Arsenic in the Food Chain in Pakistan: Assessing Risks to Human Health and Ensuring Food Security Through Comprehensive Contamination Mitigation Strategies.

Arsenic is a natural element found in the earth's crust and is extensively present in various environmental components. Anthropogenic activities and a few natural events have generated contaminants that have led to massive environmental pollution, one form of which is arsenic contamination. Arsenic enters the human food chain via contaminated crops, water, seafood, and dairy products. In Pakistan, the increasing concentration of arsenic in the water is causing major health problems. Due to the serious health risks posed by arsenic, it is crucial to design and implement strategies for reducing and preventing the bioaccumulation of arsenic and its entry into the human food chain. There is a need for an institutional framework for arsenic mitigation, accountability, and systemic checks and balances. Targeted short- and long-term policies are required for effective and sustainable management.

Bidirectionality of smoking and depression in adolescents: a systematic review.

INTRODUCTION: Recently, evidence has been accumulating that both smoking and mental health disorders are continuously increasing among adolescents. This systematic review elucidates the research into evidence of the direction of the association and risk factors influencing the relationship between smoking and depression. We also highlight recent studies on the effects of electronic cigarettes and developments on the association between depression and smoking. METHODS: A literature search was conducted on databases including PubMed, Ovid Medline, EMBASE, and PsycINFO and in relevant neurology and psychiatry journals. Terms used for electronic searches included smoking, tobacco, cigarettes; depression; adolescent, youth; direction. Relevant information was then utilized to synthesize findings on the association between smoking and depression among adolescent population. RESULTS: The initial database searches yielded 2,738 related articles. After screening and cross-referencing, duplicate articles, articles published in languages other than English, and studies on animals, social and lifestyle factors, mood disorders, and substance use were excluded. Of these, a total of 122 publications only focusing on smoking and depression in the adolescent population were selected for synthesis in this qualitative systemic review. These include 110 original research articles, eight meta-analyses and reviews, and four reports and websites. CONCLUSION: The relationship between smoking and depression in the literature does not reflect the cause-effect relationship. The lack of evidence on the direction of the association may reflect futile study designs, confounding factors and/or use of indirect measures of depression and quantification of smoking. Future prospective randomized studies should target elucidation of the causal association.

Bidirectionality of smoking and depression in adolescents: a systematic review

Abstract Introduction Recently, evidence has been accumulating that both smoking and mental health disorders are continuously increasing among adolescents. This systematic review elucidates the research into evidence of the direction of the association and risk factors influencing the relationship between smoking and depression. We also highlight recent studies on the effects of electronic cigarettes and developments on the association between depression and smoking. Methods A literature search was conducted on databases including PubMed, Ovid Medline, EMBASE, and PsycINFO and in relevant neurology and psychiatry journals. Terms used for electronic searches included smoking, tobacco, cigarettes; depression; adolescent, youth; direction. Relevant information was then utilized to synthesize findings on the association between smoking and depression among adolescent population. Results The initial database searches yielded 2,738 related articles. After screening and cross-referencing, duplicate articles, articles published in languages other than English, and studies on animals, social and lifestyle factors, mood disorders, and substance use were excluded. Of these, a total of 122 publications only focusing on smoking and depression in the adolescent population were selected for synthesis in this qualitative systemic review. These include 110 original research articles, eight meta-analyses and reviews, and four reports and websites. Conclusion The relationship between smoking and depression in the literature does not reflect the cause-effect relationship. The lack of evidence on the direction of the association may reflect futile study designs, confounding factors and/or use of indirect measures of depression and quantification of smoking. Future prospective randomized studies should target elucidation of the causal association.

Forecasting immune effector cell-associated neurotoxicity syndrome after chimeric antigen receptor t-cell therapy.

BACKGROUND: Immune effector cell-associated neurotoxicity syndrome (ICANS) is a clinical and neuropsychiatric syndrome that can occur days to weeks following administration chimeric antigen receptor (CAR) T-cell therapy. Manifestations of ICANS range from encephalopathy and aphasia to cerebral edema and death. Because the onset and time course of ICANS is currently unpredictable, prolonged hospitalization for close monitoring following CAR T-cell infusion is a frequent standard of care. METHODS: This study was conducted at Brigham and Women's Hospital from April 2015 to February 2020. A cohort of 199 hospitalized patients treated with CAR T-cell therapy was used to develop a combined hidden Markov model and lasso-penalized logistic regression model to forecast the course of ICANS. Model development was done using leave-one-patient-out cross validation. RESULTS: Among the 199 patients included in the analysis 133 were male (66.8%), and the mean (SD) age was 59.5 (11.8) years. 97 patients (48.7%) developed ICANS, of which 59 (29.6%) experienced severe grades 3-4 ICANS. Median time of ICANS onset was day 9. Selected clinical predictors included maximum daily temperature, C reactive protein, IL-6, and procalcitonin. The model correctly predicted which patients developed ICANS and severe ICANS, respectively, with area under the curve of 96.7% and 93.2% when predicting 5 days ahead, and area under the curve of 93.2% and 80.6% when predicting the entire future risk trajectory looking forward from day 5. Forecasting performance was also evaluated over time horizons ranging from 1 to 7 days, using metrics of forecast bias, mean absolute deviation, and weighted average percentage error. CONCLUSION: The forecasting model accurately predicts risk of ICANS following CAR T-cell infusion and the time course ICANS follows once it has begun.Cite Now.

Aerococcus Urinae Endocarditis: A Case Report and Literature Review.

A 75-year-old male, with a past medical history of chronic kidney disease stage 3 (CKD3) and a recent diagnosis of bilateral hydronephrosis and Foley catheter placement, presented to the emergency department for fever. Blood cultures grew Aerococcus urinae. Transthoracic echo (TTE) demonstrated thickened aortic valve leaflets with perforation, multiple echo densities, and severe aortic regurgitation. The patient developed decompensated congestive heart failure and cardiogenic shock. En route to surgery for emergent aortic valve replacement, the patient lost pulse and was resuscitated. The patient was subsequently transferred to the ICU where the family decided to initiate comfort care measures. This case highlights the importance and necessity of the prompt diagnosis and treatment of infective endocarditis and makes the reader aware of uncommon and rare organisms, such as Aerococcus urinae, as potential etiologies.

EEG-based grading of immune effector cell-associated neurotoxicity syndrome.

CAR-T cell therapy is an effective cancer therapy for multiple refractory/relapsed hematologic malignancies but is associated with substantial toxicity, including Immune Effector Cell Associated Neurotoxicity Syndrome (ICANS). Improved detection and assessment of ICANS could improve management and allow greater utilization of CAR-T cell therapy, however, an objective, specific biomarker has not been identified. We hypothesized that the severity of ICANS can be quantified based on patterns of abnormal brain activity seen in electroencephalography (EEG) signals. We conducted a retrospective observational study of 120 CAR-T cell therapy patients who had received EEG monitoring. We determined a daily ICANS grade for each patient through chart review. We used visually assessed EEG features and machine learning techniques to develop the Visual EEG-Immune Effector Cell Associated Neurotoxicity Syndrome (VE-ICANS) score and assessed the association between VE-ICANS and ICANS. We also used it to determine the significance and relative importance of the EEG features. We developed the Visual EEG-ICANS (VE-ICANS) grading scale, a grading scale with a physiological basis that has a strong correlation to ICANS severity (R = 0.58 [0.47-0.66]) and excellent discrimination measured via area under the receiver operator curve (AUC = 0.91 for ICANS ≥ 2). This scale shows promise as a biomarker for ICANS which could help to improve clinical care through greater accuracy in assessing ICANS severity.

Crafting ɣ-L-Glutamyl-l-Cysteine layered Human Serum Albumin-nanoconstructs for brain targeted delivery of ropinirole to attenuate cerebral ischemia/reperfusion injury via "3A approach".

Treatment of Ischemic Stroke is inordinately challenging due to its complex aetiology and constraints in shuttling therapeutics across blood-brain barrier. Ropinirole hydrochloride (Rp), a propitious neuroprotectant with anti-oxidant, anti-inflammatory, and anti-apoptotic properties (3A) is repurposed for remedying ischemic stroke and reperfusion (I/R) injury. The drug's low bioavailability in brain however, limits its therapeutic efficacy. The current research work has reported sub-100 nm gamma-L-Glutamyl-L-Cysteine coated Human Serum Albumin nanoparticles encapsulating Rp (C-Rp-NPs) for active targeting in ischemic brain to encourage in situ activity and reduce unwanted toxicities. Confocal microscopy and brain distribution studies confirmed the enhanced targeting potentiality of optimized C-Rp-NPs. The pharmacokinetics elucidated that C-Rp-NPs could extend Rp retention in systemic circulation and escalate bioavailability compared with free Rp solution (Rp-S). Additionally, therapeutic assessment in transient middle cerebral occlusion (tMCAO) model suggested that C-Rp-NPs attenuated the progression of I/R injury with boosted therapeutic index at 1000 times less concentration compared to Rp-S via reinstating neurological and behavioral deficits, while reducing ischemic neuronal damage. Moreover, C-Rp-NPs blocked mitochondrial permeability transition pore (mtPTP), disrupted apoptotic mechanisms, curbed oxidative stress and neuroinflammation, and elevated dopamine levels post tMCAO. Thus, our work throws light on fabrication of rationally designed C-Rp-NPs with enormous clinical potential.

Vascular invasion identifies the most aggressive histologic subset of stage I lung adenocarcinoma: Implications for adjuvant therapy.

OBJECTIVES: Approximately 15% of stage I lung adenocarcinomas will recur despite adequate surgical therapy. Adjuvant therapy may benefit specific high-risk subsets; however, it is unclear which patients are sufficiently predisposed to recurrence to warrant intensified therapy. MATERIALS AND METHODS: 517 AJCC 8th edition stage I/0 lung adenocarcinomas ≤ 4 cm total size were graded (WHO-2015 and WHO-2021) and compared to stage subgroupings using 7-year recurrence free (RFS), disease specific (DSS), and overall survival (OS). Low malignant potential (LMP) adenocarcinoma was assigned as previously defined. Univariate/multivariate analysis was performed to assess risk factors associated with aggressive behavior. RESULTS: Vascular invasion was the most significant histologic feature on multivariate analysis for both RFS (HR = 4.68, p < 0.001) and DSS (HR = 3.67, p = 0.001) and nearly reached significance for OS (HR = 1.47, p = 0.060). Angioinvasive adenocarcinomas comprised 26 % of the cohort and exhibited a 7-year 64 % RFS, 73 % DSS, and 50 % OS; in contrast to 20 % WHO-2015-G3 (7-year 71 % RFS, 79 % DSS, & 54 % OS), 44 % WHO-2021-G3 (7-year 79 % RFS, 85 % DSS, & 56 % OS), and 21 % stage IB (7-year 72 % RFS, 79 % DSS, and 50 % OS) adenocarcinomas. The majority (>50 %) of overall mortality was disease specific for angioinvasive adenocarcinoma whereas ≤25 % of overall mortality was disease specific for the remaining tumors. Angioinvasive adenocarcinomas were proportionally more common among those still smoking at diagnosis (49 %), male sex (49 %), and black race (16 %) than other subtypes. CONCLUSION: Patients with AJCC 8th ed. stage I angioinvasive lung adenocarcinomas are at high-risk of cancer-specific mortality and should be considered for clinical trials evaluating benefit of adjuvant therapy.

Densitometric Quantification and Optimization of Polyphenols in Phyllanthus maderaspatensis by HPTLC.

Quantifying and optimizing the polyphenol content of Phyllanthus maderaspatensis was accomplished using a single-solvent HPTLC system. Analyzing hydroalcoholic extracts for kaempferol, rutin, ellagic acid, quercetin, catechin, and gallic acid, we simultaneously quantified and optimized their concentration. In the experiment, the methanol to water ratio (%), temperature (°C), and time of extraction (min) were all optimized using a Box-Behnken statistical design. Kaempferol, rutin, ellagic acid, quercetin, catechin, and gallic acid were among the dependent variables analyzed. In the HPTLC separation, silica gel 60F254 plates were used, and toluene, ethyl acetate, and formic acid (5:4:1) made up the mobile phase. For kaempferol, rutin, ellagic acid, quercetin, catechin, and gallic acid, densitometric measurements were carried out using the absorbance mode at 254 nm. Hydroalcoholic extract of P. maderaspatensis contains rutin (0.344), catechin (2.62), gallic acid (0.93), ellagic acid (0.172), quercetin (0.0108) and kaempferol (0.06). Further, it may be affected by more than one factor at a time, resulting in a varying degree of reaction. A negative correlation was found between X1 (extraction time (min)) and X2 (temperature), as well as X1 and X3 (solvent ratios). Taking these characteristics into consideration, the method outlined here is a validated HPTLC method for measuring kaempferol, rutin, ellagic acid, quercetin, catechin, and gallic acid.

Developing basic robotic skills using virtual reality simulation and automated assessment tools: a multidisciplinary robotic virtual reality-based curriculum using the Da Vinci Skills Simulator and tracking progress with the Intuitive Learning platform.

This study sought to develop basic robotic surgical skills among surgical trainees across multiple specialties using a VR-based curriculum and provided objective, on-demand, automated assessments using the Intuitive Learning platform. This curriculum was developed using the Da Vinci Skills Simulator and included 24 exercises. A pre-test and post-test were required for completion of the curriculum. Scores > 90 on individual exercises and the post-test were required for successful completion. The Intuitive learning platform provided automated performance metrics and tracked trainee progression. The curriculum was implemented and data collected over a 12-month period. 21 trainees completed the entire curriculum. Post-test scores were significantly higher than pre-test scores and trainees reported improvement in their robotic skills after curriculum completion. A comparison based on training level revealed that junior residents had significantly lower number of attempts per exercise, fewer penalties, and higher completion scores when compared to senior residents and fellows. Individual exercise analysis demonstrated that exercises, such as 'Three-Arm Relay' and 'Ring Rollercoaster', required the longest time and most attempts to achieve a passing score. The 'Energy Pedals' and 'Knot Tying' skills were the least-utilized skills addressed in the curriculum. Virtual reality-based curriculums using the Intuitive Learning platform can be standardized across multiple specialties allowing for the development of basic robotic skills, shared interdisciplinary surgical education, and provides powerful objective and automated performance metrics of trainees.

Thymoquinone-rich black cumin oil attenuates ibotenic acid-induced excitotoxicity through glutamate receptors in Wistar rats.

Inflammation-mediated alterations in glutamate neurotransmission constitute the most important pathway in the pathophysiology of various brain disorders. The excessive signalling of glutamate results in excitotoxicity, neuronal degeneration, and neuronal cell death. In the present study, we investigated the relative efficacy of black cumin (Nigella sativa) oil with high (5 % w/w) and low (2 % w/w) thymoquinone content (BCO-5 and BCO-2, respectively) in alleviating ibotenic acid-induced excitotoxicity and neuroinflammation in Wistar rats. It was found that BCO-5 reversed the abnormal behavioural patterns and the key inflammatory mediators (TNF-α and NF-κB) when treated at 5 mg/kg body weight. Immunohistochemical studies showed the potential of BCO-5 to attenuate the glutamate receptor subunits NMDA and GluR-2 along with increased glutamate decarboxylase levels in the brain tissues. Histopathological studies revealed the neuroprotection of BCO-5 against the inflammatory lesions, as evidenced by the normal cerebellum, astrocytes, and glial cells. BCO-2 on the other hand showed either a poor protective effect or no effect even at a 4-fold higher concentration of 20 mg/kg body weight indicating a very significant role of thymoquinone content on the neuroprotective effect of black cumin oil and its plausible clinical efficacy in counteracting the anxiety and stress-related neurological disorders under conditions such as depression and Alzheimer's disease.

Conversion to Thoracotomy During Thoracoscopic vs Robotic Lobectomy: Predictors and Outcomes.

BACKGROUND: Conversion to thoracotomy during minimally invasive lobectomy for lung cancer is occasionally necessary. Differences between video-assisted thoracoscopic surgery (VATS) and robotic-assisted thoracoscopic surgery (RATS) lobectomy conversion have not been described. METHODS: We queried The Society of Thoracic Surgeons General Thoracic Surgery Database from January 1, 2015 to December 31, 2018. Patients with prior thoracic operations and metastatic disease were excluded. Univariable comparisons with χ2 and Kruskal-Wallis tests and multivariable logistic regression modeling were performed. RESULTS: There were 27,695 minimally invasive lobectomies from 269 centers. Conversion to thoracotomy occurred in 11.0% of VATS and 6.0% of RATS (P < .001). Conversion was associated with increased mortality (P < .001), major complications (P < .001), and intraoperative (P < .001) and postoperative (P < .001) blood transfusions. Conversion from RATS occurred emergently (P < .001) and for vascular injury (P < .001) more frequently than from VATS, but there was no difference in overall major complications or mortality. Mortality after conversion was 3.1% for RATS and 2.2% for VATS (P = .24). Clinical cancer stage II or III (P < .001), preoperative chemotherapy (P = .003), forced expiratory volume in 1 second (P = .006), body mass index (P < .001), and left-sided resection (P = .0002) independently predicted VATS conversion. For RATS clinical stage III (P = .037), left-sided resection (P = .041), and forced expiratory volume in 1 second (P = .002) predicted conversion. Lower volume centers had increased rates of conversion (P < .001) in both groups. CONCLUSIONS: Conversion from minimally invasive to open lobectomy is associated with increased morbidity and mortality. Conversion occurs more frequently during VATS compared with RATS, albeit less often emergently, and with similar rates of overall mortality and major complications. Predictors, urgency, and reasons for conversion differ between RATS and VATS lobectomy and may assist in patient selection.

Surgeon Experience Is Associated With Prolonged Air Leak After Robotic-assisted Pulmonary Lobectomy.

BACKGROUND: Prolonged air leak (PAL) (>5 days) after robotic-assisted pulmonary lobectomy is a significant complication. This study aimed to determine patient- and surgeon-related factors that can predict PAL after robotic lobectomy for lung cancer. METHODS: This study was a retrospective review of a single-center experience of robotic-assisted lobectomy for lung cancer. Perioperative variables, including surgeon case experience, patient demographics, diffusion capacity of lung for carbon monoxide, forced expiratory volume in 1 second, body mass index, and smoking status were evaluated. RESULTS: A total of 305 robotic-assisted lobectomies performed by 4 surgeons met inclusion criteria from June 2016 to February 2019. The 30-day postoperative mortality was 1.2%. PAL developed in 27 of 305 (8.8%) patients. Surgeons' robotic experience was grouped by 10-case increments. When adjusted for age and sex, the odds for PAL decreased by 15% for every 10 robotic lobectomies the surgeons performed (odds ratio [OR], 0.85; 95% CI, 0.74-0.99; P = .0384). Logistic regression models showed a linear transition curve at the 50th case. Female sex (OR, 2.62; 95% CI, 1.03-6.69; P = .0314) and younger age (OR, 0.61; 95% CI, 0.41-0.91; P = .0184) were statistically significant risk factors for PAL. Cumulative sum analysis similarly showed a strong association between experience and PAL. Preoperative diffusing capacity of lung for carbon monoxide, forced expiratory volume in 1 second, body mass index, and smoking status were not statistically significant predictive factors. CONCLUSIONS: These results show that surgeon robotic case experience is associated with the rate of postoperative PAL: as the number of robotic lobectomies increases, the rate of PAL significantly decreases. It is imperative to emphasize that a learning curve exists for this approach that directly affects patient outcomes.

Pharmacological properties of durva swaras (Cynodon dactylon L. Pers.) in an ovariectomised rat model mimicking chronic menopausal syndrome.

Hormonal replacement therapy (HRT), as the first-line management of chronic menopausal syndrome (CMS) in women, has limited application due to adverse effects. We aimed to evaluate the therapeutic potential of a herbal alternative (HALT), durva swaras (DS) of Cynodon dactylon L. Pers., in a CMS rat model. Female Sprague-Dawley rats were subjected to Sham and ovariectomy (OVX) surgery. OVX rats received either 0.11 mg/kg oestrogen as a positive treatment control or 1 (DS1), 2 (DS2), and 4 (DS3) g/kg DS for 160 days. Vaginal smear tests indicated the menopausal status. Routine clinical examinations, weekly body weights (BW), serum calcium, proinflammatory cytokines, and reproductive hormones levels were monitored. Clinical chemistry, body composition, bone mineral density (BMD), uterotrophic response, bone morphometry, and histopathology of major organs were evaluated. BW of OVX rats increased by 18-25% compared to Sham. Total fat and fat percentage were significantly elevated in the oestrogen group compared to DS2, DS3, and OVX group. DS treatment groups showed the levels of TNF- α was slightly reduced, while IL-1ß and IL-6 levels were significantly reduced (P < 0.05) compared to the oestrogen treated group. DS treatment restored serum calcium levels, while BMD, bone quality, osteoblast/osteoclast ratio, and collagen levels improved in both DS and oestrogen treatment groups. The uterotrophic assay demonstrated non-oestrogenic activity of DS. Endometrial hyperplastic change was observed in oestrogen-treated rats. The preclinical non-oestrogenic activity of DS has therapeutic potential in CMS through anti-inflammatory and osteo-protective effects. Further clinical research into DS, as a viable HALT to HRT, is required.

A phase 2a randomized clinical trial of intravenous vedolizumab for the treatment of steroid-refractory intestinal acute graft-versus-host disease.

Steroid-refractory (SR) acute graft-versus-host disease (aGvHD) remains a significant complication after allogeneic hematopoietic cell transplantation. Systemic corticosteroids are first-line therapy for aGvHD, but apart from ruxolitinib, there are no approved treatments for SR aGvHD. Vedolizumab is approved for treatment of ulcerative colitis and Crohn's disease, and may be effective for treatment of SR intestinal aGvHD. We conducted a phase 2a trial (NCT02993783) to evaluate the clinical efficacy, tolerability, and safety of vedolizumab 300 and 600 mg for SR intestinal aGvHD. This study was terminated before full enrollment was completed because early results failed to demonstrate positive proof-of-concept in efficacy. Before termination, 17 participants had enrolled and an early response in intestinal aGvHD was observed in 11 and eight participants at days 15 and 28, respectively. All adverse events observed were consistent with those expected in a population with SR intestinal aGvHD. Overall, vedolizumab did not meet the primary efficacy endpoint (overall response at day 28), likely owing to premature study drug discontinuation, lack of efficacy, and the competing risks inherent with a population with advanced SR intestinal aGvHD. Nevertheless, this study provides valuable insights into the considerations needed when conducting studies in patients with SR intestinal aGvHD.

Robotic-Assisted Complex Pulmonary Resection: Sleeve Lobectomy for Cancer.

The use of robotic assistance for complex pulmonary resections such as segmentectomy and sleeve lobectomy has steadily increased in recent years. These operations are technically challenging as they require fine dissection and suturing, which is often difficult to perform using traditional minimally invasive techniques. Robotic surgery is well-suited for complex pulmonary surgery given its specific advantages related to superior optics and precise tissue manipulation and dissection. Herein we describe our technique for robotic-assisted complex pulmonary surgery with a specific focus on right upper sleeve lobectomy for cancer, including associated video case demonstration. The principles discussed are generalizable to other complex lung and tracheobronchial operations and highlight the benefits of the robotic platform.

Arrhythmias in Cardiac Sarcoidosis Bench to Bedside: A Case-Based Review.

Cardiac sarcoidosis is a component of an often multiorgan granulomatous disease of still uncertain cause. It is being recognized with increasing frequency, mainly as the result of heightened awareness and new diagnostic tests, specifically cardiac magnetic resonance imaging and 18F-fluorodeoxyglucose positron emission tomography scans. The purpose of this case-based review is to highlight the potentially life-saving importance of making the early diagnosis of cardiac sarcoidosis using these new tools and to provide a framework for the optimal care of patients with this disease. We will review disease mechanisms as currently understood, associated arrhythmias including conduction abnormalities, and atrial and ventricular tachyarrhythmias, guideline-directed diagnostic criteria, screening of patients with extracardiac sarcoidosis, and the use of pacemakers and defibrillators in this setting. Treatment options, including those related to heart failure, and those which may help clarify disease mechanisms are included.

Oxidative stress and redox signaling in CRPC progression: therapeutic potential of clinically-tested Nrf2-activators.

Androgen deprivation therapy (ADT) is the mainstay regimen in patients with androgen-dependent prostate cancer (PCa). However, the selection of androgen-independent cancer cells leads to castrate resistant prostate cancer (CRPC). The aggressive phenotype of CRPC cells underscores the need to elucidate mechanisms and therapeutic strategies to suppress CRPC outgrowth. Despite ADT, the activation of androgen receptor (AR) transcription factor continues via crosstalk with parallel signaling pathways. Understanding of how these signaling cascades are initiated and amplified post-ADT is lacking. Hormone deprivation can increase oxidative stress and the resultant reactive oxygen species (ROS) may activate both AR and non-AR signaling. Moreover, ROS-induced inflammatory cytokines may further amplify these redox signaling pathways to augment AR function. However, clinical trials using ROS quenching small molecule antioxidants have not suppressed CRPC progression, suggesting that more potent and persistent suppression of redox signaling in CRPC cells will be needed. The transcription factor Nrf2 increases the expression of numerous antioxidant enzymes and downregulates the function of inflammatory transcription factors, e.g., nuclear factor kappa B. We documented that Nrf2 overexpression can suppress AR-mediated transcription in CRPC cell lines. Furthermore, two Nrf2 activating agents, sulforaphane (a phytochemical) and bardoxolone-methyl (a drug in clinical trial) suppress AR levels and sensitize CRPC cells to anti-androgens. These observations implicate the benefits of potent Nrf2-activators to suppress the lethal signaling cascades that lead to CRPC outgrowth. This review article will address the redox signaling networks that augment AR signaling during PCa progression to CRPC, and the possible utility of Nrf2-activating agents as an adjunct to ADT.

Surgery and invasive diagnostic procedures for benign disease are rare in a large low-dose computed tomography lung cancer screening program.

OBJECTIVE: Lung cancer screening with low-dose chest computed tomography improves survival. However, concerns about overdiagnosis and unnecessary interventions persist. We reviewed our lung cancer screening program to determine the rate of surgery and invasive procedures for nonmalignant disease. METHODS: We reviewed all patients undergoing lung cancer screening from January 2012 to June 2017 with follow-up through January 2019. Patients with suspicious findings (Lung CT Screening Reporting and Data System 4) were referred for further evaluation. RESULTS: Of 3280 patients screened, 345 (10.5%) had Lung CT Screening Reporting and Data System 4 findings. A total of 311 patients had complete follow-up, of whom 93 (29.9%) were diagnosed with lung cancer. Eighty-three patients underwent lung surgery (2.5% of screened patients). Forty patients underwent lobectomy (48.2%), 3 patients (3.6%) underwent bilobectomy, and 40 patients (48.2%) underwent sublobar resection. Fourteen patients underwent surgery for benign disease (0.43% of screened patients). Fifty-four patients, 5 with benign disease, had at least 1 invasive diagnostic procedure but never underwent surgery. The incidence of any invasive intervention for nonmalignant disease was 0.95% (31/3280 patients). There were no postprocedural deaths within 60 days. Twenty-five patients (0.76%) underwent stereotactic body radiation therapy; 19 patients (76%) had presumed lung cancer without pretreatment pathologic confirmation. CONCLUSIONS: Surgical resection for benign disease occurred in 0.43% of patients undergoing lung cancer screening. The combined incidence of any invasive diagnostic or therapeutic intervention, including surgical resection, for benign disease was only 0.95%. Periprocedural complications were rare. These results indicate that concern over unnecessary interventions is overstated and should not hinder adoption of lung cancer screening. A multidisciplinary team approach, including thoracic surgeons, is critical to maintain an appropriate rate of interventions in lung cancer screening.

Pulmonary Adenocarcinomas of Low Malignant Potential: Proposed Criteria to Expand the Spectrum Beyond Adenocarcinoma In Situ and Minimally Invasive Adenocarcinoma.

Lung cancer screening has improved mortality among high-risk smokers but has coincidentally detected a fraction of nonprogressive adenocarcinoma historically classified as bronchoalveolar carcinoma (BAC). In the National Lung Screening Trial (NLST) the majority of BAC-comprising 29% of computed tomography-detected stage I lung adenocarcinoma-were considered overdiagnosis after extended follow-up comparison with the control arm. In the current classification, adenocarcinoma in situ and minimally invasive adenocarcinoma have replaced BAC but together comprise only ∼5% of stage I lung adenocarcinoma. Lepidic and subsets of papillary and acinar adenocarcinoma also infrequently recur. We, therefore, propose criteria for low malignant potential (LMP) adenocarcinoma among nonmucinous adenocarcinoma measuring ≤3 cm in total, exhibiting ≥15% lepidic growth, and lacking nonpredominant high-grade patterns (≥10% cribriform, ≥5% micropapillary, ≥5% solid), >1 mitosis per 2 mm2, angiolymphatic or visceral pleural invasion, spread through air spaces or necrosis. We tested these criteria in a multi-institutional cohort of 328 invasive stage I (eighth edition) and in situ adenocarcinomas and observed 16% LMP and 7% adenocarcinoma in situ/minimally invasive adenocarcinoma which together (23%) approximated the frequency of overdiagnosed stage I BAC in the NLST. The LMP group had 100% disease-specific survival. The proposed LMP criteria, incorporating multiple histologic parameters, may be a clinically useful "low-grade" prognostic group. Validation of these criteria in additional retrospective cohorts and prospective screen-detected cohorts should be considered.