Germline and somatic testing for homologous repair deficiency in patients with prostate cancer (part 1 of 2).

Background/objectives: Unfortunately, not all metastatic castration resistant prostate cancer (mCRPC) patients receive available life-prolonging systemic therapies, emphasizing the need to optimize mCRPC treatment selections. Better guidelines are necessary to determine genetic testing in prostate cancer.

Subjects/methods: In this two-part expert opinion-based guide, we provide an expert consensus opinion on the utilization of germline and somatic testing to detect HRR alterations in patients with mCRPC.

Therapeutic implications of homologous repair deficiency testing in patients with prostate cancer (Part 2 of 2).

Background/objectives: Unfortunately, not all metastatic castration-resistant prostate cancer (mCRPC) patients receive available life-prolonging systemic therapies, emphasizing the need to optimize mCRPC treatment selections. Better guidelines are necessary to determine genetic testing for prostate cancer.

Subjects/methods: In this two-part expert opinion-based guide, we provide an expert consensus opinion on the utilization of germline and somatic testing to detect HRR alterations in patients with mCRPC.

A phase I/II trial of sapanisertib in advanced anaplastic and radioiodine refractory differentiated thyroid carcinoma.

Background: There are limited therapeutic options for patients with recurrent/metastatic anaplastic thyroid carcinoma (ATC), and radioiodine refractory (RAIR) differentiated thyroid carcinoma (DTC) refractory to multi-kinase inhibitors. This multi-center trial evaluated sapanisertib, a next generation oral kinase inhibitor of mTOR complexes 1/2, in ATC and RAIR DTC.

Methods: A safety run-in phase I was followed by non-randomized phase II trial in ATC, with an exploratory cohort in RAIR DTC.

Metastatic Hormone-Sensitive Prostate Cancer in the Era of Doublet and Triplet Therapy.

Treatment for metastatic hormone-sensitive prostate cancer has undergone significant evolution in recent years, leading to substantial improvements in overall survival. Men are living longer than ever before with a median survival now which is almost 6 years. The timing and extent of metastatic disease combined with individual patient factors helps treatment recommendation of doublet therapy including androgen deprivation (ADT) plus either chemotherapy or androgen receptor signaling inhibition (ARSI) or triplet therapy with ADT+ARSI+chemotherapy.

The Human Soluble NKG2D Ligand Differentially Impacts Tumorigenicity and Progression in Temporal and Model-Dependent Modes.

NKG2D is an activating receptor expressed by all human NK cells and CD8 T cells. Harnessing the NKG2D/NKG2D ligand axis has emerged as a viable avenue for cancer immunotherapy. However, there is a long-standing controversy over whether soluble NKG2D ligands are immunosuppressive or immunostimulatory, originating from conflicting data generated from different scopes of pre-clinical investigations.

Large Cell Neuroendocrine Prostate Cancer: Large Is Not Small.

Neuroendocrine prostate cancer is complex, comprising a wide spectrum of phenotypes, which has led to very different entities being inappropriately lumped together or assumed to behave like more common entities. Elucidating subtle differences is critical for treatment decision making, as this commentary describes.

Nivolumab Plus Ipilimumab vs Nivolumab Alone in Advanced Cancers Other Than Melanoma: A Meta-Analysis.

Importance: Although the combination of nivolumab plus ipilimumab has unquestionable benefit over nivolumab monotherapy in advanced melanoma, currently no summative analyses have compared the combination with nivolumab monotherapy for advanced cancers other than melanoma.

Objective: To examine whether the addition of ipilimumab to standard-dose nivolumab safely improves clinical outcomes in patients with advanced cancers other than melanoma.

Data Sources: Electronic databases (PubMed, EBSCO Information Services, Embase, and Cochrane Library) were systematically searched for studies of standard-dose nivolumab plus ipilimumab vs nivolumab alone in the treatment of advanced cancers other than melanoma published from database inception to October 31, 2022.

Utilizing metformin to prevent metabolic syndrome due to androgen deprivation therapy (ADT): a randomized phase II study of metformin in non-diabetic men initiating ADT for advanced prostate cancer.

Background: Androgen deprivation therapy (ADT) can lead to metabolic syndrome (MS) and is implicated in ADT-resistance. Metformin showed antineoplastic activity through mTOR inhibition secondary AMPK-activation.

Materials And Methods: To investigate whether metformin mitigated ADT-related MS, we conducted a randomized double-blind phase II trial of metformin 500 mg TID or placebo in non-diabetic patients with biochemically-relapsed or advanced PC due for ADT.

Long-Term Outcomes of Patients With Pulmonary Embolism Managed With Endovascular Therapies Compared to Medical Therapy.

Background: Guidelines on the management of acute pulmonary embolism (PE) recommend consideration of endovascular therapies (EVT) for patients at intermediate-high risk. However, long-term data on the outcomes of patients after EVT as compared to medical therapy is lacking. This study aimed to compare outcomes of patients receiving EVT as compared to medical therapy alone at 3 to 6 months.

Intermittent Androgen Deprivation for Biochemically Recurrent Prostate Cancer: First Do No Harm.

Intermittent androgen deprivation therapy in patients with prostate cancer and biochemical relapse does not prolong survival or improve quality of life.

Alternative trastuzumab dosing strategies in HER2-positive early breast cancer are associated with patient out-of-pocket savings.

Patients with breast cancer frequently experience financial hardship, often due to the high costs of anti-cancer drugs. We sought to develop alternative trastuzumab dosing strategies, compare their pharmacokinetic effectiveness to standard dosing, and assess the expected financial implications of transitioning to them. We extracted clinical data from the records of 135 retrospectively identified patients with HER2-positive early breast cancer at a single, urban comprehensive cancer center who were treated with trastuzumab between 2017 and 2019.

Phase I/II Trial of Enzalutamide and Mifepristone, a Glucocorticoid Receptor Antagonist, for Metastatic Castration-Resistant Prostate Cancer.

Purpose: Although androgen deprivation therapy (ADT) and androgen receptor (AR) signaling inhibitors are effective in metastatic prostate cancer, resistance occurs in most patients. This phase I/II trial assessed the safety, pharmacokinetic impact, and efficacy of the glucocorticoid receptor (GR) antagonist mifepristone in combination with enzalutamide for castration-resistant prostate cancer (CRPC).

Patients And Methods: One hundred and six patients with CRPC were accrued.

Safety and efficacy of catheter-directed therapy versus anticoagulation alone in a higher-risk acute pulmonary embolism population.

There is little data comparing safety and efficacy outcomes in patients with pulmonary embolism (PE) receiving catheter directed therapies (CDT) compared to a similar-risk cohort of PE patients receiving anticoagulation alone. 1094 patients with acute PE were studied. CDT and conservatively-managed patients were compared using propensity score matching to assess safety outcomes, which included bleeding and acute kidney injury at 2 and 7 days after PE diagnosis.

Autologous stem cell transplantation after anti-PD-1 therapy for multiply relapsed or refractory Hodgkin lymphoma.

Autologous stem cell transplantation (ASCT) can be curative for patients with relapsed/refractory Hodgkin lymphoma (HL). Based on studies suggesting that anti-PD-1 monoclonal antibodies (mAbs) can sensitize patients to subsequent chemotherapy, we hypothesized that anti-PD-1 therapy before ASCT would result in acceptable outcomes among high-risk patients who progressed on or responded insufficiently to ≥1 salvage regimen, including chemorefractory patients who are traditionally considered poor ASCT candidates. We retrospectively identified 78 HL patients who underwent ASCT after receiving an anti-PD-1 mAb (alone or in combination) as third-line or later therapy across 22 centers.

Allogeneic transplantation after PD-1 blockade for classic Hodgkin lymphoma.

Anti-PD-1 monoclonal antibodies yield high response rates in patients with relapsed/refractory classic Hodgkin lymphoma (cHL), but most patients will eventually progress. Allogeneic hematopoietic cell transplantation (alloHCT) after PD-1 blockade may be associated with increased toxicity, raising challenging questions about the role, timing, and optimal method of transplantation in this setting. To address these questions, we assembled a retrospective cohort of 209 cHL patients who underwent alloHCT after PD-1 blockade.

Spatial and Temporal Heterogeneity of PD-L1 Expression and Tumor Mutational Burden in Gastroesophageal Adenocarcinoma at Baseline Diagnosis and after Chemotherapy.

Purpose: Intrapatient heterogeneity of programmed death ligand 1 (PD-L1) expression and tumor mutational burden (TMB) in gastroesophageal adenocarcinoma (GEA) could influence their roles as predictive biomarkers for response to immune checkpoint inhibitors (ICI). In this retrospective analysis, we evaluated the spatiotemporal heterogeneity and prognostic relevance of PD-L1 expression and TMB in GEA.

Experimental Design: A cohort of 211 patients with stage II-IV GEA was retrospectively reviewed for a total of 407 tumor samples with PD-L1 expression data and 319 tumor samples with TMB data.

Interventional Pharmacoeconomics.

The increasing cost of health care is a major challenge around the world, but particularly in the United States. One reason for increased costs is the rapidly rising cost of oncology drugs. Potential solutions to this problem involve broad changes to health policy.

Anaplastic Lymphoma Kinase Mutation-Positive Non-Small Cell Lung Cancer.

The treatment of patients with advanced non-small cell lung cancer with anaplastic lymphoma kinase chromosomal rearrangements has been revolutionized by the development of tyrosine kinase inhibitors (TKIs). Excellent progress has been made over the past decade, with 4 TKIs now approved in the front-line setting. Alectinib is the preferred first-line option based on its efficacy and side-effect profile.

Interventional Pharmacoeconomics: A Novel Mechanism for Unlocking Value.

Cancer care's sustainability is challenged by drug expenditures. In the absence of systemic change, innovation is needed to curtail drug costs. Interventional pharmacoeconomics (IVPE) utilizes clinical research to identify safe, efficacious, cost-conscious dosing regimens to extract maximum value from expensive therapies.

Performance of the right ventricular outflow tract/aortic diameter as a novel predictor of risk in patients with acute pulmonary embolism.

Right ventricular (RV) enlargement, determined via the ratio of the right to left ventricular diameters (RV/LV) by CT imaging is used to classify the severity of acute pulmonary embolism (PE) and impacts treatment decisions. The RV/LV ratio may be an unreliable marker of RV dysfunction, due in part to the complex RV geometry. This study compared the RV/LV ratio to a novel metric, the ratio of the right ventricular to aortic outflow tract diameters (RVOT/Ao) in patients with acute PE treated with catheter-directed therapies (CDT).

Implications for reactive oxygen species in schizophrenia pathogenesis.

Oxidative stress is a well-recognized participant in the pathophysiology of multiple brain disorders, particularly neurodegenerative conditions such as Alzheimer's and Parkinson's diseases. While not a dementia, a wide body of evidence has also been accumulating for aberrant reactive oxygen species and inflammation in schizophrenia. Here we highlight roles for oxidative stress as a common mechanism by which varied genetic and epidemiologic risk factors impact upon neurodevelopmental processes that underlie the schizophrenia syndrome.

Behavioral effects of cocaine mediated by nitric oxide-GAPDH transcriptional signaling.

Cocaine's behavioral-stimulant effects derive from potentiation of synaptic signaling by dopamine and serotonin leading to transcriptional alterations in postsynaptic cells. We report that a signaling cascade involving nitric oxide (NO) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mediates cocaine's transcriptional and behavioral actions. Lower, behavioral-stimulant doses enhance the cAMP response element-binding (CREB) signaling system, while higher, neurotoxic doses stimulate the p53 cytotoxic system.

Glutathione is a physiologic reservoir of neuronal glutamate.

Glutamate, the principal excitatory neurotransmitter of the brain, participates in a multitude of physiologic and pathologic processes, including learning and memory. Glutathione, a tripeptide composed of the amino acids glutamate, cysteine, and glycine, serves important cofactor roles in antioxidant defense and drug detoxification, but glutathione deficits occur in multiple neuropsychiatric disorders. Glutathione synthesis and metabolism are governed by a cycle of enzymes, the γ-glutamyl cycle, which can achieve intracellular glutathione concentrations of 1-10mM.