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This overview of the molecular pathology of lung cancer includes a review of the most salient molecular alterations of the genome, transcriptome, and the epigenome. The insights provided by the growing use of next-generation sequencing (NGS) in lung cancer will be discussed, and interrelated concepts such as intertumor heterogeneity, intratumor heterogeneity, tumor mutational burden, and the advent of liquid biopsy will be explored. Moreover, this work describes how the evolving field of molecular pathology refines the understanding of different histologic phenotypes of non-small-cell lung cancer (NSCLC) and the underlying biology of small-cell lung cancer. This review will provide an appreciation for how ongoing scientific findings and technologic advances in molecular pathology are crucial for development of biomarkers, therapeutic agents, clinical trials, and ultimately improved patient care.

Insights into the genetic basis of human disease are helping to address some of the key challenges in new drug development including the very high rates of failure. Here we review the recent history of an emerging, genomics-assisted approach to pharmaceutical research and development, and its relationship to Mendelian randomization (MR), a well-established analytical approach to causal inference. We demonstrate how human genomic data linked to pharmaceutically relevant phenotypes can be used for (1) drug target identification (mapping relevant drug targets to diseases), (2) drug target validation (inferring the likely effects of drug target perturbation), (3) evaluation of the effectiveness and specificity of compound-target engagement (inferring the extent to which the effects of a compound are exclusive to the target and distinguishing between on-target and off-target compound effects), and (4) the selection of end points in clinical trials (the diseases or conditions to be evaluated as trial outcomes). We show how genomics can help identify indication expansion opportunities for licensed drugs and repurposing of compounds developed to clinical phase that proved safe but ineffective for the original intended indication. We outline statistical and biological considerations in using MR for drug target validation (drug target MR) and discuss the obstacles and challenges for scaled applications of these genomics-based approaches.

IntroductionWhile phosphodiesterase type 5 inhibitors (PDE5is) and others are used to treat Erectile dysfunction (ED), many patients are either unresponsive or resistant to it. Stem cell therapy (SCT) is a promising alternative approach. Numerous preclinical trials have demonstrated improved erectile function in animal models using SCT, although the number of clinical trials investigating SCT for men with ED is limited. Nonetheless, findings from human clinical trials suggest that SCT may be a useful treatment option.Areas coveredBiomedical literature, including PubMed, ClinicalTrials.gov, and European Union Clinical Trials Registry, were analyzed to summarize and synthesize information on stem cell therapy for ED in this narrative review. The achievements in preclinical and clinical evaluations are presented and critically analyzed.Expert opinionSCT has demonstrated some benefits in improving erectile function, while further studies are urgently needed. Such studies would provide valuable insights into the optimal use of stem cell therapy and its potential as a therapeutic option for ED. Taking advantage of different mechanisms of action involved in various regenerative therapies, combination therapies such as SCT and low-energy shock waves or platelet-rich plasma may provide a more effective therapy and warrant further research.

Background: Multiple clinical trials of modern antipsychotics have failed in pediatric samples. One possibility for these failures is the use of a primary outcome measure that was developed for adults. Surprisingly, the psychometric properties of primary outcome measures have never been reported for a pediatric sample using modern methods. The present study’s aim is to use a pediatric sample to evaluate the psychometrics of the most used primary outcome measure in pediatric schizophrenia trials, the Positive and Negative Syndrome Scale (PANSS). Methods: To evaluate the factor structure, item characteristics, and treatment sensitivity of the PANSS in a pediatric sample, secondary analyses of PANSS data at baseline and weekly throughout an 8-week randomized double-blind study of three antipsychotic agents (registered and previously published) were conducted. Subjects were 118 youths receiving outpatient psychiatric treatment for schizophrenia spectrum disorders (Mage=14.26(2.41) years). Outcomes: A 10-item short form, keeping two strongest items for each factor, had r=.89 with the full-length scale. Each of the 5 2-item subscales has alphas ranging from .66 to .84. Item Response Theory (IRT) found that the 10-item scale and 2-item subscores had high reliability across the severity range typical of clinical trials. Criterion validity was high, with equal sensitivity to treatment effects. Interpretation: The short version eliminates weaker items in the pediatric population without loss of sensitivity to treatment effects and thus may be more appropriate for subsequent pediatric trials. Funding: NIMH funded the original protocol; NDA archived the data; Signant paid for secondary statistical analyses. Declaration of Interest: Dr. Findling receives or has received research support, acted as a consultant and/or has received honoraria from Acadia, Adamas, Aevi, Afecta, Akili, Alkermes, Allergan, American Academy of Child & Adolescent Psychiatry, American Psychiatric Press, Arbor, Axsome, Daiichi-Sankyo, Emelex, Gedeon Richter, Genentech, Idorsia, Intra-Cellular Therapies, Kempharm, Luminopia, Lundbeck, MedAvante-ProPhase, Merck, MJH Life Sciences,NIH, Neurim, Otsuka, PaxMedica, PCORI, Pfizer, Physicians Postgraduate Press, Q BioMed, Receptor Life Sciences, Roche, Sage, Signant Health, Sunovion, Supernus Pharmaceuticals, Syneos, Syneurx, Takeda, Teva, Tris, and Validus. Dr. Youngstrom has received royalties from the American Psychological Association and Guilford Press, consulted with Signant Health about psychological assessment, and received funding from NIMH. He is the founder and Executive Director of Helping Give Away Psychological Science (HGAPS.org). Dr. Sikich receives or has received research support from NIMH, NICHD, and Roche. She has received partial salary support from Tris. She has a patent submission through Duke University for a new formulation of intranasal oxytocin. Dr. Frazier receives or has received funding from NIMH, NICHD, Autism Speaks, Roche pharmaceuticals, and Fulcrum. Dr. McClellan receives or has received funding from NIMH. Dr. Daniel is an employee and equity holder in Signant Health. Dr. Busner is an employee and equity holder in Signant Health. Ethical Approval: The secondary analyses were reviewed and approved by the UNC Chapel Hill IRB.

Objective: to evaluate the effect of nursing home care interventions on the quality of life in family caregivers of aged stroke survivors. Method: a Randomized Clinical Trial, blinded for outcome evaluation. Forty-eighty family caregivers of aged stroke survivors participated in the study. The Intervention Group received three home visits by nurses one month after hospital discharge to provide stroke-related education (i.e., how to access health services and perform care activities) and emotional support. The Control Group received the usual guidance from the health services. Quality of life was assessed using the World Health Organization Quality of Life Assessment (WHOQOL-BREF) instrument and the Old Module(WHOQOL-OLD) 1 week, 2 months, and 1 year after discharge. Results: the caregivers were mainly women, children, or spouses. The caregivers in the Intervention Group and Control Group did not significantly differ in terms of their Overall Quality of Life at baseline. There was no interaction effect between group allocation and Overall Quality of Life(p=0.625) over time. However, there was an interaction effect for Social Relations(p=0.019) and Autonomy (p=0.004). Conclusion: the intervention exerted a statistically significant effect on the quality of life of family caregivers with respect to social relationships and autonomy. Trial registration: NCT02807012. Resumo Objetivo: avaliar o efeito de intervenção educativa domiciliar de enfermagem na qualidade de vida de cuidadores familiares de idosos sobreviventes de acidente vascular cerebral (AVC). Método: Ensaio Clínico Randomizado, cego para avaliação de resultados. Quarenta e oito cuidadores familiares de idosos sobreviventes de AVC participaram do estudo. O Grupo de Intervenção recebeu três visitas domiciliares de enfermeiros, um mês após a alta hospitalar, para fornecer educação relacionada ao AVC (como acessar os serviços de saúde e realizar atividades de cuidado) e apoio emocional. O Grupo Controle recebeu as orientações habituais dos serviços de saúde. A qualidade de vida foi avaliada usando o instrumento Avaliação da Qualidade de Vida da Organização Mundial da Saúde (WHOQOL-BREF) e o Módulo Old (WHOQOL-OLD) em 1 semana, 2 meses e 1 ano após a alta. Resultados: os cuidadores eram principalmente mulheres, filhos ou cônjuges. Os cuidadores do Grupo Intervenção e do Grupo Controle não diferiram significativamente em termos de Qualidade de Vida Geral no início do estudo. Não houve efeito de interação entre a alocação do grupo e a Qualidade de Vida Geral (p=0,625) ao longo do tempo. No entanto, houve efeito de interação para Relações Sociais (p=0,019) e Autonomia (p=0,004). Conclusão: a intervenção apresentou efeito estatisticamente significativo na qualidade de vida dos cuidadores familiares no que diz respeito às relações sociais e autonomia. Registro do ensaio clínico: NCT02807012. Resumen Objetivo: evaluar el efecto de intervenciones de atención domiciliaria de enfermería sobre la calidad de vida en cuidadores familiares de adultos mayores sobrevivientes de accidentes cerebrovasculares. Método: Ensayo Clínico Aleatorizado, cegado para la evaluación de los desenlaces. Los participantes del estudio fueron 48cuidadores familiares de adultos mayores sobrevivientes de accidentes cerebrovasculares (ACV). El Grupo Intervención recibió tres visitas domiciliarias a cargo de enfermeros un mes después del alta hospitalaria, en las que se les ofreció instrucción relacionada con ACV (es decir, cómo acceder a los servicios de salud y realizar las actividades inherentes a los cuidados) y apoyo emocional. Al Grupo Control se le brindó la orientación habitual de los servicios de salud. La calidad de vida se evaluó mediante el instrumento World Health Organization Quality of Life Assessment (WHOQOL-BREF) y el módulo Old(WHOQOL-OLD) 1semana, 2meses y 1año después del alta. Resultados: en su mayoría, los cuidadores fueron mujeres, hijos o cónyuges. Los cuidadores de los grupos Intervención y Control no presentaron diferencias significativas en términos de su Calidad de Vida general de base. La intervención no ejerció ningún efecto entre la asignación a los grupos y la Calidad de Vida general(p=0,625) con el transcurso del tiempo. Sin embargo, la intervención sí tuvo efecto sobre las Relaciones Sociales (p=0,019) y la Autonomía(p=0,004). Conclusión: la intervención ejerció un efecto estadísticamente significativo sobre la calidad de vida de los cuidadores familiares con respecto a las relaciones sociales y a la autonomía. Registro del ensayo: NCT02807012.

Objective To examine the relationship between enoxaparin dose adequacy, quantified with anti-Factor Xa (aFXa) levels, and 90-day symptomatic venous thromboembolism (VTE) and post-operative bleeding. Summary background data Surgical patients often develop "breakthrough" VTE events-those which occur despite receiving chemical anticoagulation. We hypothesize that surgical patients with low aFXa levels will be more likely to develop 90-day VTE, and those with high aFXa will be more likely to bleed. Methods Pooled analysis of eight clinical trials (N = 985) from a single institution over a four year period. Patients had peak steady state aFXa levels in response to a known initial enoxaparin dose, and were followed for 90 days. Survival analysis log-rank test examined associations between aFXa level category and 90-day symptomatic VTE & bleeding. Results Among 985 patients, 2.3% (n = 23) had symptomatic 90-day VTE, 4.2% (n = 41) had 90-day clinically relevant bleeding, and 2.1% (n = 21) had major bleeding. Patients with initial low aFXa were significantly more likely to have 90-day VTE than patients with adequate or high aFXa (4.2% vs. 1.3%, p = 0.007). In a stratified analysis, this relationship was significant for patients who received twice daily (6.2% vs. 1.5%, p = 0.003), but not once daily (3.0% vs. 0.7%, p = 0.10) enoxaparin. No association was seen between high aFXa and 90-day clinically relevant bleeding (4.8% vs. 2.9%, p = 0.34) or major bleeding (3.6% vs. 1.6%, p = 0.18). Conclusions This manuscript establishes inadequate enoxaparin dosing as a plausible mechanism for breakthrough VTE in surgical patients, and identifies anticoagulant dose adequacy as a novel target for process improvement measures.

OBJECTIVE: To evaluate whether pathologic complete response (pCR) exclusively defines major pathologic response to treatment with improved survival. SUMMARY BACKGROUND DATA: pCR following trimodality therapy for esophagogastric adenocarcinoma is infrequent but associated with improved prognosis. Yet most clinical trials and correlative studies designate pCR as the primary endpoint. METHODS: We analyzed our prospectively maintained database for patients who underwent trimodality therapy for locally advanced esophageal adenocarcinoma between 1995 and 2017. Overall survival (OS) was examined by percentage treatment response (TR) in the primary tumor bed and pathologic nodal stage (ypN0) using Kaplan-Meier plots. Optimal thresholds of TR for differentiating patients in terms of OS were investigated with descriptive plots using restricted cubic spline functions; associations were quantified using Cox multivariable analysis. RESULTS: Among 788 patients, median follow-up was 37.5 months (range, 0.4–210.6); median OS was 48.3 months (95% CI, 42.2–58.8). Absence of residual nodal disease was independently associated with improved survival (P

Mesenchymal stromal cells (MSCs) have recently emerged as an interesting therapeutic approach for patients with progressive systemic sclerosis (SSc), a rare and life-threatening orphan autoimmune disease. Whereas MSC immunomodulatory potential is considered as a central mechanism for their clinical benefit, very few data are available on the impact of MSCs on immune cell subsets in vivo. In the current extended study of a phase I/II clinical trial exploring the injection of a single dose of allogeneic bone marrow-MSCs (alloBM-MSCs) in patients with severe SSc (NCT02213705), we performed a longitudinal in-depth characterization of circulating immune cells in 19 MSC-treated patients, including 14 responders and 5 non-responders. By a combination of flow cytometry and transcriptomic analyses, we highlighted an increase in circulating CD24hiCD27posCD38lo/neg memory B cells, the main IL-10-producing regulatory B cell (Breg) subset, and an upregulation of IL10 expression in ex-vivo purified B cells, specifically in responder patients, early after the alloBM-MSC infusion. In addition, a deeper alteration of the B-cell compartment before alloBM-MSC treatment, including a higher expression of profibrotic cytokines IL6 and TGFβ by sorted B cells was associated with a non-responder clinical status. Finally, BM-MSCs were able to directly upregulate IL-10 production in activated B cells in vitro. These data suggest that cytokine-producing B cells, in particular Breg, are pivotal effectors of BM-MSC therapeutic activity in SSc. Their quantification as activity biomarkers in MSC potency assays and patient selection criteria may be considered to reach optimal clinical benefit when designing MSC-based clinical trials.

PURPOSE Overexpression of the HER2 protein occurs in 25% to 30% of human breast cancers and leads to a particularly aggressive form of the disease. Efficacy and safety of recombinant humanized anti-HER2 monoclonal antibody as a single agent was evaluated in women with HER2-overexpressing metastatic breast cancer that had progressed after chemotherapy for metastatic disease. PATIENTS AND METHODS Two hundred twenty-two women, with HER2-overexpressing metastatic breast cancer that had progressed after one or two chemotherapy regimens, were enrolled. Patients received a loading dose of 4 mg/kg intravenously, followed by a 2-mg/kg maintenance dose at weekly intervals. RESULTS Study patients had advanced metastatic disease and had received extensive prior therapy. A blinded, independent response evaluation committee identified eight complete and 26 partial responses, for an objective response rate of 15% in the intent-to-treat population (95% confidence interval, 11% to 21%). The median duration of response was 9.1 months; the median duration of survival was 13 months. The most common adverse events, which occurred in approximately 40% of patients, were infusion-associated fever and/or chills that usually occurred only during the first infusion, and were of mild to moderate severity. These symptoms were treated successfully with acetaminophen and/or diphenhydramine. The most clinically significant adverse event was cardiac dysfunction, which occurred in 4.7% of patients. Only 1% of patients discontinued the study because of treatment-related adverse events. CONCLUSION Recombinant humanized anti-HER2 monoclonal antibody, administered as a single agent, produces durable objective responses and is well tolerated by women with HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. Side effects that are commonly observed with chemotherapy, such as alopecia, mucositis, and neutropenia, are rarely seen.

Introduction: One target of rheumatoid arthritis (RA) treatment is to achieve early sustained remission; over the long term, patients in sustained remission have less structural joint damage and physical disability. We evaluated Simplified Disease Activity Index (SDAI) remission with abatacept + methotrexate versus abatacept placebo + methotrexate and impact of de-escalation (DE) in anti-citrullinated protein antibody (ACPA)-positive patients with early RA. Methods: The phase IIIb, randomized, AVERT-2 two-stage study (NCT02504268) evaluated weekly abatacept + methotrexate versus abatacept placebo + methotrexate. Primary endpoint: SDAI remission (& LE; 3.3) at week 24. Pre-planned exploratory endpoint: maintenance of remission in patients with sustained remission (weeks 40 and 52) who, from week 56 for 48 weeks (DE period), (1) continued combination abatacept + methotrexate, (2) tapered abatacept to every other week (EOW) + methotrexate for 24 weeks with subsequent abatacept withdrawal (abatacept placebo + methotrexate), or (3) withdrew methotrexate (abatacept monotherapy). Results: Primary study endpoint was not met: 21.3% (48/225) of patients in the combination and 16.0% (24/150) in the abatacept placebo + methotrexate arm achieved SDAI remission at week 24 (p = 0.2359). There were numerical differences favoring combination therapy in clinical assessments, patient-reported outcomes (PROs) and week 52 radiographic non-progression. After week 56, 147 patients in sustained remission with abatacept + methotrexate were randomized (combination, n = 50; DE/withdrawal, n = 50; abatacept monotherapy, n = 47) and entered DE. At DE week 48, SDAI remission (74%) and PRO improvements were mostly maintained with continued combination therapy; lower remission rates were observed with abatacept placebo + methotrexate (48.0%) and with abatacept monotherapy (57.4%). Before withdrawal, de-escalating to abatacept EOW + methotrexate preserved remission. Conclusions: The stringent primary endpoint was not met. However, in patients achieving sustained SDAI remission, numerically more maintained remission with continued abatacept + methotrexate versus abatacept monotherapy or withdrawal.

BACKGROUND: Enrichment strategies from clinical trials for progressive systemic sclerosis-associated interstitial lung disease (SSc-ILD) have not been tested in a real-life cohort.RESEARCH QUESTION: Do enrichment strategies for progressive ILD impact efficacy, repre-sentativeness, and feasibility in patients with SSc-ILD from the European Scleroderma Trials and Research (EUSTAR) database?STUDY DESIGN AND METHODS: We applied the inclusion criteria of major recent SSc-ILD trials (Study of the Efficacy and Safety of Tocilizumab in Participants With Systemic Sclerosis [focuSSced], Scleroderma Lung Study II [SLS II], and Safety and Efficacy of Nintedanib in Systemic Sclerosis [SENSCIS]) and assessed progressive ILD, which was defined as absolute change in FVC and as significant progression (FVC decline $10%). Data were compared with all patients and with patients who did not fulfill any inclusion criteria. RESULTS: In total, 2,258 patients with SSc-ILD were included: 31.2% of the patients met SENSCIS criteria; 5.8% of the patients met SLS II criteria; 1.6% of the patients met focuSSced criteria, and 67.7% (1,529) of the patients did not meet any criteria. In the first 12 + 3 months, the absolute FVC decline in all patients and in patients who fulfilled criteria from SENSCIS was -0.1%, in patients who fulfilled criteria from focuSSced was -3.7%, and in patients who fulfilled criteria from SLS II was 2.3%, with accompanying more progressors in focuSSced. The patient populations that fulfilled the different study inclusion criteria significantly differed in various clinical parameters. In the second 12-month period, SENSCIS-enriched patients had a further absolute FVC% decline as described for the total cohort. In contrast, patients who fulfilled the focuSSced and SLS II criteria showed numeric improvement of lung function. There were no significant associations of enrichment criteria and ILD progression.INTERPRETATION: The application of enrichment criteria from previous clinical trials showed enrichment for progression with variable success, which led to selected patient populations reducing feasibility of recruitment. These findings are important for future clinical trial design and interpretation of the results of published trials.CHEST 2023; 163(3):586-598

International audience; Kidney transplant survival is shortened by chronic rejection and side effects of standard immunosuppressive drugs. Cell-based immunotherapy with tolerogenic dendritic cells has long been recognized as a promising approach to reduce general immunosuppression. Published trials report the safety and the absence of therapy-related adverse reactions in patients treated with tolerogenic dendritic cells suffering from several inflammatory diseases. Here, we present the first phase I clinical trial results using human autologous tolerogenic dendritic cells (ATDC) in kidney transplantation. Eight patients received ATDC the day before transplantation in conjunction with standard steroids, mycophenolate mofetil and tacrolimus immunosuppression with an option to taper mycophenolate mofetil. ATDC preparations were manufactured in a Good Manufacturing Practice-compliant facility and fulfilled cell count, viability, purity and identity criteria for release. A control group of nine patients received the same standard immunosuppression, except basiliximab induction replaced ATDC therapy and mycophenolate tapering was not allowed. During the three-year follow-up, no deaths occurred and there was 100% graft survival. No significant increase of adverse events was associated with ATDC infusion. Episodes of rejection were observed in two patients from the ATDC group and one patient from the control group. However, all rejections were successfully treated by glucocorticoids. Mycophenolate was successfully reduced/stopped in five patients from the ATDC group, allowing tacrolimus monotherapy for two of them. Regarding immune monitoring, reduced CD8 T cell activation markers and increased Foxp3 expression were observed in the ATDC group. Thus, our results demonstrate ATDC administration safety in kidney-transplant recipients.

KRAS is one of the most commonly mutated oncogenes in cancers and therapeutics directly targeting the KRas have been challenging. Among the different known mutants, KRasG12C has been proved to be successfully targeted recently. Several covalent inhibitors selectively targeting KRasG12C have shown promising efficacy against cancers harboring KRASG12C mutation in clinical trials and AMG510 (sotorasib) has been approved for the treatment of KRASG12C-mutated locally advanced or metastatic non-small cell lung cancer. However, the overall responsive rate of KRasG12C inhibitors was around 50% in patients with non-small cell lung cancer and the efficacy in patients with colorectal cancer or appendiceal cancer appears to be less desirable. It is of great importance to discover biomarkers to distinguish patients who are likely benefitted. Moreover, adaptive resistance would occur inevitably with the persistent administration like other molecularly targeted therapies. Several combinatorial regimens have been studied in an effort to potentiate the efficacy of KRasG12C inhibitors in preclinical settings. This review summarized the recent progress of covalent KRasG12C inhibitors with a focus on identifying biomarkers to predict or monitor the efficacy and proposing rational drug combinations based on elucidation of the mechanisms of drug resistance.

Resumo O objetivo deste artigo é avaliar o efeito do programa comportamental educação em grupo e intervenção telefônica na modificação das atitudes psicológicas, melhora do empoderamento e das práticas de autocuidado visando à melhora do controle clínico em diabetes mellitus tipo 2. Trata-se de um ensaio clínico com cluster randomizado, realizado em 199 pessoas com diabetes. Para realizar as comparações intragrupos (tempos final e inicial) e entre grupos quanto aos valores das variáveis atitudes psicológicas, empoderamento, autocuidado e medidas da hemoglobina glicada, foi utilizada a abordagem das Generalizing Estimating Equations (GEE). Em todas as análises, utilizou-se um nível de significância de 5% e intervalos de 95% de confiança. Quando comparado ao GC, o GI apresentou uma redução significativa nos valores médios de hemoglobina glicada (IC95%: -1,49 a - 0,45), aumento estatisticamente significativo na modificação dos escores de atitudes psicológicas (IC95%: 9,70 a 15,40), na escala do empoderamento (IC95%: 0,81 a 2,72) e na adesão às práticas de autocuidado (IC95%: 1,44 a 2,10) ao final do estudo. O programa comportamental se mostrou capaz de modificar as atitudes psicológicas, melhorar o empoderamento, as práticas de autocuidado e o controle clínico. Abstract The scope of this article was to evaluate the effect of the behavioral group education program and telephone intervention in modifying psychological attitudes, enhancing empowerment, and self-care practices aimed at improving clinical control in type 2 diabetes mellitus. It involved a randomized cluster clinical trial, carried out with 199 people with diabetes. In order to perform intragroup comparisons (final and initial phases) and between groups with respect to the indices of the psychological attitude, empowerment, self-care and glycated hemoglobin level variables, the Generalizing Estimating Equation (GEE) approach was used. In all analyses, a 5% significance level and 95% confidence interval were used. When compared to the CG, the IG showed a significant reduction in the mean values of glycated hemoglobin (95%CI: -1.49 to -0.45), a statistically significant increase in the change in psychological attitude scores (95%CI: 9.70 to 15.40), on the empowerment scale (95%CI: 0.81 to 2.72) and adherence to self-care practices (95%CI: 1.44 to 2.10) at the end of the study. The behavioral program proved to be capable of modifying psychological attitudes, improving empowerment, self-care practices and clinical control.

PURPOSE To evaluate the efficacy and tolerability of two doses of gefitinib (Iressa [ZD1839]; AstraZeneca, Wilmington, DE), a novel epidermal growth factor receptor tyrosine kinase inhibitor, in patients with pretreated advanced non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS This was a randomized, double-blind, parallel-group, multicenter phase II trial. Two hundred ten patients with advanced NSCLC who were previously treated with one or two chemotherapy regimens (at least one containing platinum) were randomized to receive either 250-mg or 500-mg oral doses of gefitinib once daily. RESULTS Efficacy was similar for the 250- and 500-mg/d groups. Objective tumor response rates were 18.4% (95% confidence interval [CI], 11.5 to 27.3) and 19.0% (95% CI, 12.1 to 27.9); among evaluable patients, symptom improvement rates were 40.3% (95% CI, 28.5 to 53.0) and 37.0% (95% CI, 26.0 to 49.1); median progression-free survival times were 2.7 and 2.8 months; and median overall survival times were 7.6 and 8.0 months, respectively. Symptom improvements were recorded for 69.2% (250 mg/d) and 85.7% (500 mg/d) of patients with a tumor response. Adverse events (AEs) at both dose levels were generally mild (grade 1 or 2) and consisted mainly of skin reactions and diarrhea. Drug-related toxicities were more frequent in the higher-dose group. Withdrawal due to drug-related AEs was 1.9% and 9.4% for patients receiving gefitinib 250 and 500 mg/d, respectively. CONCLUSION Gefitinib showed clinically meaningful antitumor activity and provided symptom relief as second- and third-line treatment in these patients. At 250 mg/d, gefitinib had a favorable AE profile. Gefitinib 250 mg/d is an important, novel treatment option for patients with pretreated advanced NSCLC.

Background The impact of online care on patients’ functional and psychological outcomes is critical to determine yet still unknown. Objective To evaluate how a novel online health model that facilitates physician-patient collaboration compares with in-person care for improving psoriasis patients’ functional status and mental health. Methods This 12-month randomized controlled equivalency trial randomized psoriasis patients 1:1 to online or in-person care. Functional impairment and depression were assessed at baseline and at 3-month intervals using the 5-level EuroQol-5 Dimensions (EQ-5D-5L) and Patient Health Questionnare-9 (PHQ-9). Results 296 patients were randomized to online or in-person groups. The between-group difference in overall improvement in EQ VAS (EuroQol Visual Analogue Scale) was -0.002 (95% CI -2.749, 2.745), falling within equivalence margin ±8. The between-group difference in overall improvement in EQ-5D-5L index was 0 (95% CI -0.003, 0.003), falling within equivalence margin ±0.1. The between-group difference in overall improvement in PHQ-9 was -0.33 (95% CI -1.20, 0.55), falling within equivalence margin ±3. Limitations Slightly different attrition rates between online and in-person arms (11% versus 9%), but no impact on outcomes. Conclusion The online health model was equivalent to in-person care for reducing functional impairment and depressive symptoms in psoriasis patients.

More than a decade after the Clinical Outcomes Utilising Revascularization and Aggressive Drug Evaluation (COURAGE) trial, International Study of Comparative Health Effectiveness With Medical And Invasive Approaches (ISCHEMIA) is the second large clinical trial to challenge the concept of revascularization in chronic coronary syndromes whilst addressing some of the shortfalls of its predecessor.

Because human fetal ventral mesencephalic tissue grafts provide promising results in ameliorating Parkinson's disease-implicated motor dysfunctions, human fetal midbrain-derived dopamine neuronal precursor cells are considered good candidates for cell-based therapy for Parkinson's disease in that large quantities of cells can be supplied through a good manufacturing practice-compliant system.We conducted a prospective, phase I/IIa, dose-escalation, open-label 'first-in-human' clinical trial with fetal neural precursor cells to assess their safety and therapeutic efficacy in patients with idiopathic Parkinson's disease.Fifteen patients were assigned to receive three different doses of cells (4 × 106 , 12 × 106 , and 40 × 106 cells) and completed a 12-month follow-up. The primary outcome was safety, by measuring the presence of grade 3 or higher cells according to National Cancer Institute guidelines and any contaminated cells. Secondary outcomes assessed motor and neurocognitive function, as well as the level of dopamine transporters, by positron emission tomography-computed tomography.Although a pronation-supination and hand/arm movement performance was remarkably enhanced in all three groups (all P < 0.05), the medium- and high-dose-treated groups exhibited significant improvement in Unified Parkinson's Disease Rating Scale Part III only up to 26.16% and 40%, respectively, at 12 months after transplantation without any serious clinical complications or graft-induced dyskinesia in all patients. However, the motor improvements did not correlate with increase in the dopamine transporter on positron emission tomography images.Our results primarily demonstrate the safety and plausible dose-dependent efficacy of human fetal midbrain-derived dopamine neuronal precursor cells for idiopathic Parkinson's disease. © 2023 International Parkinson and Movement Disorder Society.

The prediction of the disease course is one of the main targets of ALS research, particularly considering its wide phenotypic heterogeneity. Despite many attempts to classify patients in prognostic categories according to the different spreading patterns at diagnosis, a precise regional progression rate and the time of involvement of each region has yet to be clarified.In a population-based dataset of ALS patients, we analyse the functional decline in different body regions according to time and order of regional involvement. We calculated the regional progression intervals (RPIs) from the initial involvement (Inv) to the severe functional impairment (SevI), using the ALS Functional Rating Scale revised (ALSFRS-r) subscores of bulbar, upper limbs, lower limbs and respiratory/thoracic regions. Time-to-event analyses, adjusted for age, sex, ALSFRS-r pre-slope (ΔALSFRS-R), cognitive and mutational status were performed.RPI duration differed significantly among ALS phenotypes, being the RPI of first region involved significantly longer than RPIs of regions involved later. Cox proportional hazard models showed that the time between disease onset and initial regional involvement is invariably related to a reduced RPI duration in each different body region (bulbar region, HR 1.11, 95% CI 1.06-1.16, p0.001; upper limbs region, HR 1.16, 95% CI 1.06-1.28, p=0.002; lower limbs region, HR 1.11, 95% CI 1.03-1.19, p=0.009; respiratory/thoracic region, HR 1.10, 95% CI 1.06-1.14, p=0.005).We found that the progression of functional decline accelerates in regions involved later during disease course. Our findings can be useful in patients' management and prognosis prediction.

PURPOSE In patients with resectable gastric/gastroesophageal junction (GEJ) adenocarcinoma, surgery plus perioperative platinum-based chemotherapy is the standard of care. Perioperative chemotherapy remains debatable for gastric/GEJ adenocarcinoma with deficient mismatch repair (dMMR)/microsatellite instability–high (MSI-H). PATIENTS AND METHODS NEONIPIGA (ClinicalTrials.gov identifier: NCT04006262 ) phase II study evaluated neoadjuvant nivolumab 240 mg once every two weeks ×6 and ipilimumab 1 mg/kg once every six weeks ×2, followed by surgery and adjuvant nivolumab 480 mg once every four weeks (nine injections) in patients with locally advanced resectable dMMR/MSI-H, clinical (c) tumor (T)2-T4 node (N)x metastasis (M)0 gastric/GEJ adenocarcinoma. The primary end point was a pathological complete response (pCR) rate. RESULTS Between October 2019 and June 2021, 32 patients with dMMR/MSI-H gastric/GEJ adenocarcinoma were enrolled. The median age was 65.5 years (range, 40-80). Clinical stages were cT2-T3N0 (n = 9), cT2-T3N1 (n = 22), and cT3N1M1 (n = 1, wrongly included). With a median follow-up of 14.9 months (95% CI, 10.6 to 17.6), 32 patients received neoadjuvant immunotherapy (27 patients completed all cycles). Neoadjuvant therapy-related grade 3/4 adverse events occurred in six patients (19%). Twenty-nine patients underwent surgery; three did not have surgery and had complete endoscopic response with tumor-free biopsies and a normal computed tomography scan (two refused surgery and one had metastasis at inclusion). The rate of surgical morbidity (Clavien-Dindo classification) was 55% (one postoperative death occurred). All 29 patients had an R0 resection, and 17 (58.6%; 90% CI, 41.8 to 74.1) had pCR (pathological T0N0). Becker tumor regression grades 1a, 1b, 2, and 3 were observed in 17 patients, three (including two pathological T0N1), two, and seven patients, respectively. Of the 29 patients with surgery, 23 received adjuvant nivolumab. At database lock, no patient had relapse and one died without relapse. CONCLUSION Nivolumab and ipilimumab-based neoadjuvant therapy is feasible and associated with no unexpected toxicity and a high pCR rate in patients with dMMR/MSI-H resectable gastric/GEJ adenocarcinoma.

Background There has been a growing interest in the use of ketamine following orthopedic surgeries. We hypothesized that low dose intravenous ketamine during surgery would help in mobilization following total knee replacement (TKR) in oncology patients as assessed by the timed to up and go (TUG) test at 72 hours post-surgery. Our secondary objectives were to compare the opioid requirement at the end of 72 hours, pain scores, satisfaction with pain management, adverse effects, range of joint movement achieved in the post-operative period and the functional recovery at the end of 1 month. Methods After the ethics commitee approval, registration of the trial with the Clinical Trial Registry - India (CTRI), and informed consent, this double-blinded trial was conducted. Using computer generated randomization chart, an independent team randomized the patients into ketamine group which received at induction, a ketamine bolus dose of 0.5 mg.kg-1 before the incision followed by 10 µg.kg-1min-1 infusion which was maintained intraoperatively till skin closure and the saline group received an equivalent volume of saline. Postoperatively, patient controlled morphine pumps were attached and the pain score with morphine usage were recorded for 72 hours. The TUG tests and range of motion were assessed by the physiotherapists until 72 hours. Results Fifty-two patients were enrolled in the trial. Demographics were comparable. No significant intraoperative hemodynamic changes and post-operative adverse events were noted between the groups. A decrease in the TUG test, along with decreased opioid usage with a better range of movements was noted in the ketamine group, but this was not statistically significant. Day of discharge, patient satisfaction score, and functional recovery assessed by Oxford Knee Score (OKS) were comparable between the groups. Conclusion In conclusion, low dose intraoperative ketamine infusion does not provide clinical benefit in perioperative pain management and postoperative rehabilitation following total knee endoprosthetic replacement in oncology.

Bladder cancer is an aggressive and lethal disease. Even when presenting as localized muscle-invasive disease, the 5-year survival rate is about 70%, and the recurrence rate after radical cystectomy is approximately 50%. Neoadjuvant chemotherapy (NAC) has the potential to downstage the primary tumor and treat micrometastases, leading to a decrease in recurrence rates and an increase in cure rates. There is level 1 evidence in favor of neoadjuvant cisplatin-based chemotherapy prior to radical cystectomy. However, data from clinical trials evaluating NAC for patients undergoing bladder-sparing treatments are less robust, so this strategy remains controversial. The response to NAC is prognostic and patients with favorable pathological response have better overall survival. Strategies to select patients based on molecular biomarkers have the potential to guide treatment decisions and even de-intensify treatment, avoiding local treatment for those with complete responses to systemic therapy. This review outlines the current literature on the use of NAC in the context of bladder preservation for muscle-invasive bladder cancer, highlights neoadjuvant studies in patients ineligible for cisplatin-based NAC, and discusses novel bladder-preservation strategies, including multimodality combinations and biomarker-driven studies of definitive chemotherapy.

Spinal muscular atrophy (SMA) is a rare neuromuscular condition, characterized by loss of motor neurons as a result of a mutation in the survival motor neuron gene. This results in muscle wasting and in the most common and severe type, death before 24 months. Over the recent years there has been a dynamic shift in the therapeutic options for these patients involving both clinical trials in genetic modifying therapies to indirectly improve the survival motor neuron protein level and hence strength, muscle promotor therapies, up/down regulation of modifier genes and more recently gene therapy to replace the mutated survival motor neuron gene. This review addresses the pathogenesis of SMA and the resultant therapeutic approaches as well as the current state in clinical trials and future development.

Introduction Advances in the development of drugs with novel mechanisms of action have not been sufficient to significantly reduce the percentage of patients presenting drug-resistant epilepsy. This lack of satisfactory clinical results has led to the search for more effective treatment alternatives with new mechanisms of action. Development The aim of this study is to examine epidemiological aspects of the use of cannabis-based products for the treatment of epilepsy, with particular emphasis on the main mechanisms of action, indications for use, clinical efficacy, and safety. We conducted a narrative review of articles gathered from the PubMed, EMBASE, and Google Scholar databases and from the reference sections of relevant publications. Conclusions In recent years there has been growing interest in the use of cannabis-based products for the treatment of a wide range of diseases, including epilepsy. The cannabis plant is currently known to contain more than 100 terpenophenolic compounds, known as cannabinoids. The 2 most abundant are delta-9-tetrahydrocannabinol and cannabidiol. Studies of preclinical models of epilepsy have shown that these cannabinoids have anticonvulsant properties, and 100% purified cannabidiol and cannabidiol-enriched cannabis extracts are now being used to treat epilepsy in humans. Several open-label studies and randomised controlled clinical trials have demonstrated the efficacy and safety of these products.

Radical cystectomy with bilateral pelvic lymphadenectomy and trimodality bladder-sparing therapy or TMT, are both curative options for patients with nonmetastatic muscle invasive bladder cancer. Patients should be afforded the opportunity for a multidisciplinary evaluation with equipoise in discussing these options for eligible patients. We discuss the barriers to broader acceptance and utilization of TMT and encourage support of clinical trials of TMT.

The use of molecular biomarkers to support disease diagnosis, monitor its progression, and guide drug treatment has gained traction in the last decades. While only a dozen biomarkers have been approved for their exploitation in the clinic by the FDA, many more are evaluated in the context of translational research and clinical trials. Furthermore, the information on which biomarkers are measured, for which purpose, and in relation to which conditions are not readily accessible: biomarkers used in clinical studies available through resources such as ClinicalTrials.gov are described as free text, posing significant challenges in finding, analyzing, and processing them by both humans and machines. We present a text mining strategy to identify proteomic and genomic biomarkers used in clinical trials and classify them according to the methodologies by which they are measured. We find more than 3000 biomarkers used in the context of 2600 diseases. By analyzing this dataset, we uncover patterns of use of biomarkers across therapeutic areas over time, including the biomarker type and their specificity. These data are made available at the Clinical Biomarker App at https://www.disgenet.org/biomarkers/, a new portal that enables the exploration of biomarkers extracted from the clinical studies available at ClinicalTrials.gov and enriched with information from the scientific literature. The App features several metrics that assess the specificity of the biomarkers, facilitating their selection and prioritization. Overall, the Clinical Biomarker App is a valuable and timely resource about clinical biomarkers, to accelerate biomarker discovery, development, and application. This work was partially funded by IMI2-JU grants, resources which are composed of financial contributions from the European Union’s Horizon 2020 Research and Innovation Programme and EFPIA [GA: 116030 TransQST and GA: 777365 eTRANSAFE], and the EU H2020 Programme [GA: 871075 Elixir-CONVERGE and GA:964537 RISKHUNT3R, which is part of the ASPIS cluster]; Project 001-P-001647—Valorisation of EGA for Industry and Society funded by the European Regional Development Fund (ERDF) and Generalitat de Catalunya; Agència de Gestió d’Ajuts Universitaris i de Recerca Generalitat de Catalunya [2017SGR00519], and the Institute of Health Carlos III (project IMPaCT-Data, exp. IMP/00019), co-funded by the European Union, European Regional Development Fund (ERDF, “A way to make Europe”). The Research Programme on Biomedical Informatics (GRIB) is a member of the Spanish National Bioinformatics Institute (INB), funded by ISCIII and ERDF (PRB2-ISCIII [PT13/0001/0023, of the PE I + D + i 2013-2016]). The MELIS is a ‘Unidad de Excelencia María de Maeztu’, funded by the MINECO [MDM-2014-0370]. This work reflects only the author’s view and that the IMI2-JU is not responsible for any use that may be made of the information it contains. The European Commission is not responsible for any use that may be made of the information it contains.

Contains fulltext : 291402.pdf (Publisher’s version ) (Open Access) BACKGROUND: Familial dysbetalipoproteinemia (FD) is the second most common monogenic lipid disorder (prevalence 1 in 850-3500), characterized by postprandial remnant accumulation and associated with increased cardiovascular disease (CVD) risk. Many FD patients do not achieve non-HDL-C treatment goals, indicating the need for additional lipid-lowering treatment options. OBJECTIVES: To evaluate the effect of the PCSK9 monoclonal antibody evolocumab added to standard lipid-lowering therapy on fasting and post fat load lipids and lipoproteins in patients with FD. METHODS: A randomized placebo-controlled double-blind crossover trial comparing evolocumab (140 mg subcutaneous every 2 weeks) with placebo during two 12-week treatment periods. At the start and end of each treatment period patients received an oral fat load. The primary endpoint was the 8-hour post fat load non-HDL-C area under the curve (AUC). Secondary endpoints included fasting and post fat load lipids and lipoproteins. RESULTS: In total, 28 patients completed the study. Mean age was 62±9 years and 93% had an Ɛ2Ɛ2 genotype. Evolocumab reduced the 8-hour post fat load non-HDL-C AUC with 49% (95%CI 42-55) and apolipoprotein B (apoB) AUC with 47% (95%CI 41-53). Other fasting and absolute post fat load lipids and lipoproteins including triglycerides and remnant-cholesterol were also significantly reduced by evolocumab. However, evolocumab did not have significant effects on the rise above fasting levels that occurred after consumption of the oral fat load. CONCLUSIONS: Evolocumab added to standard lipid-lowering therapy significantly reduced fasting and absolute post fat load concentrations of non-HDL-C, apoB and other atherogenic lipids and lipoproteins in FD patients. The clinically significant decrease in lipids and lipoproteins can be expected to translate into a reduction in CVD risk in these high-risk patients.

BACKGROUND: Coronary care units are sophisticated clinics established to reduce deaths due to acute cardiovascular events. Current data on coronary care unit mortality rates and predictors of mortality in Turkey are very limited. The MORtality predictors in CORonary care units in TURKey (MORCOR-TURK) trial was designed to provide information on the mortality rates and predictors in patients followed in coronary care units in Turkey. METHODS: The MORCOR-TURK trial will be a national, observational, multicenter, and noninterventional study conducted in Turkey. The study population will include coronary care unit patients from 50 centers selected from all regions in Turkey. All consecutive patients admitted to coronary care units with cardiovascular diagnoses between 1 and 30 September 2022 will be prospectively enrolled. All data will be collected at one point in time, and the current clinical practice will be evaluated (ClinicalTrials.gov number NCT05296694). In the first step of the study, admission diagnoses, demographic characteristics, basic clinical and laboratory data, and in-hospital management will be assessed. At the end of the first step, the predictors and rates of in-hospital mortality will be documented. The second step will be in cohort design, and discharged patients will be followed up till 1 year. Predictors of short- and long-term mortality will be assessed. Moreover, a new coronary care unit mortality score will be generated with data acquired from this cohort. RESULTS: The short-term outcomes of the study are planned to be shared by early 2023. CONCLUSION: The MORCOR-TURK trial will be the largest and most comprehensive study in Turkey evaluating the rates and predictors of in-hospital mortality of patients admitted to coronary care units.

Objective: To evaluate the serotype distribution and antibiotic resistance in pneumococcal infections in adults and to provide a perspective regarding serotype coverage of both current and future pneumococcal vaccines. Patients and methods: This passive surveillance study was conducted with the Streptococcus pneumoniae strains isolated from the specimens of patients with pneumonia (materials isolated from bronchoalveolar lavage), bacteraemia, meningitis, pleuritis and peritonitis between 2015 and 2018. Serogrouping and serotyping were performed by latex particle agglutination and by conventional Quellung reaction using commercial type-specific antisera, respectively. The strains were analysed for penicillin, cefotaxime, erythromycin and moxifloxacin susceptibilities by E-test. Results: In the whole study group (410 samples from adults aged ≥18 years), the most frequent serotypes were 3 (14.1%), 19 F (12%) and 1 (9.3%). The vaccine coverage for PCV13, PCV15, PCV20 and PPV23 was 63.9%, 66.6%, 74.1% and 75.9%, respectively, in all isolates. Penicillin non-susceptibility in invasive pneumococcal disease (IPD) was 70.8% and 57.1% in the patients aged

BACKGROUND: Patient and public involvement in randomised clinical trials has received increased focus, including in intensive care trials, but the frequency, method and extent is unknown. This meta-epidemiological study investigated patient and public involvement in contemporary, large ICU trials.METHODS: We systematically searched PubMed for large (≥225 randomised patients), contemporary trials (published between 1 January 2019 and 31 January 2022) assessing interventions in adult patients in ICU settings. Abstracts and full-text articles were assessed independently and in duplicate. Data were extracted using a pre-defined, pilot-tested data extraction form with details on trials, patient and public involvement including categories and numbers of individuals involved, methods of involvement, and trial stage(s) with involvement. Trials authors were contacted as necessary.RESULTS: We included 100 trials, with 18 using patient and public involvement; these were larger and conducted in more centres than trials without patient and public involvement. Among trials with patient and public involvement, patients (in 14/18 trials), clinicians (13 trials), and family members (12 trials) were primarily involved, mainly in the development of research design (15 trials) and development of research focus (13 trials) stages and mostly by discussion (12 trials) and solo interviews (10 trials). A median of 65 individuals (range 1-6894) were involved.CONCLUSIONS: We found patient and public involvement in a fifth of large, contemporary ICU trials. Primarily patients, families, and clinicians were included, particularly in the trial planning stages and mostly through interviews and discussions. Increased patient and public involvement in ICU trials is warranted.

Lactoferrin (LF) has in vitro antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This study aimed to determine the effect of bovine lactoferrin (bLF) in the prevention of SARS-CoV-2 infection in health care personnel. A randomized, double-blinded, placebo-controlled clinical trial was conducted in two tertiary hospitals that provide care to patients with SARS-CoV-2 infection in Lima, Peru. Daily supplementation with 600 mg of enteral bLF versus placebo for 90 days was compared. Participants were weekly screened for symptoms suggestive of SARS-CoV-2 infection and molecular testing was performed on suspected episodes. A serological test was obtained from all participants at the end of the intervention. The main outcome included symptomatic and asymptomatic cases. A sub-analysis explored the time to symptomatic infection. Secondary outcomes were the severity, frequency, and duration of symptomatic infection. The study was prematurely cancelled due to the availability of vaccines against SARS-CoV-2 in Peru. 209 participants were enrolled and randomized, 104 received bLF and 105 placebo. SARS-CoV-2 infection occurred in 11 (10.6%) participants assigned to bLF and in 9 (8.6%) participants assigned to placebo without significant differences (Incidence Rate Ratio = 1.23, 95%CI 0.51-3.06, p-value = 0.64). There was no significant effect of bLF on time to symptomatic infection (Hazard Ratio = 1.61, 95%CI 0.62-4.19, p-value = 0.3). There were no significant differences in secondary outcomes. A significant effect of bLF in preventing SARS-CoV-2 infection was not proven. Further studies are needed to assess the effect of bLF supplementation on SARS-CoV-2 infection.Clinical trial registration ClinicalTrials.gov Identifier: NCT04526821, https://clinicaltrials.gov/ct2/show/NCT04526821?term=LACTOFERRINcond=COVID-19cntry=PEcity=Limadraw=2rank=1 .

Low molecular weight heparins (LMWH) are used extensively for prophylaxis and treatment of venous thromboembolism (VTE), bridging therapy for warfarin, and standard of care in cancer-associated VTE. Tinzaparin has the highest molecular weight of all LMWH, and relies least on renal clearance to Cockcroft-Gault creatinine clearance (CrCl) of 20ml/min. Previous pharmacological studies have demonstrated safety and effectiveness in elderly patients. Prospective clinical trials have confirmed these findings to CrCl 20ml/min and in cancer-associated VTE. We describe the pilot program developed at Concord Repatriation General Hospital for tinzaparin. Twenty patients were established on tinzaparin as therapeutic anticoagulation with CrCl or CKD-EPI estimated glomerular filtration rate (eGFR) 20-50ml/min with an indication for anticoagulation. Tinzaparin anti-Xa levels were tested at days 2, 7 and 14 (+/- one day) and transition to oral anticoagulants were allowed at clinician discretion. No accumulation of tinzaparin was seen into day 14. Two patients required dose-adjustment, five patients had bleeding complications (two major, three minor), and four patients died during follow-up, all attributable to patients' comorbidities. CrCl and BSA-standardised CrCl were significantly correlated with tinzaparin anti-Xa level only on day 2, and this effect was lost when patients with CrCl >50ml/min were excluded. Data from our cohort confirms previous pharmacokinetic studies using therapeutic tinzaparin in patients with CrCl or CKD-EPI eGFR 20-50ml/min with no signs of accumulation. Bleeding and death outcomes were also comparable to other trials using tinzaparin in cancer-associated VTE. Tinzaparin is an attractive alternative anticoagulant with once-daily administration in a range of potential indications. This article is protected by copyright. All rights reserved.

Intraoral stents have been provided to minimize acute and chronic toxicities induced by radiotherapy, including oral mucositis, salivary changes, trismus, radiation-related caries, and osteoradionecrosis. However, a systematic review and meta-analysis is necessary to determine their effectiveness.The purpose of this systematic review and meta-analysis was to determine the effectiveness of intraoral stent use and determine whether these prosthetic devices can reduce radiation dosage to nontargeted oral tissues and adverse effects related to head and neck radiation.Two independent reviewers made a systematic search for articles published from January 2010 to March 2020 in 3 databases, supplemented by a manual search. Studies were included if they were clinical trials (randomized controlled trials, both prospective and retrospective), published in English, and evaluated radiation dose and oral adverse side effects (acute or chronic) induced by radiotherapy of participants with and without intraoral stents.The search strategy identified 201 studies; of which, 9 were included. A total of 251 participants were evaluated; of whom, 168 (77.3%) used intraoral stents and 57 (22.7%) were treated with radiotherapy without a prosthetic device. A statistically significant difference was found regarding the use of intraoral stents for preventing oral mucositis (P.001), salivary changes (P=.003), and trismus (P.02). A funnel plot showed asymmetry among the differences of means in all selected studies.Intraoral stents have a positive effect on preventing oral mucositis. Further clinical trials are needed to address the flaws identified in the present systematic review.

Statement of problem Prosthetic rehabilitation, especially with removable complete dentures (CDs), can contribute to speech problems, although the prevalence of the problem is unclear. Purpose The purpose of this systematic review was to examine the influence of implant-supported fixed complete dentures (FCDs), implant-supported overdentures, and removable CDs on speech articulation disorders in patients with at least 1 completely edentulous jaw. Material and methods This study was prepared according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and registered in the International Prospective Register of Systematic Reviews (CRD42020182705). The PubMed/Medline, Embase, Web of Science, Scopus, Latin American and Caribbean Health Sciences, Brazilian Clinical Trials Registry, and Cochrane Library databases were searched through April 2020 to identify clinical trials comparing maxillary and/or mandibular implant-supported dentures with removable CD use in terms of speech articulation in participants with at least 1 completely edentulous jaw. The risk of bias of selected studies was assessed with the Joanna Briggs Institute critical appraisal tools, and the quality of evidence was tested by using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Results Initially, 2586 articles were identified, and their titles and abstracts were read. Sixteen articles were read in full, and 8 studies (4 paired clinical trials and 4 cross-sectional studies) were included in this review. In total, 290 prosthesis users aged 29 to 90 years, approximately 44 of whom had hearing difficulties, were included. Four studies had a low risk of bias, and 4 studies had a high risk of bias. Distortions of the /s/ phoneme were observed more often in the first 6 months of maxillary FCD use than with removable CD use. Speech articulation did not differ between mandibular FCD and removable CD users. The quality of evidence for speech articulation disorders was low. Conclusions Given the low quality of evidence on speech articulation disorders, further research on speech articulation disorders in prosthesis wearers is needed.

OBJECTIVE Trigeminal postherpetic neuralgia (PHN) is often refractory to treatment. Pulsed radiofrequency (PRF) neuromodulation can help in preventing PHN after herpes zoster. This study aimed to compare the efficacy and safety of two different PRF modes on gasserian ganglion neuromodulation in elderly patients with acute/subacute trigeminal herpes zoster. MATERIALS AND METHODS A total of 120 elderly patients with acute or subacute (within past three months) trigeminal herpes zoster were randomized to receive either a single cycle of high-voltage, long-duration PRF (HL-PRF group; N = 60) or three cycles of standard PRF (S-PRF group; N = 60). Patients were followed up for six months after treatment. Visual analog scale (VAS) pain score, 36-Item Short Form Health Survey (SF-36) score, and pregabalin at baseline and at different time points during follow-up were recorded. RESULTS VAS and SF-36 scores declined significantly from baseline levels in both groups (p

Pharmacogenomics (PGx) utilizes an individual’s germline genetic profile to identify those who are at higher risk for ADRs or lack of efficacy. This information can be used by healthcare professionals (HCPs) to guide dose and drug selection before drug initiation in an effort to optimize drug therapy through precision medicine. Despite both the promise of and the progress in the field of PGx to achieve precision medicine, it is still not routinely applied in patient care. As such, a number of barriers preventing implementation have been identified. These include the undetermined model for delivering PGx, the lack of evidence supporting a PGx panel approach and the lack of tools supporting implementation. Therefore, the work of this thesis aims to support the implementation of precision medicine using PGx panel testing. It reports on generating evidence for PGx panel testing (Part I) and the development of tools facilitating implementation (Part II), evaluates the implementation process utilizing these tools (Part III) and quantifies the impact of PGx implementation on patient outcomes and cost-effectiveness (Part IV).

Introduction: Clinical trials remain the gold standard for evaluating efficacy, but there is increasing interest in using real-world evidence (RWE) to inform health care decision making. The aims of this observational study were to describe patterns of medical cannabis use, associated changes in symptom severity over time, and to evaluate change in cannabis dose over time for pain-related symptoms. Methods: Data were collected by Strainprint™, an application that is HIPAA, PIPEDA, and PHIPA compliant. A total of 629 participants recorded data between May 2017 and August 2019. A total of 65 symptoms were grouped as Pain, Mental Health, Physical Symptoms, Seizures, Headaches/Migraines, and Other. Descriptive statistics and mixed-effects modeling were applied. Results: THC-dominant products were more frequently consumed for symptoms of pain and sleep, while CBD-dominant products were more frequently consumed for anxiety and depression. Male and female participants demonstrated significant differences in the type of cannabis they consumed. Females more frequently consumed CBD-dominant products, and males more frequently consumed balanced (THC:CBD) products. Oil use was more prominent among females, while vaping was more common among males. Product use also varied by age tertiles ( 40 years). CBD-dominant products were more common among younger participants, 41 years. Dosages of CBD-dominant and balanced (THC:CBD) products increased over time irrespective of symptom response. THC-dominant products demonstrated a significant relationship between dose and symptom reduction over time. Conclusions: Recognizing that RWE has important methodological limitations, we observed cannabis product preferences based on demographic characteristics, such as gender and age and the primary symptom treated such as pain and anxiety. Our study offers real-world insights into how participants use and respond to cannabis products and suggests important avenues and methodologies for future research.

RESUMO Objetivo: Comparar as complicações entre o Cateter Central de Inserção Periférica com ajuste de comprimento com corte e sem corte. Método: Ensaio clínico randomizado controlado. Compuseram a amostra 46 neonatos internados num serviço de Unidade de Terapia Intensiva Neonatal no Paraná, Brasil, entre abril e julho de 2021, com indicação do cateter. Os participantes foram randomizados eletronicamente e divididos em grupo controle, cujo comprimento do cateter foi ajustado com o corte do mesmo, e grupo experimental, cujo cateter foi mantido sem corte. Os dados foram analisados por teste de Mann-Whitney e Teste de Fisher. Resultados: A média do tempo de permanência dos cateteres foi de dez dias em ambos os grupos (p=0,79). Não foi identificada diferença relevante quanto às complicações, como infiltração, obstrução e infecção. Conclusão: O corte do cateter para ajuste do comprimento não interfere nas complicações apresentadas. Registro no REBEC: RBR-2w4dpg5. ABSTRACT Objective: To compare the complications between the Peripherally Inserted Central Catheter with length adjustment with cut and without cut. Method: Randomized controlled trial. Composed the sample 46 neonates admitted to a Neonatal Intensive Care Unit service in Paraná, Brazil, between April and July 2021, with catheter indication. Participants were electronically randomized and divided into a control group, whose catheter length was adjusted by cutting it, and an experimental group, whose catheter was kept uncut. Data were analyzed by Mann-Whitney test and Fisher’s test. Results: The mean length of catheter stay was ten days in both groups (p=0.79). No relevant difference was identified regarding complications, such as infiltration, obstruction, and infection. Conclusion: Catheter cutting for length adjustment does not interfere in the complications presented. REBEC Register: RBR-2w4dpg5. RESUMEN Objetivo: Comparar las complicaciones entre el catéter central de inserción periférica con ajuste de longitud con corte y sin corte. Método: Ensayo clínico controlado aleatorio. La muestra fue compuesta por 46 neonatos ingresados en una Unidad de Cuidados Intensivos Neonatales en Paraná, Brasil, entre abril y julio de 2021, con indicación de catéter. Los participantes fueron aleatorizados electrónicamente y divididos en un grupo de control, cuya longitud de catéter se ajustó cortándolo, y un grupo experimental, cuyo catéter se mantuvo sin cortar. Los datos se analizaron mediante la prueba de Mann-Whitney y la prueba de Fisher. Resultados: La duración media de la estancia del catéter fue de diez días en ambos grupos (p=0,79). No se identificaron diferencias relevantes en cuanto a las complicaciones, como la infiltración, la obstrucción y la infección. Conclusión: El corte del catéter para el ajuste de la longitud no interfiere en las complicaciones presentadas. Registro REBEC: RBR-2w4dpg5.

Background: Hepatocellular carcinoma (HCC) is the most frequent liver malignancy and a leading cause of cancer death in the world. In unresectable HCC patients, transcatheter arterial (chemo-) embolization (TAE/TACE) has shown a disease response in 15–55% of cases. Though multiple TAE/TACE courses can be administered in principle, Stereotactic Body Radiotherapy (SBRT) has emerged as an alternative option in the case of local relapse following multiple TAE/TACE courses. Methods: This is a single-center, prospective, randomized, controlled, parallel-group superiority trial of SBRT versus standard TAE/TACE for the curative treatment of the intermediate stage of HCC after an incomplete response following TAE/TACE (NCT02323360). The primary endpoint is 1-year local control (LC): 18 events were needed to assess a 45% difference (HR: 0.18) in favor of SBRT. The secondary endpoints are 1-year Progression-Free Survival (PFS), Distant Recurrence-Free Survival (DRFS), Overall Survival (OS) and the incidence of acute and late complications. Results: At the time of the final analysis, 40 patients were enrolled, 19 (49%) in the TAE/TACE arm and 21 (51%) in the SBRT arm. The trial was prematurely closed due to slow accrual. The 1- and 2-year LC rates were 57% and 36%. The use of SBRT resulted in superior LC as compared to TAE/TACE rechallenge (median not reached versus 8 months, p = 0.0002). PFS was 29% and 16% at 1 and 2 years, respectively. OS was 86% and 62% at 1 year and 2 years, respectively. In the TAE arm, PFS was 13% and 6% at 1 and 2 years, respectively. In the SBRT arm, at 1 and 2 years, PFS was 37% and 21%, respectively. OS at 1 and 2 years was 75% and 64% in the SBRT arm and 95% and 57% in the TACE arm, respectively. No grade >3 toxicity was recorded. Conclusions: SBRT is an effective treatment option in patients affected by inoperable HCC experiencing an incomplete response following ≥1 cycle of TAE/TAC.

Objectives: This study aimed to assess the productivity of clinical trials in the Gulf Cooperation Council (GCC) region, including Oman, Saudi Arabia, United Arab Emirates, Qatar, Bahrain and Kuwait and to address the existing research gap. Specifically, this paper aimed to estimate the number of clinical trials conducted and estimate the proportion of clinical trials conducted in the GCC countries published in peer-reviewed journals. Methods: The clinical trials registry of the US National Library of Medicine was searched for clinical trials conducted from January 2000 to October 2019. The productivity was assessed by the publication status of the trials in the registry and through the search in MEDLINE indexed journals. Results: A total of 682 trials were found from the GCC region, with an overall trend of 4.1 trials each year. However, the clinical trial productivity from the region contributes to only 0.37% of the trials globally. When comparing the raw data, Saudi Arabia showed the highest proportion, contributing 66.6% of the clinical trials from the region (P

Pancreatic cancer (PC) is a major gastrointestinal cancer in terms of worldwide incidence and mortality. Despite advances in diagnostic and treatment modalities, the mortality of PC is still a serious concern in both sexes. Immune therapy using inhibitors of immune checkpoints, especially inhibitors of programmed cell death protein 1/programmed cell death ligand-1(PD-1/PD-L1), offer huge benefits to cancer patients. This review describes an up-to-date information on the role of PD-1 and PD-L1 in the development of immune tolerance in PC alongside the current clinical trials and the known outcomes citing the available literature. We also included the details on PD-1/PD-L1-mediated signalling in maintenance of PC stem cells and metastasis. We reviewed the critical information on safety, tolerance, and efficacy of clinically important regimens of PD-1/PD-L1 blocking agents and targeted therapeutics. This review elucidates the underlying mechanisms of PD-1/PD-L1 alliance in tolerance of the immune system, maintenance of stem cells, and metastasis promotion as well as design regimens with high safety and excellent tolerability and efficacy for management of PC in advanced stages.

Background and objectives In the BLISS-LN study, belimumab improved kidney outcomes in adult patients with active lupus nephritis. This 28-week open-label extension of BLISS-LN assessed belimumab's safety and efficacy. Design, setting, participants, & measurements Eligible patients completing BLISS-LN received monthly intravenous belimumab 10 mg/kg plus standard therapy. End points included safety, open-label week 28 primary efficacy renal response (urine protein-creatinine ratio [UPCR] _60 ml/min per 1.73 m2, no prohibited medications) and complete renal response (UPCR < 0.5, eGFR no more than 10% below open-label baseline value or >_90 ml/min per 1.73 m2, no prohibited medications), and UPCR and eGFR by visit. Responses were also analyzed post hoc using the double-blind phase criteria. Results Of 257 enrolled patients, 255 were treated (safety population: n=123 switched from placebo-tobelimumab; n=132 remained on belimumab); 245 (97%) patients completed the study. Adverse events and serious adverse events were experienced by 62% and 4% of placebo-to-belimumab patients, respectively, and by 70% and 8% of belimumab-to-belimumab patients, respectively. One death occurred in the placebo-to-belimumab group. From open-label baseline to week 28, increases occurred in the proportions of patients achieving primary efficacy renal response (placebo-to-belimumab: from 60% to 67%; belimumab-to-belimumab: from 70% to 75%) and complete renal response (placebo-to-belimumab: from 36% to 48%; belimumab-to-belimumab: from 48% to 62%). Based on double-blind phase criteria, changes also occurred in the proportions achieving primary efficacy renal response (placebo-to-belimumab: from 54% to 53%; belimumab-to-belimumab: from 66% to 52%) and complete renal response (placebo-to-belimumab: from 34% to 35%; belimumab-to-belimumab: from 46% to 41%). The seeming decrease in response rates in the belimumab-to-belimumab groups was attributed to discontinuations/administration of glucocorticoids for non-SLE reasons as opposed to nephritis. Median UPCR and eGFR values were similar at open-label baseline and week 28. Conclusions No new safety signals were identified, and efficacy was generally maintained throughout the open label phase. contributing the affiliations listed at the article. Correspondence: Dr. Richard Division of Rheumatology, Northwell Donald and Zucker School Medicine, Northwell Suite 302, NY 11021. RFurie@northwell.edu

Despite the use of acetazolamide in the management of CSF leak in most patients after CNS surgeries, there is scant evidence in the literature about the efficacy of this established protocol among adult patients in post-spinal surgery observations. We investigated the potential positive effect of acetazolamide in reducing CSF leak after spine surgery.We conducted a single-center, double-blind, randomized -controlled trial comparing Oral Acetazolamide plus Corrected body (prone) position (CP+A) versus Corrected body (prone) position alone (CP-A) from January 2014 to September 2015 in the Neurosurgery ward of Shariati Teaching Hospital, Tehran University of Medical Sciences, Tehran, Iran. Seventy-two Patients divided into two groups [CP-A group (n = 36, 50%) and CP+A group (n = 36, 50%)] were randomly assigned to this Clinical Trial study. CP+A group (maintained the 3/4 lateral position + dose of acetazolamide 20 mg/kg/day in 3-4 divided doses for 7 days), and CP-A group (Control group) (maintained the 3/4 lateral position for 7 days with no acetazolamide).Baseline characteristics between the two groups showed no significant differences: Sex (P .637), Age (P .988) and previous CNS operation at other location besides the spine (P .496). Although we reported post-surgical CSF leak in 2/36 (5.55%) of CP+A group and 4/36 (11.11%) of CP-A (control) group, there was no significant difference observed between the two groups (95%CI, 0.081-2.748; OR = 0.471; P .402; Adjusted P .247). Additionally, no significant differences were observed when we examined surgical characteristics, such as the size of the dural opening (P .489) and type of operation (P .465).Acetazolamide has no positive effect in controlling CSF leak after dural opening/dural tear in adult patients who undergo spinal surgery, when we considered alongside the one-week prone position. Therefore, acetazolamide administration may not be essential for postoperative spinal surgery for dural tear. Prospective studies involving a larger sample size may be needed to track long-term acetazolamide complications on patients with CSF leak.

Mutant isocitrate dehydrogenase (IDH) in chondrosarcoma produces the oncometabolite 2-hydroxyglutarate (2-HG) and contributes to malignant progression, and is therefore a potential therapeutic target for chondrosarcoma. Robust historical control data are important in clinical trials of rare cancers such as chondrosarcoma in order to show a clear benefit of new drugs. However, it remains controversial whether IDH mutation status is associated with the clinical outcome of chondrosarcoma, and this hinders the development of mutant IDH inhibitors in clinical trials.background METHODS: We investigated the relationship between IDH gene status and clinicopathological data in 38 chondrosarcoma patients from whom frozen tumor samples were obtained at the time of biopsy or surgery. Targeted next-generation sequencing was also performed to compare genetic alterations between patients with and without IDH mutations.The results revealed 15 cases (40%) of heterozygous IDH1 mutations and five cases (13%) of IDH2 mutations. IDH-mutant chondrosarcoma was associated with worse overall survival than IDH-wild-type chondrosarcoma (IDH1/2 Mut vs. IDH Wt, P = 0.006; IDH1 Mut vs. IDH Wt, P = 0.030; IDH2 Mut vs. IDH Wt, P 0.0001). IDH mutation was also a significant poor prognostic factor both in univariate (P = 0.026) and multivariate (P = 0.048) analyses. Targeted next-generation sequencing revealed that characteristic mutations in chondrosarcoma, including TP53 and COL2A1, were more common in the IDH-mutant group than in the IDH-wild-type group.results CONCLUSION: This study is the first to report in detail the characteristics and clinical courses of IDH-mutant chondrosarcoma patients in Japan. Our data suggested that IDH-mutant chondrosarcomas might have a worse prognosis than that of IDH-wild-type chondrosarcoma, possibly through the more aggressive characters after metastasis. This information will be useful for designing clinical trials of mutant IDH inhibitors for treatment of advanced chondrosarcoma.

The intentional use of viruses for cancer therapy dates back over a century. As viruses are inherently immunogenic and naturally optimized delivery vehicles, repurposing viruses for drug delivery, tumor antigen presentation, or selective replication in cancer cells represents a simple and elegant approach to cancer treatment. While early virotherapy was fraught with harsh side effects and low response rates, virus-based therapies have recently seen a resurgence due to newfound abilities to engineer and tune oncolytic viruses, virus-like particles, and virus-mimicking nanoparticles for improved safety and efficacy. However, despite their great potential, very few virus-based therapies have made it through clinical trials. In this review, we present an overview of virus-inspired approaches for cancer therapy, discuss engineering strategies to enhance their mechanisms of action, and highlight their application for overcoming the challenges of traditional cancer therapies.

Introduction Manual therapy has been shown to reduce self-reported symptoms in patients with chronic tension-type headache (CTTH). However, simultaneous application of suboccipital muscle inhibition and interferential current has not previously been investigated. This study evaluates the effectiveness of combined treatment with suboccipital muscle inhibition and interferential current compared to standard treatment for pain, disability, and headache impact in patients with CTTH. Methods Patients were randomly allocated to receive either standard treatment (n = 13) or the experimental treatment (n = 12), consisting of 20 minutes of suboccipital muscle inhibition plus interferential current twice weekly for 4 weeks. The primary outcome was improvement in pain, and secondary outcomes included improvement in headache-related disability and reduction in headache impact, which were assessed at baseline and at 4 weeks by a blinded rater. Results Statistical analysis showed improvements in the experimental treatment group at 4 weeks for headache-related disability (Neck Disability Index: Hedges' g = 1.01, P = .001; and Headache Disability Inventory: Hedges' g = 0.48, P = .022) and headache impact (6-item Headache Impact Test: Hedges' g = 0.15, P = .037) but not for self-reported pain (numerical rating scale: Hedges' g = 1.13, P = .18). Conclusions Combined treatment with suboccipital muscle inhibition and interferential current in patients with CTTH did not significantly improve self-reported pain but did reduce disability and the impact of headache on daily life at 4 weeks. These improvements exceed the minimum clinically important difference, demonstrating the clinical relevance of our findings.

International audience; Background: Following European guidelines, patients with aggressive metastatic or locally advanced, non-resectable, duodeno-pancreatic (DP) neuroendocrine tumours (NETs) should receive systemic combination chemotherapy until progression. Aggressive disease is defined as progressive and/or symptomatic metastases with or without significant hepatic invasion (>30–50%), and/or bone metastases. Methods: This academic randomised, double-blind, placebo-controlled phase II study aims to evaluate lanreotide autogel 120 mg (LAN) as maintenance treatment after at least 2 months of first-line treatment (L1) in aggressive G1-G2 DP-NET. Patients were randomly assigned in a 1:1 ratio to receive LAN or placebo (PBO), every 28 days, until progression or toxicity. The primary end-point was progression-free survival (PFS) at 6 months. Results: Among the 118 planned patients, 53 were included. Of these, 81.1% had a G2 tumour, and 90.6% had metastatic disease. L1 therapy consisted of chemotherapy (96.8%). Median duration of L1 was 4.6 months (range: 2.0–7.7). At the time of randomisation, 81.1% of patients had stable disease. Median follow-up was 27.0 months (95% CI: 19.5; 31.2). PFS at 6 months was 73.1% (90% CI: 55.3; 86.6) in LAN versus 54.2% (90% CI: 35.8; 71.8) in PBO. Median PFS was 19.4 months (95% CI: 7.6; 32.6) and 7.6 months (95% CI: 3.0; 9.0), respectively. Median overall survival was 41.9 months in PBO and was not reached in LAN. The toxicity profile was mainly grade 1–2 expected toxicities. Conclusions: The encouraging results of lanreotide autogel 120 mg as a maintenance treatment after L1 in aggressive G1/2 DP-NET should be confirmed. Trial registration: NCT02288377 (clinicaltrials.gov). © 2022 The Authors

Objectives To compare the percentage of mean root coverage (MRC%) obtained in the treatment of multiple Miller class III/RT2 gingival recessions using the modified VISTA (m-VISTA) technique versus the coronally advanced flap (CAF) technique, using a connective tissue graft (CTG) in both cases. Materials and methods Twenty-four patients were randomly treated with m-VISTA (test group (TG) = 12) or CAF (control group (CG) = 12). A calibrated, experienced, and blinded examiner collected data related to multiple periodontal clinical variables, especially the recession (REC) in order to calculate the MRC% at 6 and 12 months, which was the primary outcome of the study. Also, the radiological bone level, the characteristics of the CTG, and postsurgical incidences were assessed. Finally, a descriptive and an analytical statistical analysis of the variables and their associations was performed. Results The recessions (n = 84) were located mainly in the mandible (n = 65) and in posterior sectors (premolars: n = 35; molars: n = 8). At 6 months, the MRC% was 61% (2 mm) for both study groups, and at 12 months, it increased to 73.26% (2.11 mm) in the TG and decreased to 56.49% (1.78 mm) in the CG. Conclusion When approaching multiple Miller class III/RT2 recessions, there were no statistically significant differences in the MRC% at 6 and 12 months between the group treated with the m-VISTA technique and the group treated with the CAF. Clinical relevance The characteristics of the m-VISTA technique, such as the closed approach, the mobilization of the papilla, and the coronal stabilization of the CTG, could facilitate the maturation of the tissues in the treatment of Miller class III/RT2 recessions. This would favor better root coverage. Trial registration NCT03258996.