Docetaxel Provides Oncological Benefits in the Era of New-Generation Androgen Receptor Inhibitors - or Is Three a Crowd?

In recent years, several systemic therapies have been introduced for metastatic hormone-sensitive prostate cancer, including androgen deprivation therapy (ADT) combined with docetaxel (Doc) and/or new-generation androgen receptor signaling inhibitors (ARSI). Trials evaluating ADT + ARSI have consistently demonstrated an overall survival (OS) benefit for doublet therapy over ADT alone. Similarly, the STOPCaP meta-analysis showed an OS benefit in favor of ADT + Doc versus ADT alone. ARSI, Doc, and ADT have different antitumor mechanisms, thus potentiating the effect of combination therapy. Two randomized trials showed that the addition of ARSI to ADT + Doc improves OS, especially for synchronous high-volume disease. However, the real question about triplet therapy remains unanswered: whether combining Doc with ARSI improves outcomes compared to ADT + ARSI. As there are no head-to-head comparisons, this narrative review aims to summarize the current evidence regarding triplet therapy versus doublet therapy including ADT+ ARSI.

A systematic review of diversity, equity, and inclusion and antiracism training studies: Findings and future directions.

A growing number of organizations are prioritizing diversity, equity, and inclusion (DEI) and antiracism in the workplace, including investing resources in DEI or antiracism training. However, such trainings vary widely in curriculum, objectives, delivery, and evaluation, with little known about the efficacy of existing trainings. The aim of this systematic review is to evaluate training characteristics, measures, and results of peer-reviewed studies (published between 2000 and 2022) testing DEI or antiracism trainings. Studies were identified using Google Scholar, JSTOR, and a university library database. Key search terms included "diversity, equity, and inclusion training"; "antiracism training"; and "effect," "impact," "outcome," or "evaluation." The search yielded N = 15 DEI training studies and N = 8 antiracism training studies. The majority of studies (75% of antiracism training; 66.6% of DEI training) utilized a one-time training session. Content, objectives, measures, and impact varied widely across studies. Randomized designs were uncommon (13%), and over 70% of studies had majority female participants. Findings highlight several strategies to advance the field of DEI and antiracism training, such as shifting curriculum from targeting individual knowledge to supporting behavioral and organizational change, providing longitudinal training, standardizing outcomes of interest, and implementing rigorous evaluation methods.

Despite the increased number of organizations dedicating resources to diversity, equity, and inclusion training and/or antiracism training, little is known about which strategies yield successful results. This systematic review synthesizes research findings on diversity, equity, and inclusion and antiracism training studies over the past two decades and presents research and practice-based recommendations for how to move the field forward.

Role of Radiotherapy and Hormone Therapy in Patients with Node-Positive Locally Advanced Prostate Cancer

New-generation imaging techniques and the increasing use of surgery in high-risk prostate cancer (PCa) allow usto detect many cases of nodal disease at initial diagnosis or after resection. The treatment of PCa with pathologic regional nodeshas evolved from the exclusive use of systemic therapy to its combination with locoregional treatment. It can also represent abenefit in the overall survival. However, the evidence from randomised studies is limited. Thus, we review the most relevantresults in this scenario.Materials and Methods: A literature search was conducted in MEDLINE, PubMed, EMBASE, Clinical-Trials.gov and Webof Science on January 2023 to review node-positive PCa by considering the relevant literature on this topic published with norestrictions on date and language. The search keywords used were “Prostatic Neoplasms” (MeSh) and “Node-positive” (TextWord) and “Radiotherapy” (MeSh) and (“Androgen Antagonists” (MeSh) or “Antineoplastic Agents, Hormonal” (MeSh)), whichare indexed within the Medical Subject Headings database.Results: The management of node-positive PCa has no clear definitive consensus at the initial disease diagnosis or after surgery.However, in this review, we summarise the existing literature for the management of these patients in both scenarios, consideringimaging tests, radiotherapy, hormone therapy and second-generation hormonal treatments.Conclusions: The combination of radiotherapy and androgen-deprivation therapy is the treatment of choice. The addition ofsecond-generation hormone therapy, plus the intensification of radiotherapy schedules, will likely change the treatment paradigm for these patients. (AU)

Jorge clinical study: 10-year outcomes of risk-adapted radiotherapy defined by multiparametric MRI for prostate cancer.

PURPOSE: To analyze the 10-year biochemical relapse-free survival (BRFS), locoregional relapse-free survival (LRFS), metastasis-free survival (MFS), and overall survival (OS) in patients diagnosed with localized prostate adenocarcinoma treated with radiotherapy (RT) ± androgen deprivation therapy (ADT), according to the risk groups based on multiparametric magnetic resonance imaging (mpMRI) instead of digital rectal exam (DRE). METHODS: We retrospectively evaluated 140 consecutive patients diagnosed with localized prostate adenocarcinoma, stratified into different risk groups-low (LR), intermediate (IR), and high (HR) by mpMRI results. RESULTS: After a median follow-up of 104 months, in LR group (n = 15), 10-year BRFS was 86.7%, 10-year LRFS was 86.7%, 10-year MFS was 93.3%, and 10-year OS was 100%. In IR group (n = 80), 10-year BRFS was 80.5%, 10-year LRFS was 86.1%, 10-year MFS was 92.6%, and 10-year OS was 76%. In HR group (n = 45), 10-year BRFS was 72.8%, 10-year LRFS was 78.7%, 10-year MFS was 82.1%, and 10-year OS was 77% (2 deaths from prostate cancer). According to mpMRI results, 36 (25.7%) patients change the risk group and 125 (89.28%) patients change the TNM stage. There was a trend for higher metastatic relapse in patients who switched from IR to HR (due to mpMRI) versus the patients who remained in the IR (20%, vs. 1.81% p = 0.059). Multivariate analysis showed that locoregional relapse was strongly associated with distant relapse (OR = 9.28; 95%CI: 2.60-33.31). There were no cases of acute grade 3 toxicity. Late grade 3 genitourinary, gastrointestinal, and sexual toxicity were 2.8%, 0.7%, and 1.2%, respectively. CONCLUSION: This is the first study with a 10-year median follow-up of patients diagnosed with localized prostate cancer treated with radiotherapy according to the risk groups established by mpMRI. Our findings show that mpMRI is a key tool to diagnose and establish risk groups in these patients, to optimize their treatment.

Outcomes of SARS-CoV-2 infection in 126 children and adolescents with central nervous system tumors.

BACKGROUND: The Global Registry of COVID-19 in Childhood Cancer (GRCCC) seeks to describe the natural history of SARS-CoV-2 in children with cancer across the world. Here, we report the disease course and management of coronavirus disease 2019 (COVID-19) infection in the subset of children and adolescents with central nervous system (CNS) tumors who were included in the GRCCC until February 2021, the first data freeze. PROCEDURE: The GRCCC is a deidentified web-based registry of patients less than 19 years of age with cancer or recipients of a hematopoietic stem cell transplant and laboratory-confirmed SARS-CoV-2 infection. Demographic data, cancer diagnosis, cancer-directed therapy, and clinical characteristics of SARS-CoV-2 infection were collected. Outcomes were collected at 30 and 60 days post infection. RESULTS: The GRCCC included 1500 cases from 45 countries, including 126 children with CNS tumors (8.4%). Sixty percent of the cases were from middle-income countries, while no cases were reported from low-income countries. Low-grade gliomas, high-grade gliomas, and CNS embryonal tumors were the most common CNS cancer diagnoses (67%, 84/126). Follow-up at 30 days was available for 107 (85%) patients. Based on the composite measure of severity, 53.3% (57/107) of reported SARS-CoV-2 infections were asymptomatic, 39.3% (42/107) were mild/moderate, and 6.5% (7/107) were severe or critical. One patient died from SARS-CoV-2 infection. There was a significant association between infection severity and absolute neutrophil count less than 500 (p = .04). Of 107 patients with follow-up available, 40 patients (37.4%) were not receiving cancer-directed therapy. Thirty-four patients (50.7%) had a modification to their treatment due to withholding of chemotherapy or delays in radiotherapy or surgery. CONCLUSION: In this cohort of patients with CNS tumors and COVID-19, the frequency of severe infection appears to be low, although severe disease and death do occur. We found that greater severity was seen in patients with severe neutropenia, although treatment modifications were not associated with infection severity or cytopenias. Additional analyses are needed to further describe this unique group of patients.

Addressing the Gap in Research Methodologies Education in Pediatric Oncology in the Eastern Mediterranean Region.

PURPOSE: Formal training in clinical research methodologies is limited in limited-resource countries. Through collaboration among high- and middle-resource settings and in response to an identified need verbalized by regional pediatric oncology practitioners, Pediatric Oncology East & Mediterranean Group and St Jude Global developed a workshop focused on capacity building in research skills. Here, we describe its structure, implementation, and early results. METHODS: Leveraging virtual capabilities, the format included lectures and small group breakout exercise sessions, for 3 hours per day on 2 consecutive days per week for 2 consecutive weeks. Topics included basics of study design, introduction to health care statistics, research ethics, data registries, and scientific writing. Applicants were required to submit an abstract for a potential research project. Each breakout group selected one abstract for further development and presented the final version in a groupwide session. The participants' experience was evaluated through an online survey. RESULTS: Attendance included 29 registrants from 12 countries and six disciplines. Each breakout group was assigned a themed category: cohort studies, clinical trials, or registries. Critical feedback from the breakout sessions helped strengthen the selected projects, which included a retrospective study, a prospective observational study, a prospective interventional study, and a registry proposal. After the workshop, participants were invited to further develop their original abstracts, and three proposals received additional mentoring, one of which was a multi-institutional prospective study that was subsequently submitted through the Pediatric Oncology East & Mediterranean Group network for implementation. The postworkshop survey revealed an overall highly positive experience, and feedback provided potential themes for future workshops. CONCLUSION: This workshop demonstrated the potential for collaborative network partnerships in targeting research training gaps in pediatric oncology. Lessons learned will be applied to future workshops to strengthen research in limited-resource settings.

Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio as Prognostic Factors in Locally Advanced Rectal Cancer.

INTRODUCTION: The standard therapy for locally advanced rectal cancer (LARC) is based on neoadjuvant chemoradiotherapy (nCRT) with fluoropyrimidines. There are different biomarkers used as prognostic factors in these tumors. Some studies advocate the use of the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) as prognostic factors in this clinical scenario. The aim of the study was to evaluate NLR and PLR as prognostic factors of disease-free survival (DFS) and overall survival (OS) and as predictive factors of pathologic complete response (pCR) using Ryan tumor regression scoring system on surgical specimens, in patients with locally advanced rectal adenocarcinoma who received nCRT and radical surgery. METHODS: We retrospectively evaluated patients with locally advanced rectal adenocarcinoma (T3-T4, N1-N3, M0 according to the TNM classification, AJCC 8th edition) who received nCRT based on fluoropyrimidines and radical surgery. Complete blood cell count before nCRT was obtained to calculate NLR and PLR. We made subgroups of patients according to NLR and PLR. We obtained the cut-off point for these ratios based on receiver operating characteristic analysis. We analyzed OS and DFS using the Kaplan-Meier method and Cox proportional hazard models. The relationships between NLR/PLR and pCR, along with other clinical-pathological characteristics, were evaluated by Pearson's χ2 or Fisher's exact test as appropriate. Multivariate analyses were performed using Cox proportional hazard regression models. RESULTS: Between February 2012 and February 2017, 100 consecutive patients were treated according to the reported schedules. Median age was 76 years (68-83). All patients received radiotherapy up to 50.4 Gy and 5-FU-based chemotherapy. 100% completed nCRT and surgery, 38% had elevated basal NLR (cut-off >1.95), and 50% had elevated basal PLR (cut-off >133). After a median follow-up of 72 months (55-88), a lower DFS was obtained in the high NLR subgroup (log-rank, Mantel-Cox 5.165, p = 0.023) and in the high PLR subgroup (log-rank, Mantel-Cox 13.971, p = 0.001). Multivariate analysis showed that PLR (p = 0.006) was a strong significant predictor of DFS. A lower OS was observed in the high NLR and PLR subgroup without significant differences (log-rank, Mantel-Cox 1.245, p = 0.265; 0.578, p = 0.447). No significant differences were obtained in any of the subgroup analysis regarding pCR rates. CONCLUSION: In light of our results, both NLR and PLR could be considered prognostic factors for DFS in patients with LARC that receive treatment with nCRT followed by surgery.

Oligometastatic Hormone-Sensitive Prostate Cancer. Why Radiotherapy?

Androgen deprivation therapy (ADT) has been considered for years the standard initial treatment for patients with metastatic prostate cancer (mPC). Recently published results support the use of taxanes, second-generation antiandrogens or radiotherapy to the primary tumor as part of the treatment in these patients, considering ADT alone as suboptimal. Metastasis-directed therapy (MDT) is used as part of the treatment for oligometastatic patients in different tumor types. In oligometastatic hormone-sensitive prostate cancer the role of MDT is being studied with promising results. In the present review we assess the available evidence for radiotherapy to the primary tumor in newly diagnosed mPC and for MDT in oligometastatic prostate cancer, as well as future directions in this clinical setting.

Role of Radiotherapy and Hormone Therapy in Patients with Node-Positive Locally Advanced Prostate Cancer.

BACKGROUND: New-generation imaging techniques and the increasing use of surgery in high-risk prostate cancer (PCa) allow us to detect many cases of nodal disease at initial diagnosis or after resection. The treatment of PCa with pathologic regional nodes has evolved from the exclusive use of systemic therapy to its combination with locoregional treatment. It can also represent a benefit in the overall survival. However, the evidence from randomised studies is limited. Thus, we review the most relevant results in this scenario. MATERIALS AND METHODS: A literature search was conducted in MEDLINE, PubMed, EMBASE, Clinical-Trials.gov and Web of Science on January 2023 to review node-positive PCa by considering the relevant literature on this topic published with no restrictions on date and language. The search keywords used were "Prostatic Neoplasms" (MeSh) and "Node-positive" (Text Word) and "Radiotherapy" (MeSh) and ("Androgen Antagonists" (MeSh) or "Antineoplastic Agents, Hormonal" (MeSh)), which are indexed within the Medical Subject Headings database. RESULTS: The management of node-positive PCa has no clear definitive consensus at the initial disease diagnosis or after surgery. However, in this review, we summarise the existing literature for the management of these patients in both scenarios, considering imaging tests, radiotherapy, hormone therapy and second-generation hormonal treatments. CONCLUSIONS: The combination of radiotherapy and androgen-deprivation therapy is the treatment of choice. The addition of second-generation hormone therapy, plus the intensification of radiotherapy schedules, will likely change the treatment paradigm for these patients.

Misdiagnoses in a Brazilian population with amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects the upper and lower motor neurons. The correct diagnosis at the onset of the disease is sometimes very difficult, due to the symptoms being very similar to those of other neurological syndromes. OBJECTIVE: This study aimed to analyze the initial manifestations, the specialty of the first physician visited due the initial complaint, the misdiagnoses, as well as the unnecessary surgical interventions in a new ALS Brazilian population. METHODS: The medical records of 173 patients with typical ALS were reviewed. RESULTS: The present study demonstrated that other symptoms, besides weakness, were very frequent as initial presentation of ALS, and orthopedics was the medical specialty most sought by patients at the onset of symptoms. Our frequency of misdiagnoses was 69.7%, and in 7.1% of them, an unnecessary surgical intervention was performed. CONCLUSIONS: Amyotrophic lateral sclerosis presents a very large pool of signs and symptoms; therefore, there is an urgent need of increasing the disease awareness to other specialties due to the high frequency of misdiagnoses observed in clinical practice.

ANTECEDENTES: A esclerose lateral amiotrófica (ELA) é uma doença neurodegenerativa que afeta os neurônios motores superior e inferior. O diagnóstico correto no início da doença é, às vezes, muito difícil, pois os sintomas de início são muito semelhantes aos de outras síndromes neurológicas. OBJETIVO: Este estudo teve como objetivo analisar as manifestações iniciais, a especialidade do primeiro médico visitado devido à queixa inicial, os diagnósticos errôneos, bem como as intervenções cirúrgicas desnecessárias em uma nova população brasileira acometida por ELA. MéTODOS: Os prontuários médicos de 173 pacientes com ELA típica foram revisados. RESULTADOS: O presente estudo demonstrou que outros sintomas, além da fraqueza, foram muito frequentes como apresentação inicial da ELA, sendo a ortopedia a especialidade médica mais procurada pelos pacientes no início dos sintomas. Nossa frequência de diagnósticos errôneos foi de 69,7%, e em 7,1% deles foi realizada intervenção cirúrgica desnecessária. CONCLUSõES: A ELA apresenta um conjunto amplo de sinais e sintomas; portanto, há necessidade urgente de uma melhor educação de outras especialidades devido à alta frequência de diagnósticos equivocados observada na prática clínica.

Dose-escalated neoadjuvant chemoradiotherapy for locally advanced oesophageal or oesophagogastric junctional adenocarcinoma.

Background: Neoadjuvant chemoradiotherapy with CROSS-protocol is the standard of care for locally advanced esophageal cancer. The purpose of this study was to demonstrate an improvement in complete pathological response (ypCR) after a dose-escalation neoadjuvant protocol compared to standard treatment. Secondary endpoints were disease-free survival (DFS) and acute gastrointestinal toxicity. Material and methods: We prospectively evaluated patients with locally advanced esophageal adenocarcinoma who received neoadjuvant chemoradiotherapy. The radiation dose was 41.4 Gy in 23 fractions or 50.4 Gy in 28 fractions with weekly administration of six intravenous cycles of carboplatin AUC 2 mg/mL and intravenous paclitaxel 50 mg/m2 followed by surgery. Results: Between December 2015 and July 2020, 21 patients were treated according to the reported radiation schedules. Median age was 61 years (57-67). 20 (95.2%) tumors were located at the esophagogastric junction and 1 (4.8%) in the middle esophagus. Five (23.8%) were stage II and 16 (76.2%) stage III. Twelve (57.1%) patients received 41.4 Gy (standard group) and 9 (42.9%) received 50.4 Gy (intensification group), with 5 (41.67%) and 5 (55.6%) presenting ypCR in the standard and intensification group, respectively (p = 0.67). After a median follow-up of 17 months (8-30), DFS in the standard group was 17.78 months [95% (CI, confidence interval): 12.9-22.6] and 45.5 months (95% CI: 24.4-66.05) in the intensification group (p = 0.299). Grade III acute gastrointestinal toxicity was 16% and 33.33%, respectively (p = 0.552). Postoperative toxicity events ≥ Grade III were 5 (41.7%) and 4 (44.4%), respectively (p = 0.623). Conclusions: In our study we found a trend towards a higher complete pathological response-rate and disease-free survival in the intensification group compared to the standard group, with no differences in gastrointestinal toxicity. Well-designed randomized and controlled trials are needed to obtain conclusive data.

Síndrome de burnout en cirujanos generales en tiempos de la pandemia COVID-19

Objetivo: Evaluar el síndrome de burnout (SB) en cirujanos generales. Material y Método: Se realizó un estudio de corte transversal en nuestro centro hospitalario, en agosto de 2021. La muestra estuvo formada por 56 profesionales de la salud que incluyeron a residentes y especialistas en cirugia general quienes prestaron servicio en el contexto de la COVID-19. Resultados: La prevalencia del burnout fue del 71%, la edad media fue de 34 años y los residentes fueron los más afectados (62,5%). La distribución por sexo fue de 82,5% en masculinos y 17,5% en el sexo femenino. Del total de evaluados, 23 son casados y 17 solteros, predominando los cirujanos con hijos (60%). Discusión: Entre los pocos estudios publicados sobre el SB en trabajadores de la salud en tiempos de COVID-19 se ubican como posibles factores predisponentes: a las privaciones de sueño, el riesgo biológico ocupacional intrínseco, la cuarentena obligada a la que tienen que someterse los trabajadores de la salud fuera de casa y los dilemas éticos en la toma de decisiones de atención a pacientes. Sin embargo, un estudio ha mostrado que los estresores vinculados al SB más importantes son la falta de equipo de protección personal, el miedo al contagio de COVID-19 y el miedo de contagiar a los familiares. Conclusión: Existe una alta prevalencia del SB en cirujanos generales en el contexto de la pandemia COVID-19. Los más afectados fueron residentes jóvenes de sexo masculino, casados, con hijos y con bajos ingresos económicos.

Objective: To evaluate the burnout syndrome (BS) in general surgeons. Material and Method: A cross-sectional study was carried out in our hospital in August 2021. The sample consisted of 56 health professionals that included residents and specialists in general surgery who provided service in the context of COVID-19 Results: The prevalence of burnout was 71%, the mean age was 34 years and the residents were the most affected (62.5%). Sex was 82.5% in males and 17.5% in females. Of the total evaluated, 23 are married and 17 are single, with a predominance of surgeons with children (60%). Discussion: Among the few studies published on BS in health workers in times of COVID-19, the following are located as possible predisposing factors: sleep deprivation, intrinsic occupational biological risk, the forced quarantine that patients have to undergo. out-of-home health workers and ethical dilemmas in patient care decision-making. However, a study has shown that the most important stressors linked to BS are the lack of personal protective equipment, the fear of contagion of COVID-19 and the fear of infecting family members. Conclusion: There is a high prevalence of BS in general surgeons in the context of the COVID-19 pandemic. The most affected were young male residents, married, with children and with low income.

Assessing radiation dose for postoperative radiotherapy in prostate cancer: Real world data.

BACKGROUND: Approximately 30% of patients with localized prostate cancer (PCa) who undergo radical prostatectomy will develop biochemical recurrence. In these patients, the only potentially curative treatment is postoperative radiotherapy (PORT) with or without hormone therapy. However, the optimal radiotherapy dose is unknown due to the limited data available. AIM: To determine whether the postoperative radiotherapy dose influences biochemical failure-free survival (BFFS) in patients with PCa. METHODS: Retrospective analysis of patients who underwent radical prostatectomy for PCa followed by PORT-either adjuvant radiotherapy (ART) or salvage radiotherapy (SRT)-between April 2002 and July 2015. From 2002 to 2010, the prescribed radiation dose to the surgical bed was 66-70 Gy in fractions of 2 Gy; from 2010 until July 2015, the prescribed dose was 70-72 Gy. Patients were grouped into three categories according to the total dose administered: 66-68 Gy, 70 Gy, and 72 Gy. The primary endpoint was BFFS, defined as the post-radiotherapy prostate-specific antigen (PSA) nadir + 0.2 ng/mL. Secondary endpoints were overall survival (OS), cancer-specific survival (CSS), and metastasis-free survival (MFS; based on conventional imaging tests). Treatment-related genitourinary (GU) and gastrointestinal (GI) toxicity was evaluated according to Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer criteria. Finally, we aimed to identify potential prognostic factors. BFFS, OS, CSS, and MFS were calculated with the Kaplan-Meier method and the log-rank test. Univariate and multivariate Cox regression models were performed to explore between-group differences in survival outcome measures. RESULTS: A total of 301 consecutive patients were included. Of these, 93 (33.6%) received ART and 186 (66.4%) SRT; 22 patients were excluded due to residual macroscopic disease or local recurrence in the surgical bed. In this subgroup (n = 93), 43 patients (46.2%) were Gleason score (GS) ≤ 6, 44 (47.3%) GS 7, and 6 (6.5%) GS ≥ 8; clinical stage was cT1 in 51 (54.8%), cT2 in 35 (39.3%), and cT3 in one patient (1.1%); PSA was < 10 ng/mL in 58 (63%) patients, 10-20 ng/mL in 28 (30.6%), and ≥ 20 ng/mL in 6 (6.4%) patients. No differences were found in BFFS in this patient subset versus the entire cohort of patients (P = 0.66). At a median follow-up of 113 months (range, 4-233), 5- and 10-year BFFS rates were 78.8% and 73.7%, respectively, with OS rates of 93.3% and 81.4%. The 5-year BFFS rates in three groups were as follows: 69.6% (66-68 Gy), 80.5% (70 Gy) and 82.6% (72 Gy) (P = 0.12):the corresponding 10-year rates were 63.9%, 72.9%, and 82.6% (P = 0.12), respectively. No significant between-group differences were observed in MFS, CSS, or OS. On the univariate analysis, the following variables were significantly associated with BFFS: PSA at diagnosis; clinical stage (cT1 vs cT2); GS at diagnosis; treatment indication (ART vs SRT); pre-RT PSA levels; and RT dose 66 -68 Gy vs. 72 Gy (HR: 2.05; 95%CI: 1.02-4.02, P = 0.04). On the multivariate analysis, the following variables remained significant: biopsy GS (HR: 2.85; 95%CI: 1.83-4.43, P < 0.001); clinical stage (HR: 2.31; 95%CI: 1.47-4.43, P = 0.01); and treatment indication (HR: 4.11; 95%CI: 2.06-8.17, P < 0.001). Acute grade (G) 1 GU toxicity was observed in 11 (20.4%), 17 (19.8%), and 3 (8.3%) patients in each group (66-68 Gy, 70 Gy and 72 Gy), respectively (P = 0.295). Acute G2 toxicity was observed in 2 (3.7%), 4 (4.7%) and 2 (5.6%) patients, respectively (P = 0.949). Acute G1 GI toxicity was observed in 16 (29.6%), 23 (26.7%) and 2 (5.6%) patients in each group, respectively (P = 0.011). Acute G2 GI toxicity was observed in 2 (3.7%), 6 (6.9%) and 1 (2.8%) patients, respectively (P = 0.278). No cases of acute G3 GI toxicity were observed. CONCLUSION: The findings of this retrospective study suggest that postoperative radiotherapy dose intensification in PCa is not superior to conventional radiotherapy treatment.

Water-Based Dynamic Depsipeptide Chemistry: Building Block Recycling and Oligomer Distribution Control Using Hydration-Dehydration Cycles.

The high kinetic barrier to amide bond formation has historically placed narrow constraints on its utility in reversible chemistry applications. Slow kinetics has limited the use of amides for the generation of diverse combinatorial libraries and selection of target molecules. Current strategies for peptide-based dynamic chemistries require the use of nonpolar co-solvents or catalysts or the incorporation of functional groups that facilitate dynamic chemistry between peptides. In light of these limitations, we explored the use of depsipeptides: biorelevant copolymers of amino and hydroxy acids that would circumvent the challenges associated with dynamic peptide chemistry. Here, we describe a model system of N-(α-hydroxyacyl)-amino acid building blocks that reversibly polymerize to form depsipeptides when subjected to two-step evaporation-rehydration cycling under moderate conditions. The hydroxyl groups of these units allow for dynamic ester chemistry between short peptide segments through unmodified carboxyl termini. Selective recycling of building blocks is achieved by exploiting the differential hydrolytic lifetimes of depsipeptide amide and ester bonds, which we show are controllable by adjusting the solution pH, temperature, and time as well as the building blocks' side chains. We demonstrate that the polymerization and breakdown of the depsipeptides are facilitated by cyclic morpholinedione intermediates, and further show how structural properties dictate half-lives and product oligomer distributions using multifunctional building blocks. These results establish a cyclic mode of ester-based reversible depsipeptide formation that temporally separates the polymerization and depolymerization steps for the building blocks and may have implications for prebiotic polymer chemical evolution.

Selective Oxidations in the Synthesis of Complex Natural ent-Kauranes and ent-Beyeranes.

Syntheses of two natural products derived from the ent-kaurene kaurenoic acid are described for the first time using regio- and diastereoselective oxidations. Palladium- and manganese-mediated oxidations were used to accomplish the syntheses of two ent-beyerane metabolites. The use of the White-Gormisky-Zhao catalyst Mn(CF3-PDP) enabled the first application of a nondirected metal-catalyzed oxidation in an unactivated C-H bond in a total synthesis.

Misdiagnoses in a Brazilian population with amyotrophic lateral sclerosis / Erros de diagnóstico em uma população brasileira com esclerose lateral amiotrófica

Abstract Background Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects the upper and lower motor neurons. The correct diagnosis at the onset of the disease is sometimes very difficult, due to the symptoms being very similar to those of other neurological syndromes. Objective This study aimed to analyze the initial manifestations, the specialty of the first physician visited due the initial complaint, the misdiagnoses, as well as the unnecessary surgical interventions in a new ALS Brazilian population. Methods The medical records of 173 patients with typical ALS were reviewed. Results The present study demonstrated that other symptoms, besides weakness, were very frequent as initial presentation of ALS, and orthopedics was the medical specialty most sought by patients at the onset of symptoms. Our frequency of misdiagnoses was 69.7%, and in 7.1% of them, an unnecessary surgical intervention was performed. Conclusions Amyotrophic lateral sclerosis presents a very large pool of signs and symptoms; therefore, there is an urgent need of increasing the disease awareness to other specialties due to the high frequency of misdiagnoses observed in clinical practice.

Resumo Antecedentes A esclerose lateral amiotrófica (ELA) é uma doença neurodegenerativa que afeta os neurônios motores superior e inferior. O diagnóstico correto no início da doença é, às vezes, muito difícil, pois os sintomas de início são muito semelhantes aos de outras síndromes neurológicas. Objetivo Este estudo teve como objetivo analisar as manifestações iniciais, a especialidade do primeiro médico visitado devido à queixa inicial, os diagnósticos errôneos, bem como as intervenções cirúrgicas desnecessárias em uma nova população brasileira acometida por ELA. Métodos Os prontuários médicos de 173 pacientes com ELA típica foram revisados. Resultados O presente estudo demonstrou que outros sintomas, além da fraqueza, foram muito frequentes como apresentação inicial da ELA, sendo a ortopedia a especialidade médica mais procurada pelos pacientes no início dos sintomas. Nossa frequência de diagnósticos errôneos foi de 69,7%, e em 7,1% deles foi realizada intervenção cirúrgica desnecessária. Conclusões A ELA apresenta um conjunto amplo de sinais e sintomas; portanto, há necessidade urgente de uma melhor educação de outras especialidades devido à alta frequência de diagnósticos equivocados observada na prática clínica.

Evaluating blinatumomab implementation in low- and middle-income countries: a study protocol.

BACKGROUND: The recent implementation of novel therapies has accelerated progress in pediatric cancer care. Despite the significantly poorer survival of patients in low- and middle-income countries (LMICs), administation complexities and other significant resource barriers have limited the translation of these novel therapies in these regions. This study aims to develop a model that can be used to support the implementation of novel therapies, such as blinatumomab (bispecific antibody therapy for B-cell acute lymphoblastic leukemia [B-ALL]) in LMIC centers, with the long-term goal of developing an implementation framework for similar future efforts. METHODS: In this study, mixed methods will be applied to understand the key contextual considerations that can be accounted for through a training program and prospectively designed implementation activities. The Consolidated Framework for Implementation Research will guide the activities related to implementation evaluation in parallel with a drug donation program. A multidisciplinary research team comprising high- and low-middle income healthcare professionals, industry, and implementation scientists has been assembled with the common goal of improving safe access to blinatumomab. To assess the factors affecting blinatumomab administration, semi-structured interviews with diverse collaborators and quantitative assessments of organizational characteristics will be conducted, together with quantitative and qualitative assessments of feasibility, acceptability, appropriateness, and cost of blinatumomab implementation. A quantitative assessment of stakeholder perceptions of different implementation strategies used as part of the multifaceted approach will also be performed. Finally, we will examine the key domains and processes used and construct the implementation roadmap for translation of novel therapies. DISCUSSION: This study will rigorously develop an implementation roadmap for translation of novel therapies in low-resource settings. The knowledge gained in the formative assessment will reveal the priority areas and key implementation strategies. Thereby, the resultant roadmap will facilitate future scale-out strategies for novel therapies in LMICs, thus increasing access, building capacity for management, and ultimately improving the care for children in LMICs.

Health Equity in Pediatric Drug Development: Translating Aspiration into Operation.

The concept of health equity-the attainment of the highest possible level of health for all members of society-requires equitable access to all aspects of healthcare, including pediatric drug development. However, many communities are under-represented in pediatric drug development programs. Barriers to participation include geographic, economic, racial/ethnic bias, legal, cultural, linguistic, and other factors. While there is no "one size fits all" approach to addressing these barriers, community engagement and collaboration is recognized by the Centers for Disease Control, the World Health Organization, and other global health organizations as a cornerstone for building a more equitable healthcare system. In this article, we will present case studies of stakeholder and community engagement in clinical research for rare diseases and other areas of healthcare, as examples of strategies and practices for actively involving under-represented communities and fostering their participation in pediatric drug development programs. These studies may serve as templates for facilitating equity in pediatric drug development from aspiration into operation.

Risk factors associated with metastatic site failure in patients with high-risk neuroblastoma.

Purpose: This retrospective study sought to identify predictors of metastatic site failure (MSF) at new and/or original (present at diagnosis) sites in high-risk neuroblastoma patients. Methods and materials: Seventy-six high-risk neuroblastoma patients treated on four institutional prospective trials from 1997 to 2014 with induction chemotherapy, surgery, myeloablative chemotherapy, stem-cell rescue, and were eligible for consolidative primary and metastatic site (MS) radiotherapy were eligible for study inclusion. Computed-tomography and I-123 MIBG scans were used to assess disease response and Curie scores at diagnosis, post-induction, post-transplant, and treatment failure. Outcomes were described using the Kaplan-Meier estimator. Cox proportional hazards frailty (cphfR) and CPH regression (CPHr) were used to identify covariates predictive of MSF at a site identified either at diagnosis or later. Results: MSF occurred in 42 patients (55%). Consolidative MS RT was applied to 30 MSs in 10 patients. Original-MSF occurred in 146 of 383 (38%) non-irradiated and 18 of 30 (60%) irradiated MSs (p = 0.018). Original- MSF occurred in post-induction MIBG-avid MSs in 68 of 81 (84%) non-irradiated and 12 of 14 (85%) radiated MSs (p = 0.867). The median overall and progression-free survival rates were 61 months (95% CI 42.6-Not Reached) and 24.1 months (95% CI 16.5-38.7), respectively. Multivariate CPHr identified inability to undergo transplant (HR 32.4 95%CI 9.3-96.8, p < 0.001) and/or maintenance chemotherapy (HR 5.2, 95%CI 1.7-16.2, p = 0.005), and the presence of lung metastases at diagnosis (HR 4.4 95%CI 1.7-11.1, p = 0.002) as predictors of new MSF. The new MSF-free survival rate at 3 years was 25% and 87% in patients with and without high-risk factors. Conclusions: Incremental improvements in systemic therapy influence the patterns and type of metastatic site failure in neuroblastoma. Persistence of MIBG-avidity following induction chemotherapy and transplant at MSs increased the hazard for MSF.