Some new soliton solutions of a semi-discrete fractional complex coupled dispersionless system.

In this paper, a semi-discrete fractional derivative complex coupled dispersionless system is proposed. The properties of M-fractional derivative are utilized to convert discrete M-fractional derivative system to a classical discrete differential system. Then the invariant subspace method (ISM) is utilized to find dark, bright, kink and W-shaped soliton solutions for the proposed system.

Therapeutic approaches for anti-sperm-antibodies in the testicular sperm aspiration rat model.

Background and Aim: Anti-sperm antibodies (ASAs) treatment continued to be neglected. This study aimed to generate ASAs using the testicular sperm aspiration (TSA) rat model, which allowed for investigation of four distinct therapeutic approaches to find potential treatments for ASAs. Materials and Methods: Adult Wistar albino male rats were divided into six equal groups (n = 12). The negative control group underwent scrotal sac surgery without having their testicles punctured. Punctures were made in the remaining 5 groups, with one group left untreated to serve as the positive control group. The remaining 4 groups were treated with either dexamethasone (DEX), azathioprine (AZA), frankincense, or anti-ASAs secondary antibodies. For 10 weeks, serum samples were collected every 2 weeks for specific quantification of ASAs. Testis and epididymis tissues were collected for histopathological analysis. Results: The ASAs concentrations of the positive controls were significantly higher (p ≤ 0.001) than their negative control counterparts during the examined weeks. However, The ASAs indices (%) differed according to the treatment type. While the ASAs indices at the 2nd and 4th weeks in the AZA-treated group were significantly reduced compared to the positive control group (p ≤ 0.001), no significant differences were observed at any of the sample collection week for the DEX-treated rats. The ASAs indices were significantly decreased only at weeks 6 and 8 of treatment in the frankincense-treated group (p ≤ 0.001). In the secondary antibodies-treated group, the antibody indices were significantly decreased in all weeks except for samples collected at week 4 (p ≤ 0.001). The testosterone levels reverted to normal only in TSA rats treated with either Frankincense or secondary antibodies, as they were significantly higher than the positive controls (p ≤ 0.05). Tissue samples from the secondary antibody-treated rats showed a generally normal histological appearance. Conclusion: This study tried to offer realistic therapy suggestions; however, caution should be applied when extrapolating findings from experimental models to meet clinical requirements.

Effect of Various Intermittent Fasting Protocols on Hyperglycemia-Induced Cognitive Dysfunction in Rats.

Diabetes mellitus is a highly prevalent metabolic disorder that causes cognitive decline. Here, we investigated the impact of various intermittent fasting protocols on type 2 diabetes mellitus (T2DM)-induced cognitive dysfunction in a rodent model. Male Sprague-Dawley rats (aged 3 months) were randomly assigned to five groups (n = 6 per group) and T2DM was induced by streptozotocin (60 mg/kg, IM). The control group was untreated. Cognitive function was tested (Y-maze, novel object recognition, and elevated plus maze tests) and glucose was assessed. The T2DM rats exhibited significantly higher blood glucose, which is associated with cognitive dysfunction. Compared to the validated animal model of T2DM in rats, various intermittent fasting protocols decreased blood glucose and improved cognitive function. These results indicate that various intermittent fasting protocols may be a potential strategy for managing the hyperglycemia-associated cognitive dysfunction.

Tumor necrosis factor-alpha antibody labeled-polyethylene glycol-coated nanoparticles: A mesenchymal stem cells-based drug delivery system in the rat model of cisplatin-induced nephrotoxicity.

Background and Aim: A delivery system consisting of bone marrow mesenchymal stem cells (MSCs) loaded with polyethylene glycol (PEG) coated superparamagnetic iron oxide nanoparticles (SPIONs) was constructed to treat a rat model of cisplatin (Cis)-induced nephrotoxicity with 1/10 of the common dose of anti-tumor necrosis factor-alpha (TNF-α) antibodies (infliximab). Materials and Methods: Morphology, size, crystallinity, molecular structure, and magnetic properties of uncoated and PEG-coated SPIONs were analyzed. A delivery system consisting of MSCs containing infliximab-labeled PEG-coated SPIONs (Infliximab-PEG-SPIONs-MSCs) was generated and optimized before treatment. Fifty female Wistar rats were divided into five equal groups: Group 1: Untreated control; Group 2 (Cis): Rats were administered Cis through intraperitoneal (i.p.) injection (8 mg/kg) once a week for 4 weeks; Group 3 (Infliximab): Rats were injected once with infliximab (5 mg/kg), i.p. 3 days before Cis administration; Group 4 (Cis + MSCs): Rats were injected with Cis followed by an injection of 2 × 106 MSCs into the tail vein twice at a 1-week interval; and Group 5 (Cis + Infliximab (500 mg/kg)-PEG-SPIONs-MSCs): Rats were injected with the delivery system into the tail vein twice at a 1-week interval. Besides histological examination of the kidney, the Doppler ultrasound scanner was used to scan the kidney with the Gray-color-spectral mode. Results: In vivo, intra-renal iron uptake indicates the traffic of the delivery system from venous blood to renal tissues. Cis-induced nephrotoxicity resulted in a significant increase in TNF-α and malondialdehyde (MDA) (p < 0.05), bilirubin, creatinine, and uric acid (p < 0.01) levels compared with the untreated control group. The different treatments used in this study resulted in the amelioration of some renal parameters. However, TNF-α levels significantly decreased in Cis + Infliximab and Cis + MSCs (p < 0.05) groups. The serum levels of MDA significantly decreased in Cis + Infliximab (p < 0.05), Cis + MSCs (p < 0.05), and Cis + Infliximab-PEG-SPIONs-MSCs (p < 0.01). Furthermore, the serum activities of antioxidant enzymes were significantly elevated in the Cis + MSCs and Cis + Infliximab-PEG-SPIONs-MSCs groups (p < 0.05) compared to the Cis-induced nephrotoxicity rat model. Conclusion: With the support of the constructed MSCs-SPIONs infliximab delivery system, it will be possible to track and monitor cell homing after therapeutic application. This infliximab-loading system may help overcome some challenges regarding drug delivery to the target organ, optimize therapeutics' efficacy, and reduce the dose. The outcomes of the current study provide a better understanding of the potential of combining MSCs and antibodies-linked nanoparticles for the treatment of nephrotoxicity. However, further investigation is recommended using different types of other drugs. For new approaches development, we should evaluate whether existing toxicity analysis and risk evaluation strategies are reliable and enough for the variety and complexity of nanoparticles.

Amelioration of aflatoxin acute hepatitis rat model by bone marrow mesenchymal stem cells and their hepatogenic differentiation.

Background and Aim: Bone marrow-derived mesenchymal stem cells (BM-MSCs) transplantation and their hepatogenic differentiated cells (HDCs) can be applied for liver injury repair by tissue grafting. Regenerative potentiality in liver cirrhosis models was widely investigated; however, immunomodulation and anti-inflammation in acute hepatitis remain unexplored. This study aimed to explore the immunomodulatory and evaluate twice intravenous (IV) or intrahepatic (IH) administration of either BM-MSCs or middle-stage HDCs on aflatoxin (AF) acute hepatitis rat model. Materials and Methods: BM-MSCs viability, phenotypes, and proliferation were evaluated. Hepatogenic differentiation, albumin, and mmmmmmmm-fetoprotein gene expression were assessed. AF acute hepatitis was induced in rats using AFB1 supplementation. The transplantation of BM-MSCs or their HDCs was done either by IV or IH route. Hepatic ultrasound was performed after 3-weeks of therapy. Cytokines profile (tumor necrosis factor-α [TNF-α], interleukin [IL]-4, and IL-10) was assessed. Hepatic bio-indices, serum, and hepatic antioxidant activity were evaluated, besides examining liver histological sections. Results: Acute AFB1 showed a significant increase in TNF-α (p<0.01), liver enzyme activities (p<0.05), as well as decrease in IL-4, IL-10, and antioxidant enzyme activities (p<0.05). Cytokines profile was ameliorated in groups treated with IV and IH BM-MCs, showed a negative correlation between IL-4 and TNF-α (p<0.05), and a positive correlation between IL-10 upregulation and TNF-α (p<0.01). In IV HDCs treated group, positive correlations between IL-4 and IL-10 downregulation and TNF-α were observed. However, in IH HDCs group, a significant positive correlation between IL-4 and IL-10 upregulation and TNF-α, were recorded (p<0.05). In addition, IV BM-MSCs and IH HDCs treatments significantly increased antioxidant enzymes activity (p<0.05). IV and IH BM-MSCs significantly ameliorated liver transaminase levels, whereas IH HDCs significantly ameliorated alanine aminotransferase activity and nitric oxide concentration (p<0.05). Conclusion: The administration routes of BM-MSCs did not demonstrate any significant difference; however, the IH route of HDCs showed significant amelioration from the IV route. On the other hand, it showed noticeable anti-inflammatory and immunomodulatory improvements in aflatoxicosis rats. Therefore, it can be concluded that acute hepatitis can be treated by a noninvasive IV route without the expense of hepatogenic differentiation. Further research using clinical trials that address several problems regarding engraftment and potentiation are needed to determine the optimal manipulation strategy as well as to achieve better long term effects.

Impact of age on treatment response in men with prostate cancer treated with radiotherapy.

Objective: To analyse the effect of age at diagnosis on clinical outcomes of localized prostate cancer (PCa) treated with radiation therapy. Subjects and methods: We identified 12 784 patients with intermediate- or high-risk localized PCa treated with radiation therapy (RT) and neoadjuvant androgen deprivation therapy (ADT) between 2000 and 2015 from nationwide Veterans Affairs data. Patients were grouped into three age categories (≤59, 60-69, and ≥70 years old). Outcomes included immediate PSA response (3-month post-RT PSA and 2-year PSA nadir, grouped into <0.10 ng/ml, 0.10-0.49 ng/ml, and ≥0.50 ng/ml), biochemical recurrence, and PCa-specific mortality. Multivariable regression models included ordinal logistic regression for short-term PSA outcomes, Cox regression for biochemical recurrence, and Fine-Gray competing risks regression for PCa-specific mortality. Results: A total of 2136 patients (17%) were ≤59 years old at diagnosis, 6107 (48%) were 60-69 years old, and 4541 (36%) were ≥70 years old. Median follow-up was 6.3 years. Younger age was associated with greater odds of higher 3-month PSA group (≤59 vs. ≥70: adjusted odds ratio [aOR] 1.90, 95% CI 1.64-2.20; p < 0.001) and higher 2-year PSA nadir group (≤59 vs. ≥70: aOR 1.89, 95% CI 1.62-2.19, p < 0.001). Younger age was associated with greater risk of biochemical recurrence (≤59 vs. ≥70: adjusted hazard ratio 1.45, 95% CI 1.26-1.67, p < 0.001) but not PCa-specific mortality (p = 0.16). Conclusion: In a large nationwide sample of US veterans treated with ADT and RT for localized PCa, younger age was associated with inferior short-term PSA response and higher risk of biochemical recurrence.

An evaluation of trends in the representation of patients by age, sex, and diverse race/ethnic groups in bladder and kidney cancer clinical trials.

OBJECTIVES: To determine the representation of women, minorities, and the elderly groups in clinical trials and whether participation has changed over time. METHODS: Retrospective study in the National Cancer Institute (NCI) Clinical Data Update System and Center for Disease Control and Prevention United States Cancer Statistics 2000 to 2019. We compared cancer incidence proportion to proportion of patients enrolled in an NCI trial when stratified by race/ethnicity, sex, and age. We performed multivariable analysis to determine the odds of participating in a clinical trial in 2015 to 2019 when compared to 2000 to 2004. RESULTS: This study included 14,094 patients, 12,169 (86.3%) non-Hispanic White patients, 662 (4.7%) Black patients, and 660 (4.7%) Hispanic patients. There were 3,701 (26.3%) female patients and 10,393 (73.7%) male patients. For bladder cancer clinical trials, Black patients and Hispanic patients were underrepresented in clinical trials compared to Non-Hispanic White patients (odds ratio [OR] 0.71, 95% confidence interval [CI] 0.57-0.88, P = 0.002) and (OR 0.69, 95%CI 0.54-0.88, P = 0.003), respectively. For kidney cancer trials, Black and Hispanic patients were underrepresented in clinical trials compared to Non-Hispanic White patients (OR 0.42, OR 0.33-0.54, P < 0.001) and (OR 0.68, 95% CI 0.55-0.83, P < 0.001), respectively. Women were underrepresented in kidney cancer trials compared to men (OR 0.80, 95% CI 0.72-0.89) and similarly for bladder cancer trials (OR 0.72, 95% CI 0.64-0.81, P < 0.001). For bladder cancer trials, the participation of Black patients over time (OR 1.04, P = 0.814) and female patients over time (OR 1.03, P = 0.741) were unchanged. For kidney cancer trials, the participation of Black patients over time (OR 1.17, P = 0.293) and female patients over time (OR 1.03, P = 0.663) participation was also unchanged. CONCLUSION: In this study of clinical trials in bladder and kidney cancer, we identified that Blacks, Hispanics, and females were underrepresented. Additionally, Black and female participation was unchanged over the span of 20 years.

Metastasis and Mortality in Men With Low- and Intermediate-Risk Prostate Cancer on Active Surveillance.

BACKGROUND: Active surveillance (AS) is a safe treatment option for men with low-risk, localized prostate cancer. However, the safety of AS for patients with intermediate-risk prostate cancer remains unclear. PATIENTS AND METHODS: We identified men with NCCN-classified low-risk and favorable and unfavorable intermediate-risk prostate cancer diagnosed between 2001 and 2015 and initially managed with AS in the Veterans Health Administration. We analyzed progression to definitive treatment, metastasis, prostate cancer-specific mortality (PCSM), and all-cause mortality using cumulative incidences and multivariable competing-risks regression. RESULTS: The cohort included 9,733 men, of whom 1,007 (10.3%) had intermediate-risk disease (773 [76.8%] favorable, 234 [23.2%] unfavorable), followed for a median of 7.6 years. The 10-year cumulative incidence of metastasis was significantly higher for patients with favorable (9.6%; 95% CI, 7.1%-12.5%; P<.001) and unfavorable intermediate-risk disease (19.2%; 95% CI, 13.4%-25.9%; P<.001) than for those with low-risk disease (1.5%; 95% CI, 1.2%-1.9%). The 10-year cumulative incidence of PCSM was also significantly higher for patients with favorable (3.7%; 95% CI, 2.3%-5.7%; P<.001) and unfavorable intermediate-risk disease (11.8%; 95% CI, 6.8%-18.4%; P<.001) than for those with low-risk disease (1.1%; 95% CI, 0.8%-1.4%). In multivariable competing-risks regression, favorable and unfavorable intermediate-risk patients had significantly increased risks of metastasis and PCSM compared with low-risk patients (all P<.001). CONCLUSIONS: Compared with low-risk patients, those with favorable and unfavorable intermediate-risk prostate cancer managed with AS are at increased risk of metastasis and PCSM. AS may be an appropriate option for carefully selected patients with favorable intermediate-risk prostate cancer, though identification of appropriate candidates and AS protocols should be tested in future prospective studies.

Association of Health-Care System and Survival in African American and Non-Hispanic White Patients With Bladder Cancer.

BACKGROUND: African American patients with bladder cancer have inferior outcomes compared with non-Hispanic White (White) patients. We hypothesize that access to health care is a primary determinant of this disparity. We compared outcomes by race for patients with bladder cancer receiving care within the predominant hybrid-payer health-care model of the United States captured in the Surveillance, Epidemiology, and End Results (SEER) database with those receiving care within the equal-access model of the Veterans' Health Administration (VHA). METHODS: African American and White patients diagnosed with bladder cancer were identified in SEER and VHA. Stage at presentation, bladder cancer-specific mortality (BCM), and overall survival (OS) were compared by race within each health-care system. RESULTS: The SEER cohort included 122 449 patients (93.7% White, 6.3% African American). The VHA cohort included 36 322 patients (91.0% White, 9.0% African American). In both cohorts, African American patients were more likely to present with muscle-invasive disease and metastases, but the differences between races were statistically significantly smaller in VHA. In SEER multivariable models, African American patients had worse BCM (hazard ratio [HR] = 1.22, 95% confidence interval [CI] = 1.15 to 1.29) and OS (HR = 1.26, 95% CI = 1.20 to 1.31). In contrast within the VHA, African American patients had similar BCM (HR = 0.97, 95% CI = 0.88 to 1.07) and OS (HR = 0.99, 95% CI = 0.93 to 1.05). CONCLUSIONS: In this study of contrasting health-care models, receiving medical care in an equal-access system was associated with reduced differences in stage at presentation and eliminated disparities in survival outcomes for African American patients with bladder cancer. Our findings highlight the importance of reducing financial barriers to care to notably improve health equity and oncologic outcomes for African American patients.

Disparities and trends in the participation of minorities, women, and the elderly in breast, colorectal, lung, and prostate cancer clinical trials.

BACKGROUND: This study was done to determine the representation of minorities, women, and the elderly in National Cancer Institute (NCI) clinical trials. METHODS: This is an analysis in the NCI Clinical Data Update System. Patients were evaluated in breast, colorectal, lung, and prostate cancer trials from 2000 to 2019. Representation in a trial was determined by race/ethnicity, sex, and age. Secondarily, the change in trial participation by multivariable analysis by comparing years 2000 through 2004 to 2015 through 2019 was evaluated. RESULTS: The cohort included 242,720 participants: 197,320 Non-Hispanic White (81.3%), 21,190 Black (8.7%), 11,587 Hispanic (4.8%), and 6880 Asian/Pacific Islander (2.8%). Black and Hispanic patients were underrepresented for colorectal (odds ratio [OR], 0.58; 95% confidence interval [CI], 0.50-0.67; P < .001 and OR, 0.74; 95% CI, 0.64-0.87; P < .001, respectively), lung (OR, 0.83; 95% CI, 0.76-0.91; P < .001 and 0.66; 95% CI, 0.57-0.77; P < .001, respectively), and prostate cancer trials (OR, 0.85; 95% CI, 0.79-0.92; P < .001 and OR, 0.58; 95% CI, 0.51-0.66; P < .001) between 2015 and 2019. The odds of participation in 2015 to 2019 increased among Black patients in breast (OR, 2.19; 95% CI, 2.07-%2.32; P < .001), lung (OR, 1.54; 95% CI, 1.38-1.73; P < .001), and prostate cancer trials (OR, 1.14; 95% CI, 1.04-1.26; P < .001). The odds of participation in a trial among Hispanic patients increased for breast (OR, 3.32; 95% CI, 3.09-3.56; P < .001), colorectal (OR, 2.46; 95% CI, 2.04-2.96; P < .001), lung (OR, 3.88; 95% CI, 3.20-4.69; P < .001), and prostate cancer (OR, 1.70; 95% CI, 1.42-2.04; P = .005). CONCLUSIONS: This study identified that Black and Hispanic patients remain underrepresented in trials, but in recent years, participation has increased. These findings indicate that minority participation has increased over time, but further efforts are needed.

Outcomes for Muscle-invasive Bladder Cancer with Radical Cystectomy or Trimodal Therapy in US Veterans.

BACKGROUND: Muscle-invasive bladder cancer (MIBC) remains undertreated despite multiple potentially curative options. Both radical cystectomy (RC) with or without neoadjuvant chemotherapy and trimodal therapy (TMT), including transurethral resection of bladder tumor followed by chemoradiotherapy, are standard treatments. OBJECTIVE: To evaluate real-world clinical outcomes of RC with neoadjuvant chemotherapy (RC-NAC), RC without NAC, TMT with National Comprehensive Cancer Network guideline-preferred radiosensitizing chemotherapy including cisplatin or mitomycin-C and 5-fluorouracil (pTMT), and TMT with nonpreferred chemotherapy (npTMT). DESIGN SETTING AND PARTICIPANTS: US veterans with nonmetastatic MIBC (T2-4aN0-3M0) were studied. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Overall mortality (OM) was evaluated with multivariable Cox proportional hazard model. Bladder cancer-specific mortality (BCSM) was evaluated with multivariable Fine-Gray regression. Salvage cystectomy rates were obtained by chart review. RESULTS AND LIMITATIONS: Overall 2306 patients were included: 1472 (64%) with RC without NAC, 506 (22%) with RC-NAC, 163 (7%) with pTMT, and 165 (7%) with npTMT. On multivariable analysis, pTMT was associated with similar OM (hazard ratio [HR] 1.19; 95% confidence interval [CI] 0.94-1.50; p = 0.15) and BCSM (HR 1.34; 95% CI 0.99-1.83; p = 0.06) to RC-NAC; npTMT was associated with worse OM (HR 1.30; 95% CI 1.04-1.61; p = 0.02) and BCSM (HR 1.45; 95% CI 1.09-1.94; p = 0.01). RC without NAC was associated with similar OM (HR 1.08; 95% CI 0.95-1.24; p = 0.24) and BCSM (HR 1.02; 95% CI 0.86-1.21; p = 0.79). When stratified by age, among patients ≥65 yr of age, treatment with pTMT was associated with similar OM (HR 1.14; 95% CI 0.87-1.50; p = 0.35) and BCSM (HR 1.11; 95% CI 0.76-1.62; p = 0.60). Among patients <65 yr of age, pTMT was associated with worse OM (HR 1.82; 95% CI 1.14-2.91; p = 0.01) and BCSM (HR 2.51; 95% CI 1.52-4.13; p < 0.01). The 5-yr cumulative incidence of salvage cystectomy in the TMT group was 3.6%. CONCLUSIONS: In MIBC, patients receiving pTMT have comparable survival in RC-NAC patients ≥65 yr and inferior survival in RC-NAC patients <65 yr. Salvage cystectomy rates were low. PATIENT SUMMARY: Management of muscle-invasive bladder cancer is a multidisciplinary effort requiring thoughtful discussions with patients about treatment options, including trimodal therapy, which is an effective treatment option.

Active surveillance for intermediate-risk prostate cancer in African American and non-Hispanic White men.

BACKGROUND: The safety of active surveillance (AS) for African American men compared with non-Hispanic White (White) men with intermediate-risk prostate cancer is unclear. METHODS: The authors identified patients with modified National Comprehensive Cancer Network favorable ("low-intermediate") and unfavorable ("high-intermediate") intermediate-risk prostate cancer diagnosed between 2001 and 2015 and initially managed with AS in the Veterans Health Administration database. They analyzed definitive treatment, disease progression, metastases, prostate cancer-specific mortality (PCSM), and all-cause mortality by using cumulative incidences and multivariable competing-risks (disease progression, metastasis, and PCSM) or Cox (all-cause mortality) regression. RESULTS: The cohort included 1007 men (African Americans, 330 [32.8%]; Whites, 677 [67.2%]) followed for a median of 7.7 years; 773 (76.8%) had low-intermediate-risk disease, and 234 (23.2%) had high-intermediate-risk disease. The 10-year cumulative incidences of definitive treatment were not significantly different (African Americans, 83.5%; 95% confidence interval [CI], 78.5%-88.7%; Whites, 80.6%; 95% CI, 76.6%-84.4%; P = .17). Among those with low-intermediate-risk disease, there were no significant differences in the 10-year cumulative incidences of disease progression (African Americans, 46.8%; 95% CI, 40.0%-53.3%; Whites, 46.9%; 95% CI, 42.1%-51.5%; P = .91), metastasis (African Americans, 7.1%; 95% CI, 3.7%-11.8%; Whites, 10.8%; 95% CI, 7.6%-14.6%; P = .17), or PCSM (African Americans, 3.8%; 95% CI, 1.6%-7.5%; Whites, 3.8%; 95% CI, 2.0%-6.3%; P = .69). In a multivariable regression including the entire cohort, African American race was not associated with increased risks of definitive treatment, disease progression, metastasis, PCSM, or all-cause mortality (all P > .30). CONCLUSIONS: Outcomes in the Veterans Affairs Health System were similar for African American and White men treated for low-intermediate-risk prostate cancer with AS.

Clarifying the Trade-Offs of Risk-Stratified Screening for Prostate Cancer: A Cost-Effectiveness Study.

Cancer risk prediction is necessary for precision early detection, which matches screening intensity to risk. However, practical steps for translating risk predictions to risk-stratified screening policies are not well established. We used a validated population prostate-cancer model to simulate the outcomes of strategies that increase intensity for men at high risk and reduce intensity for men at low risk. We defined risk by the Prompt Prostate Genetic Score (PGS) (Stratify Genomics, San Diego, California), a germline genetic test. We first recalibrated the model to reflect the disease incidence observed within risk strata using data from a large prevention trial where some participants were tested with Prompt PGS. We then simulated risk-stratified strategies in a population with the same risk distribution as the trial and evaluated the cost-effectiveness of risk-stratified screening versus universal (risk-agnostic) screening. Prompt PGS risk-adapted screening was more cost-effective when universal screening was conservative. Risk-stratified strategies improved outcomes at a cost of less than $100,000 per quality-adjusted life year compared with biennial screening starting at age 55 years, but risk stratification was not cost-effective compared with biennial screening starting at age 45. Heterogeneity of risk and fraction of the population within each stratum were also important determinants of cost-effectiveness.

Bone marrow mesenchymal stem cell co-adjuvant therapy with albendazole for managing Toxocara vitulorum-rat model.

BACKGROUND AND AIM: Toxocara vitulorum is a bovine intestinal nematode. Immune pictures following infection are conflicting and stopping anthelmintic albendazole treatment recording reversed liver abnormalities. The purpose of this work was to evaluate the therapeutic potential of bone marrow mesenchymal stem cells (BMMSCs) therapy, subsequent to albendazole administration in rats infected with T. vitulorum. MATERIALS AND METHODS: The ultrasonographic and histopathological examinations as well as serum liver enzymes activity and the kinetics of recovery were investigated. The correlation of cell-mediated and humoral immune pictures was assessed by assaying immunoglobulins, splenocytes viability, phagocytic index, and Th1/Th2 cytokines. RESULTS: The cultured BMMSCs counting were 4.21×104 cells/cm2 with 96.03% viability. Flow-cytometric analysis indicated positive CD90 (82%), CD105 (79%) and negative CD34 (0.37%), CD45 (0.42%), attesting to the suitability of the isolated BMMSCs for use in therapy. Transplantation of BMMSCs after albendazole administration significantly reduced the release of liver enzymes (p<0.05) indicating liver cellularity improvement. The ultrasonographic, macroscopic, and histopathological findings confirmed the biochemical results. Significant elevation in the levels of tumor necrosis factor (TNF)-α and interferon (INF)-γ with a decline in interleukin (IL)-4 was observed in the untreated model (p<0.05). However, albendazole treatment followed by BMMSCs therapy significantly lowered the release of TNF-α and INF-γ, associated with significant production of IL-4 and IL-10 (p<0.05). CONCLUSION: The final results indicated that the liver functions, histopathological findings, and immune parameters were aggravated after experimental T. vitulorum infection. Albendazole treatment followed by BMMSCs therapy was found to assist in regeneration of injured hepatic tissue. Besides, it appeared to modulate host defensive immune responses against T. vitulorum antigens. This work could define more clearly the events that manipulate the host immune, histopathological, and biochemical responses to minimize obstacles in using stem cell therapy in animal toxocariosis.

Pathologic nodal downstaging in men with clinically involved lymph nodes undergoing radical prostatectomy: Implications for definitive locoregional therapy.

A prostate cancer (CaP) patient with nonmetastatic but clinical positive lymph nodes (cN+) represents a difficult clinical scenario. We compare overall survival (OS) between cN+ men that underwent radical prostatectomy (RP) and were found to have negative node status (pN) with those found to have positive nodal status (pN+), and assess predictors of discordant nodal status. We queried the National Cancer Data Base between 2004 and 2015 for patients that were cT1-3 cN+ cM0 CaP treated with RP. Patients with 0 nodes, cT4, or cM1 disease were excluded. We compared groups based on pathologic nodal status: Discordant (cN+ -> pN) & Concordant (cN+ -> pN+). Kaplan Meier estimations were used to compare OS. Logistic regression was used to determine possible predictors of nodal status. We find that of 6470 cN+ patients, 1,367 (21.1%) underwent RP, 866 (13.4%) had confirmed nodal status. Discordant status was found in 159 (18.4%) and concordant staging in 707 (81.6%). Differences exist in PSA at diagnosis (7.3 vs. 11.2), biopsy group, # of nodes examined (7 vs. 10), race, and Charlson index. Discordant staging had longer OS compared to Concordant staging (P = 0.007) and similar OS to a 3:1 matched cohort of high risk localized CaP patients used as reference (P = 0.46). Lower Gleason Score (GG1-3) was associated with an increased likelihood of discordant staging. Clinical nodal staging is associated with a substantial false positive rate. Discordant status had better OS than Concordant status and similar OS to matched patients with localized CaP. Clinical nodal staging may inappropriately lead to noncurative therapy in a substantial number of men with potentially curable disease.

Impact of Late Dosing on Testosterone Suppression with 2 Different Leuprolide Acetate Formulations: In Situ Gel and Microsphere. An Analysis of United States Clinical Data.

PURPOSE: Nonadherence to dosing schedules for androgen deprivation therapy increases the risk of testosterone escape for patients with prostate cancer. Two approved formulations of leuprolide acetate, the most commonly prescribed androgen deprivation therapy in the United States, use different extended release delivery technologies: an in situ gel and microspheres. We evaluated the prevalence and impact of late dosing on testosterone suppression for gel and microsphere formulations of leuprolide acetate. MATERIALS AND METHODS: We retrospectively analyzed records of patients with prostate cancer treated with gel or microsphere delivery of leuprolide acetate. Analyses used 2 definitions of "month," "28-day" (late dosing after day 28, 84, 112 or 168) and "extended" (late dosing after day 32, 97, 128 and 194). Frequencies of late dosing and associated testosterone values were calculated. RESULTS: A total of 2,038 patients received gel and 8,360 received microsphere formulations of leuprolide acetate. More than 80% and 27% of injections were late for 28-day and extended month, respectively. For 28-day month late injections 10% (gel delivery) and 14% (microsphere delivery) of testosterone values were above 50 ng/dl, and 25% (gel) vs 33% (microsphere) were above 20 ng/dl. For extended month 18% (gel) vs 25% (microsphere) were above 50 ng/dl, and 34% (gel) vs 44% (microsphere) were above 20 ng/dl. Microsphere leuprolide acetate was 1.5 times more likely to have testosterone above 50/20 ng/dl vs gel. Least square mean testosterone was 34 ng/dl (gel) vs 46 ng/dl (microsphere) for 28-day month, and 48 ng/dl (gel) vs 76 ng/dl (microsphere) for extended month. CONCLUSIONS: Leuprolide acetate therapies were frequently administered late. Gel formulation demonstrated higher rates of testosterone 50 ng/dl or less and 20 ng/dl or less than microsphere formulation. Optimal testosterone suppression can impact prostate cancer progression and patient survival, and differences in extended release technology for androgen deprivation therapy appear relevant.

Comparative characterization and osteogenic / adipogenic differentiation of mesenchymal stem cells derived from male rat hair follicles and bone marrow.

Clinical applications of cell therapy and tissue regeneration under different conditions need a multiplicity of adult stem cell sources. Up to date, little is available on the comparative isolation, characterization, proliferation, rapid amplification, and osteogenic/adipogenic differentiation of rat mesenchymal stem cells (MSCs) isolated from living bulge cells of the hair follicle (HF) and bone marrow (BM) from the same animal. This work hopes to use HF-MSCs as an additional adult stem cell source for research and application. After reaching 80% confluence, the cell counting, viability %, and yields of HF-MSCs and BM-MSCs were nearly similar. The viability % was 91.41 ± 2.98 and 93.11 ± 3.06 while the cells yield of initial seeding was 33.15 ± 2.76 and 34.22 ± 3.99 and of second passage was 28.76 ± 1.01 and 29.56 ± 3.11 for HF-MSCs and BM-MSCs respectively. Clusters of differentiation (CDs) analysis revealed that HF-MSCs were positively expressed CD34, CD73 and CD200 and negatively expressed CD45. BM-MSCs were positively expressed CD73 and CD200 and negatively expressed of CD34 and CD45. The proliferation of HF-MSCs and BM-MSCs was determined by means of incorporation of Brd-U, population doubling time (PDT) assays and the quantity of formazan release. The percentage of Brd-U positive cells and PDT were relatively similar in both types of cells. The proliferation, as expressed by the quantity of formazan assay in confluent cells, revealed that the quantity of release by BM-MSCs was slightly higher than HF-MSCs. Adipogenic differentiated BM-MSCs showed moderate accumulation of oil red-O stained lipid droplets when compared to that of HF-MSCs which exhibited high stain. The total lipid concentration was significantly higher in adipogenic differentiated HF-MSCs than BM-MSCs (P < 0.05). It was found that activity of bone alkaline phosphatase and calcium concentration were significantly higher (P < 0.01 and P < 0.05 respectively) in osteogenic differentiated BM-MSCs than that of HF-MSCs. The present findings demonstrate that the HF-MSCs are very similar in most tested characteristics to BM-MSCs with the exception of differentiation. Additionally; no issues have been reported during the collection of HF-MSCs. Therefore, the HF may represent a suitable and accessible source for adult stem cells and can be considered an ideal cell source for adipogenesis research.

Testosterone therapy does not increase the risks of prostate cancer recurrence or death after definitive treatment for localized disease.

BACKGROUND: The safety of testosterone therapy (TT) after definitive treatment for localized prostate cancer remains undefined. We analyzed the risks of biochemical recurrence and mortality in men receiving TT after treatment for localized prostate cancer. METHODS: Cohort analysis using the national US Veterans Affairs Informatics and Computing Infrastructure. We identified 69,984 patients with localized prostate cancer diagnosed from 2001 to 2015 treated with surgery or radiation. We coded receipt of TT after treatment as a time-dependent covariate; used the National Death Index to identify cause of death; and defined biochemical recurrence as PSA > 0.2 ng/mL after surgery and nadir + 2 ng/mL after radiation. We analyzed recurrence and mortality using cumulative incidence curves, Fine-Gray competing risk regression, and Cox regression. RESULTS: This cohort included 28,651 surgery patients and 41,333 radiation patients, of whom 469 (1.64%) and 543 (1.31%), respectively, received TT with a median follow-up of 6.95 years. Comparing testosterone users to nonusers, there were no between-group differences in biochemical recurrence, prostate cancer-specific mortality, or overall mortality after surgery [hazard ratios (HR): 1.07; HR: 0.72 (p = 0.43); and HR: 1.11 (p = 0.43), respectively] or radiation [HR: 1.07; HR: 1.02 (p = 0.95); and HR: 1.02 (p = 0.86), respectively]. Limitations included lack of detailed data on TT duration and serum testosterone concentrations. CONCLUSIONS: In this multi-ethnic national cohort, TT did not increase the risks of biochemical recurrence or prostate cancer-specific or overall mortality after surgery or radiation. These data suggest that TT is safe in appropriate men after definitive treatment of localized prostate cancer.

African-American men with low-risk prostate cancer treated with radical prostatectomy in an equal-access health care system: implications for active surveillance.

BACKGROUND: There is concern that African-American men (AA) with low-risk prostate cancer may present with more aggressive disease and thus may not be candidates for active surveillance (AS). However, it is uncertain if poorer outcomes are due to disparities in access to medical care rather than true biological differences. METHODS: Observational cohort study of patients diagnosed with low-risk PC-Gleason score ≤6, clinical tumor stage ≤2A, and prostate specific antigen (PSA) level ≤10-at US Department of Veterans Affairs between January 1, 2001 and October 31, 2015 and treated with radical prostatectomy. Outcomes included upgrading to Gleason Grade Group 2 (GG2), GG ≥ 3, PSA recurrence, pathologic tumor stage ≥3, positive surgical margins, and all-cause mortality. RESULTS: A total of 2857 men (AA: 835 White: 2022) with a median follow-up of 7.1 years. Overall, there was no significant difference between AA and White men in upgrading to GG ≥ 3 (RR = 1.18, p = 0.43), tumor stage ≥3 (RR = 0.95, p = 0.74), positive surgical margins (RR = 1.14, p = 0.20), PSA recurrence (SHR = 1.26, p = 0.06), and all-cause mortality (SHR = 1.26, p = 0.16). However, there was a significant increase in upgrading for AA to GG2 (RR = 1.49, p < 0.01). CONCLUSIONS: There was no significant difference in most adverse pathologic outcomes between AA and White patients. However, GG2 upgrading was more common in AA men. The implication is that AA may need to undergo additional evaluation, such as a biopsy MRI, before initiating AS. Whether the increase in GG2 upgrading will lead to poorer long-term clinical outcomes such as metastasis and PCSM also requires further investigation.

Bladder Cancer, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology.

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Bladder Cancer focuses on the clinical presentation and workup of suspected bladder cancer, treatment of non-muscle-invasive urothelial bladder cancer, and treatment of metastatic urothelial bladder cancer because important updates have recently been made to these sections. Some important updates include recommendations for optimal treatment of non-muscle-invasive bladder cancer in the event of a bacillus Calmette-Guérin (BCG) shortage and details about biomarker testing for advanced or metastatic disease. The systemic therapy recommendations for second-line or subsequent therapies have also been revised. Treatment and management of muscle-invasive, nonmetastatic disease is covered in the complete version of the NCCN Guidelines for Bladder Cancer available at NCCN.org. Additional topics covered in the complete version include treatment of nonurothelial histologies and recommendations for nonbladder urinary tract cancers such as upper tract urothelial carcinoma, urothelial carcinoma of the prostate, and primary carcinoma of the urethra.