The dual endothelin A and angiotensin II type 1 receptor antagonist sparsentan (FILSPARI®) exhibits a safe nonclinical male fertility toxicity profile.

Marketed endothelin receptor antagonists (ERAs) have been associated with testicular tubular atrophy and decreases in male animal fertility in chronic toxicity studies in rats and dogs. Consistent with these findings, reduced sperm count has been observed in the clinical setting and is considered a potential class risk with chronic administration of ERAs. In contrast, no such effects on male animal fertility are noted with angiotensin II type 1 receptor blocker (ARB) treatment.

Long-term Relapse and Survival in Clinical Stage I Testicular Teratoma.

Background And Objective: Studies in metastatic nonseminomatous germ-cell tumor (NSGCT) suggest that the presence of teratomatous elements in the primary tumor is a risk factor for poor survival. Many guidelines have extrapolated this observation and recommend adjuvant retroperitoneal lymph-node dissection (RPLND) even for clinical stage I (CSI) teratoma confined to the testicle. Our objective was to assess relapse-free survival (RFS), cancer-specific survival (CSS), overall survival (OS) among patients with CSI pure teratoma in comparison to CSI NSGCT.

The Role of Stereotactic Body Radiotherapy in Oligoprogressive Malignant Disease (RADIANT): Oncologic Outcomes From a Phase 2 Nonrandomized Controlled Trial.

Purpose: In oligoprogressive (OP) cancer, there are a limited number of metastatic areas progressing on a background of stable or responding to widespread cancer. Although the standard of care for OP is changing systemic therapy (ST), stereotactic body radiation therapy (SBRT) is being explored as an alternative local therapy targeting the sites of progression.

Methods And Materials: RADIANT (NCT04122469) was a single-center phase 2 study of patients with metastatic genitourinary (GU), breast, and gastrointestinal (GI) cancers, receiving ST for ≥3 months, with radiographic OP disease in ≤5 sites.

Combined Transcriptome and Circulating Tumor DNA Longitudinal Biomarker Analysis Associates With Clinical Outcomes in Advanced Solid Tumors Treated With Pembrolizumab.

Purpose: Immune gene expression signatures are emerging as potential biomarkers for immunotherapy (IO). VIGex is a 12-gene expression classifier developed in both nCounter (Nanostring) and RNA sequencing (RNA-seq) assays and analytically validated across laboratories. VIGex classifies tumor samples into hot, intermediate-cold (I-Cold), and cold subgroups.

Psychological distress following multi-gene panel testing for hereditary breast and ovarian cancer risk.

Advances in our understanding of the genetic landscape of hereditary breast and ovarian cancer (HBOC) have led to the clinical adoption of multi-gene panel testing. Panel testing introduces new sources of genetic uncertainty secondary to the inclusion of moderate- and low-penetrance genes, as well as the increased likelihood of identifying a variant of uncertain significance (VUS). This cross-sectional study explored the post-test psychological functioning of women who underwent multi-gene panel testing for HBOC susceptibility genes.

Primary retroperitoneal lymph node dissection for metastatic non-seminomatous germ cell tumours: outcomes and adjuvant chemotherapy.

Objectives: To compare the outcomes and treatment burden of primary retroperitoneal lymph node dissection (pRPLND) alone versus pRPLND + adjuvant chemotherapy (AC) in patients with pathological stage II (PSII) non-seminomatous germ cell tumours (NSGCT).

Patients And Methods: Retrospective review of the Princess Margaret Cancer Center eTestes cancer database identified patients with PSII NSGCT after pRPLND between 1995 and 2020. The primary outcome was relapse-free survival (RFS).

A Phase II, Open-Label, Randomized Trial of Durvalumab With Olaparib or Cediranib in Patients With Mismatch Repair-Proficient Colorectal or Pancreatic Cancer.

Background: The use of immunotherapy in mismatch repair proficient colorectal cancer (pMMR-CRC) or pancreatic adenocarcinoma (PDAC) is associated with limited efficacy. DAPPER (NCT03851614) is a phase 2, basket study randomizing patients with pMMR CRC or PDAC to durvalumab with olaparib (durvalumab + olaparib) or durvalumab with cediranib (durvalumab + cediranib).

Methods: PDAC or pMMR-CRC patients were randomized to either durvalumab+olaparib (arm A), or durvalumab + cediranib (arm B).

Clinical Utility of Tumor Next-Generation Sequencing Panel Testing to Inform Treatment Decisions for Patients With Advanced Solid Tumors in a Tertiary Care Center.

Purpose: There is limited information about the clinical utility of targeted next-generation sequencing (NGS) panel testing to inform decision making for patients with advanced solid tumors. The Ontario-wide Cancer Targeted Nucleic Acid Evaluation (OCTANE) is a prospective study that enrolled more than 4,500 patients with solid tumor for NGS panel testing. We performed a retrospective survey of medical oncologists to evaluate the impact of NGS testing on treatment decisions.

Lumbar Paraspinal Compartment Syndrome in an Active-Duty Army Special Operations Aviation Soldier.

Lumbar paraspinal muscle compartment syndrome is an uncommon, rapidly progressive, and potentially devastating injury with fewer than 40 cases reported in the literature. It initially mimics nonemergent causes of low back pain, disproportionately affects young men, and is most often secondary to acute physical exertion. The disease process is commonly associated with rhabdomyolysis.

Safety of Direct Drug Provocation for the Evaluation of Penicillin Allergy in Low-Risk Adults.

Background: About 10% of patients have a penicillin allergy label, but less than 5% of them are actually allergic. Unnecessary penicillin avoidance is associated with serious medical consequences. Given the growing number of these labels, it is imperative that our diagnostic strategy for penicillin allergy be as efficient as possible.

Biomarker Inference and the Timing of Next-Generation Sequencing in a Multi-Institutional, Cross-Cancer Clinicogenomic Data Set.

Purpose: Observational clinicogenomic data sets, consisting of tumor next-generation sequencing (NGS) data linked to clinical records, are commonly used for cancer research. However, in real-world practice, oncologists frequently request NGS in search of treatment options for progressive cancer. The extent and impact of this dynamic on analysis of clinicogenomic research data are not well understood.

Early Changes in Tumor-Naive Cell-Free Methylomes and Fragmentomes Predict Outcomes in Pembrolizumab-Treated Solid Tumors.

Unlabelled: Early kinetics of circulating tumor DNA (ctDNA) in plasma predict response to pembrolizumab but typically requires sequencing of matched tumor tissue or fixed gene panels. We analyzed genome-wide methylation and fragment-length profiles using cell-free methylated DNA immunoprecipitation and sequencing (cfMeDIP-seq) in 204 plasma samples from 87 patients before and during treatment with pembrolizumab from a pan-cancer phase II investigator-initiated trial (INSPIRE). We trained a pan-cancer methylation signature using independent methylation array data from The Cancer Genome Atlas to quantify cancer-specific methylation (CSM) and fragment-length score (FLS) for each sample.

Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome.

Post-infectious myalgic encephalomyelitis/chronic fatigue syndrome (PI-ME/CFS) is a disabling disorder, yet the clinical phenotype is poorly defined, the pathophysiology is unknown, and no disease-modifying treatments are available. We used rigorous criteria to recruit PI-ME/CFS participants with matched controls to conduct deep phenotyping. Among the many physical and cognitive complaints, one defining feature of PI-ME/CFS was an alteration of effort preference, rather than physical or central fatigue, due to dysfunction of integrative brain regions potentially associated with central catechol pathway dysregulation, with consequences on autonomic functioning and physical conditioning.

Genomic Characterization and Clinical Outcomes of Patients with Peritoneal Metastases from the AACR GENIE Biopharma Collaborative Colorectal Cancer Registry.

Unlabelled: Peritoneal metastases (PM) are common in metastatic colorectal cancer (mCRC). We aimed to characterize patients with mCRC and PM from a clinical and molecular perspective using the American Association of Cancer Research Genomics Evidence Neoplasia Information Exchange (GENIE) Biopharma Collaborative (BPC) registry. Patients' tumor samples underwent targeted next-generation sequencing.

Tumor reactive γδ T cells contribute to a complete response to PD-1 blockade in a Merkel cell carcinoma patient.

Immunotherapies targeting PD-1/PD-L1 are now widely used in the clinic to treat a variety of malignancies. While most of the research on T cell exhaustion and PD-1 blockade has been focused on conventional αβ T cells, the contribution of innate-like T cells such as γδ T cells to anti-PD-1/PD-L1 mediated therapy is limited. Here we show that tumor reactive γδ T cells respond to PD-1 blockade in a Merkel cell carcinoma (MCC) patient experiencing a complete response to therapy.

Seize the engine: Emerging cell cycle targets in breast cancer.

Breast cancer arises from a series of molecular alterations that disrupt cell cycle checkpoints, leading to aberrant cell proliferation and genomic instability. Targeted pharmacological inhibition of cell cycle regulators has long been considered a promising anti-cancer strategy. Initial attempts to drug critical cell cycle drivers were hampered by poor selectivity, modest efficacy and haematological toxicity.

Ziv-aflibercept plus pembrolizumab in patients with advanced melanoma resistant to anti-PD-1 treatment.

Background: Vascular endothelial growth factor is associated with reduced immune response and impaired anti-tumor activity. Combining antiangiogenic agents with immune checkpoint inhibition can overcome this immune suppression and enhance treatment efficacy.

Methods: This study investigated the combination of ziv-aflibercept anti-angiogenic therapy with pembrolizumab in patients with advanced melanoma resistant to anti-PD-1 treatment.

Pharmacokinetics (PK) of Tiragolumab in First-in-Human Study in Patients with Mixed Solid Tumors (GO30103).

Tiragolumab is a first-in-class, fully human IgG1/kappa anti-TIGIT monoclonal antibody that blocks the binding of TIGIT to CD155 (the poliovirus receptor). We summarize the pharmacokinetics (PK) data from the phase 1a/1b GO30103 study of Q3W (every 3 weeks) sequential dosing of tiragolumab (2, 8, 30, 100, 400, 600, or 1200 mg) followed by atezolizumab (1200 mg), Q4W (every 4 weeks) sequential dosing (tiragolumab 840 mg followed by atezolizumab 1680 mg), and Q4W co-infusion (tiragolumab 840 mg plus atezolizumab 1680 mg). Serum samples were collected at multiple time points following tiragolumab and atezolizumab intravenous infusion in patients with solid tumors for PK and immunogenicity assessment.

Autoimmune PaneLs as PrEdictors of Toxicity in Patients TReated with Immune Checkpoint InhibiTors (ALERT).

Background: Immune-checkpoint inhibitors (ICI) can lead to immune-related adverse events (irAEs) in a significant proportion of patients. The mechanisms underlying irAEs development are mostly unknown and might involve multiple immune effectors, such as T cells, B cells and autoantibodies (AutoAb).

Methods: We used custom autoantigen (AutoAg) microarrays to profile AutoAb related to irAEs in patients receiving ICI.