplementation group and 181 to the control group. In the multivariate analyses, having been randomised to the non-supplemented control group (IRR 1.73, 95% CI 1.52-1.97, p<0.001), and nursery attendance (IRR 1.41, 95% CI 1.07-1.87, p=0.016) were independently linked to the number of URTI. Likewise, having been randomised to the non-supplemented group (IRR 1.43, 95% CI 1.20-1.71, p<0.001), and lower socioeconomic status (IRR 1.86, 95% CI 1.11-3.13, p=0.018) were independently associated to the number of diarrhoeal disease episodes. CONCLUSIONS: Daily supplementation of 5mg of zinc during 12 months significantly decreased the incidence of URTI and diarrhoeal disease episodes in a healthy population of children aged between 6 and 12 months.

Immunogenicity and safety of the 9-valent HPV vaccine in men.

OBJECTIVES: This study was designed to evaluate the immunogenicity and tolerability of a prophylactic 9-valent HPV (types 6/11/16/18/31/33/45/52/58) VLP (9vHPV) vaccine in young men 16-26 years of age in comparison to young women 16-26 years of age (the population that was used to establish 9vHPV vaccine efficacy). Safety and immunogenicity data from this study will be used to bridge 9vHPV vaccine efficacy findings in 16-26 year old women to 16-26 year old men. METHODS: This study enrolled 1106 heterosexual men (HM) and 1101 women who had not yet received HPV vaccination. In addition, 313 men having sex with men (MSM) were enrolled and were evaluated separately for immunogenicity because previous results showed that antibody responses to quadrivalent HPV (types 6/11/16/18) VLP (qHPV) vaccine were lower in MSM than in HM. All subjects were administered a 3-dose regimen (Day 1, Month 2, Month 6) of 9vHPV vaccine. Serum samples were collected for anti-HPV assays. Safety information was collected for ∼ 12 months. RESULTS: The geometric mean titers (GMTs) for HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58 for HM were non-inferior to those of women at Month 7. For all vaccine HPV types, Month 7 GMTs were numerically lower in MSM than in HM. Over 99.5% of subjects were seropositive at Month 7 for each vaccine HPV type. Administration of 9vHPV vaccine to both 16-26 year old men and women was generally well tolerated. CONCLUSIONS: These results support bridging the efficacy findings with 9vHPV vaccine in young women 16-26 years of age to men 16-26 years of age.

Utilidad de la pet/tac en la estadificación mediastínica del cáncer pulmonar de células no pequeñas en estadio iii (N2) / Usefulness of ct and pet scans in mediastinal stagingof stage iii (n2) non-small-cell lung cancer

OBJETIVO: Evaluar la validez diagnóstica de la tomografía por emisión de positrones con 18F-fluoro-2-deoxi-D-glucosa y la tomografía computerizada (PET/TAC), como de las maniobras quirúrgicas de estadificación mediastínica (N2) en pacientes con carcinoma broncogénico no microcítico, analizando ambos resultados. MATERIAL Y MÉTODOS: Estudio prospectivo de pacientes con diagnóstico o alta sospecha de carcinoma broncogénico, y posible afectación N2 mediante TAC con contraste y PET/TAC. Se analizaron por pacientes y grupos adenopáticos, confirmándose mediante análisis histopatológico. Se calcularon sensibilidad, especificidad, valor predictivo positivo y valor predictivo negativo del estudio PET/TAC así como de las maniobras quirúrgicas. RESULTADOS: Se incluyeron 67 pacientes clasificados como N2 mediante TAC con contraste. El PET/TAC clasificó a 63 pacientes como N2. Se encontraron discrepancias en 7 pacientes, 6 como falsos positivos y 1 como falso negativo. Las maniobras invasivas de estadificación analizaron 123 estaciones ganglionares, obteniendo resultado histopatológico en 98 de ellas. La PET/TAC clasificó como positivas 78, 10 falsos positivos y 10 falsos negativos. Para las maniobras invasivas se obtuvieron un total de 97 estaciones ganglionares, 75 positivas, 2 falsos positivos y 5 falsos negativos. CONCLUSIONES: El estudio PET/TAC presenta buena sensibilidad, más una especificidad discreta, en la correcta clasificación de pacientes N2 debido a limitaciones clínico-quirúrgicas. Las técnicas para la comprobación histológica de los hallazgos obtenidos en imagen, presentaron una alta validez diagnóstica. Los resultados delimitan tres subgrupos clínicos de utilidad, en los que cumpliendo unos requisitos radiológicos y clínicos, la cirugía de estadificación puede reservarse, seleccionando los pacientes y evitando la morbimortalidad de la cirugía

OBJECTIVE: To assess the diagnostic validity of FDG-PET, PET-CT, and surgical mediastinal staging (N2) in patients with non-small-cell lung cancer (NSCLC), comparing the outcomes obtained with such diagnostic procedures. MATERIAL AND METHODS: Prospective study of patients with diagnosis of bronchogenic carcinoma and suspected N2 disease by CT and PET-CT. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated and compared among each diagnostic procedure. The analysis was performed both for patients and for lymph node stations. RESULTS: 67 patients with N2 disease by CT were included in disease by CT were included in the analysis. PET-CT identified 63 patients as being N2. Dis-crepancies were observed in 7 patients: 6 false positive, and 1 false negative. Invasive surgical mediastinal staging analyzed 123 lymph node stations, achieving the pathological diagnosis in 98. PET-CT identified positive 78 lymph nodes, 10 false po-sitive and 10 false negative. For invasive procedures, 97 lymph node stations were obtained, 75 positive, 2 false positive, and 5 false negative. CONCLUSIONS: PET-CT has a high sensitivity but only a modest specificity for the correct N2 staging of patients with NSCLC. Diagnostic methods of pathological confirmation of findings observed in imaging procedures, presented a high diagnostic validity. Our results delineate three clinical subgroups of pa-tients in that invasive procedures for mediastinal staging could be reserved, avoiding surgical morbidity and mortality

T helper cell IL-4 drives intestinal Th2 priming to oral peanut antigen, under the control of OX40L and independent of innate-like lymphocytes.

Intestinal T helper type 2 (Th2) immunity in food allergy results in IgG1 and IgE production, and antigen re-exposure elicits responses such as anaphylaxis and eosinophilic inflammation. Although interleukin-4 (IL-4) is critically required for allergic sensitization, the source and control of IL-4 during the initiation of Th2 immunity in vivo remains unclear. Non-intestinal and non-food allergy systems have suggested that natural killer-like T (NKT) or γδ T-cell innate lymphocytes can supply the IL-4 required to induce Th2 polarization. Group 2 innate lymphoid cells (ILCs) are a novel IL-4-competent population, but their contribution to initiating adaptive Th2 immunity is unclear. There are also reports of IL-4-independent Th2 responses. Here, we show that IL-4-dependent peanut allergic Th2 responses are completely intact in NKT-deficient, γδ T-deficient or ILC-deficient mice, including antigen-specific IgG1/IgE production, anaphylaxis, and cytokine production. Instead, IL-4 solely from CD4(+) Th cells induces full Th2 immunity. Further, CD4(+) Th cell production of IL-4 in vivo is dependent on OX40L, a costimulatory molecule on dendritic cells (DCs) required for intestinal allergic priming. However, both Th2 cells and ILCs orchestrated IL-13-dependent eosinophilic inflammation. Thus, intestinal Th2 priming is initiated by an autocrine/paracrine acting CD4(+) Th cell-intrinsic IL-4 program that is controlled by DC OX40L, and not by NKT, γδ T, or ILC cells.