Sequential intravesical gemcitabine/docetaxel provides a durable remission in recurrent high-risk NMIBC following BCG therapy.

PURPOSE: Bacillus Calmette-Guerin (BCG) is the standard of care for high-risk nonmuscle invasive bladder cancer (NMIBC), but half of patients develop disease recurrence. Intravesical regimens for BCG unresponsive NMIBC are limited. We report the safety, efficacy, and differential response of sequential gemcitabine/docetaxel (gem/doce) depending on BCG failure classification. METHODS: Multi-institutional retrospective analysis of patients treated with induction intravesical gem/doce (≥5/6 instillations) for recurrent high-risk NMIBC after BCG therapy from May 2018 to December 2021. Maintenance therapy was provided to those without high-grade (HG) recurrence on surveillance cystoscopy. Kaplan-Meier curves and Cox regression analyses were utilized to assess survival and risk factors for disease recurrence. RESULTS: Our cohort included 102 patients with BCG-unresponsive NMIBC. Median age was 72 years and median follow-up was 18 months. Six-, 12-, and 24-month high-grade recurrence-free survival was 78%, 65%, and 49%, respectively. Twenty patients underwent radical cystectomy (median 15.5 months from induction). Six patients progressed to muscle invasive disease. Fifty-seven percent of patients experienced mild/moderate adverse effects (AE), but only 6.9% experienced a delay in treatment schedule. Most common AE were urinary frequency/urgency (41%) and dysuria (21%). Patients with BCG refractory disease were more likely to develop HG recurrence when compared to patients with BCG relapsing disease (HR 2.14; 95% CI 1.02-4.49). CONCLUSIONS: In patients with recurrence after BCG therapy, sequential intravesical gem/doce is an effective and well-tolerated alternative to early cystectomy. Patients with BCG relapsing disease are more likely to respond to additional intravesical gem/doce. Further investigation with a prospective trial is imperative.

Preoperative anemia is associated with increased radical cystectomy complications.

PURPOSE: The impact of anemia in postoperative complications following radical cystectomy (RC) is not completely elucidated and its association with direct hospital costs has not been characterized in depth. Our goal is to determine the association between anemia, 90-day surgical complications and the expenditure attributed to preoperative anemia in patients undergoing RC. MATERIALS AND METHODS: We captured all patients who underwent RC between 2003 and 2017 using the Premier Hospital Database (Premier Inc, Charlotte, NC). Patient, hospital and surgical characteristics were evaluated. Anemia was defined by a corresponding diagnostic code that was present on admission prior to RC. Unadjusted patients' demographic characteristics with and without anemia, hospital and surgeon characteristics were compared, and multivariable regression models were developed to evaluate 90-day complications and total direct hospital costs. RESULTS: The cohort included 83,470 patients that underwent RC between 2003 and 2017 and 11% were found to be anemic. On multivariable analysis, preoperative anemia more than doubled the odds of having a complication (odds ratio 2.19 (1.89-2.53)) and significantly increased the risk of major complications (odds ratio 1.51 (1.31-1.75)) at 90-days after RC. Anemic patients had significantly higher 90-days total direct costs due to higher laboratory, pharmacologic, radiology and operating room costs. CONCLUSIONS: Anemic cystectomy patients face a 50% increase in the risk of major complications within the first 90-days after surgery. This increased risk persisted after adjusting for patient, hospital and surgical factors. Our study suggests hematocrit level prior to RC may be used as a pre-exisitng condition for increased risk of surgical complications.

Active surveillance for intermediate-risk prostate cancer.

INTRODUCTION: Active surveillance (AS) is an established approach in the management of low-risk, localized prostate cancer. While the use of AS to manage intermediate-risk (IR) disease has gradually increased over time, there remains uncertainty with regards to its safety, with only a minority of IR patients currently being managed with this approach. MATERIALS AND METHODS: We conducted a narrative review based on an analysis of the literature focusing on articles describing AS for IR prostate cancer. We focus on the uncertainty surrounding AS in IR disease by discussing variations in the definitions and guideline recommendations associated with IR disease, and describing the limitations of the evidence from observational studies and randomized trials. CONCLUSION: The safety of AS for IR disease remains unknown, given the lack of randomized trials and the limitations of the current observational studies. Further research is needed to identify select patients with IR prostate cancer that can be managed safely with AS.

Integrative clinical and molecular characterization of translocation renal cell carcinoma.

Translocation renal cell carcinoma (tRCC) is a poorly characterized subtype of kidney cancer driven by MiT/TFE gene fusions. Here, we define the landmarks of tRCC through an integrative analysis of 152 patients with tRCC identified across genomic, clinical trial, and retrospective cohorts. Most tRCCs harbor few somatic alterations apart from MiT/TFE fusions and homozygous deletions at chromosome 9p21.3 (19.2% of cases). Transcriptionally, tRCCs display a heightened NRF2-driven antioxidant response that is associated with resistance to targeted therapies. Consistently, we find that outcomes for patients with tRCC treated with vascular endothelial growth factor receptor inhibitors (VEGFR-TKIs) are worse than those treated with immune checkpoint inhibitors (ICI). Using multiparametric immunofluorescence, we find that the tumors are infiltrated with CD8+ T cells, though the T cells harbor an exhaustion immunophenotype distinct from that of clear cell RCC. Our findings comprehensively define the clinical and molecular features of tRCC and may inspire new therapeutic hypotheses.

Genomic Features of Muscle-invasive Bladder Cancer Arising After Prostate Radiotherapy.

BACKGROUND: Muscle-invasive bladder cancer (MIBC) is a rare but serious event following definitive radiation for prostate cancer. Radiation-associated MIBC (RA-MIBC) can be difficult to manage given the challenges of delivering definitive therapy to a previously irradiated pelvis. The genomic landscape of RA-MIBC and whether it is distinct from non-RA-MIBC are unknown. OBJECTIVE: To define mutational features of RA-MIBC and compare the genomic landscape of RA-MIBC with that of non-RA-MIBC. DESIGN, SETTING, AND PARTICIPANTS: We identified patients from our institution who received radiotherapy for prostate cancer and subsequently developed MIBC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We performed whole exome sequencing of bladder tumors from RA-MIBC patients. Tumor genetic alterations including mutations, copy number alterations, and mutational signatures were identified and were compared with genetic features of non-RA-MIBC. We used the Kaplan-Meier method to estimate recurrence-free (RFS) and overall (OS) survival. RESULTS AND LIMITATIONS: We identified 19 RA-MIBC patients with available tumor tissue (n = 22 tumors) and clinical data. The median age was 76 yr, and the median time from prostate cancer radiation to RA-MIBC was 12 yr. The median RFS was 14.5 mo and the median OS was 22.0 mo. Compared with a cohort of non-RA-MIBC analyzed in parallel, there was no difference in tumor mutational burden, but RA-MIBCs had a significantly increased number of short insertions and deletions (indels) consistent with previous radiation exposure. We identified mutation signatures characteristic of APOBEC-mediated mutagenesis, aging, and homologous recombination deficiency. The frequency of mutations in many known bladder cancer genes, including TP53, KDM6A, and RB1, as well as copy number alterations such as CDKN2A loss was similar in RA-MIBC and non-RA-MIBC. CONCLUSIONS: We identified unique mutational properties that likely contribute to the distinct biological and clinical features of RA-MIBC. PATIENT SUMMARY: Bladder cancer is a rare but serious diagnosis following radiation for prostate cancer. We characterized genetic features of bladder tumors arising after prostate radiotherapy, and identify similarities with and differences from bladder tumors from patients without previous radiation.

Cyclophosphamide-associated bladder cancers and considerations for survivorship care: A systematic review.

PURPOSE: We performed a systematic review to assess the clinical features of cyclophosphamide-associated bladder cancer. MATERIALS AND METHODS: MEDLINE, Web of Science, and Cochrane Library were searched from inception to August 2020 according to PRISMA guidelines. Studies that associated bladder cancer with prior cyclophosphamide use on an individual level were included. RESULTS: We identified 121 studies spanning over a 50-year period with 285 patients. The most common malignant indication for cyclophosphamide was lymphoma (25%), while the most common non-malignant indication was ANCA-associated vasculitides (26%). Hematuria and dysuria were the most prevalent symptoms prior to a cyclophosphamide-associated bladder cancer diagnosis, and median age at diagnosis was 55 years. Conventional urothelial carcinoma (UC) was the most common bladder-associated diagnosis (74%), although a broad range of cancer types were represented, notably leiomyosarcoma and squamous cell carcinoma. About half of bladder cancers were muscle invasive at diagnosis and median latency time was 10.0 years; 33% of patients had a bladder cancer related death. CONCLUSIONS: We describe the largest pooled analysis of patients with cyclophosphamide-associated bladder cancer. These bladder cancers have a propensity for younger age at diagnosis, more advanced stage at diagnosis, and variant histology. There was a substantial number of patients with latency time of ≥20 years independent of cumulative cyclophosphamide dose. These findings support consideration of screening and long-term surveillance of cancer survivors with a history of cyclophosphamide therapy for bladder cancer.

Retzius-sparing Robot-assisted Radical Prostatectomy Leads to Durable Improvement in Urinary Function and Quality of Life Versus Standard Robot-assisted Radical Prostatectomy Without Compromise on Oncologic Efficacy: Single-surgeon Series and Step-by-step Guide.

BACKGROUND: Retzius-sparing robot-assisted radical prostatectomy (RS-RARP) has been shown to improve continence. However, questions remain regarding feasibility and generalizability of technique and outcomes. OBJECTIVE: To compare the outcomes of 140 consecutive standard robot-assisted radical prostatectomy (S-RARP) versus RS-RARP. DESIGN, SETTING, AND PARTICIPANTS: A total of 70 S-RARPs were performed followed by 70 RS-RARPs. Demographic, pathologic, and functional outcomes were compared preoperatively and through 12 mo. Expanded Prostate Cancer Index Composite for Clinical Practice (EPIC-CP) was used to compare functional outcomes. Logistic and linear regression analyses were utilized to analyze variables associated with EPIC-CP urinary incontinence and overall quality of life (QOL) scores, and oncologic outcomes. Cox regression analysis was used to analyze incontinence at 12 mo. SURGICAL PROCEDURE: RS-RARP versus S-RARP. MEASUREMENTS: Patient and tumor characteristics (age, body mass index, prostate-specific antigen, Charlson Comorbidity Index, Gleason group, clinical stage, and Prostate Imaging Reporting and Data System score), perioperative outcomes (console time, estimated blood loss, postoperative complications, and length of stay), oncologic outcomes (positive surgical margin [PSM], and biochemical recurrence), overall and 12-mo continence rates (zero pads and zero to one safety pad), time to continence, potency (erection sufficient for sexual activity), EPIC-CP urinary incontinence, sexual function, and overall QOL scores. RESULTS AND LIMITATIONS: Median follow-up for S-RARP versus RS-RARP was 46.3 versus 12.3 mo. RS-RARP versus S-RARP had improved overall continence rates at total follow-up (95.7% vs 85.7%, p = 0.042) and 12-mo follow-up (97.6% vs 81.4%, p = 0.002), and faster return to continence (zero to one safety pad, 44 vs 131 d, p < 0.001). RS-RARP EPIC-CP urinary incontinence and overall QOL scores remained significantly better at 12 mo. There were no differences in overall PSM rates, although RS-RARP had lower rates of nonfocal PSMs. There were no differences in sexual function. In multivariate analysis, RS-RARP was significantly associated with improved 12-mo EPIC-CP urinary incontinence and improved QOL scores, but was not associated with PSM or biochemical recurrence. Limitations include retrospective study design and unequal follow-up; however, significantly better RS-RARP continence at 12 mo is striking despite fewer patients attaining 12-mo follow-up. CONCLUSIONS: RS-RARP significantly improves early and long-term continence without compromising oncologic outcomes and leads to overall improved QOL. PATIENT SUMMARY: Retzius-sparing robot-assisted radical prostatectomy is an emerging technique for robotic radical prostatectomy that improves urinary function and quality of life without compromising cancer control.

Complications associated with perioperative use of tyrosine kinase inhibitor in cytoreductive nephrectomy.

Recent clinical trials have investigated the benefit of combining tyrosine kinase inhibitors (TKIs) and cytoreductive nephrectomy (CN) in patients with metastatic renal cell carcinoma. Our goal is to determine whether the perioperative use of TKIs increases the postoperative morbidity following CN in renal cell carcinoma patients. We identified 627 patients with Stage IV renal cell carcinoma who underwent CN from 2007-2010 utilizing the SEER-Medicare database. Eighty-two patients treated with TKIs were matched (3:1) to 246 controls. We calculated 30- and 90-day incidence rates of postoperative complications and mortality. On unadjusted analysis, TKI use prior to CN was associated with higher overall complication rate within 30 days (HR = 2.73, 95% CI: 1.09-6.8) after surgery. On multivariate analysis, perioperative TKI use was independently associated with higher risk for postoperative complications within 30 days (HR = 2.93, 95% CI: 1.17-7.36), as well as 90 days (HR = 1.84, 95% CI: 1.02-3.32) after nephrectomy. A higher Charlson comorbidity index also emerged to represent an independent risk factor for postoperative complications within 30 days (HR = 2.41, 95% CI: 1.44-4.02) and 90 days (HR = 2.23, 95% CI: 1.51-3.29) after nephrectomy. TKI treatment was not associated with an increased postoperative mortality at 30 and 90 days after surgery. Thus, TKI treatment was associated with an increased complication rate but not overall mortality following CN. Our results suggest that renal surgeons should be aware of possibly increased complications following CN in renal cell carcinoma patients, when TKI treatment is administered.

Survival and secondary interventions following treatment for locally-advanced prostate cancer.

INTRODUCTION: The utility of radical prostatectomy (RP) for locally-advanced prostate cancer remains unknown. Retrospective data has shown equivalent oncologic outcomes compared to radiation therapy (RT). RP may provide local tumor control and prevent secondary interventions from local invasion, and may decrease costs. MATERIALS AND METHODS: Using SEER-Medicare data from 1995-2011 we identified men with locally-advanced prostate cancer undergoing RP or RT. Rates of post-treatment diagnoses and interventions were identified using ICD-9 and CPT codes. Skeletal related events (SRE), androgen deprivation therapy (ADT) utilization, all-cause mortality, prostate cancer-specific mortality, and costs were compared. RESULTS: A total of 8367 men with locally-advanced prostate cancer were identified (6200 RP, 2167 RT). RT was associated with increased urinary obstruction, hematuria, infection, and cystoscopic intervention while RP was associated with increased urethral stricture intervention and erectile dysfunction. Compared to RT, RP was associated with decreased all-cause mortality (3.1 versus 5.2 deaths/100-person-years, p < 0.001), prostate cancer-specific mortality (0.8 versus 2.0 deaths/100-person-years, p < 0.001), SREs (2.0 versus 3.4 events/100 person-years, p < 0.001), and ADT utilization overall (7.4 versus 33.8 doses/100-person-years, p < 0.001) and > 3 years after treatment (3.6 versus 4.6 doses/100-person-years, p < 0.001). Overall and cancer specific costs were significantly lower for RP versus RT. CONCLUSIONS: RT for locally-advanced prostate cancer has a higher incidence of mortality, secondary diagnoses and interventions, SRE, and ADT utilization compared to RP. This may lead to increased costs and have implications for quality of life. Our findings support the utility of RP in appropriately selected men with locally-advanced prostate cancer given the possible decreased morbidity and survival benefit.

Incidental bladder cancers found on multiparametric MRI of the prostate gland: a single center experience.

PURPOSE: In the era of multiparametric magnetic resonance imaging (mpMRI) of the prostate gland, incidental findings are occasionally discovered on imaging. We aimed to report our experience of detecting incidental bladder cancers on mpMRI of the prostate in asymptomatic patients without irritative voiding symptoms or microscopic or gross hematuria. METHODS: A retrospective review was performed on a prospectively maintained database of all men who underwent prostate mpMRI at our institution from 2012 to 2018. Patients who were found to have incidental bladder lesions were identified and baseline demographics, imaging and histopathologic data were recorded. All patients with incidental bladder lesion detection on mpMRI, not attributable to extension of prostate cancer, underwent cystoscopy in addition to a biopsy and/or transurethral resection of bladder tumor (TURBT) if warranted on cystoscopy. RESULTS: There were 3147 prostate mpMRIs performed during this period and 25 cases (0.8%) of incidental bladder lesions were detected. These patients did not have any presenting symptoms such as gross or microscopic hematuria to prompt bladder lesion workup. The largest diameter of incidentally discovered bladder lesions ranged from 0.4 cm to 1.7 cm. Of the 25 cases of incidental bladder lesions, five were suspected to be due to prostate cancer invasion into the bladder. Only two of these five patients underwent biopsy, which confirmed prostate adenocarcinoma in both cases. Of the 20 patients without suspected prostate cancer invasion of the bladder, four had no suspicious lesions on cystoscopy to warrant a biopsy. The remaining 16 patients had bladder lesions seen on cystoscopy and underwent a biopsy and/or TURBT. Three of these patients had benign features on pathology (urachal remnant, amyloidosis and inflammation) and the remaining 13 had stage Ta urothelial carcinoma. Seven of these patients had low-grade Ta tumors and six had high-grade Ta tumors. All patients were treated with standard management of TURBT with or without intravesical BCG. There have been no reported cases of recurrence or progression in any of the patients in our cohort at the median follow-up of 26 months (interquartile range,19-40 months). CONCLUSION: mpMRI of the prostate may yield incidental findings, such as small bladder tumors. Awareness of the possibility of incidental bladder lesions is important as 65% of lesions reported in the bladder, not attributable to extension of prostate cancer, proved to be bladder cancer. This may allow for early intervention for asymptomatic patients with undetected bladder cancer prior to disease progression.

DNA Methylation Patterns Separate Senescence from Transformation Potential and Indicate Cancer Risk.

Overall shared DNA methylation patterns between senescence (Sen) and cancers have led to the model that tumor-promoting epigenetic patterns arise through senescence. We show that transformation-associated methylation changes arise stochastically and independently of programmatic changes during senescence. Promoter hypermethylation events in transformation involve primarily pro-survival and developmental genes, similarly modified in primary tumors. Senescence-associated hypermethylation mainly involves metabolic regulators and appears early in proliferating "near-senescent" cells, which can be immortalized but are refractory to transformation. Importantly, a subset of transformation-associated hypermethylated developmental genes exhibits highest methylation gains at all age-associated cancer risk states across tissue types. These epigenetic changes favoring cell self-renewal and survival, arising during tissue aging, are fundamentally important for stratifying cancer risk and concepts for cancer prevention.

A new immunohistochemistry prognostic score (IPS) for recurrence and survival in resected pancreatic neuroendocrine tumors (PanNET).

Pancreatic neuroendocrine tumor (PanNET) is a neoplastic entity in which few prognostic factors are well-known. Here, we aimed to evaluate the prognostic significance of N-myc downstream-regulated gen-1 (NDRG-1), O6-methylguanine DNA methyltransferase (MGMT) and Pleckstrin homology-like domain family A member 3 (PHLDA-3) by immunohistochemistry (IHC) and methylation analysis in 92 patients with resected PanNET and follow-up longer than 24 months. In multivariate analyses, ki-67 and our immunohistochemistry prognostic score (IPS-based on MGMT, NDRG-1 and PHLDA-3 IHC expression) were independent prognostic factors for disease-free-survival (DFS), while age and IPS were independent prognostic factors for overall survival (OS). Our IPS could be a useful prognostic biomarker for recurrence and survival in patients following resection for PanNET.

HES6 promotes prostate cancer aggressiveness independently of Notch signalling.

Notch signalling is implicated in the pathogenesis of a variety of cancers, but its role in prostate cancer is poorly understood. However, selected Notch pathway members are overrepresented in high-grade prostate cancers. We comprehensively profiled Notch pathway components in prostate cells and found prostate cancer-specific up-regulation of NOTCH3 and HES6. Their expression was particularly high in androgen responsive lines. Up- and down-regulating Notch in these cells modulated expression of canonical Notch targets, HES1 and HEY1, which could also be induced by androgen. Surprisingly, androgen treatment also suppressed Notch receptor expression, suggesting that androgens can activate Notch target genes in a receptor-independent manner. Using a Notch-sensitive Recombination signal binding protein for immunoglobulin kappa J region (RBPJ) reporter assay, we found that basal levels of Notch signalling were significantly lower in prostate cancer cells compared to benign cells. Accordingly pharmacological Notch pathway blockade did not inhibit cancer cell growth or viability. In contrast to canonical Notch targets, HES6, a HES family member known to antagonize Notch signalling, was not regulated by Notch signalling, but relied instead on androgen levels, both in cultured cells and in human cancer tissues. When engineered into prostate cancer cells, reduced levels of HES6 resulted in reduced cancer cell invasion and clonogenic growth. By molecular profiling, we identified potential roles for HES6 in regulating hedgehog signalling, apoptosis and cell migration. Our results did not reveal any cell-autonomous roles for canonical Notch signalling in prostate cancer. However, the results do implicate HES6 as a promoter of prostate cancer progression.

Notch signaling in prostate cancer: a moving target.

INTRODUCTION: By regulating cell fate, proliferation, and survival, Notch pathway signaling provides critical input into differentiation, organization, and function of multiple tissues. Notch signaling is also becoming an increasingly recognized feature in malignancy, including prostate cancer, where it may play oncogenic or tumor suppressive roles. METHODS: Based on an electronic literature search from 2000 to 2013 we identified, summarized, and integrated published research on Notch signaling dynamics in prostate homeostasis and prostate cancer. RESULTS: In benign prostate, Notch controls the differentiation state and architecture of the gland. In prostate cancer, similar features correlate with lethal potential and may be influenced by Notch. Increased Notch1 can confer a survival advantage on prostate cancer cells, and levels of Notch family members, such as Jagged2, Notch3, and Hes6 increase with higher cancer grade. However, Notch signaling can also antagonize growth and survival of both benign and malignant prostate cells, possibly through antagonistic effects of the Notch target HEY1 on androgen receptor function. DISCUSSION: Notch signaling can dramatically influence prostate development and disease. Determining the cellular contexts where Notch promotes or suppresses prostate growth could open opportunities for diagnostic and therapeutic interventions.

Tumorigenic potential of circulating prostate tumor cells.

Circulating tumor cells (CTCs) have received intense scientific scrutiny because they travel in the bloodstream and are therefore well situated to mediate hematogenous metastasis. However, the potential of CTCs to actually form new tumors has not been tested. Popular methods of isolating CTCs are biased towards larger, more differentiated, non-viable cells, creating a barrier to testing their tumor forming potential. Without relying on cell size or the expression of differentiation markers, our objective was to isolate viable prostate CTCs from mice and humans and assay their ability to initiate new tumors. Therefore, blood was collected from transgenic adenocarcinoma of the mouse prostate (TRAMP) mice and from human patients with metastatic castration-resistant prostate cancer (PCa). Gradient density centrifugation or red cell lysis was used to remove erythrocytes, and then leukocytes were depleted by magnetic separation using CD45 immunoaffinity beads. CTCs fractions from TRAMP mice and PCa patients were verified by immunocytochemical staining for cytokeratin 8 and EpCAM, and inoculated into immunodeficient mice. TRAMP tumor growth was monitored by palpation. Human tumor growth formation was monitored up to 8 months by ultrasensitive PSA assays performed on mouse serum. We found viable tumor cells present in the bloodstream that were successfully isolated from mice without relying on cell surface markers. Two out of nine immunodeficient mice inoculated with TRAMP CTCs developed massive liver metastases. CTCs were identified in blood from PCa patients but did not form tumors. In conclusion, viable CTCs can be isolated without relying on epithelial surface markers or size fractionation. TRAMP CTCs were tumorigenic, so CTCs isolated in this way contain viable tumor-initiating cells. Only two of nine hosts grew TRAMP tumors and none of the human CTCs formed tumors, which suggests that most CTCs have relatively low tumor-forming potential. Future studies should identify and target the highly tumorigenic cells.