PIONEER-Panc: a platform trial for phase II randomized investigations of new and emerging therapies for localized pancreatic cancer

Background Personalized and effective treatments for pancreatic ductal adenocarcinoma (PDAC) continue to remain elusive. Novel clinical trial designs that enable continual and rapid evaluation of novel therapeutics are needed. Here, we describe a platform clinical trial to address this unmet need. Methods This is a phase II study using a Bayesian platform design to evaluate multiple experimental arms against a control arm in patients with PDAC. We first separate patients into three clinical stage groups of localized PDAC (resectable, borderline resectable, and locally advanced disease), and further divide each stage group based on treatment history (treatment naïve or previously treated). The clinical stage and treatment history therefore define 6 different cohorts, and each cohort has one control arm but may have one or more experimental arms running simultaneously. Within each cohort, adaptive randomization rules are applied and patients will be randomized to either an experimental arm or the control arm accordingly. The experimental arm(s) of each cohort are only compared to the applicable cohort specific control arm. Experimental arms may be added independently to one or more cohorts during the study. Multiple correlative studies for tissue, blood, and imaging are also incorporated. Discussion To date, PDAC has been treated as a single disease, despite knowledge that there is substantial heterogeneity in disease presentation and biology. It is recognized that the current approach of single arm phase II trials and traditional phase III randomized studies are not well-suited for more personalized treatment strategies in PDAC. The PIONEER Panc platform clinical trial is designed to overcome these challenges and help advance our treatment strategies for this deadly disease. Trial registration This study is approved by the Institutional Review Board (IRB) of MD Anderson Cancer Center, IRB-approved protocol 2020-0075. The PIONEER trial is registered at the US National Institutes of Health (ClinicalTrials.gov) NCT04481204.

Risk factors associated with drug-resistant tuberculosis in prisons in Sāo Paulo State, Brazil (2006-2016)

Introduction: Prisons are high-risk settings for drug-resistant tuberculosis because the prevalence of the tuberculosis (TB) is much higher than in the general population. This study to investigated the factors associated with drug-resistant tuberculosis in prisons in the state of São Paulo, Brazil. Methodology: Retrospective cohort of drug-resistant TB cases for incarcerated people in São Paulo state, reported in the Tuberculosis Patient Control System between 2006 and 2016. To analyze the factors associated with drug-resistant TB, the backward method (likelihood ratio) was used, determining the adjusted odds ratio and respective 95%CI coefficients. Multiple models were proposed to adjust for potential confusion and interaction. The best fit model was selected based on the lowest Akaike information criterion coefficient. Results: In total, 473 drug-resistant tuberculosis cases were reported in the prison population of Sāo Paulo state, the majority were male. The cases that presented negative results for sputum smear and sputum culture had, respectively, an aOR=0.6 and aOR=0.16 for drug-resistant tuberculosis in relation to the cases with positive results. The cases where the patient had AIDS and reported alcoholism, respectively, an aOR=1.47 and aOR=1.60 for drug-resistant TB. Individuals with a background treatment history for TB presented a stronger association with drug-resistant tuberculosis, aOR=35.08. Conclusions: Sputum spear, sputum culture, chest X-ray, AIDS, alcoholism and background treatment history for TB were factors associated with resistance to antituberculosis drugs among prisoners. This is useful for the implementation of disease control measures related to the detection and monitoring of cases in the prison system.

Effect of refractive error type in the amblyopic eyes on factors for treatment success in anisometropic amblyopia

To investigate the factors for treatment success in anisometropic amblyopia according to the spherical equivalent (SE) type of amblyopic eyes. Medical records of 397 children with anisometropic amblyopia aged 3 to 12 years who presented in a secondary referral eye hospital during 2010 ~ 2016 were retrospectively reviewed. Anisometropia was defined as ≥ 1 diopter (D) difference in SE, or ≥ 1.5 D difference of cylindrical error between the eyes. According to the SE of amblyopic eyes, patients were categorized into hyperopia (SE ≥ 1D), emmetropia (− 1 < SE < + 1) and myopia (SE ≤ − 1D) groups. Treatment success was defined as achieving interocular logMAR visual acuity difference < 0.2. Multivariate logistic regression was used to analyze the factors for treatment success. Significant factors for the amblyopia treatment success in hyperopia group (n = 270) were younger age [adjusted odds ratio (aOR) (95% confidence interval, CI) = 0.529 (0.353, 0.792)], better BCVA in amblyopic eyes at presentation [aOR (95% CI) 0.004 (0, 0.096)], longer follow-up period [aOR (95%CI) = 1.098 (1.036, 1.162)], and no previous amblyopia treatment history [aOR (95% CI) 0.059 (0.010, 0.364)]. In myopia group (n = 68), younger age [aOR (95% CI) 0.440 (0.208, 0.928)] and better BCVA in amblyopic eyes [aOR (95% CI) 0.034 (0.003, 0.469)] were associated with higher odds of treatment success. There was no significant factor for treatment success in emmetropia group (n = 59) in this population. The refractive error type of amblyopic eyes at presentation affects the factors for treatment success in anisometropic amblyopia.

Effectiveness of Nifurtimox Eflornithine Combination Therapy (NECT) in T. b. gambiense second stage sleeping sickness patients in the Democratic Republic of Congo: Report from a field study

Background Nifurtimox-eflornithine combination therapy (NECT) for the treatment of second stage gambiense human African trypanosomiasis (HAT) was added to the World Health Organization’s Essential Medicines List in 2009 after demonstration of its non-inferior efficacy compared to eflornithine therapy. A study of NECT use in the field showed acceptable safety and high efficacy until hospital discharge in a wide population, including children, pregnant and breastfeeding women, and patients with a HAT treatment history. We present here the effectiveness results after the 24-month follow-up visit. Methodology/Principal findings In a multicenter, open label, single arm phase IIIb study, second stage gambiense HAT patients were treated with NECT in the Democratic Republic of Congo. Clinical cure was defined 24 months after treatment as survival without clinical and/or parasitological signs of HAT. Of the 629 included patients, 619 (98.4%) were discharged alive after treatment and were examined for the presence of trypanosomes, white blood cell count in cerebro-spinal fluid, and disease symptoms. The clinical cure rate of 94.1% was comparable for all subpopulations analyzed at the 24-month follow-up visit. Self-reported adverse events during follow-up were few and concerned mainly nervous system disorders, infections, and gastro-intestinal disorders. Overall, 28 patients (4.3%) died during the course of the trial. The death of 16 of the 18 patients who died during the follow-up period was assessed as unlikely or not related to NECT. Within 24 months, eight patients (1.3%) relapsed and received rescue treatment. Sixteen patients were completely lost to follow-up. Conclusions/Significance NECT treatment administered under field conditions was effective and sufficiently well tolerated, no major concern arose for children or pregnant or breastfeeding women. Patients with a previous HAT treatment history had the same response as those who were naïve. In conclusion, NECT was confirmed as effective and appropriate for use in a broad population, including vulnerable subpopulations. Trial registration The trial is registered at ClinicalTrials.gov, number NCT00906880.

Associations Between Relapses and Psychosocial Outcomes in Patients With Schizophrenia in Real-World Settings in the United States

Aim: To assess associations between relapses and psychosocial outcomes in adult patients with schizophrenia treated in United States (US) healthcare settings.Methods: Data were derived from a point-in-time survey of psychiatrists and their patients with schizophrenia conducted across the US, France, Spain, China, and Japan between July and October 2019. For the purposes of this analysis, only data from US practitioners and patients were included. Disease-specific programmes (DSPs) are large surveys with a validated methodology conducted in clinical practise; they describe current disease management, disease burden, and associated treatment effects (clinical and physician-perceived). Participating psychiatrists completed patient record forms for their next 10 consecutive adult consulting patients with schizophrenia, with the same patients invited to voluntarily complete a patient self-completion (PSC) questionnaire. Surveys contained questions on the patients' disease background, treatment history, prior hospitalisation due to schizophrenia relapse and a series of psychosocial outcomes. Associations between relapses in the last 12 months and psychosocial outcomes were examined using multiple regression.Results: A total of 124 psychiatrists provided data on 1,204 patients. Of these, 469 patients (mean age, 39.6 years; 56.5% male) had known hospitalisation history for the last 12 months and completed a PSC; 116 (24.7%) patients had ≥1 relapse. Compared to patients without relapses, patients who relapsed were more likely to be homeless, unemployed, previously incarcerated, and currently have difficulties living independently (all p &lt; 0.05). Patients who experience a relapse also had greater working impairment and poorer quality of life compared with those who did not relapse. In general, psychosocial outcomes became poorer with an increasing number of relapses.Conclusions: In this population of patients with schizophrenia from the US, relapse was significantly associated with poor psychosocial outcomes, with a greater number of relapses predicting worse outcomes. Early intervention to reduce the risk of relapse may improve psychosocial outcomes in patients with schizophrenia.

History of Methadone and Buprenorphine Opioid Agonist Therapy Among People Who Died of an Accidental Opioid-Involved Overdose: Rhode Island, January 1, 2018–June 30, 2020

To guide intervention efforts, we identified the proportion of individuals previously engaged in opioid agonist therapy among people who died of an accidental opioid-involved overdose. Most individuals (60.9%) had never received any prior buprenorphine or methadone treatment. Individuals who died of an overdose in 2020 had a similar demographic profile and treatment history compared with prior years. To prevent additional accidental opioid-involved overdose deaths, efforts should be directed toward linking individuals to care. (Am J Public Health. Published online ahead of print August 19, 2021: e1–e4. https://doi.org/10.2105/AJPH.2021.306395 )

Collaborative Care Improves Treatment Outcomes for Dogs with Chronic Otitis Externa: A Collaborative Care Coalition Study

ABSTRACT The purpose of this retrospective study was to compare outcome measures in dogs treated by a primary care veterinarian (pcDVM) before referral and after seeking collaboration with a board-certified veterinary dermatologist (BCVD) for cases of severe recurrent chronic otitis externa. Medical records of 65 client-owned dogs were retrospectively reviewed, and data were obtained regarding treatment history, referral timeframe, recurrence rate, clinical signs, and resolution of signs. The median number of otitis recurrences while under the care of the pcDVM was 4 (range 1–40) versus collaborative BCVD care of 2 (P &lt; .01). There was a longer median time to otitis recurrence with collaborative care (171 days) compared with dogs managed by the pcDVM before referral (21 days; P &gt; .01). Proliferative changes in the ear canals improved in 41/45 (91%) of cases under BCVD care compared with 6/45 (13%) under care by the pcDVM (P &lt; .01). Dogs with chronic otitis had better long-term outcomes when collaboration with a BCVD was pursued within 6 mo of treatment. Referral or consultation with a BCVD should be considered for cases of chronic canine otitis that are persistent or quickly recurrent (20–30 days) over a 6 mo period.