Proton pump inhibitors are detrimental to overall survival of patients with glioblastoma: Results from a nationwide real-world evidence database.

Background: Proton pump inhibitors (PPIs) are often prescribed to manage corticosteroid-induced gastrointestinal toxicity during glioblastoma (GBM) treatment, but were recently identified as strong inducers of aldehyde dehydrogenase-1A1 (ALDH1A1). ALDH1A1 is a primary metabolic enzyme impacting the outcome of chemotherapy, including temozolomide. High expression of ALDH1A1 is associated with poor prognosis in multiple cancers, suggesting PPIs may have a negative impact on survival.

Network targeting combination therapy of synthetic lethal vulnerabilities in deficient glioblastoma: A case report.

Background: Patients with relapsed or progressive glioblastoma only rarely respond to salvage therapies. Nevertheless, comprehensive genomic profiling can provide insight that can identify promising approaches. Signaling pathway analyses have revealed synthetic lethal partnerships, which create the possibility of targeting vulnerabilities arising from the loss of tumor suppressor genes.

Network-targeting combination therapy of leptomeningeal glioblastoma using multiple synthetic lethal strategies: a case report.

Network targeting of disease-specific nodes represents a useful principle for designing combination cancer therapy. In this case of a patient with relapsed leptomeningeal glioblastoma, comprehensive molecular diagnosis led to the identification of a disease network characterized by multiple disease-specific synthetic lethal vulnerabilities involving DNA repair, REDOX homeostasis, and impaired autophagy which suggested a novel network-targeting combination therapy (NTCT). A treatment regimen consisting of lomustine, olaparib, digoxin, metformin, and high dose intravenous ascorbate was employed using the principle of intra-patient dose escalation to deliver the treatment with adequate safety measures to achieve a definitive clinical result.

Elranatamab in relapsed or refractory multiple myeloma: phase 2 MagnetisMM-3 trial results.

Elranatamab is a humanized B-cell maturation antigen (BCMA)-CD3 bispecific antibody. In the ongoing phase 2 MagnetisMM-3 trial, patients with relapsed or refractory multiple myeloma received subcutaneous elranatamab once weekly after two step-up priming doses. After six cycles, persistent responders switched to biweekly dosing.

Contrast-enhanced ultrasound for abdominal image-guided procedures.

Introduction: Since FDA approval for contrast-enhanced ultrasound (CEUS), clinical applications have increased to include diagnostic imaging of hepatic, renal, and other abdominal lesions. The modality has also demonstrated utility in certain image-guided procedures. Intravascular ultrasound contrast agents use microbubbles to improve visibility of solid tumors.

MRTX-500 Phase 2 Trial: Sitravatinib With Nivolumab in Patients With Nonsquamous NSCLC Progressing On or After Checkpoint Inhibitor Therapy or Chemotherapy.

Introduction: Sitravatinib, a receptor tyrosine kinase inhibitor targeting TYRO3, AXL, MERTK receptors, and vascular epithelial growth factor receptor 2, can shift the tumor microenvironment toward an immunostimulatory state. Combining sitravatinib with checkpoint inhibitors (CPIs) may augment antitumor activity.

Methods: The phase 2 MRTX-500 study evaluated sitravatinib (120 mg daily) with nivolumab (every 2 or 4 wk) in patients with advanced nonsquamous NSCLC who progressed on or after previous CPI (CPI-experienced) or chemotherapy (CPI-naive).

Targeting chromosome 12q amplification in relapsed glioblastoma: the use of computational biological modeling to identify effective therapy-a case report.

Background: Relapsed glioblastoma (GBM) is often an imminently fatal condition with limited therapeutic options. Computation biological modeling, i.e.

Combined epigenetic and immunotherapy for blastic and classical mantle cell lymphoma.

Classical MCL (cMCL) constitutes 6-8% of all B cell NHL. Despite recent advances, MCL is incurable except with allogeneic stem cell transplant. Blastic mantle cell lymphoma (bMCL) is a rarer subtype of cMCL associated with an aggressive clinical course and poor treatment response, frequent relapse and poor outcomes.

Randomized Phase 2 Studies of Checkpoint Inhibitors Alone or in Combination With Pegilodecakin in Patients With Metastatic NSCLC (CYPRESS 1 and CYPRESS 2).

Introduction: Checkpoint inhibitors (CPIs) have been approved to treat metastatic NSCLC. Pegilodecakin + CPI suggested promising efficacy in phase 1 IVY, providing rationale for randomized phase 2 trials CYPRESS 1 and CYPRESS 2.

Methods: CYPRESS 1 (N = 101) and CYPRESS 2 (N = 52) included Eastern Cooperative Oncology Group performance status of 0 to 1 and first-line/second-line metastatic NSCLC, respectively, without known EGFR/ALK mutations.

Safety, Efficacy, and Pharmacokinetics of Almonertinib (HS-10296) in Pretreated Patients With EGFR-Mutated Advanced NSCLC: A Multicenter, Open-label, Phase 1 Trial.

Introduction: Almonertinib (HS-10296) is a novel, third-generation EGFR tyrosine kinase inhibitor (EGFR TKI) that targets both EGFR-sensitizing and T790M resistance mutations. This first-in-human trial aimed to evaluate the safety, efficacy, and pharmacokinetics of almonertinib in patients with locally advanced or metastatic EGFR mutation-positive NSCLC that had progressed after pevious EGFR TKI therapy.

Methods: This phase 1, open-label, multicenter clinical trial (NCT0298110) included dose-escalation (55, 110, 220, and 260 mg) and dose-expansion cohorts (55, 110, and 220 mg) with once daily oral administration of almonertinib.

Rlip Depletion Suppresses Growth of Breast Cancer.

RLIP76 (RAL-binding protein-1, Rlip) is a stress-protective mercapturic-acid-pathway transporter protein that also plays a key role in regulating clathrin-dependent endocytosis as a Ral effector. Targeted inhibition or depletion of Rlip causes regression of xenografts of many cancers and is capable of abrogating tumor formation in p53-null mice. This is associated with the reversion of the abnormal methylomic profile of p53-null mice to wild-type.

Anticancer activity of 2'-hydroxyflavanone towards lung cancer.

In previous studies, we found that 2'-hydroxyflavonone (2HF), a citrus flavonoid, inhibits the growth of renal cell carcinoma in a VHL-dependent manner. This was associated with the inhibition of glutathione S-transferases (GSTs), the first step enzyme of the mercapturic acid pathway that catalyzes formation of glutathione-electrophile conjugates (GS-E). We studied 2HF in small cell (SCLC) and non-small cell (NSCLC) lung cancer cell lines for sensitivity to 2HF antineoplastic activity and to determine the role of the GS-E transporter Rlip (Ral-interacting protein; RLIP76; RALBP1) in the mechanism of action of 2HF.

A Phase Ib/II Study of the JAK1 Inhibitor, Itacitinib, plus -Paclitaxel and Gemcitabine in Advanced Solid Tumors.

Lessons Learned: Itacitinib in combination with -paclitaxel plus gemcitabine demonstrated an acceptable safety profile with clinical activity in patients with advanced solid tumors including pancreatic cancer.The results support future studies of itacitinib as a component of combination regimens with other immunologic and targeted small molecule anticancer agents.

Background: Cytokine-mediated signaling via JAK/STAT is central to tumor growth, survival, and systemic inflammation, which is associated with cancer cachexia, particularly in pancreatic cancer.

Longitudinal monitoring of ctDNA EGFR mutation burden from urine correlates with patient response to EGFR TKIs: A case series.

Targetable, somatic EGFR mutations are highly prevalent in patients with non-small cell lung cancer (NSCLC), making them eligible for tyrosine kinase inhibitor (TKI) therapy. Circulating tumor DNA (ctDNA), isolated from blood or urine, has been demonstrated to reliably identify somatic tumor associated EGFR mutations, specifically in patients with inconclusive biopsy. When conventional imaging modalities are inconclusive, quantitative assessment of systemic ctDNA burden has the potential to assess therapeutic response.

Mutation-Enrichment Next-Generation Sequencing for Quantitative Detection of Mutations in Urine Cell-Free DNA from Patients with Advanced Cancers.

Tumor-derived cell-free DNA (cfDNA) from urine of patients with cancer offers noninvasive biological material for detection of cancer-related molecular abnormalities such as mutations in Exon 2 of A quantitative, mutation-enrichment next-generation sequencing test for detecting mutations in urine cfDNA was developed, and results were compared with clinical testing of archival tumor tissue and plasma cfDNA from patients with advanced cancer. With 90 to 110 mL of urine, the cfDNA test had an analytical sensitivity of 0.002% to 0.

Health-related quality of life in the randomised KEYNOTE-002 study of pembrolizumab versus chemotherapy in patients with ipilimumab-refractory melanoma.

Background: In KEYNOTE-002, pembrolizumab significantly prolonged progression-free survival and was associated with a better safety profile compared with chemotherapy in patients with advanced melanoma that progressed after ipilimumab. We present health-related quality of life (HRQoL) outcomes from KEYNOTE-002.

Methods: Patients were randomly assigned 1:1:1 to pembrolizumab 2 or 10 mg/kg every 3 weeks (Q3W) or investigator-choice chemotherapy.

A Highly Sensitive and Quantitative Test Platform for Detection of NSCLC EGFR Mutations in Urine and Plasma.

Introduction: In approximately 60% of patients with NSCLC who are receiving EGFR tyrosine kinase inhibitors, resistance develops through the acquisition of EGFR T790M mutation. We aimed to demonstrate that a highly sensitive and quantitative next-generation sequencing analysis of EGFR mutations from urine and plasma specimens is feasible.

Methods: Short footprint mutation enrichment next-generation sequencing assays were used to interrogate EGFR activating mutations and the T790M resistance mutation in urine or plasma specimens from patients enrolled in TIGER-X (NCT01526928), a phase 1/2 clinical study of rociletinib in previously treated patients with EGFR mutant-positive advanced NSCLC.

Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial.

Background: Patients with melanoma that progresses on ipilimumab and, if BRAF(V600) mutant-positive, a BRAF or MEK inhibitor or both, have few treatment options. We assessed the efficacy and safety of two pembrolizumab doses versus investigator-choice chemotherapy in patients with ipilimumab-refractory melanoma.

Methods: We carried out a randomised phase 2 trial of patients aged 18 years or older from 73 hospitals, clinics, and academic medical centres in 12 countries who had confirmed progressive disease within 24 weeks after two or more ipilimumab doses and, if BRAF(V600) mutant-positive, previous treatment with a BRAF or MEK inhibitor or both.

Phase II Study of Nilotinib in Melanoma Harboring KIT Alterations Following Progression to Prior KIT Inhibition.

Purpose: Although durable responses can be achieved with tyrosine kinase inhibitors such as imatinib in melanomas harboring KIT mutations, the efficacy of alternative inhibitors after progression to imatinib and the activity of these agents on brain metastases are unknown.

Experimental Design: We conducted a phase II study of nilotinib 400 mg twice a day in two cohorts of patients with melanomas harboring KIT mutations or amplification: (A) those refractory or intolerant to a prior KIT inhibitor; and (B) those with brain metastases. The primary endpoint was 4-month disease control rate.

Non-invasive urine testing of EGFR activating mutation and T790M resistance mutation in non-small cell lung cancer.

Background: The increasing understanding of non-small cell lung cancer (NSCLC) biology over the last two decades has led to the identification of multiple molecular targets. This led to the development of multiple targeted therapies in the primary and secondary resistance setting and the epidermal growth factor receptor (EGFR) gene remains the most frequently observed molecular target in NSCLC. Tissue biopsies remain the standard for the identification of such EGFR mutations.

Survival follow-up and ipilimumab retreatment of patients with advanced melanoma who received ipilimumab in prior phase II studies.

Background: This report provides a survival update at a follow-up of >5 years (5.5-6 years) for patients with advanced melanoma who previously received ipilimumab in phase II clinical trials. Safety and efficacy data following ipilimumab retreatment are also reported.

Clinical Benefit from Ipilimumab Therapy in Melanoma Patients may be Associated with Serum CTLA4 Levels.

Stage IV metastatic melanoma patients historically have a poor prognosis with 5-10% 5-year survival. Ipilimumab, a monoclonal antibody against cytotoxic T-lymphocyte antigen 4 (CTLA4), is one of the first treatments to provide beneficial durable responses in advanced melanoma. However, less than 25% of those treated benefit, treatment is expensive, and side effects can be fatal.

Safety and efficacy of vemurafenib in BRAF(V600E) and BRAF(V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study.

Background: In the BRIM-3 trial, vemurafenib was associated with risk reduction versus dacarbazine of both death and progression in patients with advanced BRAF(V600) mutation-positive melanoma. We present an extended follow-up analysis of the total population and in the BRAF(V600E) and BRAF(V600K) mutation subgroups.

Methods: Patients older than 18 years, with treatment-naive metastatic melanoma and whose tumour tissue was positive for BRAF(V600) mutations were eligible.

Surrogate endpoints for overall survival in metastatic melanoma: a meta-analysis of randomised controlled trials.

Background: Recent phase 3 trials have shown an overall survival benefit in metastatic melanoma. We aimed to assess whether progression-free survival (PFS) could be regarded as a reliable surrogate for overall survival through a meta-analysis of randomised trials.

Methods: We systematically reviewed randomised trials comparing treatment regimens in metastatic melanoma that included dacarbazine as the control arm, and which reported both PFS and overall survival with a standard hazard ratio (HR).