Long-term Outcomes with Nivolumab as First-line Treatment in Recurrent or Metastatic Head and Neck Cancer: Subgroup Analysis of CheckMate 141.

In the randomized, phase 3 CheckMate 141 trial, nivolumab significantly improved overall survival (OS) versus investigator's choice (IC) of chemotherapy at primary analysis among 361 patients with recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) post-platinum therapy. Nivolumab versus IC as first-line treatment also improved OS among patients with R/M SCCHN who progressed on platinum therapy for locally advanced disease in the adjuvant or primary setting at 1-year follow-up. In the present long-term follow-up analysis of patients receiving first-line treatment, OS benefit with nivolumab (n = 50) versus IC (n = 26) was maintained (median: 7.7 months versus 3.3 months; hazard ratio: 0.56; 95% confidence interval, 0.34-0.94) at 2 years. No new safety signals were identified. In summary, this long-term 2-year analysis of CheckMate 141 supports the use of nivolumab as a first-line treatment for patients with platinum-refractory R/M SCCHN.

Cecal ameboma and a liver abscess mimicking metastatic colonic cancer. An autochthonous infectious disease in Spain?

We present the case of 52 years-old male without any recent travel. He was admitted to our department for a history of fever and abdominal pain. A CT scan showed a cecal thickening and liver mass with suspected cecal carcinoma with infected necrotic liver metastasis. Although the colonoscopy revealed a bulky submucosal wall thickening with a fibrined ulcer with yellow granulating located in the cecum, the percutaneous drainage revealed a positive PCR for Entamoeba histolytica, with improvement with metronidazole treatment. Ameboma are ulcerative, exophytic, inflammatory masses up to 15 cm in diameter in patients with long standing colonic amoebic infections containing granulation tissue with pseudotumor appearance. It affects less than 1.5% of colonic invasive amebiasis. Moreover, concomitant hepatic amoebic can be observed up to 30%, mimicking colonic cancer with necrotic liver metastasis. Although no epidemiological risk factor for amoebic infection was detected. We therefore highlight the awareness of amoebic infection and different manifestation even in non-endemic areas.

Endogenous B-ring oxysterols inhibit the Hedgehog component Smoothened in a manner distinct from cyclopamine or side-chain oxysterols.

Cellular lipids are speculated to act as key intermediates in Hedgehog signal transduction, but their precise identity and function remain enigmatic. In an effort to identify such lipids, we pursued a Hedgehog pathway inhibitory activity that is particularly abundant in flagellar lipids of Chlamydomonas reinhardtii, resulting in the purification and identification of ergosterol endoperoxide, a B-ring oxysterol. A mammalian analog of ergosterol, 7-dehydrocholesterol (7-DHC), accumulates in Smith-Lemli-Opitz syndrome, a human genetic disease that phenocopies deficient Hedgehog signaling and is caused by genetic loss of 7-DHC reductase. We found that depleting endogenous 7-DHC with methyl-ß-cyclodextrin treatment enhances Hedgehog activation by a pathway agonist. Conversely, exogenous addition of 3ß,5α-dihydroxycholest-7-en-6-one, a naturally occurring B-ring oxysterol derived from 7-DHC that also accumulates in Smith-Lemli-Opitz syndrome, blocked Hedgehog signaling by inhibiting activation of the essential transduction component Smoothened, through a mechanism distinct from Smoothened modulation by other lipids.

CheckMate 141: 1-Year Update and Subgroup Analysis of Nivolumab as First-Line Therapy in Patients with Recurrent/Metastatic Head and Neck Cancer.

Nivolumab significantly improved overall survival (OS) vs investigator's choice (IC) of chemotherapy at the primary analysis of randomized, open-label, phase 3 CheckMate 141 in patients with recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN). Here, we report that OS benefit with nivolumab was maintained at a minimum follow-up of 11.4 months. Further, OS benefit with nivolumab vs IC was also noted among patients who received first-line treatment for R/M SCCHN after progressing on platinum therapy for locally advanced disease in the adjuvant or primary (i.e., with radiation) setting.

Crohn's disease and Sweet's syndrome: A debut together.

The association of Sweet's syndrome and Crohn's disease is unusual, with less than 50 reported cases. We report a case in which these entities debut together.

Cohort Profile: The Zurich Primary HIV Infection Study.

The Zurich Primary HIV Infection (ZPHI) study is a longitudinal cohort study established in 2002, aiming to study the clinical, epidemiological, and biological characteristics of primary HIV infection. The ZPHI enrolls individuals with documented primary HIV-1 infection. At the baseline and thereafter, the socio-demographic, clinical, and laboratory data are systematically collected, and regular blood sampling is performed for biobanking. By the end of December 2022, 486 people were enrolled, of which 353 were still undergoing active follow-up. Of the 486 participants, 86% had an acute infection, and 14% a recent HIV-1 infection. Men who have sex with men accounted for 74% of the study population. The median time from the estimated date of infection to diagnosis was 32 days. The median time from diagnosis to the initiation of antiretroviral therapy was 11 days, and this has consistently decreased over the last two decades. During the seroconversion phase, 447 (92%) patients reported having symptoms, of which only 73% of the patients were classified as having typical acute retroviral syndrome. The ZPHI study is a well-characterized cohort belonging to the most extensively studied primary HIV infection cohort. Its findings contribute to advancing our understanding of the early stages of HIV infection and pathogenesis, and it is paving the way to further improve HIV translational research and HIV medicine.

The integral inventory for depression, a new, self-rated clinimetric instrument for the emotional and painful dimensions in major depressive disorder.

OBJECTIVE: To assess the reliability and validity of the Integral Inventory for Depression (IID) scale using post hoc analyses of data from a multi-country study (ClinicalTrials.gov: NCT00561509) of patients with major depressive disorder (MDD). METHODS: Patients (N = 1629) completed the IID (comprising two separate dimensions for emotional and physically painful symptoms; maximum score of 65) and a reference scale (16-item Quick Inventory of Depressive Symptomatology Self-Report) at baseline and at follow-up (8 and 24 weeks). Physicians rated MDD symptoms using the Clinical Global Impressions of Severity scale at each visit. Inter-item correlation, internal consistency, external validity, factor structure, and exploratory analysis of an optimal severity cut-off point were assessed. RESULTS: The IID displayed two distinct dimensions (i.e. painful and emotional) with little item redundancy and good internal consistency (Cronbach's α > 0.83 at each visit). The IID displayed good external validity (Pearson's correlations coefficients >0.60 at each visit) and statistically significant agreement (McNemar's test; P < 0.001 at follow-up) with the reference scale. Results suggest that a cut-off score of ≤24 had adequate precision (>80%) to identify patients with and without moderate MDD. CONCLUSIONS: Results suggest that the IID may be a reliable and valid tool for assessing emotional and painful symptoms of MDD.

Current approach and novel perspectives in nasopharyngeal carcinoma: the role of targeting proteasome dysregulation as a molecular landmark in nasopharyngeal cancer.

Nasopharyngeal carcinoma (NPC) represents a molecularly paradigmatic tumor given the complex diversity of environmental as well as host dependent factors that are closely implicated in tissue transformation and carcinogenesis. Epstein Barr Virus (EBV) plays a key role in tissue invasion, hyperplasia and malignant transformation. Therefore, EBV related oncoviral proteins such as Latent Membrane Protein family (LMP1, LMP2), Epstein Barr Nuclear Antigen 1 (EBNA1) and EBV related glycoprotein B (gB) are responsible for inducing intracellular signalling aberrations leading to sustained proliferation and further acquisition of NPC related invasive nature and metastatic potential.Dysregulation of proteasome signaling seems to be centrally implicated in oncoviral protein stabilization as well as in modulating tumor microenvironment. Different studies in vitro and in vivo suggest a potential role of proteasome inhibitors in the therapeutic setting of NPC. Furthermore, alterations affecting proteasome signalling in NPC have been associated to tumor growth and invasion, distant metastasis, immune exclusion and resistance as well as to clinical poor prognosis. So on, recent studies have shown the efficacy of immunotherapy as a suitable therapeutic approach to NPC. Nevertheless, novel strategies seem to look for combinatorial regimens aiming to potentiate immune recognition as well as to restore both primary and acquired immune resistance.In this work, our goal is to thoroughly review the molecular implications of proteasome dysregulation in the molecular pathogenesis of NPC, together with their direct relationship with EBV related oncoviral proteins and their role in promoting immune evasion and resistance. We also aim to hypothesize about the feasibility of the use of proteasome inhibitors as part of immunotherapy-including combinatorial regimens for their potential role in reversing immune resistance and favouring tumor recognition and eventual tumor death.

Age differences in the prevalence and co-morbidity of DSM-IV major depressive episodes: results from the WHO World Mental Health Survey Initiative.

BACKGROUND: Although depression appears to decrease in late life, this could be due to misattribution of depressive symptoms to physical disorders that increase in late life. METHODS: We investigated this issue by studying age differences in co-morbidity of DSM-IV major depressive episodes (MDE) with chronic physical conditions in the WHO World Mental Health (WMH) surveys, a series of community epidemiological surveys of respondents in 10 developed countries (n=52,485) and 8 developing countries (n=37,265). MDE and other mental disorders were assessed with the Composite International Diagnostic Interview (CIDI). Organic exclusion rules were not used to avoid inappropriate exclusion of cases with physical co-morbidity. Physical conditions were assessed with a standard chronic conditions checklist. RESULTS: Twelve-month DSM-IV/CIDI MDE was significantly less prevalent among respondents ages 65+ than younger respondents in developed but not developing countries. Prevalence of co-morbid mental disorders generally either decreased or remained stable with age, while co-morbidity of MDE with mental disorders generally increased with age. Prevalence of physical conditions, in comparison, generally increased with age, while co-morbidity of MDE with physical conditions generally decreased with age. Depression treatment was lowest among the elderly in developed and developing countries. CONCLUSIONS: The weakening associations between MDE and physical conditions with increasing age argue against the suggestion that the low estimated prevalence of MDE among the elderly is due to increased confounding with physical disorders. Future study is needed to investigate processes that might lead to a decreasing impact of physical illness on depression among the elderly.

Early childhood adversity and later hypertension: data from the World Mental Health Survey.

BACKGROUND: Although many studies have indicated that psychosocial factors contribute to hypertension, and that early childhood adversity is associated with long-term adverse mental and physical health sequelae, the association between early adversity and later hypertension is not well studied. METHOD: Data from 10 countries participating in the World Health Organization (WHO) World Mental Health (WHM) Surveys (N = 18,630) were analyzed to assess the relationship between childhood adversity and adult-onset hypertension, as ascertained by self-report. The potentially mediating effect of early-onset depression-anxiety disorders, as assessed by the WHM Survey version of the International Diagnostic Interview (WMH-CIDI), on the relationship between early adversity and hypertension was also examined. RESULTS: Two or more early childhood adversities, as well as early-onset depression-anxiety, were significantly associated with hypertension. A range of specific childhood adversities, as well as early-onset social phobia and panic/agoraphobia, were significantly associated with hypertension. In multivariate analyses, the presence of 3 or more childhood adversities was associated with hypertension, even when early-onset depression-anxiety or current depression-anxiety was included in the model. CONCLUSIONS: Although caution is required in the interpretation of self-report data on adult-onset hypertension, the results of this study further strengthen the evidence base regarding the role of psychosocial factors in the pathogenesis of hypertension.

[Can we prevent falls in the elderly from primary care?]. / ¿Podemos desde atención primaria prevenir las caídas en las personas mayores?

OBJECTIVE: To determine the effectiveness of multifactorial intervention by Primary Care in the prevention of falls in the elderly who had fallen the year before. DESIGN: Intervention study with a control group. SETTING: Three clinics in a rural area. SUBJECTS: 224 patients > or = 65 years, independent for mobility (113 in the intervention (IG) and 111 in the control (GC) group. INTERVENTIONS: Intervention Group. INITIAL ASSESSMENT: 1) Demographic data questionnaire, number, circumstances and consequences of falls, comorbidity and drugs. 2) Oriented examination. 3) Home risks assessment. INTERVENTIONS: referred to cardiology if arrhythmia or bradycardia, referred for eye examination if changes in acute vision, recommendation for systems support if gait or balance problems, postural measures if orthostatic hypotension, behavioural measures in urinary incontinence and recommendations to modify home risks. CONTROL GROUP: Questionnaire on: demographic data, number, circumstances and consequences of falls and medication use. They received normal medical care. RESULTS: At one year 44% of the IG and 33% in the CG fell again (P=0.123). In the sub-group with more than one fall at the beginning of the study, 63% in the IG, and 56% in CG fell again (P=0.599). There were serious consequences in 6% of the IG compared to 14% in the CG (P=0.277). CONCLUSIONS: Multifactorial intervention from primary care is not effective in reducing falls or for reducing the severity of their consequences.

Mental disorders among persons with diabetes--results from the World Mental Health Surveys.

OBJECTIVE: To estimate 12-month prevalence rate of mood, anxiety, and alcohol-use disorders among community samples of diabetic persons. We assess whether associations of specific mental disorders with diabetes are consistent across diverse countries after controlling for age and gender. RESEARCH DESIGN AND METHODS: Eighteen surveys of household-residing adults were conducted in two phases across 17 countries in Europe, the Americas, the Middle East, Africa, Asia, and the South Pacific (Part 1, N=85,088). Mental disorders, identified by the World Mental Health-Composite International Diagnostic Interview, included anxiety disorders (generalized anxiety disorder, panic disorder/agoraphobia, posttraumatic stress disorder, and social phobia), mood disorders (dysthymia and major depressive disorder), and alcohol abuse/dependence. Diabetes was ascertained by self-report (Part 2, N=42,697). Association was assessed by age-gender adjusted odds ratios. RESULTS: Risk of mood and anxiety disorders was slightly higher among persons with diabetes relative to those without: odds ratio of 1.38 for depression (95% CI=1.15-1.66) and 1.20 for anxiety disorders, (95 % CI=1.01-1.42), after adjusting for age and gender. Odds ratio estimates across countries did not differ more than chance expectation. Alcohol-use disorders were uncommon among persons with diabetes in most countries, and not associated with diabetes in pooled survey data. CONCLUSIONS: Population sample surveys revealed mood and anxiety disorders occurred with somewhat greater frequency among persons with diabetes than those without diabetes. Prevalence of major depression among persons with diabetes was lower in the general population than suggested by prior studies of clinical samples. Strength of association did not differ significantly across disorders or countries.

Phase IV noninferiority controlled randomized trial to evaluate the impact on diagnostic thinking and patient management and the test-retest reproducibility of the Gaxilose test for hypolactasia diagnosis.

BACKGROUND: The diagnostic accuracy of the Gaxilose test (GT) for hypolactasia diagnosis has already been proved. The objectives of this clinical trial were to demonstrate the noninferiority of the GT compared to the hydrogen breath test (HBT) on the impact on diagnostic thinking and patient management, to evaluate the GT reproducibility with urine accumulated from 0 to 4 hours and from 0 to 5 hours and to assess test safety. METHODS: We conducted a randomized, parallel, noninferiority clinical trial. Patients with clinical symptoms suggestive of lactose intolerance were screened for inclusion and randomly assigned to the GT arm or the HBT arm of the study. The impact on diagnostic thinking and patient management was analyzed with pretest and posttest questionnaires in which the investigators indicated their estimated probability of hypolactasia diagnosis and the intended management before and after the GT or the HBT (noninferiority margin: -10%). The primary outcome of the study was the impact on diagnostic thinking, expressed as the mean of the absolute values of the differences between the pretest and posttest probabilities of hypolactasia diagnosis. Patients randomized to the GT arm performed also the retest to evaluate the reproducibility of the GT. RESULTS: A total of 147 patients were included in the intend-to-treat (ITT) population. Among them, 74 performed the HBT and 73 performed the GT. The results proved the noninferiority of the GT compared to the HBT on the impact on diagnostic thinking (ImpactGT = 31.74 ±â€Š23.30%; ImpactHBT = 24.28 ±â€Š19.87%; ΔGT-HBT = 7.46%; 95% confidence interval of ΔGT-HBT: 1.55%, infinite) and on patient management. The test-retest reproducibility was better for the GT with urine accumulated from 0 to 5 h: the intraclass correlation coefficient (ICC) was 0.5761, and the Kappa coefficient was 0.7548, indicative of substantial agreement between both tests. No serious adverse events were reported during the study. CONCLUSIONS: The GT has an impact on diagnostic thinking and patient management noninferior to that of the HBT, is reproducible and well tolerated. These results prove the clinical benefit of its use in the clinical practice (ClinicalTrials.gov identifier: NCT02636413).

Nivolumab vs investigator's choice in recurrent or metastatic squamous cell carcinoma of the head and neck: 2-year long-term survival update of CheckMate 141 with analyses by tumor PD-L1 expression.

OBJECTIVES: We report 2-year results from CheckMate 141 to establish the long-term efficacy and safety profile of nivolumab and outcomes by tumor PD-L1 expression in patients with recurrent or metastatic (R/M),platinum-refractory squamous cell carcinoma of the head and neck (SCCHN). METHODS: Patients with R/M SCCHN with tumor progression/recurrence within 6 months of platinum therapy were randomized 2:1 to nivolumab 3 mg/kg every 2 weeks or investigator's choice (IC). Primary endpoint: overall survival (OS). Data cutoff: September 2017. RESULTS: With 24.2 months' minimum follow-up, nivolumab (n = 240) continued to improve OS vs IC (n = 121), hazard ratio (HR) = 0.68 (95% CI 0.54-0.86). Nivolumab nearly tripled the estimated 24-month OS rate (16.9%) vs IC (6.0%), and demonstrated OS benefit across patients with tumor PD-L1 expression ≥1% (HR [95% CI] = 0.55 [0.39-0.78]) and  < 1% (HR [95% CI] = 0.73 [0.49-1.09]), and regardless of tumor HPV status. Estimated OS rates at 18, 24, and 30 months with nivolumab were consistent irrespective of PD-L1 expression (<1%/≥1%). In the nivolumab arm, there were no observed differences in baseline characteristics or safety profile between long-term survivors and the overall population. Grade 3-4 treatment-related adverse event rates were 15.3% and 36.9% for nivolumab and IC, respectively. CONCLUSION: Nivolumab significantly improved OS at the primary analysis and demonstrated prolonged OS benefit vs IC and maintenance of a manageable and consistent safety profile with 2-year follow-up. OS benefit was observed with nivolumab irrespective of PD-L1 expression and HPV status. (Clinicaltrials.gov: NCT02105636).

Delay of first treatment of mental and substance use disorders in Mexico.

OBJECTIVES: We studied failure and delay in making initial treatment contact after the first onset of a mental or substance use disorder in Mexico as a first step to understanding barriers to providing effective treatment in Mexico. METHODS: Data were from the Mexican National Comorbidity Survey (2001-2002), a representative, face-to-face household survey of urban residents aged 18 to 65 years. The age of onset for disorders was compared with the age of first professional treatment contact for each lifetime disorder (as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition). RESULTS: Many people with lifetime disorders eventually made treatment contact, although the proportions varied for mood (69.9%), anxiety (53.2%), and substance use (22.1%) disorders. Delays were long: 10 years for substance use disorders, 14 years for mood disorders, and 30 years for anxiety disorders. Failure and delay in making initial treatment contact were associated with earlier ages of disorder onset and being in older cohorts. CONCLUSIONS: Failure to make prompt initial treatment contact is an important reason explaining why there are unmet needs for mental health care in Mexico. Meeting these needs will likely require expansion and optimal allocation of resources as well as other interventions.

The epidemiology of suicide-related outcomes in Mexico.

Nationally representative data from the Mexican National Comorbidity Survey are presented on the lifetime prevalence and age-of-onset (AOO) distributions of suicide ideation, plan and attempt and on temporally prior demographic and DSM-IV psychiatric risk factors. Lifetime ideation was reported by 8.1% of respondents, while 3.2% reported a lifetime plan and 2.7% a lifetime suicide attempt. Onset of all outcomes was highest in adolescence and early adulthood. The risk of transition from suicide ideation to plan and attempt was highest within the first year of onset of ideation. The presence of one or more temporally prior DSM-IV/CIDI (Composite International Diagnostic Instrument) disorder was strongly related to each suicide-related outcome. Suicidal outcomes are prevalent, have an early AOO, and are strongly related to temporally prior mental disorders in Mexico. Given the early AOO, intervention efforts need to focus more than currently on children and adolescents with mental disorders to be effective in prevention.

Treatment and adequacy of treatment of mental disorders among respondents to the Mexico National Comorbidity Survey.

OBJECTIVE: This study described the rate and adequacy of mental health service use among participants in the Mexico National Comorbidity Survey and the correlates of any 12-month treatment and of adequate treatment. METHOD: The authors conducted face-to-face household surveys of a probability sample of individuals ages 18 to 65 years in the noninstitutionalized population living in urban areas of Mexico from 2001 to 2002. The use of mental health services and 12-month DSM-IV disorders was assessed with the World Mental Health version of the World Health Organization Composite International Diagnostic Interview. The rates and correlates of any service use and the adequacy of treatment were identified in logistic regression analyses, taking into account the complex sample design and weighting process. RESULTS: The data reported here were based on 2,362 interviews. Fewer than one in five respondents with any psychiatric disorder during the last 12 months used any service during the prior year. The rates of service use by those with mood disorders were somewhat higher. About one in every two respondents who used services received minimally adequate care. CONCLUSIONS: The authors found large unmet needs for mental health services among those with psychiatric disorders. Those with mental illness and those who deliver or seek to improve mental health care in Mexico face enormous challenges.

[Heart transplant in "Nuevo Leon": the first 33 cases]. / Estado actual del trasplante cardíaco en Nuevo León: primeros 33 casos.

Heart failure is one of the most important causes of death worldwide. Heart transplant is the last effective alternative when the medical and surgical treatments have failed in patients with end stage heart failure, giving them an 80% one year survival rate. Unfortunately, during the outcome, the heart transplant patients can develop complications such as graft rejection and opportunistic infections because of the use of immunosuppressive therapy. In the present article we report the experience with 33 heart transplant patients. Our program not only has successfully transplanted patients with advanced age but, for the first time in Latin America we have transplanted patients assisted with the ambulatory Thoratec TLC II system. Even with limited resources, we have managed the same complications than other heart transplant programs, our 82% one year survival rate is similar than reports in medical literature.

Uni-directional ciliary membrane protein trafficking by a cytoplasmic retrograde IFT motor and ciliary ectosome shedding.

The role of the primary cilium in key signaling pathways depends on dynamic regulation of ciliary membrane protein composition, yet we know little about the motors or membrane events that regulate ciliary membrane protein trafficking in existing organelles. Recently, we showed that cilium-generated signaling in Chlamydomonas induced rapid, anterograde IFT-independent, cytoplasmic microtubule-dependent redistribution of the membrane polypeptide, SAG1-C65, from the plasma membrane to the periciliary region and the ciliary membrane. Here, we report that the retrograde IFT motor, cytoplasmic dynein 1b, is required in the cytoplasm for this rapid redistribution. Furthermore, signaling-induced trafficking of SAG1-C65 into cilia is unidirectional and the entire complement of cellular SAG1-C65 is shed during signaling and can be recovered in the form of ciliary ectosomes that retain signal-inducing activity. Thus, during signaling, cells regulate ciliary membrane protein composition through cytoplasmic action of the retrograde IFT motor and shedding of ciliary ectosomes.