Tissue-Agnostic Targeting of Neurotrophic Tyrosine Receptor Kinase Fusions: Current Approvals and Future Directions.

fusions are oncogenic drivers for multiple tumor types. Therefore, the development of selective tropomyosin receptor kinase (TRK) inhibitors, including larotrectinib and entrectinib, has been transformative in the context of clinical management, given the high rates of responses to these drugs, including intracranial responses in patients with brain metastases. Given their promising activity in pan-cancer cohorts, larotrectinib and entrectinib received U.

Target-Driven Tissue-Agnostic Drug Approvals-A New Path of Drug Development.

The regulatory approvals of tumor-agnostic therapies have led to the re-evaluation of the drug development process. The conventional models of drug development are histology-based. On the other hand, the tumor-agnostic drug development of a new drug (or combination) focuses on targeting a common genomic biomarker in multiple cancers, regardless of histology.

Combining Poly (ADP-Ribose) Polymerase (PARP) Inhibitors with Chemotherapeutic Agents: Promise and Challenges.

Better understanding of molecular drivers and dysregulated pathways has furthered the concept of precision oncology and rational drug development. The role of DNA damage response (DDR) pathways has been extensively studied in carcinogenesis and as potential therapeutic targets to improve response to chemotherapy or overcome resistance. Treatment with small molecule inhibitors of PARP has resulted in clinical response and conferred survival benefit to patients with ovarian cancer, BRCA-mutant breast cancer, HRD-deficient prostate cancer and BRCA-mutant pancreatic cancer, leading to US Food and Drug Administration (FDA) approvals.

Selinexor: Changing the paradigm in patients with TP53 wild-type endometrial cancer?

Recurrent endometrial cancer (EC) remains a therapeutic challenge despite advancements in personalized medicine. SIENDO trial showed the potential clinical benefit of selinexor in patients with TP53 wild-type advanced/recurrent EC. The quest for novel therapeutic avenues and approaches continues as researchers seek a glimmer of hope in an area of uncertainty.

Updated meta-analysis of randomized controlled trials on primary outpatient thromboprophylaxis in patients with gastric and gastroesophageal junction cancers receiving chemotherapy.

Advanced gastric cancer is a highly thrombogenic cancer per Khorana score. Recent clinical practice guidelines suggest primary outpatient thromboprophylaxis (POTP) for patients with a Khorana score ≥2. We performed an updated meta-analysis to evaluate the benefit of POTP in patients with gastric cancer and gastroesophageal junction cancers receiving chemotherapy.

Heparin-Induced Thrombocytopenia at the Emergency Department Due to Intermittent Heparin Flush in a Patient Undergoing Stem Cell Transplant.

Heparin-induced thrombocytopenia (HIT) is an adverse reaction to heparin products, but not warfarin. HIT usually occurs 5‒10 days after exposure to heparin. Here, we report a case of HIT with multiple thrombotic events and severe thrombocytopenia resulting from intermittent intravenous heparin flushes for maintenance of a newly placed subclavian central venous catheter (CVC) for stem cell transplant.

The contemporary management of cancers of the sinonasal tract in adults.

Sinonasal malignancies make up <5% of all head and neck neoplasms, with an incidence of 0.5-1.0 per 100,000.

Identification of Mutations in Circulating Tumor DNA in Patients With Cancer.

Purpose: is the most mutated proto-oncogene that has been identified in cancer, and treatment of patients with mutations remains an arduous challenge. Recently, mutation has attracted special interest because it is now considered potentially druggable with recently developed covalent small-molecule inhibitors. Nevertheless, to date, there have been no large-scale analyses of liquid biopsy that include testing for .

Acalabrutinib-Related Cardiac Toxicities in Patients with Chronic Lymphocytic Leukemia: A Meta-Analysis of Randomized Controlled Trials.

Acalabrutinib, a second-generation and more selective Bruton's tyrosine kinase inhibitor, was developed to potentiate efficacy while minimizing ibrutinib-associated side effects. We undertook a systematic review and meta-analysis of randomized clinical trials to determine the risks of acalabrutinib-related cardiac toxicities in patients with chronic lymphocytic leukemia. Patients on acalabrutinib experienced higher risk of any-grade cardiac events (risk ratio, 1.

Primary ambulatory thromboprophylaxis in patients with pancreatic cancer receiving chemotherapy: hope or hype?

Thrombosis is the second leading cause of death in cancer patients. Patients with pancreatic cancer (PC) have a very high risk of developing venous thromboembolism (VTE). Even though primary ambulatory thromboprophylaxis (PATP) could decrease this risk, there are uncertain issues with regard to the choice and dose of anticoagulants, duration of anticoagulant therapy, and patient selection criteria.

Meta-analysis of randomized controlled trials on primary ambulatory thromboprophylaxis in patients with ovarian cancer receiving chemotherapy.

Ovarian cancer (OC) is highly associated with venous thromboembolism (VTE). The OC cells stimulate thrombin generation, and chemotherapy potentiates the prothrombotic effect of cancer cells by damaging endothelium and enhancing hypercoagulability. Recently, primary ambulatory thromboprophylaxis (PATP) has been studied as a potential treatment in cancer patients undergoing chemotherapy with an aim of reducing the incidence of VTE and potentially prolonging survival.

Clinical and Molecular Characterization of Mutations as Predictive Biomarkers of Response to Immune Checkpoint Inhibitors in Advanced Cancers.

Purpose: DNA polymerase epsilon is critical to DNA proofreading and replication. Mutations in have been associated with hypermutated tumors and antitumor response to immune checkpoint inhibitor (ICI) therapy. We present a clinicopathologic analysis of patients with advanced cancers harboring mutations, the pattern of co-occurring mutations, and their response to ICI therapy within the context of mutation pathogenicity.

Meta-analysis of randomized controlled trials on primary ambulatory thromboprophylaxis in patients with nonpancreatic gastrointestinal cancers receiving chemotherapy.

Primary ambulatory thromboprophylaxis (PATP) in patients with solid malignancies is not routinely indicated. We performed a meta-analysis of randomized controlled trials (RCTs) to determine the benefit and risk of PATP in patients with nonpancreatic gastrointestinal cancers receiving chemotherapy. RCTs with venous thromboembolism (VTE) reduction as primary or secondary endpoints were included.

Selinexor in combination with standard chemotherapy in patients with advanced or metastatic solid tumors.

Selinexor, an oral selective inhibitor of nuclear export (SINE), was demonstrated to hinder the DNA damage repair (DDR) system by reducing DDR proteins while enhancing the killing of cancer cells by DDR-based therapeutics in vivo studies. In this single-center, multi-arm phase 1b study, selinexor with carboplatin, doxorubicin and cyclophosphamide (DC), irinotecan with fluorouracil and folinic acid (FOLFIRI), irinotecan, and capecitabine and oxaliplatin (XELOX), were employed as separate parallel arms. Eligible patients have relapsed/ metastatic refractory solid tumors following standard therapy or addition of selinexor to systemic therapy was appropriate.

Selinexor in combination with carboplatin and paclitaxel in patients with advanced solid tumors: Results of a single-center, multi-arm phase Ib study.

Background: Carboplatin and paclitaxel (CT) is one of the standard chemotherapy regimens used in various tumor types. Preclinical models have suggested that selinexor, a first-in-class oral potent selective inhibitor of nuclear export Exportin-1, and CT exerts antitumor activity in multiple malignancies.

Methods: This was a single-center, multi-arm phase Ib study utilizing a "basket type" expansion.

Tissue-Agnostic Drug Development: A New Path to Drug Approval.

In recent years, there has been remarkable progress in our understanding of cancer biology, host responses, and the concept of precision oncology. These advances have focused attention on biomarker-driven, tissue-agnostic drug development strategies. The recent approvals by the FDA of pembrolizumab for the treatment of unresectable or metastatic, microsatellite instability-high or deficient mismatch repair solid tumors, and more recently for the treatment of tumor mutational burden-high tumors; and of larotrectinib and entrectinib for the treatment of neurotrophic tyrosine kinase () fusion-positive solid tumors, have further heightened interest in target-driven as opposed to histology-driven drug development.

Precision therapy for RET-altered cancers with RET inhibitors.

Rearranged during transfection (RET) is involved in the physiological development of some organ systems. Activating RET alterations via either gene fusions or point mutations are potent oncogenic drivers in non-small cell lung cancer, thyroid cancer, and in multiple diverse cancers. RET-altered cancers were initially treated with multikinase inhibitors (MKIs).

Pernicious anemia: Pathophysiology and diagnostic difficulties.

Pernicious anemia (PA) is the most common cause of vitamin B12 (cobalamin) deficiency anemia in the world. It is an autoimmune disease, comprising of salient features of autoimmune chronic atrophic gastritis (CAG) and cobalamin deficiency (CD). Although the anemia was first described as pernicious, it may well be controlled with vitamin B12 replacement.

Selinexor in combination with topotecan in patients with advanced or metastatic solid tumors: Results of an open-label, single-center, multi-arm phase Ib study.

Background Selinexor, a first-in-class, oral selective inhibitor of nuclear export (SINE) compound inhibits Exportin-1(XPO1), had demonstrated synergistic activity with many chemotherapies and conferred in vivo antitumor efficacy in hematologic as well as solid tumors. Methods This open-label, single-center, multi-arm phase 1b study used a standard 3 + 3 design and a "basket type" expansion. Selinexor with intravenous topotecan was given in one of the 13 parallel arms.

First-in-human, phase I/IIa study of CRLX301, a nanoparticle drug conjugate containing docetaxel, in patients with advanced or metastatic solid malignancies.

Background This was a phase I/IIa study to investigate the tolerability, efficacy and pharmacokinetics (PK)/ pharmacodynamics (PD) of CRLX301, CDP-based nanoparticle formulation of docetaxel. Methods The study was conducted in two parts. In part 1, dose-escalation using a standard 3 + 3 design was performed in two dosing schedules (every week (QW) and every 3 weeks (Q3W)).