Association of Lateral Pelvic Lymph Nodes with Disease Recurrence and Organ Preservation in Patients with Distal Rectal Adenocarcinoma Treated with Total Neoadjuvant Therapy.

OBJECTIVE: Assess the significance of enlarged lateral lymph nodes (LLN) for disease recurrence, metastasis, and organ preservation in patients with rectal cancer. BACKGROUND: Optimal treatment of rectal adenocarcinoma involving LLN is subject to debate. METHODS: A post hoc analysis of the OPRA trial, a multicenter study of patients with rectal cancer treated with total neoadjuvant therapy (TNT) followed by total mesorectal excision or watch-and-wait management. We analyzed the association of visible LLN (LLN+), LLN≥7 mm (short axis) on baseline MRI, and LLN≥4 mm on restaging MRI with recurrence, metastasis, and rectum preservation. RESULTS: At baseline, 57 out of 324 (18%) patients had LLN+. In 30 (53%) of 57 patients with LLN+ on baseline MRI, the LLN disappeared after TNT. Disease recurrence in LLN was rare (3.5% of patients with LLN+ and 0.4% of patients with LLN-). All patients with recurrence in LLN also had distant metastasis. The rate of organ preservation was significantly lower in patients with LLN≥4 mm on restaging MRI (P=0.013). We found no significant differences in rates of local recurrence or metastasis between patients with LLN+ vs. LLN- and in patients with LLN≥7 vs.<7 mm on baseline MRI. LLN dissection was performed in 3 patients; 2 of them died of distant metastasis. CONCLUSIONS: LLN involvement is not associated with disease recurrence or metastasis, but persistence of LLN≥4 mm after TNT is negatively associated with rectum preservation in patients with locally advanced rectal cancer treated with TNT. Dissection of lateral nodes likely benefits few patients.

Potentially Modifiable Risk Factors for Dementia and Mild Cognitive Impairment: An Umbrella Review and Meta-Analysis.

INTRODUCTION: The prevalence of mild and major neurocognitive disorders (NCDs), also referred to as mild cognitive impairment and dementia, is rising globally. The prevention of NCDs is a major global public health interest. We sought to synthesize the literature on potentially modifiable risk factors for NCDs. METHODS: We conducted an umbrella review using a systematic search across multiple databases to identify relevant systematic reviews and meta-analyses. Eligible reviews examined potentially modifiable risk factors for mild or major NCDs. We used a random-effects multi-level meta-analytic approach to synthesize risk ratios for each risk factor while accounting for overlap in the reviews. We further examined risk factors for major NCD due to two common etiologies: Alzheimer's disease and vascular dementia. RESULTS: A total of 45 reviews with 212 meta-analyses were synthesized. We identified fourteen broadly defined modifiable risk factors that were significantly associated with these disorders: alcohol consumption, body weight, depression, diabetes mellitus, diet, hypertension, less education, physical inactivity, sensory loss, sleep disturbance, smoking, social isolation, traumatic brain injury, and vitamin D deficiency. All 14 factors were associated with the risk of major NCD, and five were associated with mild NCD. We found considerably less research for vascular dementia and mild NCD. CONCLUSION: Our review quantifies the risk associated with 14 potentially modifiable risk factors for mild and major NCDs, including several factors infrequently included in dementia action plans. Prevention strategies should consider approaches that reduce the incidence and severity of these risk factors through health promotion, identification, and early management.

Organ Preservation and Survival by Clinical Response Grade in Patients With Rectal Cancer Treated With Total Neoadjuvant Therapy: A Secondary Analysis of the OPRA Randomized Clinical Trial.

Importance: Assessing clinical tumor response following completion of total neoadjuvant therapy (TNT) in patients with locally advanced rectal cancer is paramount to select patients for watch-and-wait treatment. Objective: To assess organ preservation (OP) and oncologic outcomes according to clinical tumor response grade. Design, Setting, and Participants: This was secondary analysis of the Organ Preservation in Patients with Rectal Adenocarcinoma trial, a phase 2, nonblinded, multicenter, randomized clinical trial. Randomization occurred between April 2014 and March 2020. Eligible participants included patients with stage II or III rectal adenocarcinoma. Data analysis occurred from March 2022 to July 2023. Intervention: Patients were randomized to induction chemotherapy followed by chemoradiation or chemoradiation followed by consolidation chemotherapy. Tumor response was assessed 8 (±4) weeks after TNT by digital rectal examination and endoscopy and categorized by clinical tumor response grade. A 3-tier grading schema that stratifies clinical tumor response into clinical complete response (CCR), near complete response (NCR), and incomplete clinical response (ICR) was devised to maximize patient eligibility for OP. Main Outcomes and Measures: OP and survival rates by clinical tumor response grade were analyzed using the Kaplan-Meier method and log-rank test. Results: There were 304 eligible patients, including 125 patients with a CCR (median [IQR] age, 60.6 [50.4-68.0] years; 76 male [60.8%]), 114 with an NCR (median [IQR] age, 57.6 [49.1-67.9] years; 80 male [70.2%]), and 65 with an ICR (median [IQR] age, 55.5 [47.7-64.2] years; 41 male [63.1%]) based on endoscopic imaging. Age, sex, tumor distance from the anal verge, pathological tumor classification, and clinical nodal classification were similar among the clinical tumor response grades. Median (IQR) follow-up for patients with OP was 4.09 (2.99-4.93) years. The 3-year probability of OP was 77% (95% CI, 70%-85%) for patients with a CCR and 40% (95% CI, 32%-51%) for patients with an NCR (P < .001). Clinical tumor response grade was associated with disease-free survival, local recurrence-free survival, distant metastasis-free survival, and overall survival. Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, most patients with a CCR after TNT achieved OP, with few developing tumor regrowth. Although the probability of tumor regrowth was higher for patients with an NCR compared with patients with a CCR, a significant proportion of patients achieved OP. These findings suggest the 3-tier grading schema can be used to estimate recurrence and survival outcomes in patients with locally advanced rectal cancer who receive TNT. Trial Registration: ClinicalTrials.gov Identifier: NCT02008656.

Long-Term Results of Organ Preservation in Patients With Rectal Adenocarcinoma Treated With Total Neoadjuvant Therapy: The Randomized Phase II OPRA Trial.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.To assess long-term risk of local tumor regrowth, we report updated organ preservation rate and oncologic outcomes of the OPRA trial (ClinicalTrials.gov identifier: NCT02008656). Patients with stage II/III rectal cancer were randomly assigned to receive induction chemotherapy followed by chemoradiation (INCT-CRT) or chemoradiation followed by consolidation chemotherapy (CRT-CNCT). Patients who achieved a complete or near-complete response after finishing treatment were offered watch-and-wait (WW). Total mesorectal excision (TME) was recommended for those who achieved an incomplete response. The primary end point was disease-free survival (DFS). The secondary end point was TME-free survival. In total, 324 patients were randomly assigned (INCT-CRT, n = 158; CRT-CNCT, n = 166). Median follow-up was 5.1 years. The 5-year DFS rates were 71% (95% CI, 64 to 79) and 69% (95% CI, 62 to 77) for INCT-CRT and CRT-CNCT, respectively (P = .68). TME-free survival was 39% (95% CI, 32 to 48) in the INCT-CRT group and 54% (95% CI, 46 to 62) in the CRT-CNCT group (P = .012). Of 81 patients with regrowth, 94% occurred within 2 years and 99% occurred within 3 years. DFS was similar for patients who underwent TME after restaging (64% [95% CI, 53 to 78]) and patients in WW who underwent TME after regrowth (64% [95% CI, 53 to 78]; P = .94). Updated analysis continues to show long-term organ preservation in half of the patients with rectal cancer treated with total neoadjuvant therapy. In patients who enter WW, most cases of tumor regrowth occur in the first 2 years.

Morbidity and Outcomes of Primary Tumor Management in Patients with Widely Metastatic Well-Differentiated Small Bowel Neuroendocrine Tumors.

BACKGROUND: The benefit of primary tumor resection in distant metastatic small bowel neuroendocrine tumors (SBNETs) is controversial, with treatment-based morbidity not well-defined. We aimed to determine the impact of primary tumor resection on development of disease-specific complications in patients with metastatic well-differentiated SBNETs. PATIENTS AND METHODS: A retrospective analysis was performed of patients diagnosed with metastatic well-differentiated jejunal/ileal SBNETs at a single tertiary care cancer center from 1980 to 2016. Outcomes were compared on the basis of treatment selected at diagnosis between patients who underwent initial medical treatment or primary tumor resection. RESULTS: Among 180 patients, 71 underwent medical management and 109 primary tumor resection. Median follow-up was 116 months. Median event-free survival did not differ between treatment approaches (log-rank p = 0.2). In patients medically managed first, 16/71 (23%) required surgery due to obstruction, perforation, or bleeding. These same complications led to resection at presentation in 31/109 (28%) surgically treated patients. Development of an obstruction from the primary tumor was not associated with disease progression/recurrence (HR 1.14, 95% CI 0.75-1.75) with all patients recovering postoperatively. Ongoing tumor progression requiring secondary laparotomy was associated with worse mortality (HR 7.51, 95% CI 3.3-16.9; p < 0.001) and occurred in 20/109 (18%) primary tumor resection and 7/16 (44%) initially medically treated patients. CONCLUSIONS: Rates of event-free survival among patients with metastatic SBNETs do not differ on the basis of primary tumor management. The development of an obstruction from the primary tumor was not associated with worse outcomes with all patients salvaged. Regardless of initial treatment selected, patients with metastatic SBNET should be closely followed for early signs of primary tumor complications.

Endoscopic Predictors of Residual Tumor After Total Neoadjuvant Therapy: A Post Hoc Analysis From the Organ Preservation in Rectal Adenocarcinoma Trial.

BACKGROUND: Restaging endoscopy plays a critical role in selecting patients with locally advanced rectal cancer who respond to neoadjuvant therapy for nonoperative management. OBJECTIVE: This study evaluated the restaging endoscopic features that best predict the presence of residual tumor in the bowel wall. DESIGN: This was a post hoc analysis of a prospective randomized trial. SETTINGS: The Organ Preservation in Rectal Adenocarcinoma Trial randomly assigned patients across 18 institutions with stage II/III rectal adenocarcinoma to receive either induction or consolidation total neoadjuvant therapy. Surgeons completed a restaging tumor assessment form, which stratified patients across 3 tiers of clinical response. PATIENTS: Patients enrolled in the Organ Preservation in Rectal Adenocarcinoma Trial with a completed tumor assessment form were included. MAIN OUTCOME MEASURES: The main outcome was residual tumor, which was defined as either an incomplete clinical response or local tumor regrowth within 2 years of restaging. Independent predictors of residual tumor were identified using backward-selected multivariable logistic regression analysis. Subgroup analyses for complete and near complete clinical responders were performed. RESULTS: Surgeons completed restaging forms for 263 patients at a median of 7.7 weeks after neoadjuvant therapy; 128 patients (48.7%) had a residual tumor. On multivariable regression analysis, several characteristics of a near complete response, including ulcer (OR 6.66; 95% CI, 2.54-19.9), irregular mucosa (OR 3.66; 95% CI, 1.61-8.68), and nodularity (OR 2.96; 95% CI, 1.36-6.58), remained independent predictors of residual tumor. A flat scar was associated with lower odds of harboring residual disease (OR 0.32; 95% CI, 0.11-0.93) for patients categorized as clinical complete responders. LIMITATIONS: Limitations include analysis of endoscopic features at a single time point and ambiguities in tumor assessment form response criteria. CONCLUSIONS: Patients with ulcer, nodularity, or irregular mucosa, on restaging endoscopy have higher odds of residual tumor. Recognizing negative prognostic implications of these features will help surgeons better select candidates for nonoperative management and suggests that patients with high-risk characteristics would benefit from close interval surveillance. See Video Abstract . PREDICTORES ENDOSCPICOS DE TUMOR RESIDUAL DESPUS DE TERAPIA NEOADYUVANTE TOTAL UN ANLISIS POST HOC DEL ENSAYO DE PRESERVACIN DE RGANOS EN ADENOCARCINOMA RECTAL: ANTECEDENTES:La reestadificación por endoscopia juega un papel crítico en la selección de pacientes con cáncer de recto localmente avanzado que responden a la terapia neoadyuvante para el manejo no quirúrgico.OBJETIVO:Este estudio evaluó las características endoscópicas de reestadificación que mejor predicen la presencia de tumor residual en la pared intestinal.DISEÑO:Este fue un análisis post hoc de un ensayo prospectivo aleatorizado.ESCENARIO:El ensayo Organ Preservation in Rectal Adenocarcinoma aleatorizó a pacientes de 18 instituciones con adenocarcinoma de recto en estadio II/III para recibir terapia neoadyuvante total de inducción o consolidación. Los cirujanos completaron un formulario de reestadificación de evaluación del tumor, que estratificó a los pacientes en tres niveles de respuesta clínica.PACIENTES:Se incluyeron pacientes inscritos en el ensayo de preservación de órganos en adenocarcinoma rectal con un formulario de evaluación del tumor completado.PRINCIPALES MEDIDAS DE RESULTADO:El resultado principal fue presencia de tumor residual, que se definió como una respuesta clínica incompleta o un nuevo crecimiento local del tumor dentro de los dos años posteriores a la reestadificación. Los predictores independientes de tumor residual se identificaron mediante un análisis de regresión logística multivariable seleccionado hacia atrás. Se realizaron análisis de subgrupos para pacientes con respuesta clínica completa y casi completa.RESULTADOS:Los cirujanos completaron formularios de reestadificación para 263 pacientes en una mediana de 7.7 semanas después de la terapia neoadyuvante; 128 (48.7%) tenían tumor residual. En el análisis de regresión multivariable, varias características de una respuesta casi completa, incluyendo úlcera (OR 6.66; IC 95% 2.54-19.9), mucosa irregular (OR 3.66; IC 95% 1.61-8.68) y nodularidad (OR 2.96; IC 95% 1.36 -6.58) siguieron siendo predictores independientes de tumor residual. Una cicatriz plana se asoció con menores probabilidades de albergar enfermedad residual (OR 0.32; IC del 95 %: 0.11-0.93) para los pacientes clasificados como respondedores clínicos completos.LIMITACIONES:Las limitaciones de este estudio incluyen el análisis de las características endoscópicas en un solo momento y las ambigüedades en los criterios de respuesta.en la forma de evaluación del tumorCONCLUSIONES:Los pacientes con úlcera, nodularidad o mucosa irregular en la endoscopia de reestadificación tienen mayores probabilidades de tumor residual. El reconocer las implicaciones pronósticas negativas de estas características ayudará a los cirujanos a seleccionar mejor a los candidatos para el tratamiento no quirúrgico y sugiere que los pacientes con características de alto riesgo se beneficiarían de una vigilancia a intervalos estrechos. (Traducción-Dr. Jorge Silva Velazco ).

Nonoperative management of the primary tumor in patients with unresectable stage IV colon cancer treated with systemic chemotherapy: Higher complication rates for left-sided colon tumors.

INTRODUCTION: Treatment of the primary tumor in asymptomatic patients with unresectable colorectal metastases remains controversial. METHODS: Data from patients with synchronous stage IV colon cancer and an untreated primary tumor who started treatment aimed at metastatic disease at a specialized cancer center between 2014 and 2018 were analyzed retrospectively. Main outcome was primary tumor-related complications comparing left-sided and right-sided colon cancer. A competing-risk regression model was used to identify predictors of complications. RESULTS: Of 523 patients with metastatic colon cancer at presentation, 221 started treatment aimed at metastatic disease; these patients constituted the study cohort. The primary tumor was left-sided in 109 patients (49%) and right-sided in 112 patients (51%). In total, 46 patients (21%) developed a complication that required invasive intervention. Complications occurred more frequently in patients with left-sided tumors than in patients with right-sided tumors (29% vs 13%, P = 0.003). Eighteen patients (8%) underwent non-surgical intervention. Six patients (33%) failed non-surgical management and underwent surgery. Of 34 patients (15%) who underwent surgical intervention, 20 underwent an emergency colectomy and 14 underwent diversion with a permanent stoma. Overall, 10% of patients ended up with a permanent stoma. In competing-risk analysis, only left-sided primary tumor (hazard ratio 2.62; 95% CI 1.40-4.89; P = 0.003) was significantly associated with primary tumor-related complications requiring invasive intervention. CONCLUSIONS: Patients with asymptomatic metastatic left-sided tumors have a higher risk for primary tumor-related complications than patients with right-sided tumors. Close monitoring and early surgical rescue should be considered for patients with left-sided colon cancer who are managed nonoperatively.

Compliance and Toxicity of Total Neoadjuvant Therapy for Rectal Cancer: A Secondary Analysis of the OPRA Trial.

PURPOSE: Patients with locally advanced rectal cancer treated with total neoadjuvant therapy (TNT) may achieve organ preservation without a compromise to oncologic outcomes. However, reports on patient compliance with TNT and with treatment-related toxicities are limited. METHODS AND MATERIALS: The OPRA trial assessed organ preservation rates and oncologic outcomes in patients with clinical stage II/III rectal adenocarcinoma randomized to induction chemotherapy followed by chemoradiation (INCT-CRT) or chemoradiation followed by consolidation chemotherapy (CRT-CNCT). Systemic chemotherapy consisted of 8 cycles (16 weeks) of fluorouracil, leucovorin, and oxaliplatin (FOLFOX) or 5 cycles (15 weeks) of capecitabine and oxaliplatin (CAPEOX). Patients received >4500 cGy of radiation with sensitizing capecitabine or fluorouracil. In this report, we compare compliance and treatment-related toxicity in patients receiving INCT-CRT versus CRT-CNCT. Additionally, we evaluate the association of compliance to chemotherapy, compliance to chemoradiation, and toxicity with organ preservation and disease-free survival (DFS). RESULTS: Of the 324 patients randomized, fewer patients started chemoradiation in the INCT-CRT group compared with the CRT-CNCT group (93% vs 98%, P = .03), and fewer patients started systemic chemotherapy in the CRT-CNCT group compared with the INCT-CRT group (94% vs 99%, P = .04). Order of TNT did not affect the ability to complete all intended cycles of FOLFOX (86% INCT-CRT vs 83% CRT-CNCT, P = .60) or CAPEOX (74% INCT-CRT vs 77% CRT-CNCT, P = .80). A total of 97% of INCT and 98% of CRT-CNCT patients received >4500 cGy radiation (P = .93). Sixty-four patients (41%) treated with INCT-CRT and 57 CRT-CNCT patients (34%) experienced a grade 3+ adverse event (P = .30). Compliance and toxicity were not associated with organ preservation or DFS. CONCLUSIONS: We identified only minor differences in treatment compliance between patients treated with INCT-CRT and CRT-CNCT. No difference in adverse events was observed between groups. Treatment compliance and toxicity did not correlate with organ preservation rates or DFS.

Effect of perioperative benzodiazepine use on intraoperative awareness and postoperative delirium: a systematic review and meta-analysis of randomised controlled trials and observational studies.

BACKGROUND: Benzodiazepine use is associated with delirium, and guidelines recommend avoiding them in older and critically ill patients. Their perioperative use remains common because of perceived benefits. METHODS: We searched CENTRAL, MEDLINE, CINAHL, PsycInfo, and Web of Science from inception to June 2021. Pairs of reviewers identified randomised controlled trials and prospective observational studies comparing perioperative use of benzodiazepines with other agents or placebo in patients undergoing surgery. Two reviewers independently abstracted data, which we combined using a random-effects model. Our primary outcomes were delirium, intraoperative awareness, and mortality. RESULTS: We included 34 randomised controlled trials (n=4354) and nine observational studies (n=3309). Observational studies were considered separately. Perioperative benzodiazepines did not increase the risk of delirium (n=1352; risk ratio [RR] 1.43; 95% confidence interval [CI]: 0.9-2.27; I2=72%; P=0.13; very low-quality evidence). Use of benzodiazepines instead of dexmedetomidine did, however, increase the risk of delirium (five studies; n=429; RR 1.83; 95% CI: 1.24-2.72; I2=13%; P=0.002). Perioperative benzodiazepine use decreased the risk of intraoperative awareness (n=2245; RR 0.26; 95% CI: 0.12-0.58; I2=35%; P=0.001; very low-quality evidence). When considering non-events, perioperative benzodiazepine use increased the probability of not having intraoperative awareness (RR 1.07; 95% CI: 1.01-1.13; I2=98%; P=0.03; very low-quality evidence). Mortality was reported by one randomised controlled trial (n=800; RR 0.90; 95% CI: 0.20-3.1; P=0.80; very low quality). CONCLUSIONS: In this systematic review and meta-analysis, perioperative benzodiazepine use did not increase postoperative delirium and decreased intraoperative awareness. Previously observed relationships of benzodiazepine use with delirium could be explained by comparisons with dexmedetomidine. SYSTEMATIC REVIEW PROTOCOL: PROSPERO CRD42019128144.

Central Nervous System Disease in Patients With RET Fusion-Positive NSCLC Treated With Selpercatinib.

INTRODUCTION: Central nervous system (CNS) metastases develop in nearly half of patients with RET fusion-positive NSCLCs and cause morbidity and mortality. The selective RET inhibitor selpercatinib treats existing intracranial disease, but no studies have investigated whether early initiation of selpercatinib is associated with decreased development of CNS metastases. METHODS: A total of 61 patients with RET fusion-positive advanced NSCLC with and without CNS metastases treated with selpercatinib on the LIBRETTO-001 trial (NCT03157128) or the LIBRETTO-201 expanded access program (NCT03906331) were identified. Cumulative incidence rates (CIRs) for CNS metastases were assessed as an event of interest; systemic progression of disease and death were considered competing risks. RESULTS: The median age was 65 years, and the most common 5' fusion partners were KIF5B (67%) and CCDC6 (18%). There were 24 patients (39%) who received prior platinum chemotherapy and 20 patients (33%) who received prior multikinase inhibition. The median time on selpercatinib was 21.8 months. Furthermore, 30 patients (49%) had CNS disease at baseline and 31 patients (51%) had no baseline CNS disease. CIRs of CNS progression among patients with baseline CNS disease were 3% (95% confidence interval [CI]: 0%-10%), 10% (95% CI: 0%-22%), 17% (3%-30%), 17% (3%-30%), and 20% (5%-35%) at 6, 12, 18, 24, and 36 months, respectively. CIR for CNS progression among patients without baseline CNS disease was 0% at 6, 12, 18, 24, and 36 months (95% CI: 0%-0%). CONCLUSIONS: CNS progression was not observed with selpercatinib therapy in patients without baseline CNS disease. CNS progression on selpercatinib was rare in patients with baseline CNS disease. Early initiation of selpercatinib is associated with decreased rates of CNS metastasis formation and progression and may play a preventive role.

Pancreatic cancer: Cutaneous metastases, clinical descriptors and outcomes.

BACKGROUND: Cutaneous metastases in pancreatic cancer (PC) are rare. Herein, we evaluate the clinical, genomic, and other descriptors of patients with PC and cutaneous metastases. METHODS: Institutional databases were queried, and clinical history, demographics, PC cutaneous metastasis details, and overall survival (OS) from cutaneous metastasis diagnosis were abstracted. OS was estimated using Kaplan-Meier methods. RESULTS: Forty patients were identified, and median age (Q1-Q3, IQR) of PC diagnosis was 66.0 (59.3-72.3, 12.9) years. Most patients had Stage IV disease at diagnosis (n = 26, 65%). The most common location of the primary tumor was the tail of the pancreas (n = 17, 43%). The most common cutaneous metastasis site was the abdomen (n = 31, 78%), with umbilical lesions occurring in 74% (n = 23) of abdominal lesions. The median OS (95% CI) was 11.4 months (7.0, 20.4). Twenty-three patients had umbilical metastases (58%), and 17 patients had non-umbilical metastases (43%). The median OS (95% CI) was 13.7 (7.0, 28.7) months in patients with umbilical metastases and 8.9 (4.1, Not reached) months in patients with non-umbilical metastases (p = 0.1). Sixteen of 40 (40%) patients underwent somatic testing, and findings were consistent with known profiles. Germline testing in 12 (30%) patients identified pathogenic variants in patients: CHEK2, BRCA1, and ATM. CONCLUSION: Cutaneous metastases from PC most frequently arise from a pancreas tail primary site and most frequently occur in the umbilicus. Cutaneous metastases may generally be categorized as umbilical or non-umbilical metastases.

Pre-treatment with antiarrhythmic drugs for elective electrical cardioversion of atrial fibrillation: a systematic review and network meta-analysis.

AIMS: Our objective was to compare the efficacy of pre-treatment with different classes of anti-arrhythmic drugs (AADs) in patients with atrial fibrillation (AF) undergoing electrical cardioversion. METHODS AND RESULTS: We performed a systematic review and network meta-analysis (NMA) of randomized controlled trials (RCTs) comparing different AADs in patients with AF undergoing electrical cardioversion. We grouped AADs into five network nodes: no treatment or rate control, Class Ia, Class Ic, Class III, and amiodarone. Outcomes were (i) acute restoration and (ii) maintenance of sinus rhythm. We searched MEDLINE and EMBASE from inception until June 2020. We used Python 3.8.3 and R 3.6.2 for data analysis. We evaluated the overall certainty of evidence with the GRADE framework. We included 28 RCTs. Compared with no treatment or rate control, Class III AADs [odds ratio (OR): 2.41; 95% credible interval (CrI): 1.37 to 4.62, high certainty] and amiodarone (OR: 2.58; 95% CrI: 1.54 to 4.37, high certainty) improved restoration of sinus rhythm. Amiodarone improved long-term maintenance of sinus rhythm when compared with no treatment or rate control (OR: 5.37; 95% CrI: 4.00-7.39, high certainty), Class Ic (OR: 1.89; 95% CrI: 1.05-3.45, moderate certainty) and Class III AADs (OR: 2.19; 95% CrI: 1.39-3.26, high certainty). CONCLUSION: Before electrical cardioversion of AF, treatment with Class III AADs or amiodarone improves the acute restoration of sinus rhythm. Amiodarone is most likely to improve the maintenance of sinus rhythm after electrical cardioversion, but Class Ic and Class III AADs are also effective.

Organ Preservation in Patients With Rectal Adenocarcinoma Treated With Total Neoadjuvant Therapy.

PURPOSE: Prospective data on the efficacy of a watch-and-wait strategy to achieve organ preservation in patients with locally advanced rectal cancer treated with total neoadjuvant therapy are limited. METHODS: In this prospective, randomized phase II trial, we assessed the outcomes of 324 patients with stage II or III rectal adenocarcinoma treated with induction chemotherapy followed by chemoradiotherapy (INCT-CRT) or chemoradiotherapy followed by consolidation chemotherapy (CRT-CNCT) and either total mesorectal excision (TME) or watch-and-wait on the basis of tumor response. Patients in both groups received 4 months of infusional fluorouracil-leucovorin-oxaliplatin or capecitabine-oxaliplatin and 5,000 to 5,600 cGy of radiation combined with either continuous infusion fluorouracil or capecitabine during radiotherapy. The trial was designed as two stand-alone studies with disease-free survival (DFS) as the primary end point for both groups, with a comparison to a null hypothesis on the basis of historical data. The secondary end point was TME-free survival. RESULTS: Median follow-up was 3 years. Three-year DFS was 76% (95% CI, 69 to 84) for the INCT-CRT group and 76% (95% CI, 69 to 83) for the CRT-CNCT group, in line with the 3-year DFS rate (75%) observed historically. Three-year TME-free survival was 41% (95% CI, 33 to 50) in the INCT-CRT group and 53% (95% CI, 45 to 62) in the CRT-CNCT group. No differences were found between groups in local recurrence-free survival, distant metastasis-free survival, or overall survival. Patients who underwent TME after restaging and patients who underwent TME after regrowth had similar DFS rates. CONCLUSION: Organ preservation is achievable in half of the patients with rectal cancer treated with total neoadjuvant therapy, without an apparent detriment in survival, compared with historical controls treated with chemoradiotherapy, TME, and postoperative chemotherapy.

Analysis of meiosis in Pristionchus pacificus reveals plasticity in homolog pairing and synapsis in the nematode lineage.

Meiosis is conserved across eukaryotes yet varies in the details of its execution. Here we describe a new comparative model system for molecular analysis of meiosis, the nematode Pristionchus pacificus, a distant relative of the widely studied model organism Caenorhabditis elegans. P. pacificus shares many anatomical and other features that facilitate analysis of meiosis in C. elegans. However, while C. elegans has lost the meiosis-specific recombinase Dmc1 and evolved a recombination-independent mechanism to synapse its chromosomes, P. pacificus expresses both DMC-1 and RAD-51. We find that SPO-11 and DMC-1 are required for stable homolog pairing, synapsis, and crossover formation, while RAD-51 is dispensable for these key meiotic processes. RAD-51 and DMC-1 localize sequentially to chromosomes during meiotic prophase and show nonoverlapping functions. We also present a new genetic map for P. pacificus that reveals a crossover landscape very similar to that of C. elegans, despite marked divergence in the regulation of synapsis and crossing-over between these lineages.

Video bioinformatics analysis of human pluripotent stem cell morphology, quality, and cellular dynamics.

StemCellQC is a video bioinformatics software tool for the quantitative analysis of human pluripotent stem cell (hPSC) colonies. Our objective was to use StemCellQC to evaluate and compare various experimental culture conditions, cell lines, and treatments and to demonstrate its applicability to PSC problems. Seven key features were identified that provided useful information on PSC morphology, dynamic behavior, and viability. Colony attachment was better on laminin-521 than on Matrigel and Geltrex. Growth rates were similar on each matrix when data were normalized. The brightness/area ratio feature showed greater cell death in colonies grown on Matrigel and Geltrex than on laminin-521 further contributing to an overall greater yield of cells on laminin-521. Four different PSC culture media performed similarly; however, one medium produced batch-to-batch variation in colony morphology and dynamic features. Two embryonic and one induced pluripotent stem cell line showed significant differences in morphology, growth rates, motility, and death rates. Cells from the same vial that became phenotypically different in culture showed measurable differences in morphology, brightness, and motility. Likewise, differentiating and undifferentiated colonies varied in growth rate, intensity, and motility. Three pluripotent cell lines treated with a low concentration of cinnamaldehyde, a chemical used in consumer products, showed adverse effects and differed in their sensitivity to treatment. Our data demonstrate various applications of StemCellQC which could be used in basic and translational research, toxicological and drug testing, and clinical facilities engaged in stem cell therapy.

Systematic Review of Hypertension and Diabetes Burden, Risk Factors, and Interventions for Prevention and Control in Malawi: The NCD BRITE Consortium.

Recent studies have found an increasing burden of noncommunicable diseases in sub-Saharan Africa. A compressive search of PubMed, Medline, EMBASE, and the World Health Organization Global Health Library databases was undertaken to identify studies reporting on the prevalence, risk factors, and interventions for hypertension and diabetes in Malawi. The findings from 23 included studies revealed a high burden of hypertension and diabetes in Malawi, with estimates ranging from 15.8% to 32.9% and from 2.4% to 5.6%, respectively. Associated risk factors included old age, tobacco smoking, excessive alcohol consumption, obesity, physical inactivity, high salt and sugar intake, low fruit and vegetable intake, high body mass index, and high waist-to-hip ratio. Certain antiretroviral therapy regimens were also associated with increased diabetes and hypertension risk in human immunodeficiency virus patient populations. Nationwide, the quality of clinical care was generally limited and demonstrated a need for innovative and targeted interventions to prevent, control, and treat noncommunicable diseases in Malawi.

Distribution, quantification and toxicity of cinnamaldehyde in electronic cigarette refill fluids and aerosols.

OBJECTIVE: The aim of this study was to evaluate the distribution, concentration and toxicity of cinnamaldehyde in electronic cigarette (e-cigarette) refill fluids and aerosols. METHODS: The distribution and concentration of cinnamaldehyde were determined in 39 e-cigarette refill fluids plus 6 duplicates using gas chromatography and mass spectrometry (GC/MS). A cinnamaldehyde toxicity profile was established for embryonic and adult cells using a live cell imaging assay, immunocytochemistry, the comet assay and a recovery assay. RESULTS: Twenty of the 39 refill fluids contained cinnamaldehyde at concentrations that are cytotoxic to human embryonic and lung cells in the MTT assay. Cinnamon Ceylon aerosol produced in a cartomizer-style e-cigarette was cytotoxic. Cinnamon Ceylon aerosols and refill fluid aerosols (80% propylene glycol or cinnamaldehyde/propylene glycol) made using a tank/boxmod e-cigarette were more cytotoxic at 5 V than 3 V. Using GC/MS, aerosols produced at 5 V contained 10 additional peaks not present in aerosol generated at 3 V. One of these, 2,3-butandione (diacetyl), was confirmed with an authentic standard. Cinnamaldehyde depolymerised microtubules in human pulmonary fibroblasts. At concentrations that produced no effect in the MTT assay, cinnamaldehyde decreased growth, attachment and spreading; altered cell morphology and motility; increased DNA strand breaks; and increased cell death. At the MTT IC50 concentration, lung cells were unable to recover from cinnamaldehyde after 2 hours of treatment, whereas embryonic cells recovered after 8 hours. CONCLUSIONS: Cinnamaldehyde-containing refill fluids and aerosols are cytotoxic, genotoxic and low concentrations adversely affect cell processes and survival. These data indicate that cinnamaldehyde in e-cigarette refill fluids/aerosols may impair homeostasis in the respiratory system.

Evaluating Cell Processes, Quality, and Biomarkers in Pluripotent Stem Cells Using Video Bioinformatics.

There is a foundational need for quality control tools in stem cell laboratories engaged in basic research, regenerative therapies, and toxicological studies. These tools require automated methods for evaluating cell processes and quality during in vitro passaging, expansion, maintenance, and differentiation. In this paper, an unbiased, automated high-content profiling toolkit, StemCellQC, is presented that non-invasively extracts information on cell quality and cellular processes from time-lapse phase-contrast videos. Twenty four (24) morphological and dynamic features were analyzed in healthy, unhealthy, and dying human embryonic stem cell (hESC) colonies to identify those features that were affected in each group. Multiple features differed in the healthy versus unhealthy/dying groups, and these features were linked to growth, motility, and death. Biomarkers were discovered that predicted cell processes before they were detectable by manual observation. StemCellQC distinguished healthy and unhealthy/dying hESC colonies with 96% accuracy by non-invasively measuring and tracking dynamic and morphological features over 48 hours. Changes in cellular processes can be monitored by StemCellQC and predictions can be made about the quality of pluripotent stem cell colonies. This toolkit reduced the time and resources required to track multiple pluripotent stem cell colonies and eliminated handling errors and false classifications due to human bias. StemCellQC provided both user-specified and classifier-determined analysis in cases where the affected features are not intuitive or anticipated. Video analysis algorithms allowed assessment of biological phenomena using automatic detection analysis, which can aid facilities where maintaining stem cell quality and/or monitoring changes in cellular processes are essential. In the future StemCellQC can be expanded to include other features, cell types, treatments, and differentiating cells.

TargetVue: Visual Analysis of Anomalous User Behaviors in Online Communication Systems.

Users with anomalous behaviors in online communication systems (e.g. email and social medial platforms) are potential threats to society. Automated anomaly detection based on advanced machine learning techniques has been developed to combat this issue; challenges remain, though, due to the difficulty of obtaining proper ground truth for model training and evaluation. Therefore, substantial human judgment on the automated analysis results is often required to better adjust the performance of anomaly detection. Unfortunately, techniques that allow users to understand the analysis results more efficiently, to make a confident judgment about anomalies, and to explore data in their context, are still lacking. In this paper, we propose a novel visual analysis system, TargetVue, which detects anomalous users via an unsupervised learning model and visualizes the behaviors of suspicious users in behavior-rich context through novel visualization designs and multiple coordinated contextual views. Particularly, TargetVue incorporates three new ego-centric glyphs to visually summarize a user's behaviors which effectively present the user's communication activities, features, and social interactions. An efficient layout method is proposed to place these glyphs on a triangle grid, which captures similarities among users and facilitates comparisons of behaviors of different users. We demonstrate the power of TargetVue through its application in a social bot detection challenge using Twitter data, a case study based on email records, and an interview with expert users. Our evaluation shows that TargetVue is beneficial to the detection of users with anomalous communication behaviors.