Modifying Effects of Genetic Variations on the Association Between Dietary Isothiocyanate Exposure and Non-muscle Invasive Bladder Cancer Prognosis in the Be-Well Study.

SCOPE: Dietary isothiocyanate (ITC) exposure from cruciferous vegetable (CV) intake may improve non-muscle invasive bladder cancer (NMIBC) prognosis. This study aims to investigate whether genetic variations in key ITC-metabolizing/functioning genes modify the associations between dietary ITC exposure and NMIBC prognosis outcomes. METHODS AND RESULTS: In the Bladder Cancer Epidemiology, Wellness, and Lifestyle Study (Be-Well Study), a prospective cohort of 1472 incident NMIBC patients, dietary ITC exposure is assessed by self-reported CV intake and measured in plasma ITC-albumin adducts. Using Cox proportional hazards regression models, stratified by single nucleotide polymorphisms (SNPs) in nine key ITC-metabolizing/functioning genes, it is calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for recurrence and progression. The rs15561 in N-acetyltransferase 1 (NAT1) is alter the association between CV intake and progression risk. Multiple SNPs in nuclear factor E2-related factor 2 (NRF2) and nuclear factor kappa B (NFκB) are modify the associations between plasma ITC-albumin adduct level and progression risk (pint < 0.05). No significant association is observed with recurrence risk. Overall, >80% study participants are present with at least one protective genotype per gene, showing an average 65% reduction in progression risk with high dietary ITC exposure. CONCLUSION: Despite that genetic variations in ITC-metabolizing/functioning genes may modify the effect of dietary ITCs on NMIBC prognosis, dietary recommendation of CV consumption may help improve NMIBC survivorship.

Outcomes of a Dietary Intervention to Reduce Bladder Cancer Recurrence and Progression in Survivors of Non-Muscle-Invasive Bladder Cancer.

BACKGROUND: As one of the 10 most common cancers in the United States, bladder cancer is the most expensive cancer to treat. Most bladder cancers (70%-80%) are diagnosed at early stages as non-muscle-invasive bladder cancer (NMIBC), which can be removed. However, 50% to 80% of NMIBC recurs within 5 years, and 15% to 30% progresses with poor survival. Besides life-long surveillance, current treatment is limited. Preclinical and epidemiologic evidence suggest that dietary isothiocyanates (ITCs) in cruciferous vegetables (Cruciferae) could be a noninvasive and cost-effective strategy to improve NMIBC prognosis. Yet, a Cruciferae intervention that increases ITC exposure in NMIBC survivors has not been tested. Thus, the primary aim of this study was to test the effect of a Cruciferae intervention on urinary ITC levels and Cruciferae intake in NMIBC survivors. PATIENTS AND METHODS: We conducted a 2-arm, double-blinded, randomized controlled trial to test the efficacy of a Cruciferae intervention against a general fruit and vegetable intervention (control) for NMIBC survivors. Both 6-month interventions consisted of mailed educational materials, a live call with staff to review the materials, and 11 interactive voice response calls. We anticipated that our Cruciferae intervention (Power to Redefine Your Health [POW-R Health]) would increase Cruciferae intake to 1 cup/day (secondary outcome), thus raising urinary ITC levels to 10 µM (primary outcome) from baseline to 6-month follow-up. RESULTS: We randomized 49 patients with NMIBC diagnosed in 2018 through 2019, and retained 42 patients at 6-month follow-up. The treatment group reported 0.94 cups (95% CI, 0.24-1.65; P=.010) higher Cruciferae intake (treatment, 1.37 ± 1.19 cups vs control, 0.56 ± 0.72 cups) and increased urinary ITC levels by 11.1 µmol/g creatinine (treatment, 26.2 ± 20.9 vs control, 7.8 ± 11.5; P=.027) at 6-month follow-up compared with the control group. CONCLUSIONS: Our dietary intervention is the first to significantly increase Cruciferae intake and urinary ITC levels in NMIBC survivors, demonstrating an increase in ITC to levels that significantly decrease risk of disease-specific survival. A future randomized controlled trial testing POW-R Health on bladder cancer recurrence and progression is warranted. If proven to improve bladder cancer outcomes, our intervention has the potential to be a noninvasive, cost-effective, easily accessible way for NBMIC survivors to improve their bladder cancer prognosis.

Environmental and Occupational Exposures and Prognosis in Patients with Non-Muscle Invasive Bladder Cancer in the Be-Well Study.

Bladder cancer is primarily diagnosed as non-muscle invasive bladder cancer (NMIBC) with high recurrence and progression rates. Environmental and occupational exposures to carcinogens are well-known risk factors for developing bladder cancer, yet their effects on prognosis remain unknown. In the Be-Well Study, a population-based prospective cohort study of 1,472 patient with newly diagnosed NMIBC from 2015 to 2019, we examined history of environmental and occupational exposures in relation to tumor stage and grade at initial diagnosis by multivariable logistic regression, and subsequent recurrence and progression by Cox proportional hazards regression. Exposure to environmental and occupational carcinogens was significantly associated with increased risk of progression (HR = 1.79; 95% CI: 1.04, 3.09), specifically increased progression into muscle-invasive disease (HR = 2.28; 95% CI: 1.16, 4.50). Exposure to asbestos and arsenic were associated with increased odds of advanced stage at diagnosis (asbestos: OR = 1.43; 95% CI: 1.11, 1.84; arsenic, OR = 1.27; 95% CI: 1.01, 1.63), and formaldehyde exposure was associated with increased risk of recurrence (HR = 1.38; 95% CI: 1.12, 1.69). Our findings suggest that history of these exposures may benefit current risk stratification systems to tailor clinical care and improve prognosis in patients with NMIBC.

[Treatment experience of neck tumor surgeries involving carotid artery].

Objective:To investigate surgical treatment of carotid artery diseases in neck tumor surgery. Methods:A retrospective analysis of the clinical data on carotid artery treatment was conducted in the five cases of neck tumor surgeries treated at Department of Surgical Oncology, the First Peoples Hospital of Lanzhou from March 2010 to May 2020. Surgical methods, including carotid artery resection and ligation, tumor-involved artery resection and vascular reconstruction, and tumor peeling and carotid rupture repairing were used, respectively. Results:Five cases were successfully operated on. One case of carotid artery ligation was followed by intermittent dizziness and decreased contra-lateral limb strength after the surgery. The remaining patients exhibited no neurological complications. A patient with cervical low-grade myofibroblastoma developed into lung metastases 8 months after the surgery. Another patient with cervical lymph node metastases in papillary thyroid cancer developed into lung metastases 24 months after the surgery. Conclusion:Currently, surgical methods for clinical treatment of diseased carotid arteries include carotid artery resection and ligation, simple tumor peeling, tumor invasion artery resection and vascular reconstruction, and interventional therapy. Each surgical method has its own advantages and disadvantages. Therefore, the choice of treatment depends on the patient's specific conditions, physician's clinical experience, and the equipment available.

Associations of dietary isothiocyanate exposure from cruciferous vegetable consumption with recurrence and progression of non-muscle-invasive bladder cancer: findings from the Be-Well Study.

BACKGROUND: High recurrence and progression rates are major clinical challenges for non-muscle-invasive bladder cancer (NMIBC). Dietary isothiocyanates (ITCs), phytochemicals primarily from cruciferous vegetables (CV), show strong anticancer activities in preclinical BC models, yet their effect on NMIBC prognosis remains unknown. OBJECTIVES: This study aimed to investigate the associations of dietary ITC exposure at diagnosis with NMIBC recurrence and progression. METHODS: The study analyzed 1143 participants from the Be-Well study, a prospective cohort of newly diagnosed NMIBC cases in 2015-2019 with no prior history of BC. Dietary ITC exposure was indicated by self-reported CV intake, estimated ITC intake, urinary metabolites, and plasma ITC-albumin adducts. Cox proportional hazards regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for recurrence and progression, and unconditional logistic regression models were used to calculate odds ratios (ORs) and 95% CIs for delayed and multiple recurrence. RESULTS: Over a mean follow-up of 25 mo, 347 (30%) developed recurrence and 77 (6.7%) had disease progression. Despite no significant associations with the overall risk of recurrence, urinary ITC metabolites (OR: 1.96; 95% CI: 1.01, 4.43) and dietary ITC intake (OR: 2.13; 95% CI: 1.03, 4.50) were associated with late recurrence after 12-mo postdiagnosis compared with before 12-mo postdiagnosis. Raw CV intake was associated with reduced odds of having ≥2 recurrences compared with having one (OR: 0.34; 95% CI: 0.16, 0.68). Higher plasma concentrations of ITC-albumin adducts were associated with a reduced risk of progression, including progression to muscle-invasive disease (for benzyl ITC, HR: 0.40; 95% CI: 0.17, 0.93; for phenethyl ITC, HR: 0.40; 95% CI: 0.19, 0.86). CONCLUSIONS: Our findings indicate the possible beneficial role of dietary ITCs in NMIBC prognosis. Given the compelling preclinical evidence, increasing dietary ITC exposure with CV intake could be a promising strategy to attenuate recurrence and progression risks in patients with NMIBC.

Smoking Behaviors and Prognosis in Patients With Non-Muscle-Invasive Bladder Cancer in the Be-Well Study.

Importance: Tobacco smoking is an established risk factor associated with bladder cancer, yet its impact on bladder cancer prognosis is unclear. Objective: To examine associations of use of tobacco (cigarettes, pipes, and cigars), e-cigarettes, and marijuana with risk of recurrence and progression of non-muscle-invasive bladder cancer (NMIBC) and to explore use of smoking cessation interventions. Design, Setting, and Participants: The Be-Well Study is a prospective cohort study of patients with NMIBC diagnosed from 2015 to 2019 and followed-up for 26.4 months in the Kaiser Permanente Northern and Southern California integrated health care system. Eligibility criteria were age at least 21 years, first NMIBC diagnosis (stages Ta, Tis, or T1), alive, and not in hospice care. Exclusion criteria were previous diagnosis of bladder cancer or other cancer diagnoses within 1 year prior to or concurrent with NMIBC diagnosis. Data were analyzed from April 1 to October 4, 2022. Exposures: Use of cigarettes, pipes, cigars, e-cigarettes, and marijuana was reported in the baseline interview. Use of smoking cessation interventions (counseling and medications) was derived from electronic health records. Main Outcomes and Measures: Hazard ratios (HRs) and 95% CIs of recurrence and progression of bladder cancer were estimated by multivariable Cox proportional hazards regression. Results: A total of 1472 patients (mean [SD] age at diagnosis, 70.2 [10.8%] years; 1129 [76.7%] male patients) with NMIBC were enrolled at a mean (SD) of 2.3 (1.3) months after diagnosis, including 874 patients (59.4%) who were former smokers and 111 patients (7.5%) who were current cigarette smokers; 67 patients (13.7%) smoked pipes and/or cigars only, 65 patients (4.4%) used e-cigarettes, 363 patients (24.7%) used marijuana. Longer cigarette smoking duration and more pack-years were associated with higher risk of recurrence in a dose-dependent manner, with the highest risks for patients who had smoked for 40 or more years (HR, 2.36; 95% CI, 1.43-3.91) or 40 or more pack-years (HR, 1.97; 95% CI, 1.32-2.95). There was no association of having ever smoked, being a former or current cigarette smoker, and years since quit smoking with recurrence risk. No associations with pipes, cigars, e-cigarettes, or marijuana were found. Of 102 patients offered a smoking cessation intervention, 57 (53.8%) received an interventions after diagnosis, with female patients more likely than male patients to engage in such interventions (23 of 30 female patients [76.7%] vs 34 of 76 male patients [44.7%]; P = .003). Conclusions and Relevance: These findings suggest that longer duration and more pack-years of cigarette smoking were associated with higher risk of NMIBC recurrence. Cigarette smoking remains a critical exposure before and after diagnosis in survivors of NMIBC.

Single-Cell Analyses of a Novel Mouse Urothelial Carcinoma Model Reveal a Role of Tumor-Associated Macrophages in Response to Anti-PD-1 Therapy.

Approximately 80% of patients with advanced bladder cancer do not respond to immune checkpoint inhibitor (ICI) immunotherapy. Therefore, there is an urgent unmet need to develop clinically relevant preclinical models so that factors governing immunotherapy responses can be studied in immunocompetent mice. We developed a line of mouse triple knockout (TKO: Trp53, Pten, Rb1) urothelial carcinoma organoids transplanted into immunocompetent mice. These bladder tumors recapitulate the molecular phenotypes and heterogeneous immunotherapy responses observed in human bladder cancers. The TKO organoids were characterized in vivo and in vitro and compared to the widely used MB49 murine bladder cancer model. RNAseq analysis of the TKO tumors demonstrated a basal subtype. The TKO xenografts demonstrated the expression of urothelial markers (CK5, CK7, GATA3, and p63), whereas MB49 subcutaneous xenografts did not express urothelial markers. Anti-PD-1 immunotherapy resulted in a mixed pattern of treatment responses for individual tumors. Eight immune cell types were identified (basophils, B cells, dendritic cells, macrophages, monocytes, neutrophils, NK cells, and T cells) in ICI-treated xenografts. Responder xenografts displayed significantly increased immune cell infiltration (15.3%, 742 immune cells/4861 total cells) compared to the non-responder tumors (10.1%, 452 immune cells/4459 total cells, Fisher Exact Test p < 0.0001). Specifically, there were more T cells (1.0% vs. 0.4%, p = 0.002) and macrophages (8.6% vs. 6.4%, p = 0.0002) in responder xenografts than in non-responder xenografts. In conclusion, we have developed a novel preclinical model that exhibits a mixed pattern of response to anti-PD-1 immunotherapy. The higher percentage of macrophage tumor infiltration in responders suggests a potential role for the innate immune microenvironment in regulating ICI treatment responses.

A Presurgical-Window Intervention Trial of Isothiocyanate-Rich Broccoli Sprout Extract in Patients with Breast Cancer.

SCOPE: Dietary isothiocyanates (ITCs) from cruciferous vegetables have shown potent anti-breast cancer activities in preclinical models, but their anticancer effects in vivo in breast cancer patients remain elusive. A proof-of-principle, presurgical window of opportunity trial is conducted to assess the anticancer effects of dietary ITCs in breast cancer patients. METHODS AND RESULTS: Thirty postmenopausal breast cancer patients are randomly assigned to receive ITC-rich broccoli sprout extract (BSE) (200 µmol ITC per day) or a placebo for 2 weeks. Expression of biomarkers related to ITCs functions are measured in breast cancer tissue specimens at pre- and post-interventions using immunohistochemistry staining. First morning urine samples are collected at both timepoints for proteomic analysis. Overall, the study shows high compliance (100%) and low toxicity (no grade 4 adverse event). Trends of increase in cleaved caspase 3 and tumor-infiltrating lymphocytes (TILs) and trends of decrease in Ki-67 and nuclear to cytoplasm ratio of estrogen receptor (ER)-α are observed in the BSE arm only, consistent with the significantly altered signaling pathways identified in urinary proteomic analysis. CONCLUSIONS: Anticancer activities of ITCs are observed in breast cancer patients, supporting the potential beneficial roles of ITC-containing cruciferous vegetables in breast cancer prognosis.

Protective role of naringin loaded solid nanoparticles against aflatoxin B1 induced hepatocellular carcinoma.

This study examines the hepatoprotective activity of naringin loaded solid nanoparticles (NRG-SLNs) and compared with free naringin (FNRG) against aflatoxin B1 (AFB1) induced hepatocellular carcinoma. The liver's self-healing ability was studied using a self-recovery group that received no therapy. Following AFB1 therapy, rats were given NRG-SLNs produced using the ion-gelation technique. Histology, serum injury indicators, oxidative stress biomarkers, a pro-inflammatory response biomarker, and tumor indicators were used to evaluate the liver tumor and its responsiveness to therapy. At a dosage of 6.18 mg/kg BW, NRG-SLNs (128 ± 4 nm) provided substantially greater hepatoprotection than free NRG. The actions of NRG-SLNs were equivalent to those of silymarin (SILY), which was given at a dosage of 20 mg/kg BW. The lack of regeneration potential of liver tissue after the damage was verified by the self-recovery group. NRG's efficiency in treating hepatic cancer was increased by using SLN's approach. The increased impact is most likely due to: a) enhanced oral bioavailability, b) the regulated and sustained action of enclosed NRG, and c) a decrease in discomfort and toxicity if any after orally administered. NRG-SLNs may be considered as a therapeutic option for hepatic ailments as effectiveness post-induction of liver carcinoma, is demonstrated presently.

Downregulation of circ-SFMBT2 blocks the development of gastric cancer by targeting the miR-885-3p/CHD7 pathway.

Accumulating evidence insists that circular RNAs (circRNAs) play important roles in the development of human cancers, including gastric cancer. This study aimed to investigate the role of circ-SFMBT2 and provide a potential mechanism to explain its function. The expression of circ-SFMBT2, miR-885-3p and chromodomain-helicase-DNA-binding protein 7 (CHD7) mRNA was determined by quantitative real-time PCR (qRT-PCR), and the protein level of CHD7 was determined by western blot. To investigate the function of circ-SFMBT2 in vitro, the effects of circ-SFMBT2 on cell viability, colony formation, apoptosis, migration and invasion were assessed using cell counting kit-8 assay, colony formation assay, flow cytometry assay, wounding healing assay and transwell assay, respectively. The indicators of oxidative stress were assessed using matched kits. Besides, the function of circ-SFMBT2 was also investigated in animal models. The relationship between miR-885-3p and circ-SFMBT2 or CHD7 was verified by dual-luciferase reporter assay and RNA immunoprecipitation assay. Circ-SFMBT2 and CHD7 were upregulated, whereas miR-885-3p was downregulated in gastric cancer tissues and cells. In functional assay, circ-SFMBT2 knockdown suppressed gastric cancer cell viability, colony formation ability, migration, invasion and oxidative stress but induced apoptosis, and circ-SFMBT2 downregulation also blocked tumor growth in vivo. In mechanism analysis, circ-SFMBT2 regulated CHD7 expression by sponging its target miRNA, miR-885-3p. Rescue experiments manifested that miR-885-3p inhibition reversed the effects of circ-SFMBT2 knockdown, and CHD7 overexpression abolished the antitumor role of miR-885-3p overexpression. Moreover, circ-SFMBT2 knockdown inactivated the Wnt/ß-catenin signaling pathway. Circ-SFMBT2 downregulation repressed the development of gastric cancer partially by controlling the miR-885-3p/CHD7 axis, which might be a novel strategy to inhibit gastric cancer progression.

Differential Associations of SLCO Transporters with Prostate Cancer Aggressiveness between African Americans and European Americans.

BACKGROUND: Androgen receptor signaling is crucial to prostate cancer aggressiveness. Members of the solute carrier family of the organic anion transporting peptides (SLCO) are potential regulators of androgen availability in prostate tissue. It remains unknown whether genetic variations in SLCOs contribute to the differences in prostate cancer aggressiveness in African Americans (AA) and European Americans (EA). METHODS: SNPs in 11 SLCO members were selected, with addition of 139 potentially functional SNPs and 128 ancestry informative markers. A total of 1,045 SNPs were genotyped and analyzed in 993 AAs and 1,057 EAs from the North Carolina-Louisiana Prostate Cancer Project. Expression and cellular localization of SLCOs were examined using qRT-PCR, IHC, and in situ RNA hybridization in independent sets of prostate cancer cases. RESULTS: Significant associations with prostate cancer characteristics were found for SNPs in SLCO2A1 and SLCO5A1. The associations differed by race (P interaction < 0.05). SNPs in SLCO2A1 were associated with reduced tumor aggressiveness and low Gleason score in AAs; whereas, SNPs in SLCO5A1 were associated with high clinical stage in EAs. In prostate tissue, SLCO2A1 and SLCO5A1 were the most expressed SLCOs at the mRNA level and were expressed predominantly in prostate endothelial and epithelial cells at the protein level, respectively. CONCLUSIONS: SLCO2A1 and SLCO5A1 play important but different roles in prostate cancer aggressiveness in AAs versus EAs. IMPACT: The finding calls for consideration of racial differences in biomarker studies of prostate cancer and for investigations on functions of SLCO2A1 and SLCO5A1 in prostate cancer.

Effects of cooking methods on total isothiocyanate yield from cruciferous vegetables.

Cruciferous vegetables are primary sources of dietary isothiocyanates (ITCs), a group of phytochemicals showing promising cancer-chemopreventive activities in multiple cancer models. However, no study has thoroughly examined how cooking affects the yields of ITCs from cruciferous vegetables. In this study, a high-performance liquid chromatography (HPLC)-based cyclocondensation assay was performed to examine the ITC yields from four major cruciferous vegetables (broccoli, cabbage, cauliflower, and kale) under six cooking conditions (stir-frying, steaming, microwaving, boiling, stewing, and chip-baking for kale only) and measured the level of ITCs under the raw condition for a comprehensive list of cruciferous vegetables and ITC-containing condiments. A wide range of ITC yields was found across vegetables and condiments. Cooking significantly altered the ITC yields, showing an averagely four-fold increase by lightly cooking (stir-frying, steaming, and microwaving) and a 58% decrease by heavily cooking (boiling, stewing, and chip-baking). These findings will provide the evidence-based cooking guidance on cruciferous vegetable consumption and help better estimate dietary ITC exposure in epidemiologic studies.