The 5-WS of targeting DNA-damage repair (DDR) pathways in prostate cancer.

DNA-damage repair (DDR) pathways alterations, a growing area of interest in oncology, are detected in about 20% of patient with prostate cancer and are associated with improved sensitivity to poly(ADP ribose) polymerases (PARP) inhibitors. In May 2020, the Food and Drug Administration (FDA) approved two PARP inhibitors (olaparib and rucaparib) for prostate cancer treatment. Moreover, germline aberrations in DDR pathways genes have also been related to familial or hereditary prostate cancer, requiring tailored health-care programs.

REGOMA-OSS: a large, Italian, multicenter, prospective, observational study evaluating the efficacy and safety of regorafenib in patients with recurrent glioblastoma.

Background: In the randomized phase II REGOMA trial, regorafenib showed promising activity in patients with recurrent glioblastoma. We conducted a large, multicenter, prospective, observational study to confirm the REGOMA data in a real-world setting.

Patients And Methods: The major inclusion criteria were histologically confirmed diagnosis of glioblastoma according to the World Health Organization (WHO) 2016 classification and relapse after radiotherapy with concurrent/adjuvant temozolomide treatment, good performance status [Eastern Cooperative Oncology Group performance status (ECOG PS 0-1)] and good liver function.

The transcription factor HIF2α partakes in the differentiation block of acute myeloid leukemia.

One of the defining features of acute myeloid leukemia (AML) is an arrest of myeloid differentiation whose molecular determinants are still poorly defined. Pharmacological removal of the differentiation block contributes to the cure of acute promyelocytic leukemia (APL) in the absence of cytotoxic chemotherapy, but this approach has not yet been translated to non-APL AMLs. Here, by investigating the function of hypoxia-inducible transcription factors HIF1α and HIF2α, we found that both genes exert oncogenic functions in AML and that HIF2α is a novel regulator of the AML differentiation block.

miR-126 identifies a quiescent and chemo-resistant human B-ALL cell subset that correlates with minimal residual disease.

Complete elimination of B-cell acute lymphoblastic leukemia (B-ALL) by a risk-adapted primary treatment approach remains a clinical key objective, which fails in up to a third of patients. Recent evidence has implicated subpopulations of B-ALL cells with stem-like features in disease persistence. We hypothesized that microRNA-126, a core regulator of hematopoietic and leukemic stem cells, may resolve intratumor heterogeneity in B-ALL and uncover therapy-resistant subpopulations.

Avelumab First-line Maintenance Therapy for Advanced Urothelial Carcinoma: Comprehensive Clinical Subgroup Analyses from the JAVELIN Bladder 100 Phase 3 Trial.

Background: In the phase 3 JAVELIN Bladder 100 trial, avelumab first-line (1L) maintenance + best supportive care (BSC) significantly prolonged overall survival (OS) and progression-free survival (PFS) versus BSC alone in patients with advanced urothelial carcinoma (aUC) who were progression-free following 1L platinum-based chemotherapy, leading to regulatory approval in various countries.

Objective: To analyze clinically relevant subgroups from JAVELIN Bladder 100.

Design, Setting, And Participants: Patients with unresectable locally advanced or metastatic UC without progression on 1L gemcitabine + cisplatin or carboplatin were randomized to receive avelumab + BSC (n = 350) or BSC alone (n = 350).

Avelumab First-Line Maintenance for Advanced Urothelial Carcinoma: Results From the JAVELIN Bladder 100 Trial After ≥2 Years of Follow-Up.

JCO Initial results from the phase III JAVELIN Bladder 100 trial (ClinicalTrials.gov identifier: NCT02603432) showed that avelumab first-line (1L) maintenance plus best supportive care (BSC) significantly prolonged overall survival (OS) and progression-free survival (PFS) versus BSC alone in patients with advanced urothelial carcinoma (aUC) who were progression-free after 1L platinum-containing chemotherapy. Avelumab 1L maintenance treatment is now a standard of care for aUC.

Longitudinal single-cell profiling of chemotherapy response in acute myeloid leukemia.

Acute myeloid leukemia may be characterized by a fraction of leukemia stem cells (LSCs) that sustain disease propagation eventually leading to relapse. Yet, the contribution of LSCs to early therapy resistance and AML regeneration remains controversial. We prospectively identify LSCs in AML patients and xenografts by single-cell RNA sequencing coupled with functional validation by a microRNA-126 reporter enriching for LSCs.

Papillary muscle ventricular ectopy ablation in a malignant mitral valve prolapse: Ablation in Malignant Mitral Valve Prolapse: Ablation in Malignant Mitral Valve Prolapse.

Patients with mitral valve prolapse (MVP) have a heterogeneous clinical spectrum, ranging from benign to severe clinical presentations such as sudden cardiac death (SCD). Some of the markers of "arrhythmic MVP" include inverted/biphasic T-waves, QT prolongation, and polymorphic premature ventricular contractions (PVCs) originating from the left ventricular outflow tract and papillary muscles (PMs). The genesis of arrhythmias in MVP recognizes the combination of the substrate (fibrosis) and the trigger (mechanical stretch).

Targeted Approaches in Metastatic Castration-Resistant Prostate Cancer: Which Data?

Prostate cancer is the second most common diagnosed cancer and the fifth leading cause of cancer-related deaths in men worldwide. Despite significant advances in the management of castration-sensitive prostate cancer, the majority of patients develop a castration-resistant disease after a median duration of treatment of 18-48 months. The transition to a castrate resistance state could rely on alternative survival pathways, some related to androgen-independent mechanisms.

Safety of First-Line Nivolumab Plus Ipilimumab in Patients With Metastatic NSCLC: A Pooled Analysis of CheckMate 227, CheckMate 568, and CheckMate 817.

Introduction: We characterized the safety of first-line nivolumab plus ipilimumab (NIVO+IPI) in a large patient population with metastatic NSCLC and efficacy outcomes after NIVO+IPI discontinuation owing to treatment-related adverse events (TRAEs).

Methods: We pooled data from three first-line NIVO+IPI studies (NIVO, 3 mg/kg or 240 mg every 2 wk; IPI, 1 mg/kg every 6 wk) in metastatic NSCLC (CheckMate 227 part 1, CheckMate 817 cohort A, CheckMate 568 part 1). Safety end points included TRAEs and immune-mediated adverse events (IMAEs) in the pooled population and patients aged 75 years or older.

First-line avelumab for patients with PD-L1-positive metastatic or locally advanced urothelial cancer who are unfit for cisplatin.

Background: Cisplatin-based chemotherapy is the most recommended treatment for metastatic urothelial cancer (mUC). However, about 50% of patients are considered to be cisplatin ineligible. Anti-programmed cell death protein 1/programmed death-ligand 1 (PD-L1) therapies have, nevertheless, increased the options available to clinicians and are especially valuable for treating these patients.

Primary Tumor Shrinkage and the Effect on Metastatic Disease and Outcomes in Patients With Advanced Kidney Cancer With Intermediate or Poor Prognosis Treated With Nivolumab Plus Ipilimumab or Cabozantinib.

Background: Immune checkpoint inhibitor (ICI)-based combinations have become the first-line standard of care in metastatic renal cell carcinoma (mRCC), but their activity on the primary tumor is still one of the most debated issues.

Patients And Methods: The aim of our analysis was to evaluate the primary tumor's response to first-line therapy with cabozantinib or nivolumab+ipilimumab, and its correlation with metastatic response and with patient outcomes.

Results: Sixty-seven mRCC patients met the criteria for inclusion in the final analysis (30 treated with cabozantinib and 37 with nivolumab+ipilimumab).

Patient-reported Outcomes from JAVELIN Bladder 100: Avelumab First-line Maintenance Plus Best Supportive Care Versus Best Supportive Care Alone for Advanced Urothelial Carcinoma.

Background: In JAVELIN Bladder 100, avelumab first-line maintenance plus best supportive care (BSC) significantly prolonged overall survival (OS; primary endpoint) versus BSC alone in patients with advanced urothelial carcinoma (aUC) without disease progression with first-line platinum-containing chemotherapy.

Objective: To evaluate patient-reported outcomes (PROs) with avelumab plus BSC versus BSC alone.

Design, Setting, And Participants: A randomized phase 3 trial (NCT02603432) was conducted in 700 patients with locally advanced or metastatic urothelial carcinoma that had not progressed with first-line gemcitabine plus cisplatin or carboplatin.

Plain language summary of results from the JAVELIN Bladder 100 study: avelumab maintenance treatment for advanced urothelial cancer.

What Is This Summary About?: This is a plain language summary of an article originally published in . It is about initial results (collected in October 2019) from the JAVELIN Bladder 100 study (a clinical trial), which looked at avelumab maintenance treatment in people with advanced urothelial cancer. Urothelial cancer is the most common type of bladder cancer.

Looking for a Simplified Diagnostic Model to Identify Potentially Lethal Cases of Prostate Cancer at Initial Diagnosis: An ImGO Pilot Study.

The recurrent genetic anomalies used to classify prostate cancer (PC) into distinct molecular subtypes have limited relevance for clinical practice. In consideration of WHO 2016 histological classification, which includes the introduction of Gleason Score 4 for patients with cribriform component and the definition of intraductal carcinoma as a new entity, a retrospective pilot study was conducted to investigate, by histological review, if there were any variations of Gleason Score and the incidence of intraductal carcinoma and cribriform pattern, intended as "phenotypic" markers of potentially lethal PC, among metastatic castration-sensitive PC (mCSPC) and metastatic castration-resistant PC (mCRPC) samples. Potentially predictive factors were also assessed.

Nectin-4 and DNA mismatch repair proteins expression in upper urinary tract urothelial carcinoma (UTUC) as a model for tumor targeting approaches: an ImGO pilot study.

Background: Upper urinary tract urothelial carcinoma (UTUC) accounts for only about 5-10% of all urothelial cancers and is characterized by an aggressive and frequently rapidly fatal behavior. However, detailed knowledge of its molecular profile is still lacking.

Materials And Methods: We identified, by chart analysis, patients who underwent radical nephroureterectomy or diagnostic biopsy for UTUC between January 2015 and August 2020 at the Santa Maria Hospital of Terni, in Italy.

First-line pazopanib in patients with advanced non-clear cell renal carcinoma: An Italian case series.

Background: Non-clear cell (ncc) metastatic renal-cell carcinoma (RCC) has dismal results with standard systemic therapies and a generally worse prognosis when compared to its clear-cell counterpart. New systemic combination therapies have emerged for metastatic RCC (mRCC), but the pivotal phase III trials excluded patients with nccRCC, which constitute about 30% of metastatic RCC cases.

Aim: To provide a piece of real-life evidence on the use of pazopanib in this patient subgroup.

Combination Therapy in Renal Cell Carcinoma: the Best Choice for Every Patient?

Purpose Of Review: Therapeutic alternatives to treat metastatic renal cell carcinoma (mRCC) are increasing, and combination therapies, including antiangiogenic agents and tyrosine kinase/mTOR/immune checkpoint inhibitors, are identified as the gold standard driven by the results of recent clinical studies. Nevertheless, the real-world RCC population is very heterogeneous, with categories of patients not represented in the enrolled trial population who may not benefit more from these treatments. The purpose of this expert review is to assess the rationale on which tyrosine kinase alone may still be a viable first-line treatment option for some subgroups of patients with mRCC.

Analysis by region of outcomes for patients with advanced renal cell carcinoma treated with cabozantinib or everolimus: a sub-analysis of the METEOR study.

Introduction: METEOR was a phase 3 trial (NCT01865747) of cabozantinib versus everolimus in adults with advanced or metastatic clear cell RCC previously treated with VEGF receptor (VEGFR) tyrosine kinase inhibitors (TKIs). This analysis of METEOR compared outcomes for patients recruited from European and non-European countries.

Material And Methods: Adults with advanced/metastatic clear cell RCC who had received ≥ 1 prior VEGFR-TKI treatment were randomized 1:1 to receive cabozantinib or everolimus.

First-Line Nivolumab Plus Ipilimumab in Advanced NSCLC: 4-Year Outcomes From the Randomized, Open-Label, Phase 3 CheckMate 227 Part 1 Trial.

Introduction: In CheckMate 227, nivolumab plus ipilimumab prolonged overall survival (OS) versus chemotherapy in patients with tumor programmed death-ligand 1 (PD-L1) greater than or equal to 1% (primary end point) or less than 1% (prespecified descriptive analysis). We report results with minimum 4 years' follow-up.

Methods: Adults with previously untreated stage IV or recurrent NSCLC were randomized (1:1:1) to nivolumab plus ipilimumab, nivolumab, or chemotherapy (PD-L1 ≥1%); or to nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy (PD-L1 <1%).