A west African ancestry-associated SNP on 8q24 predicts a positive biopsy in African American men with suspected prostate cancer following PSA screening.

BACKGROUND: African American (AA) men have the highest incidence and mortality rates of prostate cancer (PCa) among all racial groups in the United States. While race is a social construct, for AA men, this overlaps with west African ancestry. Many of the PCa susceptibility variants exhibit distinct allele frequencies and risk estimates across different races and contribute substantially to the large disparities of PCa incidence among races. We previously reported that a single-nucleotide polymorphism (SNP) in 8q24, rs7824364, was strongly associated with west African ancestry and increased risks of PCa in both AA and Puerto Rican men. In this study, we determined whether this SNP can predict biopsy positivity and detection of clinically significant disease (Gleason score [GS] ≥ 7) in a cohort of AA men with suspected PCa. METHODS: SNP rs7824364 was genotyped in 199 AA men with elevated total prostate-specific antigen (PSA) (>2.5 ng/mL) or abnormal digital rectal exam (DRE) and the associations of different genotypes with biopsy positivity and clinically significant disease were analyzed. RESULTS: The variant allele carriers were significantly over-represented in the biopsy-positive group compared to the biopsy-negative group (44% vs. 25.7%, p = 0.011). In the multivariate logistic regression analyses, variant allele carriers were at a more than a twofold increased risk of a positive biopsy (odds ratio [OR] = 2.14, 95% confidence interval [CI] = 1.06-4.32). Moreover, the variant allele was a predictor (OR = 2.26, 95% CI = 1.06-4.84) of a positive biopsy in the subgroup of patients with PSA < 10 ng/mL and normal DRE. The variant allele carriers were also more prevalent in cases with GS ≥ 7 compared to cases with GS < 7 and benign biopsy. CONCLUSIONS: This study demonstrated that the west African ancestry-specific SNP rs7824364 on 8q24 independently predicted a positive prostate biopsy in AA men who were candidates for prostate biopsy subsequent to PCa screening.

Polyploid speciation in Zea (Poaceae): cytogenetic insights.

MAIN CONCLUSION: The analysis of meiotic pairing affinities and genomic formulae in species and hybrids of Zea allowed us to speculate an evolutionary model to recreate the ancient polyploidization of maize and allied species. The meiotic pairing affinities and the genomic formulae analysis in Zea species and hybrids obtained in new and previous crosses, together with the molecular data known in the genus, allowed us to speculate an evolutionary model to attempt to recreate the ancient polyploidization process of Zea species. We propose that x = 5 semispecies are the ancestors of all modern species of the genus. The complex evolutionary process that originated the different taxa could be included hybridization between sympatric diploid ancestral semispecies (2n = 10) and recurrent duplication of the hybrid chromosome number, resulting in distinct auto- and allopolyploids. After the merger and doubling of independent genomes would have undergone cytological and genetical diploidization, implying revolutionary changes in genome organization and genic balance processes. Based on the meiotic behaviour of the 2n = 30 hybrids, that showed homoeology between the A subgenomes of all parental species, we propose that this subgenome A would be pivotal in all the species and would have conserved the rDNA sequences and the pairing regulator locus (PrZ). In the hypothetical model postulated here, the ancestral semispecies with the pivotal subgenome A would have had a wide geographic distribution, co-occurring and hybridizing with the semispecies harbouring B subgenomes, thus enabling sympatric speciation.

Impact of age >70 years on oncological outcomes in patients with non-muscle-invasive bladder cancer treated with Bacillus Calmette-Guérin.

OBJECTIVE: To evaluate the impact of age on oncological outcomes in a large contemporary cohort of patients with non-muscle-invasive bladder cancer (NMIBC) treated with adequate Bacillus Calmette-Guérin (BCG). PATIENTS AND METHODS: We performed an Institutional Review Board-approved retrospective study analysing patients with NMIBC treated with adequate BCG at our institution from 2000 to 2020. Adequate BCG was defined as per United States Food and Drug Administration (FDA) guidelines as being receipt of at least five of six induction BCG instillations with a minimum of two additional doses (of planned maintenance or of re-induction) of BCG instillations within a span of 6 months. The study's primary outcome was to determine if age >70 years was associated with progression to MIBC cancer or distant metastasis. The cumulative incidence method and the competing-risk regression analyses were used to investigate the association of advanced age (>70 years) with progression, high-grade (HG) recurrence and cancer-specific mortality (CSM). RESULTS: Overall, data from 632 patients were analysed: 355 patients (56.2%) were aged ≤70 years and 277 (43.8%) were >70 years. Age >70 years did not adversely affect either cumulative incidence of progression or HG recurrence (P = 0.067 and P = 0.644, respectively). On competing-risk regression analyses, age >70 years did not emerge as an independent predictor of progression or HG recurrence (sub-standardised hazard ratio [SHR] 1.57, 95% confidence interval [CI] 0.87-2.81, P = 0.134; and SHR 1.05, 95% CI 0.77-1.44, P = 0.749). Not unexpectedly, patients in the older group did have higher overall mortality (P < 0.001) but not CSM (P = 0.057). CONCLUSION: Age >70 years was not associated with adverse oncological outcomes in a large contemporary cohort of patients receiving adequate intravesical BCG for NMIBC. BCG should not be withheld from older patients seeking for bladder sparing options.

Influence of lamina propria invasion extension on T1 high-grade non-muscle-invasive bladder cancer in patients undergoing BCG or radical cystectomy.

OBJECTIVE: To evaluate the prognostic value of T1 substaging in patients treated with bacillus Calmette-Guérin (BCG) or immediate radical cystectomy (iRC). MATERIALS AND METHODS: We performed an institutional review board-approved retrospective study analysing non-muscle-invasive bladder cancer (NMIBC) patients with pT1 disease treated with either BCG or iRC between 2000 and 2020. Lamina propria (LP) invasion characteristics were extracted from the pathology report. The Kaplan-Meier method was used to calculate overall survival (OS), cancer-specific survival (CSS) and metastasis-free survival (MFS). Multivariable Cox models were used to determine the association between progression-free survival (PFS) and characteristics in the BCG cohort. A logistic regression model explored the relationship between T1 substaging and upstaging to >pT2 at iRC. RESULTS: A total of 411 T1 high-grade patients were identified. LP invasion characteristics were as follows: not specified: 115 (28%); focal/superficial (F/S): 147 (35.8%); and extensive/multifocal (E/M): 149 (36.2%). Overall, 303 patients (73.7%) received BCG, and 108 patients (26.3%) underwent iRC. The median (interquartile range) follow-up was 53 (32-96) months. Patients with E/M LP invasion were significantly more likely to undergo iRC (34% vs. 19%; P = 0.003). Patients with E/M LP invasion showed poorer MFS and CSS compared to those with F/S LP invasion when treated with BCG but not when treated with iRC. Among BCG-treated patients, progression occurred in 41 patients and E/M LP invasion was independently associated with progression after BCG (hazard ratio 5.3, 95% confidence interval [CI] 2.2-13.1; P < 0.001). T1 substaging was not associated with upstaging at RC (odds ratio 3.15, 95% CI 0.82-12.12; P = 0.095). CONCLUSIONS: Extensive/multifocal LP invasion was associated with poor PFS, MFS and CSS in patients treated with BCG. T1 substaging provides valuable prognostic information and should be reported in pathology reports.

Ibrutinib-rituximab followed by R-HCVAD as frontline treatment for young patients (≤65 years) with mantle cell lymphoma (WINDOW-1): a single-arm, phase 2 trial.

BACKGROUND: Induction with ibrutinib and rituximab provides an opportunity to minimise chemotherapy exposure, because upfront use of these targeted therapies could result in remission without chemotherapy and allow for consolidation with only four cycles of chemotherapy instead of the conventional eight. We aimed to determine the activity and safety of ibrutinib-rituximab induction followed by shortened chemoimmunotherapy (four cycles) with rituximab plus hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (R-HCVAD) alternating with methotrexate-cytarabine in previously untreated patients with mantle cell lymphoma. METHODS: We did a single-centre, single-arm, phase 2 trial in previously untreated patients with mantle cell lymphoma. Eligible patients were aged 65 years or younger and had serum bilirubin of less than 1·5 mg/dL, creatinine clearance of 30 mL/min or more, Eastern Cooperative Oncology Group performance status of 2 or less, and cardiac ejection fraction 50% or more by echocardiogram. Patients received 12 cycles of ibrutinib-rituximab induction (part A; oral ibrutinib 560 mg daily and intravenous rituximab 375 mg/m2 weekly for the first 4 weeks and then on day 1 of cycles 3-12). As soon as patients had a complete response, four cycles of R-HCVAD alternating with methotrexate-cytarabine (part B) were administered. If they did not have a complete response or had a partial response, patients received two cycles of R-HCVAD alternating with methotrexate-cytarabine followed by reassessment, up to a total of eight cycles. Patients were taken off study if they had stable disease or progression during R-HCVAD. The primary outcome was the overall response rate after part A. The analyses were conducted on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT02427620. FINDINGS: 131 patients were enrolled between June 12, 2015, and Dec 6, 2018. The median age was 56 years (IQR 49-60). 58 (50%) of 117 patients had high Ki-67 (≥30%). 129 (98%, 95% CI 95-100) of 131 patients had an overall response in part A. The most common grade 3-4 adverse events were lymphocytopenia (19 [14%] of 131), skin rash (16 [12%]), thrombocytopenia (12 [9%]), infections (11 [8%]), and fatigue (ten [8%]) in part A and lymphocytopenia (96 [73%]), leukocytopenia (42 [32%]), thrombocytopenia (40 [30%]), and neutropenia (26 [20%]) in part B. There was one on-study death, which was not deemed to be treatment-related. INTERPRETATION: Induction with ibrutinib-rituximab in the frontline treatment of young patients with mantle cell lymphoma is active and safe. This approach allowed minimisation of the number of chemotherapy cycles, thereby reducing the adverse events associated with chemotherapy. Newer trials bringing the next-generation Bruton's tyrosine kinase inhibitors into the frontline setting might obviate the need for chemotherapy altogether in patients with mantle cell lymphoma. FUNDING: Pharmacyclics, Janssen.

All High-Grade Ta Tumors Should Be Classified as High Risk: Bacillus Calmette-Guérin Response in High-Grade Ta Tumors.

PURPOSE: There is variation amongst guidelines with respect to risk stratification of Ta tumors, specifically high-grade (HG) Ta tumors. We sought to investigate the response of all Ta tumors to bacillus Calmette-Guérin (BCG) and compare response rates based on European Association of Urology (EAU) classification as intermediate- (IR) or high-risk (HR). MATERIALS AND METHODS: An institutional review of all patients who received adequate BCG from 2000-2018 was conducted. EAU 2021 prognostic risk groups were used to stratify patients including by the newly proposed adverse risk factors. RESULTS: When patient with Ta tumors were stratified into IR and HR, 37 (16%) had IR low-grade (LG) Ta, 92 (40%) had IR HG Ta and 101 (44%) had HR HG Ta tumors. BCG unresponsiveness developed in 13% of HR HG Ta tumors and 14% of IR HG Ta tumors compared to 0.0% of IR LG Ta tumors (p=0.003). While no patients with IR LG Ta tumors progressed, progression rates were similar in HR HG Ta and IR HG Ta tumors (≥T2: 5.9% and 6.5%; [Formula: see text]T1: 13% and 13%, respectively). Rates of recurrence, BCG unresponsiveness and progression were similar, irrespective of number of EAU risk factors present (p=0.9, p=0.8 and p=0.9, respectively). CONCLUSIONS: All HG Ta tumors, regardless of EAU risk stratification, have inferior response to BCG and increased rates of progression compared to IR LG Ta tumors. EAU clinical risk factors did not improve prediction of oncologic outcomes among HG Ta patients who received adequate BCG. These data support consideration of all HG tumors as high risk.

Should patients with non-muscle-invasive bladder cancer discontinue fibrin clot inhibitors during bacille Calmette-Guérin?

OBJECTIVE: To determine the impact of fibrin clot inhibitor (FCI) use on oncological outcomes in a large contemporary cohort of patients with non-muscle-invasive bladder cancer (NMIBC) treated with adequate bacille Calmette-Guérin (BCG). PATIENTS AND METHODS: We performed an Institutional Review Board-approved review of patients with NMIBC treated with adequate intravesical BCG, at our institution between 2000 and 2018. FCI use at the time of BCG therapy was recorded for each patient. Patients were stratified according to use of FCI medication. Recurrence- and progression-free survival were analysed using Kaplan-Meier methods and Cox proportional hazard models. RESULTS: Overall, 226 of 526 patients (43.0%) used a FCI: aspirin (205), clopidogrel (38), warfarin (18) and novel oral anticoagulant (NOAC; seven). The use of FCIs did not adversely affect either recurrence- or progression-free survival (P = 0.385 and P = 0.131, respectively). These results did not change when the impact of aspirin, clopidogrel or warfarin/NOAC use on recurrence and progression was evaluated separately. On multivariate analysis, FCI use was neither associated with tumour recurrence nor progression. CONCLUSION: The use of FCIs was not associated with adverse oncological outcomes in a large contemporary cohort of patients receiving adequate intravesical BCG for NMIBC. Based on these results, FCIs may be safely continued during BCG immunotherapy.

Reduced-dose bacillus Calmette-Guérin (BCG) in an era of BCG shortage: real-world experience from a tertiary cancer centre.

OBJECTIVE: To evaluate the impact of one-third-dose (1/3D) bacillus Calmette-Guérin (BCG) on oncological outcomes in a large cohort of patients with non-muscle-invasive bladder cancer (NMIBC) treated with adequate BCG (as defined by the US Food & Drug Administration (FDA)) in a real-world setting. PATIENTS AND METHODS: We performed an institutional review board-approved review of patients with NMIBC treated with adequate BCG at our institution between 2000 and 2020. Patients were stratified according to whether they had received 1/3D BCG or full-dose (FD) BCG. Time to recurrence, time to progression and cancer-specific survival were estimated using Kaplan-Meier methods. RESULTS: Of 563 patients with NMIBC treated with adequate BCG, 150 (26.6%) received 1/3D and 413 (73.4%) received FD. The use of 1/3D BCG did not adversely affect time to recurrence (P = 0.449) or time to progression (P = 0.716), and this remained consistent when patients were stratified by individual 2021 European Association of Urology (EAU) prognostic factor risk groups. Cancer-specific survival was similar in patients receiving 1/3D and those receiving FD BCG (P = 0.320). CONCLUSION: The use of 1/3D BCG was not associated with adverse oncological outcomes in a large cohort of patients receiving adequate BCG for intermediate- and high-risk NMIBC. Based on this real-world experience, risk-stratified split-vial dosing may represent a valuable approach for other institutions facing BCG shortages whilst also providing reassurance to patients who may be concerned about suboptimal outcomes.

May Measurement Month 2017-19: an analysis of blood pressure screening results from Paraguay.

The aim of this study was to highlight the importance of measuring blood pressure (BP) and to identify and reduce the BPs of those people who require intervention to lower their BP according to current guidelines. A total of 7782 individuals aged ≥18 years were recruited during the 3 years of the May Measurement Month (MMM) campaign (2017: 1196, 2018: 2285, 2019: 4301). Recruitment was through opportunistic sampling at a variety of screening sites distributed throughout the country. Each participant underwent a pre-specified questionnaire with questions on risk factors concluding with three BP measurements at 1 min intervals and measurement of weight and height. Hypertension was defined as a systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg or those receiving antihypertensive therapy. Of all 7782 participants, 3323 had hypertension (42.7%) of whom 61.8% were aware and 50.4% were not receiving antihypertensive medication. Of those treated (49.6%), 43.8% had controlled BP (<140/90 mmHg). Among all hypertensive patients (with and without medication), 21.7% had controlled BP. In relation to previous surveys carried out in the country, awareness of hypertension increased two-fold, with no change in the proportion of hypertensive patients on treatment and the proportion of hypertensive patients with controlled BP which remained low.

Phase II study of azacitidine with pembrolizumab in patients with intermediate-1 or higher-risk myelodysplastic syndrome.

Programmed cell death protein 1 (PD-1) and PD-ligand 1 (PD-L1) expression is upregulated in cluster of differentiation 34 (CD34)+ bone marrow cells from patients with myelodysplastic syndromes (MDS). Hypomethylating agent (HMA) treatment results in further increased expression of these immune checkpoints. We hypothesised that combining an anti-PD-1 antibody with HMAs may have efficacy in patients with MDS. To test this concept, we designed a phase II trial of the combination of azacitidine and pembrolizumab with two cohorts. In the 17 previously untreated patients, the overall response rate (ORR) was 76%, with a complete response (CR) rate of 18% and median overall survival (mOS) not reached after a median follow-up of 12·8 months. For the HMA-failure cohort (n = 20), the ORR was 25% and CR rate was 5%; with a median follow-up of 6·0 months, the mOS was 5·8 months. The most observed toxicities were pneumonia (32%), arthralgias (24%) and constipation (24%). Immune-related adverse events requiring corticosteroids were required in 43%. Overall, this phase II trial suggests that azacitidine and pembrolizumab is safe with manageable toxicities in patients with higher-risk MDS. This combined therapy may have anti-tumour activity in a subset of patients and merits further studies in the front-line setting.

Cardiac rehabilitation availability and characteristics in Latin America and the Caribbean: A Global Comparison.

BACKGROUND: This study aimed to establish availability and characteristics of cardiac rehabilitation (CR) in Latin America and the Caribbean (LAC), where cardiovascular disease is highly prevalent. METHODS: In this cross-sectional sub-analysis focusing on the 35 LAC countries, local cardiovascular societies identified CR programs globally. An online survey was administered to identified programs, assessing capacity and characteristics. CR need was computed relative to ischemic heart disease (IHD) incidence from the Global Burden of Disease study. RESULTS: ≥1 CR program was identified in 24 LAC countries (68.5% availability; median = 3 programs/country). Data were collected in 20/24 countries (83.3%); 139/255 programs responded (54.5%), and compared to responses from 1082 programs in 111 countries. LAC density was 1 CR spot per 24 IHD patients/year (vs 18 globally). Greatest need was observed in Brazil, Dominican Republic and Mexico (all with >150,000 spots needed/year). In 62.8% (vs 37.2% globally P < .001) of CR programs, patients pay out-of-pocket for some or all of CR. CR teams were comprised of a mean of 5.0 ± 2.3 staff (vs 6.0 ± 2.8 globally; P < .001); Social workers, dietitians, kinesiologists, and nurses were significantly less common on CR teams than globally. Median number of core components offered was 8 (vs 9 globally; P < .001). Median dose of CR was 36 sessions (vs 24 globally; P < .001). Only 27 (20.9%) programs offered alternative CR models (vs 31.1% globally; P < .01). CONCLUSION: In LAC countries, there is very limited CR capacity in relation to need. CR dose is high, but comprehensiveness low, which could be rectified with a more multidisciplinary team.

Long-Term Outcomes of Whole Gland Salvage Cryotherapy for Locally Recurrent Prostate Cancer following Radiation Therapy: A Combined Analysis of Two Centers.

PURPOSE: Radiation refractory prostate cancer (RRPCa) is common and salvage cryotherapy for RRPCa is emerging as a viable local treatment option. However, there is a paucity of long-term data. The purpose of this study is to determine long-term outcomes following salvage cryotherapy for RRPca. MATERIALS AND METHODS: Patients undergoing salvage cryotherapy for biopsy-proven, localized RRPCa from 1992 through 2004 were prospectively accrued at two centers. Preoperative characteristics, perioperative morbidity and postoperative data were reviewed from our database. The primary outcomes were overall survival (OS) and disease-specific survival (DSS). The secondary outcomes were freedom from castration-resistant prostate cancer (CRPC) and freedom from androgen deprivation therapy (ADT). RESULTS: A total of 268 patients were identified with a median followup of 10.3 years. A total of 223 complication events were recorded; of them, 168 were Clavien I-II events and 55 Clavien III events. At 10 years, 69% had freedom from ADT and 76% had freedom from CRPC. The 10-year DSS rate was 81%, and the 10-year OS rate was 77%. A pre-salvage prostate specific antigen level of >10 ng/ml was associated with an increased risk of developing CRPC and initiation of ADT but was not associated with DSS or OS. The use of neoadjuvant ADT was associated with improved OS and DSS but did not affect freedom from CRPC or adjuvant ADT. CONCLUSIONS: Salvage cryotherapy for RRPCa provides excellent long-term freedom from ADT, CRPC and DSS with acceptable morbidity. OS at 10 years was 77%. Prospective trials are required for validation.

Contemporary Rates of Gynecologic Organ Involvement in Females with Muscle Invasive Bladder Cancer: A Retrospective Review of Women Undergoing Radical Cystectomy following Neoadjuvant Chemotherapy.

PURPOSE: According to the American Urological Association/American Society of Clinical Oncology/American Society for Radiation Oncology/Society of Urologic Oncology Guideline on treatment of nonmetastatic muscle invasive bladder cancer (MIBC), females requiring radical cystectomy (RC) should undergo concomitant anterior pelvic exenteration despite low rates of malignant involvement of gynecologic organs. We present the clinicopathological characteristics of patients with MIBC treated with neoadjuvant chemotherapy (NAC) and evaluate the impact of NAC on gynecologic organ involvement. MATERIALS AND METHODS: An institutional review board approved review of patients with cT2-T3 MIBC treated with RC at our institution between 2005 and 2018 was performed. Patients were stratified by receipt of NAC. RESULTS: A total of 186 females with cT2-T3 MIBC underwent RC during the study period, of whom 67.7% received NAC prior to RC. Patients who received NAC were more likely to have cT3 disease, preoperative hydronephrosis, and variant histology on transurethral resection (p <0.001, p=0.004, p=0.029, respectively). Rates of recurrence or metastasis were similar between groups (27.0% vs 26.7%, p=0.964). No patients had isolated genitourinary organ recurrence (median followup 32.1 months). Nine patients (5.7%) had gynecologic organ involvement (6 NAC vs 3 no NAC, p=0.978). Among those who underwent hysterectomy, 2 patients (3.1%) who received NAC had uterine involvement compared to none in the no NAC cohort (p=0.551). Rates of vaginal involvement were similar between the groups (4 NAC vs 3 no NAC, p=0.402). Additionally, 1 patient who received NAC had incidentally diagnosed localized endometrial cancer. No women had fallopian tube or ovarian involvement. CONCLUSIONS: Even among high risk patients with MIBC, gynecologic organ involvement of MIBC is rare, and organ preservation, especially of the ovaries, is likely safe.

Progression of Disease after Bacillus Calmette-Guérin Therapy: Refining Patient Selection for Neoadjuvant Chemotherapy before Radical Cystectomy.

PURPOSE: Data from the pre-neoadjuvant chemotherapy (NAC) era suggests patients who progress on bacillus Calmette-Guérin (BCG) to muscle-invasive bladder cancer (P-MIBC) exhibit worse outcomes compared to de novo MIBC (D-MIBC). Herein, we investigate whether P-MIBC is an independent poor risk factor in the setting of contemporary NAC use. MATERIALS AND METHODS: A review of patients who underwent radical cystectomy (RC) for cT2-3 MIBC from 2005 to 2018 was performed. Patients were stratified into high risk (lymphovascular invasion, variant histology, hydronephrosis, cT3b) vs low risk (no risk factors) and P-MIBC (≤pT1 treated with at least induction BCG who progressed to ≥cT2) vs D-MIBC. RESULTS: Among 801 patients who underwent RC 20.3% had P-MIBC and 79.7% had D-MIBC. In low-risk patients treated without NAC, P-MIBC was associated with pathological upstaging (64.9% vs 42.7%, p=0.004) and worse overall (OS, p=0.006) and cancer-specific survival (CSS, p=0.001) compared to D-MIBC. P-MIBC status conferred uniformly poor survival outcomes to patients who did not receive NAC compared to D-MIBC without NAC (median OS 51.5 months [95% CI 40.0-81.0] vs 85.1 months [95% CI 62.8-96.0], p=0.040; median CSS not reached, p=0.014). However, P-MIBC status did not remain a negative prognostic factor in the setting of NAC (median OS 90.5 months [95% CI 34.0-not estimable] vs 87.8 months [95% CI 68.7-not estimable], p=0.606; median CSS not reached, p=0.448). CONCLUSIONS: P-MIBC confers a poor prognosis when managed with RC alone. Treatment with NAC results in equivalent pathological response and survival outcomes compared to D-MIBC. P-MIBC should be included in risk-stratified approaches to NAC selection.

Randomized trial of ibrutinib vs ibrutinib plus rituximab in patients with chronic lymphocytic leukemia.

Ibrutinib, an oral covalent inhibitor of Bruton's tyrosine kinase, is an effective therapy for patients with chronic lymphocytic leukemia (CLL). To determine whether rituximab provides added benefit to ibrutinib, we conducted a randomized single-center trial of ibrutinib vs ibrutinib plus rituximab. Patients with CLL requiring therapy were randomized to receive 28-day cycles of once-daily ibrutinib 420 mg, either as a single agent (n = 104), or together with rituximab (375 mg/m2; n = 104), given weekly during cycle 1, then once per cycle until cycle 6. The primary end point was progression-free survival (PFS) in the intention-to-treat population. We enrolled 208 patients with CLL, 181 with relapsed CLL and 27 treatment-naive patients with high-risk disease (17p deletion or TP53 mutation). After a median follow-up of 36 months, the Kaplan-Meier estimates of PFS were 86% (95% confidence interval [CI], 76.6-91.9) for patients receiving ibrutinib, and 86.9% (95% CI, 77.3-92.6) for patients receiving ibrutinib plus rituximab. Similarly, response rates were the same in both arms (overall response rate, 92%). However, time to normalization of peripheral blood lymphocyte counts and time to complete remission were shorter, and residual disease levels in the bone marrow were lower, in patients receiving ibrutinib plus rituximab. We conclude that the addition of rituximab to ibrutinib in relapsed and treatment-naive high-risk patients with CLL failed to show improvement in PFS. However, patients treated with ibrutinib plus rituximab reached their remissions faster and achieved significantly lower residual disease levels. Given these results, ibrutinib as single-agent therapy remains current standard-of-care treatment in CLL. This trial was registered at www.clinicaltrials.gov as #NCT02007044.

Altered T-cell subset repertoire affects treatment outcome of patients with myelofibrosis.

Phenotypic characterization of T cells in myelofibrosis (MF) is intriguing owing to increased inflammation, markedly elevated pro-inflammatory cytokines, and altered distribution of T-cell subsets. Constitutive activation of Janus kinase-2 (JAK2) in the majority of MF patients contributes to the expression of the programmed cell death protein-1 (PD1) and T-cell exhaustion. We wondered whether T-cell activation affects treatment outcome of patients with MF and sought to determine whether the JAK1/2 inhibitor ruxolitinib affects the activation of T-cell subsets. T cells from 47 MF patients were analyzed and the percent of either helper (CD4+) or cytotoxic (CD8+) naive, central memory, effector memory, or effector T cells; and fractions of PD1-expressing cells in each subset were assessed. An increased number of T cells coexpressing CD4/PD1 and CD8/PD1 in MF compared to healthy controls (n=28) was found, and the T cells were significantly skewed toward an effector phenotype in both CD4+ and CD8+ subsets, consistent with a shift from a quiescent to an activated state. Over the course of ruxolitinib treatment, the distribution of aberrant T-cell subsets significantly reversed towards resting cell phenotypes. CD4+ and CD8+ subsets at baseline correlated with monocyte and platelet counts, and their PD1-positive fractions correlated with leukocyte counts and spleen size. Low numbers of PD1+/CD4+ and PD1+/CD8+ cells were associated with complete resolution of palpable splenomegaly and improved survival rate, suggesting that low levels of exhausted T cells confer a favorable response to ruxolitinib treatment.

Impact of upper tract urothelial carcinoma on response to BCG in patients with non-muscle-invasive bladder cancer.

OBJECTIVE: To evaluate the impact of upper tract urothelial carcinoma (UTUC) on bacillus Calmette-Guerin (BCG) response and progression in patients with non-muscle-invasive bladder cancer (NMIBC). PATIENTS AND METHODS: We performed an institutional review board-approved review of patients with NMIBC treated with adequate intravesical BCG, as defined by the US Food and Drug Administration, at our institution between 2000 and 2018. Patients were stratified by presence of any UTUC and time of UTUC diagnosis (preceding vs synchronous to NMIBC diagnosis or metachronous disease after NMIBC diagnosis). Descriptive statistics were used to summarize the data overall and by groups, and t-tests or Wilcoxon's rank sum tests and Pearson's chi-squared or Fisher's exact tests were used to analyse continuous and categorical data, respectively. RESULTS: Of 541 patients with NMIBC treated with adequate BCG, 59 (10.9 %) were diagnosed with UTUC. Of these, 34 had a history of UTUC prior to NMIBC (UTUC-P; median [interquartile range {IQR}] 13.1 [7.4-27.6] months prior), while 25 developed UTUC after diagnosis of NMIBC (six synchronous and 19 metachronous; median [IQR] 12.1 [1.7-28.1] months after). Compared to the non-UTUC group, patients with UTUC-P were more likely to exhibit Tis without papillary tumour in the bladder (20.6% vs 5.0%; P < 0.001), but were less likely to have T1 disease on index transurethral resection (8.8% vs 49.4%; P < 0.001). Patients with UTUC-P developed more recurrences (55.9% vs 34.0%; P = 0.010), any stage/grade progression (23.5% vs 9.8%; P = 0.012) and progression to muscle-invasive or metastatic disease (17.6% vs 6.4%; P = 0.014). The presence of high-grade UTUC-P compared to low-grade UTUC-P was associated with increased NMIBC recurrence (68.2% vs 25.0%; P = 0.049). There was no significant difference in rates of recurrence or progression based on timing of UTUC with respect to the index bladder tumour, although this analysis was limited by small numbers. CONCLUSIONS: Presence of UTUC prior to a diagnosis of NMIBC was associated with an almost twofold increased recurrence and progression rates after adequate BCG therapy. This should be considered when counselling patients and designing cohorts for clinical trials.

Time interval from transurethral resection of bladder tumour to bacille Calmette-Guérin induction does not impact therapeutic response.

OBJECTIVES: To investigate bacille Calmette-Guérin (BCG) tolerability and response with respect to the timing of BCG administration after transurethral resection of bladder tumour (TURBT) in patients with non-muscle-invasive bladder cancer (NMIBC). PATIENTS AND METHODS: A review of patients with NMIBC at our institution managed with at least 'adequate BCG' (defined by the United States Food and Drug Administration as at least five of six induction instillations, with two additional instillations comprising either maintenance or repeat induction) at our institution from 2000 to 2018 was performed. Time from TURBT to first instillation of induction BCG was stratified by quartile and analysed as a continuous variable. Kaplan-Meier and log-rank tests analysed differences in recurrence-free (RFS) and progression-free survival (PFS). Cox proportional hazards regression models identified associations between risk factors and survival outcomes. RESULTS: A total of 518 patients received adequate BCG at a median (range) of 26 (6-188) days from TURBT. Overall, 45 patients (9%) developed BCG intolerance at a median (range) 12 (7-33) instillations. When time from TURBT to BCG was stratified into quartiles, there was no difference with respect BCG intolerance (P = 0.966), RFS (P = 0.632) or PFS (P = 0.789). On both uni- and multivariate regression analysis for RFS and PFS, time from TURBT to BCG was not a significant predictor when analysed by quartile or as a continuous variable (the hazard ratio for RFS was 1.00, 95% confidence interval [CI] 0.99-1.00, P = 0.449; and for PFS was 0.99, 95% CI 0.98-1.00, P = 0.074). CONCLUSION: The rates of tolerability and response to adequate BCG are not predicated by the timing of induction BCG instillation after TURBT. Early administration in properly selected patients is safe and delays do not affect therapeutic response.

Comparing confirmatory biopsy outcomes between MRI-targeted biopsy and standard systematic biopsy among men being enrolled in prostate cancer active surveillance.

OBJECTIVES: To evaluate the ability of magnetic resonance imaging (MRI)-targeted biopsy combined with systematic biopsy (MRI-biopsy) to reduce negative biopsies and detect clinically significant prostate cancer compared to systematic biopsy (SB) alone in the confirmatory biopsy setting using matched cohorts. PATIENTS AND METHODS: Patients were identified from an active surveillance database who had a previously positive transrectal ultrasonography-guided SB followed by a confirmatory biopsy at a single institution between 2006 and 2019. Patients were divided into two cohorts based on confirmatory biopsy technique: SB alone or MRI-biopsy (which included MRI-targeted and systematic biopsies). Cohorts were then matched on age, prostate-specific antigen (PSA) level, number of positive cores on initial biopsy and initial biopsy Gleason grade group (GG). Logistic regression was performed to identify associations with confirmatory biopsy upgrading. RESULTS: After matching, 514 patients were identified (257 per cohort). PSA, prostate volume and PSA density prior to initial biopsy, in addition to total number of initial biopsy positive cores and GG, were similar between the matched cohorts. After confirmatory biopsy, 118/257 patients (45.9%) in the MRI-biopsy cohort were upgraded compared to 46/257 patients (17.9%) in the SB cohort (P < 0.001). The rate of negative confirmatory biopsy was 32/257 (12.5%) compared to 97/257 (37.7%) in the MRI-biopsy and SB cohorts, respectively (P < 0.001). Confirmatory MRI-biopsy was associated with greater odds of confirmatory biopsy upgrade from GG 1 to ≥GG 2 compared to SB alone (odds ratio 3.62, 95% confidence interval 1.97-6.63; P < 0.001). CONCLUSION: The addition of MRI-targeted biopsies to SB in the confirmatory biopsy setting among men with previously detected prostate cancer resulted in fewer negative confirmatory biopsies and detection of more clinically significant prostate cancer compared to SB alone.

Impact of sex on response to BCG in non-muscle invasive bladder cancer patients: a contemporary review from a tertiary care center.

PURPOSE: Female sex has been implicated with higher stage at diagnosis and as a negative prognostic factor amongst patients with non-muscle invasive bladder cancer (NMIBC). Whether this holds true with contemporary management paradigms is unknown. We analyzed a cohort of patients treated with adequate bacillus Calmette-Guerin (BCG) for NMIBC in an effort to identify sex-specific influence on BCG response. METHODS: An IRB-approved review of patients with NMIBC treated at our institution with at least 'adequate BCG', as defined by the US FDA and EAU, from 2000 to 2018 was performed. Patients were then stratified by sex and response to BCG. Non-parametric tests were used to summarize the data overall and by groups. The Kaplan-Meier product limit method was used to calculate median survival endpoints. RESULTS: Of the 541 patients treated with adequate BCG, 111 (20.5%) were female and 430 (79.5%) were male. Female patients were younger (median 66 vs. 69, p = 0.071), had a lower BMI (median 27.3 vs. 28.8, p = 0.010) and were more likely to have no smoking history (49.5% vs. 27.0%, p < 0.001). Tumor characteristics with respect to stage, size, multifocality, presence of carcinoma in situ, and presence of variant histology were similar between sexes. While rates of recurrence were higher in females than in males this, was not statistically significant (44.1% vs. 34.7%, p = 0.064) and Kaplan-Meier estimates of recurrence-free, progression-free and overall survival demonstrated no significant difference between sexes (p = 0.409, p = 0.253, p = 0.171, respectively). CONCLUSION: In a contemporary cohort of patients with NMIBC treated with adequate BCG, female sex was not associated with adverse oncologic outcomes.