Abstract Background Bacillus Calmette-Guérin (BCG) is the standard intravesical treatment of high-risk noninvasive (Ta, T1, Tis) bladder cancer. Maintenance BCG is recommended for maximum efficacy. ...Objective We compared our results in a large cohort of high-risk bladder cancer patients who received BCG without maintenance with published results from randomized maintenance BCG trials. Design, setting, and participants A cohort of 1021 patients underwent restaging transurethral resection for high-risk (Ta, T1, Tis) bladder cancer. Intervention Patients received a 6-wk induction course of BCG therapy. Responding patients did not receive maintenance BCG. Relapsing patients were eligible for retreatment with BCG. All patients were followed for a minimum of 5 yr. Measurements End points were 5-yr tumor- and progression-free survival rates. Results and limitations Of 816 complete responders to induction BCG, 2- and 5-yr recurrence-free survival rates were 73% and 46%, respectively. The progression-free survival rate was 89%. Progression-free survival time was 56 mo (95% confidence interval, 55–58 mo). Thirty-two percent of the patients required another course of BCG therapy. We cannot exclude that maintenance BCG may benefit patients beyond 5 yr over induction BCG alone and selective BCG retreatments. Conclusions Our results with BCG treatment without maintenance of patients with high-risk non–muscle-invasive bladder cancer compare favorably with trials in which comparable patients received maintenance BCG.
The aim of this study was to determine drug delivery/toxicity, and pathologic/surgical outcomes of patients with muscle-invasive bladder cancer (MIBC) receiving neoadjuvant gemcitabine-cisplatin (GC) ...plus radical cystectomy-pelvic lymph node dissection (RC-PLND).
Chemotherapy and surgical/pathologic outcomes were retrospectively analyzed with 5-year survival follow-up at a referral center. Post-neoadjuvant chemotherapy (NAC) pathologic endpoints included complete response (pT0N0), residual non-MIBC (pTa/Tis/T1N0), and ≥ MIBC (≥ pT2 and/or N+). Associations of pathologic/surgical findings with overall survival (OS), disease-free survival (DFS), and surgical management with RC-PLND were analyzed (Cox regression).
Clinical T2a-T4aN0M0 MIBC patients (n = 154) from January 2000-October 2012 received GC plus RC-PLND. Patients (n = 117; 76%) received GC × 4 and 136 (88%) GC × 3. Five-year OS was 61% (95% confidence interval CI, 53-71). Median number of resected lymph nodes (LNs) was 19. Down-staging was observed as follows: pT0N0: 21%; pTa/Tis/T1N0: 25%, with similar 5-year OS (85% and 89%, respectively). Five-year OS for < pT2 versus ≥ pT2 residual disease was 87% (95% CI, 78%-98%) versus 38% (95% CI, 27%-53%); P < .001. Post-NAC stage ≥ pT2 (HR, 6.79; 95% CI, 2.63-17.53; P < .001), positive LN (HR, 3.64; 95% CI, 1.84-7.19; P < .001), and positive margins (HR, 4.15; 95% CI, 1.68-10.25; P = .002) were associated with increased risk of all-cause death (multivariable analysis). An HR of 0.97 (95% CI, 0.94-1.00) was observed for each additional node removed, but this effect was not statistically significant (P = .056).
Neoadjuvant GC achieves meaningful pathologic responses. Patients with ≥ pT2 residual disease, positive margins, or positive LN post-chemotherapy have inferior survival.
We sought to define the efficacy and tolerability of the commonly used regimen of neoadjuvant gemcitabine and cisplatin (GC) followed by surgery at a single center. Retrospective analysis of 154 patients who received neoadjuvant GC revealed a pathologic downstaging rate of 46% and a 5-year overall survival of 87% with any degree of downstaging from muscle invasion. No significant delay to surgery or surgical complication rates were observed following GC administration, and no difference in response rates were observed when cisplatin was split over days 1 and 8. These data support the use of GC as an effective, tolerable regimen in the management of muscle-invasive bladder cancer.
Purpose The frequency of febrile urinary tract infection was determined after outpatient flexible cystoscopy in antibiotic naïve patients with bladder tumor. Materials and Methods A total of 3,108 ...outpatient cystoscopies were performed in 1,110 patients with bladder tumor. Immediately before cystoscopy patients submitted a voided urine sample for culture. Significant bacteriuria was defined as greater than 104 cfu/ml of a single organism. Patients received no antibiotics immediately before or after cystoscopy. They were followed for 30 days for onset of febrile urinary tract infection. Results Of the 3,108 patient cystoscopies 673 (22%) had asymptomatic bacteriuria and 2,435 (78%) had sterile urine. A febrile urinary tract infection developed within 30 days of cystoscopy in 59 patients (1.9%), including in 3.7% of infected and 1.4% of uninfected patients (p = 0.01). All cases resolved within 12 to 24 hours with oral antibiotics. No patient was hospitalized for bacterial sepsis. Conclusions Antibacterial therapy before outpatient flexible cystoscopy does not appear necessary in patients who have no clinical signs or symptoms of acute urinary tract infection, including bacteriuria.
The developmental effects of chemicals that co-occur in vulnerable populations with elevated psychological stress are of increasing concern to the public. To investigate these concerns, we developed ...a rodent model of co-occurring perinatal manipulations and conducted a series of cognitive assessments in male and female offspring. Manganese (Mn), a neurodevelopmental toxicant when exceeding physiological requirements, was delivered in the drinking water (0, 2, or 4 mg Mn/mL) of rats from gestational day (GD) 7 to postnatal day (PND) 22. A variable perinatal stress paradigm was applied to half of the animals from GD13 to PND9. Novel object recognition (NOR), Morris water maze (MWM), differential reinforcement of low-rates procedure (DRL) and cued and uncued choice reaction time (CRT) tests were used to assess cognitive functions in offspring. Mn (4 mg/mL) and stress impaired NOR in adolescent males but facilitated NOR performance in females. However, when stress and Mn were combined these effects were attenuated in both sexes. During training for the DRL, Mn (2 mg/mL) facilitated, while stress impaired, lever press learning in both sexes. Few effects related to the treatments were found on DRL or MWM. During cued CRT, Mn (2 and 4 mg/mL) and stress reduced accuracy in males, while stress and Mn (2 mg/mL) increased anticipatory responding and slowed decision time in both sexes. Stress combined with Mn (2 mg/mL) improved cued accuracy and decision time, and Mn attenuated the effect of stress on anticipatory responding in both sexes. Stress slowed female movement time but when combined with Mn (4 mg/mL) the effect of stress was attenuated. During uncued CRT, except for decision time (which replicated effects observed with the cued task), no other effects of Mn or its combination with stress occurred. Females remained negatively affected by stress in most uncued CRT performance measures, while stressed improved male uncued accuracy. Taken together these data do not support increased cognitive impairment produced by Mn when combined with stress. However, the effects of perinatal stress alone, on these cognitive functions may hinder the detection of effects due to chemical exposures and underscores the need to consider the psychological health and wellbeing of the mother and her environment in risk assessment for developmental neurotoxicity of chemicals.
•Manganese in drinking water and variable stress during the perinatal period affect overlapping cognitive indices in rats.•Sex-specific effects were observed on most cognitive indexes but especially memory and attention.•Mn and stress combined often attenuated the effects of each factor alone.•Stress alone hindered the detection of effects due to manganese.
Purpose We determined whether pathological findings on restaging transurethral resection predict early stage progression of T1 bladder cancer. Materials and Methods A cohort of 352 patients ...presenting with T1 bladder cancer on initial transurethral resection was evaluated by second or restaging transurethral resection. All patients received bacillus Calmette-Guerin therapy and 88% were followed for 5 years. Pathological findings on restaging transurethral resection were correlated with tumor features, stage progression frequency and progression-free survival. Results Of the 352 patients with T1 tumors 203 (58%) had residual tumor on restaging transurethral resection, including 92 (26%) with residual nonmuscle invasive (T1) cancer. During 5 years 66% of cases recurred and 35% progressed in stage. Of the 92 patients with residual T1 cancer 75 (82%) progressed to muscle invasion within 5 years compared to 49 of 260 (19%) who had no or nonT1 tumor detected on restaging transurethral resection. Conclusions Restaging transurethral resection identifies patients with T1 bladder cancer who are at high risk for early tumor progression, justifying immediate cystectomy.
Micropapillary urothelial carcinoma (MPUC) is a rare but an aggressive variant of urothelial carcinoma. MPUC has been shown to commonly exhibit ERBB2 amplification and HER2 protein overexpression, ...but the frequency and distribution of these findings within micropapillary (MP) and not otherwise specified (NOS) components of tumors with mixed histology have not been addressed. Therefore, we evaluated ERBB2 amplification and HER2 expression in 43 MPUC cases by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). Of the 35 tumors containing both MP and NOS components, ERBB2 amplification was present in both the MP and NOS components of 12 tumors (34.3%), in only the MP component of 11 tumors (31.4%), and exclusively in the NOS component of 4 tumors (11.4%). HER2 protein overexpression was significantly more commonly present in the MP component compared to the NOS component within the same tumor (68.6% versus 34.3%, P = .012). Overall, there was a moderately positive correlation between HER2 protein expression and ERBB2 amplification in both MP (ρ = 0.59, P < .001) and NOS (ρ = 0.70, P < .001) components. All MP/NOS areas with IHC score 3+ and none of MP/NOS areas with IHC score 0 were associated with ERBB2 amplification. We conclude that ERBB2 amplification and HER2 overexpression are preferentially but not exclusively identified in the MP component compared to the NOS component within the same tumor. Our findings identify the presence of intratumoral heterogeneity of ERBB2 amplification and HER2 expression in MPUC and provide grounds for further investigation into the mechanisms underlying the development of MPUC.
•ERBB2 amplification is very common in micropapillary bladder cancer.•There is intratumoral heterogeneity of ERBB2 amplification in micropapillary bladder cancer.•ERBB2 amplification is more common in micropapillary component of tumors with mixed histology.
Restaging, or second transurethral resection (TUR), is essential to successful management of high-risk, non-muscle-invasive bladder cancer. Here we review the relevant literature documenting the role ...of restaging TUR. Cohort and randomized studies show that restaging TUR detects more tumors than initial TUR, improves clinical staging, and reduces the frequency of early tumor recurrences. Our conclusions show thatrestaging TUR improves the outcomes of high-risk,non-muscle-invasive bladder neoplasms.
The aim of this phase II study was to determine the efficacy of gemcitabine administered as an intravesical agent in patients with bacille Calmette-Guérin (BCG) -refractory transitional cell ...carcinoma of the bladder.
Patients with superficial bladder cancer refractory or intolerant to intravesical BCG therapy and refusing a cystectomy were considered eligible for the trial. Eligible patients received two courses of intravesical gemcitabine twice weekly at a dose of 2,000 mg/100 mL for 3 consecutive weeks, with each course separated by 1 week of rest. Patients were evaluated for response at 8 weeks, then every 3 months to 1 year.
Thirty eligible patients were included on study. The median follow-up for all the patients was 19 months (range, 0 to 35 months). Of the 30 patients, 15 (50%; 95% CI, 32% to 68%) achieved a complete response (CR). Twelve patients had tumor recurrence with a median recurrence-free survival time of 3.6 months (95% CI, 2.9 to 11.0 months). Two patients maintained a CR at 23 and 29 months, respectively. The 1-year recurrence-free survival rate for patients with a CR was 21% (95% CI, 0% to 43%). Two patients progressed to a higher stage while receiving gemcitabine treatment. The median follow-up for patients who did not have a progression or a cystectomy was 19 months (range, 2 to 35 months). Eleven patients (37%) underwent a cystectomy subsequent to gemcitabine therapy.
Gemcitabine has activity in a high-risk patient population and remains a viable option for some patients who refuse cystectomy.
The Human Reference Atlas (HRA) is defined as a comprehensive, three-dimensional (3D) atlas of all the cells in the healthy human body. It is compiled by an international team of experts who develop ...standard terminologies that they link to 3D reference objects, describing anatomical structures. The third HRA release (v1.2) covers spatial reference data and ontology annotations for 26 organs. Experts access the HRA annotations via spreadsheets and view reference object models in 3D editing tools. This paper introduces the Common Coordinate Framework (CCF) Ontology v2.0.1 that interlinks specimen, biological structure, and spatial data, together with the CCF API that makes the HRA programmatically accessible and interoperable with Linked Open Data (LOD). We detail how real-world user needs and experimental data guide CCF Ontology design and implementation, present CCF Ontology classes and properties together with exemplary usage, and report on validation methods. The CCF Ontology graph database and API are used in the HuBMAP portal, HRA Organ Gallery, and other applications that support data queries across multiple, heterogeneous sources.
Depletion of naive T cells from donor leukapheresis products (LPs) aims at the reduction of alloreactivity, while preserving memory T-cell reactivity (for example, to pathogens). This study ...established the immunomagnetic depletion procedure under clean room conditions using CD45RA beads and analyzed LPs of six donors for cell composition and functional immune responses. CD45RA depletion resulted in 3.4-4.7 log (median 4.4) reduction of CD45RA(+) T cells, thereby eliminating naive and late effector T cells. B cells were also completely removed, whereas significant proportions of NK cells, monocytes and granulocytes persisted. CD45RA-depleted LPs contained effector and central memory CD4(+) and CD8(+) T cells that showed sustained IFN-γ secretion to CMV, EBV, Aspergillus and Candida Ags. Alloreactivity was measured in MLRs between donors with complete HLA-mismatch. Alloreactive CD8(+) T cells were strongly reduced (median >1-log) upon CD45RA depletion, whereas alloreactive CD4(+) T cells persisted in significant numbers. In conclusion, clinical grade depletion of CD45RA(+) naive T cells from donor LPs is feasible and highly efficient. The depleted products show sustained CD4(+) and CD8(+) T-cell reactivity to pathogens and effectively reduced CD8-mediated alloreactivity. Prophylactic and preemptive infusions after allogeneic SCT may improve T-cell reconstitution and pathogen-specific immunosurveillance, along with lower risk of inducing GVHD.
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