Gemcitabine as first-line therapy for high-grade non-muscle invasive bladder cancer: results from a tertiary center in the contemporary BCG-shortage era.

Background: To evaluate the safety profile and efficacy of intravesical gemcitabine as first-line adjuvant therapy for non-muscle invasive bladder cancer (NMIBC) in the setting of ongoing Bacillus Calmette-Guérin (BCG) shortage. Methods: We performed an institutional, retrospective review of patients treated with intravesical gemcitabine induction and maintenance therapy from March 2019 to October 2021. Patients with intermediate or high-risk NMIBC who were BCG-naïve or experienced a high-grade (HG) recurrence after 12 months since the last dose of BCG were included in the analysis. The primary endpoint was complete response (CR) rate at the 3-month visit. Secondary endpoints were recurrence-free survival (RFS) and assessment of adverse events. Results: A total of 33 patients were included. All had HG disease and 28 (84.8%) were BCG-naive. The median follow-up was 21.4 months (range, 4.1-39.4). Tumor stages were cTa in 39.4%, cT1 in 54.5%, and cTis in 6.1% of patients. Most patients (90.9%) were in the AUA high-risk category. The 3-month CR was 84.8%. Among patients who achieved CR with adequate follow-up, 86.9% (20/23) remained disease-free at 6 months. The 6-month and 12-month RFS were 87.2% and 76.5%, respectively. The estimated median RFS was not reached. Approximately 78.8% of patients were able to complete full induction. Common adverse events (incidence ≥10%) included dysuria and fatigue/myalgia. Conclusions: Intravesical gemcitabine for intermediate and high-risk NMIBC in areas where BCG supply is limited was safe and feasible at short-term follow-up. Larger prospective studies are needed to better ascertain the oncologic efficacy of gemcitabine.

Gender, Racial and Ethnic Differences in Pathologic Response Following Neoadjuvant Chemotherapy for Bladder Cancer Patients.

OBJECTIVE: To evaluate trends and racial variations of pathologic complete response (CR) in patients with muscle-invasive bladder cancer undergoing cystectomy. MATERIALS AND METHODS: The National Cancer Database was queried for patients with non-metastatic muscle-invasive bladder cancer who underwent neoadjuvant chemotherapy and surgery. The primary endpoints, CR and mortality, were evaluated using the Cochran-Armitage test, multivariable regression, and Kaplan-Meier analyses. RESULTS: The cohort comprised 9955 patients. Non-Hispanic Black (NHB) patients were younger (P < .001), had a higher clinical tumor (P < .001), and had higher clinical node (P = .029) stages at presentation. CR for non-Hispanic White (NHW), NHB, and Hispanic patients were 12.6%, 10.1%, and 11.8%, respectively (P = .030). There was a significant increase in CR trends for NHW patients (P < .001) and increases in NHB (P = .311) and Hispanic patients (P = .236). On multivariable analysis, NHW females had lower odds of achieving CR (odds ratio: 0.83, 95% CI: 0.71-0.97); however, NHB males (hazard ratio: 1.21, 1.01-1.44) and NHB females (hazard ratio: 1.25, 1.03-1.53) had higher overall mortality in adjusted analysis. Survival differences were not observed in patients who achieved CR, regardless of racial background; however, for those with residual disease, the 2-year survival probabilities were 60.7%, 62.5%, and 51.1% for NHW, HW, and NHB patients, respectively (log-rank P = .010). CONCLUSION: Our findings revealed differences in chemotherapy response based on gender and race or ethnicity. The CR trends for all racial or ethnic groups increased over time. However, Black patients were found to have worse survival, particularly when residual disease was present. Clinical studies with more underrepresented minorities are needed to verify biological differences in response to neoadjuvant chemotherapy.

High-fat diet plus HNF1A variant promotes polyps by activating ß-catenin in early-onset colorectal cancer.

The incidence of early-onset colorectal cancer (EO-CRC) is rising and is poorly understood. Lifestyle factors and altered genetic background possibly contribute. Here, we performed targeted exon sequencing of archived leukocyte DNA from 158 EO-CRC participants, which identified a missense mutation at p.A98V within the proximal DNA binding domain of Hepatic Nuclear Factor 1 α (HNF1AA98V, rs1800574). The HNF1AA98V exhibited reduced DNA binding. To test function, the HNF1A variant was introduced into the mouse genome by CRISPR/Cas9, and the mice were placed on either a high-fat diet (HFD) or high-sugar diet (HSD). Only 1% of the HNF1A mutant mice developed polyps on normal chow; however, 19% and 3% developed polyps on the HFD and HSD, respectively. RNA-Seq revealed an increase in metabolic, immune, lipid biogenesis genes, and Wnt/ß-catenin signaling components in the HNF1A mutant relative to the WT mice. Mouse polyps and colon cancers from participants carrying the HNF1AA98V variant exhibited reduced CDX2 and elevated ß-catenin proteins. We further demonstrated decreased occupancy of HNF1AA98V at the Cdx2 locus and reduced Cdx2 promoter activity compared with WT HNF1A. Collectively, our study shows that the HNF1AA98V variant plus a HFD promotes the formation of colonic polyps by activating ß-catenin via decreasing Cdx2 expression.

Assessment of blended biochemistry classes based on massive open online courses and a "semi-flipped" learning environment.

Flipped classroom based on active learning is becoming an increasingly popular pedagogical method in higher education capable of increasing student performance in higher-order learning outcomes including application, analysis, evaluation, and creation. However, the success of a flipped classroom model relies on various supporting elements such as the accessibility of technology, and it may not be appropriate for all students and courses. In this study, a new blended biochemistry classroom model based on massive open online courses and a "semi-flipped" environment was applied to the students enrolled in three majors (stomatology, pharmacy, and preventive medicine) at Cheeloo College of Medicine, Shandong University, China. To assess the improvement of the students' perception of self-cognition in the blended biochemistry classes, surveys were conducted before and after undertaking the biochemistry course. Survey responses and total (final) score for the biochemistry course were analyzed using appropriate statistical methods. Compared to students who received traditional classroom instruction, students who participated in the blended classroom model achieved higher academic performance (p < 0.01) and reported a significant improvement in their perception of self-cognition (p < 0.01, or p < 0.05). More than 80% of participants preferred the blended classroom model to that of traditional classroom instruction.

Wnt/beta-catenin signaling confers ferroptosis resistance by targeting GPX4 in gastric cancer.

The development of chemotherapy resistance is the most vital obstacle to clinical efficacy in gastric cancer (GC). The dysregulation of the Wnt/beta-catenin signaling pathway is critically associated with GC development and chemotherapy resistance. Ferroptosis is a form of regulated cell death, induced by an iron-dependent accumulation of lipid peroxides during chemotherapy. However, whether the Wnt/beta-catenin signaling directly controls resistance to cell death, remains unclear. Here, we show that the activation of the Wnt/beta-catenin signaling attenuates cellular lipid ROS production and subsequently inhibits ferroptosis in GC cells. The beta-catenin/TCF4 transcription complex directly binds to the promoter region of GPX4 and induces its expression, resulting in the suppression of ferroptotic cell death. Concordantly, TCF4 deficiency promotes cisplatin-induced ferroptosis in vitro and in vivo. Thus, we demonstrate that the aberrant activation of the Wnt/beta-catenin signaling confers ferroptosis resistance and suggests a potential therapeutic strategy to enhance chemo-sensitivity for advanced GC patients.

How Do Blended Biochemistry Classes Influence Students' Academic Performance and Perceptions of Self-Cognition?

The flipped classroom is becoming a popular new instructional model in higher education capable of increasing student performance in higher-order learning outcomes. However, the success of a flipped classroom model depends on various supporting elements, and it may not be appropriate for all students and courses. In this study, a new blended Biochemistry classroom model based on Massive Open Online Courses (MOOC) and a "semi-flipped" environment was applied to Biochemistry instruction of Nursing and Clinical Medicine majors. The students' academic performance and perceptions of self-cognition were used to assess the blended Biochemistry classroom. Students who participated in the blended classroom model achieved higher academic performance (p < 0.01) and reported a significant improvement in their perceptions of self-cognition (p < 0.05) compared to the control group. Moreover, the effectiveness of the blended Biochemistry classroom on the small size class (Nursing major) was stronger than on the large size class (Clinical Medicine major).

Symptom Resolution and Recurrent Urinary Incontinence Following Removal of Painful Midurethral Slings.

OBJECTIVE: To evaluate pain improvement and recurrent stress incontinence (SUI) following painful synthetic midurethral sling (MUS) removal. METHODS: We conducted a retrospective review of patients who underwent synthetic MUS removal at our institution from 2009-2016 for the indication of pain. We recorded sling type (transobturator vs retropubic), complete vs partial removal, and presenting symptoms. Postoperative pain improvement was categorized as resolved (pain resolved, requiring no further therapy), improved (pain less bothersome, may require further therapy), or unresolved (no/minimal improvement, requiring further management). Recurrent incontinence and further reconstructive procedures were assessed. RESULTS: 87 patients (49 complete and 38 partial removal) with pain as the primary indication for removal were included. Median age at intervention was 54 years with median follow-up of 8 months. Overall, pain improved or resolved in 78.1% of cases. Complete removal was associated with significantly greater percentage of pain resolution (63.3%) compared to partial removal (26.3%) (P = 0.002) regardless of sling type. No significant differences in recurrent SUI were noted in complete vs partial removal. Additional reconstructive procedures were performed in 28 patients, most commonly sling placement, with no significant difference in complete (20.4%) vs partial (28.9%) removal groups (P = 0.36). The overall complication rate was low (5.7%), a majority of which were transfusions (4.6%). CONCLUSION: Following MUS removal, most patients experienced resolution or improvement of pain. Complete sling removal was associated with significantly greater percentage of pain resolution compared to partial removal in both retropubic and transobturator slings. Rates of recurrent SUI and reintervention for SUI were not related to the extent of sling removal.

Racial and Ethnic Disparities in Preoperative Surgical Wait Time and Renal Cell Carcinoma Tumor Characteristics.

Racial/ethnic minority groups have a disproportionate burden of kidney cancer. The objective of this study was to assess if race/ethnicity was associated with a longer surgical wait time (SWT) and upstaging in the pre-COVID-19 pandemic time with a special focus on Hispanic Americans (HAs) and American Indian/Alaska Natives (AIs/ANs). Medical records of renal cell carcinoma (RCC) patients who underwent nephrectomy between 2010 and 2020 were retrospectively reviewed (n = 489). Patients with a prior cancer diagnosis were excluded. SWT was defined as the date of diagnostic imaging examination to date of nephrectomy. Out of a total of 363 patients included, 34.2% were HAs and 8.3% were AIs/ANs. While 49.2% of HA patients experienced a longer SWT (≥90 days), 36.1% of Non-Hispanic White (NHW) patients experienced a longer SWT. Longer SWT had no statistically significant impact on tumor characteristics. Patients with public insurance coverage had increased odds of longer SWT (OR 2.89, 95% CI: 1.53-5.45). Public insurance coverage represented 66.1% HA and 70.0% AIs/ANs compared to 56.7% in NHWs. Compared to NHWs, HAs had higher odds for longer SWT in patients with early-stage RCC (OR, 2.38; 95% CI: 1.25-4.53). HAs (OR 2.24, 95% CI: 1.07-4.66) and AIs/ANs (OR 3.79, 95% CI: 1.32-10.88) had greater odds of upstaging compared to NHWs. While a delay in surgical care for early-stage RCC is safe in a general population, it may negatively impact high-risk populations, such as HAs who have a prolonged SWT or choose active surveillance.

Histone chaperone FACT complex inhibitor CBL0137 interferes with DNA damage repair and enhances sensitivity of medulloblastoma to chemotherapy and radiation.

Medulloblastoma (MB) is a malignant pediatric brain tumor with a poor prognosis. Post-surgical radiation and cisplatin-based chemotherapy have been a mainstay of treatment, which often leads to substantial neurocognitive impairments and morbidity, highlighting the need for a novel therapeutic target to enhance the sensitivity of MB tumors to cytotoxic therapies. We performed a comprehensive study using a cohort of 71 MB patients' samples and pediatric MB cell lines and found that MB tumors have elevated levels of nucleosome remodeling FACT (FAcilitates Chromatin Transcription) complex and DNA repair enzyme AP-endonuclease1 (APE1). FACT interacts with APE1 and facilitates recruitment and acetylation of APE1 to promote repair of radiation and cisplatin-induced DNA damage. Further, levels of FACT and acetylated APE1 both are correlate strongly with MB patients' survival. Targeting FACT complex with CBL0137 inhibits DNA repair and alters expression of a subset of genes, and significantly improves the potency of cisplatin and radiation in vitro and in MB xenograft. Notably, combination of CBL0137 and cisplatin significantly suppressed MB tumor growth in an intracranial orthotopic xenograft model. We conclude that FACT complex promotes chemo-radiation resistance in MB, and FACT inhibitor CBL0137 can be used as a chemo-radiation sensitizer to augment treatment efficacy and reduce therapy-related toxicity in high-risk pediatric patients.

Nephrectomy Delay of More than 10 Weeks from Diagnosis Is Associated with Decreased Overall Survival in pT3 RCC.

In this study, we aimed to evaluate the impact of surgical wait time (SWT) on outcomes of patients with renal cell carcinoma (RCC), and to investigate risk factors associated with prolonged SWT. Using the National Cancer Database, we retrospectively reviewed the records of patients with pT3 RCC treated with radical or partial nephrectomy between 2004 and 2014. The cohort was divided based on SWT. The primary outcome was 5-year overall survival (OS). Logistic regression analysis was used to investigate the risk factors associated with delayed surgery. Cox proportional hazards models were fitted to assess relations between SWT and 5-year OS after adjusting for confounding factors. A total of 22,653 patients were included in the analysis. Patients with SWT > 10 weeks had higher occurrence of upstaging. Using logistic regression, we found that female patients, African-American or Spanish origin patients, treatment in academic or integrated network cancer center, lack of insurance, median household income of <$38,000, and the Charlson-Deyo score of ≥1 were more likely to have prolonged SWT. SWT > 10 weeks was associated with decreased 5-year OS (hazard ratio [HR], 1.24; 95% confidence interval [CI], 1.15-1.33). This risk was not markedly attenuated after adjusting for confounding variables, including age, gender, race, insurance status, Charlson-Deyo score, tumor size, and surgical margin status (adjusted HR, 1.13; 95% CI, 1.04-1.24). In conclusion, the vast majority of patients underwent surgery within 10 weeks. There is a statistically significant trend of increasing SWT over the study period. SWT > 10 weeks is associated with decreased 5-year OS.

APE1 and SSRP1 is overexpressed in muscle invasive bladder cancer and associated with poor survival.

BACKGROUND: Human apurinic/apyrimidinic (AP) endonuclease 1 (APE1) plays a critical role in DNA base excision repair (BER) pathway and has been reported to be overexpressed in multiple cancers. Previously, we have shown that histone chaperone FACT complex (Facilitates Chromatin Transcription, a heterodimer of SSRP1 and SPT16 proteins) facilitates the chromatin access and DNA repair function of APE1, and their expression levels are correlated with promoting drug resistance in cancer. FACT inhibitor has been introduced in phase I and II clinical trials for chemosensitization of advanced solid cancers. However, the expression profile and prognostic significance of APE1 and FACT complex in bladder cancer remains largely unknown. METHODS: Retrospectively, 69 bladder cancer samples were retrieved and submitted for immunohistochemical staining of APE1 and SSRP1. Expression profile including cytoplasmic and nuclear staining of APE1 and expression level of SSRP1 was examined and semi-quantified to render a H-score. The prognostic significance of APE1 and SSRP1 was evaluated by Kaplan-Meier survival analysis in our cohort and R2 database. RESULTS: APE1 expression is elevated in bladder cancer compared to normal adjacent tissues. Compared with low grade tumors, high grade tumors show a shift in the staining pattern including higher intensity and positive cytoplasmic staining. Carcinoma in situ has a similar staining pattern to high grade tumors. APE1 and SSRP1 staining intensity increases as tumor progresses with stage. There is a correlation between APE1 and SSRP1 staining in invasive bladder cancer (Spearman r = 0.5466, p < 0.0001). The increased expression of APE1 and SSRP1 is associated with poor survival in Kaplan-Meier analysis in our cohort and in R2-TCGA bladder cancer database. CONCLUSIONS: The expression levels of APE1 and SSRP1 are significantly elevated in bladder cancer as compared to normal adjacent tissues. APE1 correlates with SSRP1 expression in high grade tumors. Overexpression of APE1 and SSRP1 is associated with poor survival in bladder cancer. This suggests the usage of FACT inhibitor curaxins in muscle invasive bladder cancer to target FACT complex and APE1 to improve chemosensitization after further validation.

Leiomyosarcoma of the scrotum: a case report and literature review.

Leiomyosarcoma (LMS) is one of the most common forms of soft tissue sarcoma with approximately 2,500 cases per year in the United States. The symptoms LMS vary depending upon the location, size, and spread of the tumor. In early stages, it may not be associated with any obvious symptoms so diagnosis and treatment may be delayed. In some cases, it can grow quickly and behave aggressively. Most types of LMS occur in the abdomen or in the uterus; although, scrotal LMS can be a very rare presentation of the disease. Here we present our case of a large, ulcerated scrotal LMS originating from subcutaneous tissue but not invading spermatic cord or tunica. Radical orchiectomy with high ligation of spermatic cord was performed, and patient had an uneventful postoperative course. This disease entity remains rare in the literature, and warrants larger studies in order to better understand treatment and oncologic outcomes. When LMS is identified early and is removed by surgical excision, prognosis can be good and full recovery quite likely. When LMS is already large or has spread to other parts of the body, treatment is relatively more complex and the prognosis poor. Hence, prompt diagnosis and treatment of genitourinary LMS require prompt attention, referral to tertiary, referral center should be strongly considered.

Helicobacter pylori Induces a Novel NF-kB/LIN28A/let-7a/hTERT Axis to Promote Gastric Carcinogenesis.

Reactivated telomerase is a crucial event in the development and progression of a variety of tumors. However, how telomerase is activated in gastric carcinogenesis has not been fully uncovered yet. Here, we identified a key role of the NF-κB/LIN28A/let-7a axis to promote human telomerase reverse transcriptase (hTERT) expression for gastric cancer initiation. Mechanistically, LIN28A expression was upregulated by H. pylori-induced NF-κB activation. And LIN28A, in turn, suppressed let-7a expression, forming the NF-κB/LIN28A/let-7a axis to regulate gene expression upon H. pylori infection. Of note, we first discovered hTERT as a direct target of let-7a, which inhibited hTERT expression by binding to its 3'UTR of mRNA. Therefore, H. pylori-triggered let-7a downregulation enhanced hTERT protein translation, resulting in telomerase reactivation. Furthermore, hTERT enhanced LIN28A expression, forming the positive feedback regulation between hTERT and NF-κB/LIN28A/let-7a axis to maintain the sustained overexpression of hTERT in gastric cancer. IMPLICATIONS: The NF-κB/LIN28A/Let-7a axis was crucial for the overexpression of hTERT upon H. pylori infection during gastric cancer development and may serve as a potential target to suppress hTERT expression for gastric cancer prevention and treatment.

Robotic Cystoprostatectomy With Intracorporeal Ileal Conduit Diversion in a Patient With Chronic Schistosomiasis.

We present an interesting case of a patient who initially presented with urinary retention and was subsequently found to have bilateral grade 5 vesicoureteral reflux, a thick and noncompliant bladder, and biopsy proven ova of Schistosoma haematobium. This patient was subsequently managed surgically with a robotic radical cystoprostatectomy with intracorporeal ileal conduit diversion. Final pathology revealed chronic schistosomiasis with numerous ova present throughout the bladder. To our knowledge, no similar cases have been previously documented in the literature.

Partial Penectomy for Dry Penile Gangrene in a Patient With Penile Calciphylaxis.

Penile calciphylaxis is a difficult urologic condition to manage. First described by Wood et al in 1997, penile calciphylaxis is a rare cause of penile gangrene.1 One study found the overall mortality rate associated with penile calciphylaxis to be 64%, with a mean time to death of 2.5 months.2 Additionally, no statistically significant difference in survival has been seen between patients treated with penectomy and those treated nonoperatively.3 We report a case of penile calciphylaxis in a patient treated with partial penectomy with scrotoplasty who has survived greater than 1 year without any complication or progression of disease.

Holmium Laser Enucleation of the Prostate Is Safe and Feasible as a Same Day Surgery.

OBJECTIVE: To assess the safety, feasibility and treatment outcomes of holmium laser enucleation of the prostate (HoLEP) as a same day surgery (SDS). METHODS: HoLEPs performed from November 2013 to December 2018 at our institution were reviewed retrospectively. Inclusion criteria for same day surgery (SDS) included living in the local metropolitan area with access to local hospital and Eastern Cooperative Oncology Group (ECOG) 0-2, regardless of prostate size and anticoagulation status. Those patients who were discharged directly from the postoperative care unit were identified as SDS cases. Patients admitted overnight after HoLEP during the same period were used as a matched cohort. Patient demographics, disease characteristics and treatment outcomes were compared. RESULTS: A total of 377 patients were identified, including 199 SDS and 178 non-SDS patients. No statistical difference was present between the 2 groups regarding the post-op complication and readmission rates. The non-SDS group had a significantly higher percentage of patients with history of urinary retention, lower pre-op Qmax, and larger prostate volume. The SDS group had shorter operative time, length of stay (LOS), and catherization time (all P <.05). At 1-year follow-up, no statistically different change in Qmax, PVR, or IPSS score was noted between the 2 groups. CONCLUSION: Same day outpatient surgery for HoLEP is safe in patients who live in close proximity and have ECOG status 0-2. Our readmission rate and complication rate are comparable to those reported in the literature with markedly decreased LOS. Long-term functional outcome is not compromised by SDS.

Perioperative outcomes of open vs. robotic radical cystectomy: a nationwide comparative analysis (2008-2014).

INTRODUCTION: Radical cystectomy (RC) is a complex procedure with high perioperative morbidity. In an effort to reduce complications, robotic-assisted RC (RARC) has been adopted as a minimally invasive alternative to the open approach (ORC). Herein, we examine post-operative outcomes of the two surgical approaches in the United States (US) using a large all-payer database. MATERIAL AND METHODS: Using International Classification of Disease, ninth revision (ICD-9) codes, patient who underwent RC were captured from National Inpatient Sample (2008-2014). ICD-9 diagnosis and procedure codes were used to identify post-operative complications. Trends in the utilization of RARC were analyzed. Logistic and log-linear regression accounting for hospital sample weights and sampling years were performed to analyze outcomes after adjustment of pertinent covariates. RESULTS: Of 11,189 patients, 14% underwent RARC. RARC was performed in more teaching hospitals, male patients, those with private insurance, and lower comorbidity score. Performance of RARC steadily increased over the study period (p <0.01). In the last year of the study, 22.8% of cases performed robotically. The weighted average length-of-stay were 10.4 and 8.79 days for ORC and RARC, respectively (p <0.01). In multivariable analyses, RARC was associated with decreased blood transfusion, parenteral nutrition, pneumonia, surgical-site infection, wound and respiratory complications (all, p <0.05). No significant differences were found for in-hospital mortality, cardiac, genitourinary, and vascular complications. CONCLUSIONS: Performance of RARC has significantly increased in recent years. RARC appears safe and feasible for select patients. Earlier discharge and lower complications were noted for those undergoing RARC across different hospital systems nationwide.