A phase I study of MLN4924 and belinostat in relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome.

Purpose: Relapsed and/or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome continue to have a poor prognosis with limited treatment options despite advancements in rational combination and targeted therapies. Belinostat (an HDAC inhibitor) and Pevonedistat (a NEDD8 inhibitor) have each been independently studied in hematologic malignancies and have tolerable safety profiles with limited single-agent activity. Preclinical studies in AML cell lines and primary AML cells show the combination to be highly synergistic, particularly in high-risk phenotypes such as p53 mutant and FLT-3-ITD positive cells.

Specialty palliative care use among cancer patients: A population-based study.

Background: Rigorous population-based assessments of the use of specialty palliative care (SPC) in the US are rare.

Settings/subjects: This study examined SPC use among cancer patients in a mid-sized metropolitan area in Southeast US.

Measurements: In this cancer decedent cohort study, data were acquired and linked from the state-wide cancer registry; state-wide hospital discharge dataset; and local SPC providers.

An ALK Immunohistochemical Pitfall: -Positive Histiocytosis Versus Angiomatoid Fibrous Histiocytoma.

The proliferation of recognized neoplasms related to related to rearrangements involving kinase genes, arising in diverse somatic tissue lineages, poses an increasing challenge in surgical pathology. For instance, ALK rearrangements have been observed in diverse neoplasms of epithelial, connective tissue, and hematolymphoid lineages, many of which are associated with overexpression of ALK by immunohistochemistry as a useful biomarker. An even higher order challenge and pitfall would be the scenario where a tumor an ALK rearrangement nonetheless overexpresses the protein, thereby simulating an ALK-defined neoplasm.

T helper 2 cell-directed immunotherapy eliminates precancerous skin lesions.

The continuous rise in skin cancer incidence highlights an imperative for improved skin cancer prevention. Topical calcipotriol-plus-5-fluorouracil (calcipotriol-plus-5-FU) immunotherapy effectively eliminates precancerous skin lesions and prevents squamous cell carcinoma (SCC) in patients. However, its mechanism of action remains unclear.

Tobacco susceptibility and use among rural adolescents: The role of tobacco marketing exposure and screen media use.

Introduction: Tobacco marketing has been found to increase pro-tobacco attitudes and susceptibilities; yet its impact on rural adolescents lacks research. We aim to examine the association between tobacco marketing exposure, screen use, and susceptibility and use of tobacco among a rural youth sample.

Methods: Youth (N = 697) enrolled in grades 9-11 that resided in rural counties in Virginia were recruited to participate in a survey in September 2022.

Resistance to Tyrosine Kinase Inhibitors in Hepatocellular Carcinoma (HCC): Clinical Implications and Potential Strategies to Overcome the Resistance.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide, and the development of effective treatment strategies remains a significant challenge in the management of advanced HCC patients. The emergence of tyrosine kinase inhibitors (TKIs) has been a significant advancement in the treatment of HCC, as these targeted therapies have shown promise in prolonging the survival of patients with advanced disease. Although immunotherapy is currently considered as the first line of treatment for advanced HCC patients, many such patients do not meet the clinical criteria to be eligible for immunotherapy, and in many parts of the world there is still lack of accessibility to immunotherapy.

Dose finding, bioavailability, and PK-PD of oral triapine with concurrent chemoradiation for locally advanced cervical cancer and vaginal cancer (ETCTN 9892).

Background: The addition of IV triapine to chemoradiation appeared active in phase I and II studies but drug delivery is cumbersome. We examined PO triapine with cisplatin chemoradiation.

Methods: We implemented a 3 + 3 design for PO triapine dose escalation with expansion, starting at 100 mg, five days a week for five weeks while receiving radiation with weekly IV cisplatin for locally advanced cervical or vaginal cancer.

SWOG S1815: A Phase III Randomized Trial of Gemcitabine, Cisplatin, and Nab-Paclitaxel Versus Gemcitabine and Cisplatin in Newly Diagnosed, Advanced Biliary Tract Cancers.

Purpose: SWOG S1815 was a randomized, open label phase III trial, evaluating gemcitabine, nab-paclitaxel, and cisplatin (GAP) versus gemcitabine and cisplatin (GC) in patients with newly diagnosed advanced biliary tract cancers (BTCs).

Methods: Patients with newly diagnosed locally advanced unresectable or metastatic BTC, including intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC) and gallbladder carcinoma (GBC), were randomly assigned 2:1 to either GAP (gemcitabine 800 mg/m, cisplatin 25 mg/m, and nab-paclitaxel 100 mg/m intravenously once per day on days 1 and 8 of a 21-day cycle) or GC (gemcitabine 1,000 mg/m and cisplatin 25 mg/m intravenously once per day on days 1 and 8 of a 21-day cycle).

Results: Among 452 randomly assigned participants, 441 were eligible and analyzable, 67% with ICC, 16% with GBC, and 17% with ECC.

Optimizing public private partnerships to support clinical cancer research.

Public-private partnerships (PPPs) in cancer research have emerged as a pivotal model in the development of strategies to rapidly advance therapeutic innovations. The collaboration between public entities, such as government agencies and research institutions, and private entities, including pharmaceutical and biotechnology companies, as well as nonprofit organizations, brings together diverse expertise, resources, and perspectives to address the challenges of efficient drug development and equitable care delivery. This synergy has the potential to accelerate the translation of basic research findings into tangible clinical applications.

Glycosylation of ceramide synthase 6 is required for its activity.

Sphingolipids play key roles in membrane structure and cellular signaling. Ceramide synthase (CerS)-generated ceramide is implicated in cellular stress responses and induction of apoptosis. Ceramide and other sphingolipids are linked to the induction of ER stress response pathways.

FGTI-2734 Inhibits ERK Reactivation to Overcome Sotorasib Resistance in KRAS G12C Lung Cancer.

Introduction: KRAS G12C targeted therapies, such as sotorasib, represent a major breakthrough, but overall response rates and progression-free survival for patients with KRAS G12C lung cancer are modest due to the emergence of resistance mechanisms involving adaptive reactivation of ERK, which requires wild-type HRAS and NRAS membrane localization.

Methods And Results: Here, we demonstrate that the dual farnesyltransferase and geranylgeranyltransferase-1 inhibitor FGTI-2734 inhibits wild-type RAS membrane localization and sotorasib-induced ERK feedback reactivation, and overcomes sotorasib adaptive resistance. The combination of FGTI-2734 and sotorasib is synergistic at inhibiting the viability and inducing apoptosis of KRAS G12C lung cancer cells, including those highly resistant to sotorasib.

Association of oropharyngeal cancer recurrence with tumor-intrinsic and immune-mediated sequelae of reduced genomic instability.

Background: Limited understanding of the biology predisposing certain human papillomavirus-related (HPV+) oropharyngeal squamous cell carcinomas (OPSCCs) to relapse impedes therapeutic personalization. We aimed to identify molecular traits that distinguish recurrence-prone tumors.

Methods: 50 HPV+ OPSCCs that later recurred (cases) and 50 non-recurrent controls matched for stage, therapy, and smoking history were RNA-sequenced.

Proteolysis-targeting vaccines (PROTAVs) for robust combination immunotherapy of melanoma.

Protein/peptide subunit vaccines are promising to promote the tumor therapeutic efficacy of immune checkpoint blockade (ICB). However, current protein/peptide vaccines elicit limited antitumor T cell responses, leading to suboptimal therapeutic efficacy. Here, we present proteolysis-targeting vaccines (PROTAVs) that facilitate antigen proteolytic processing and cross-presentation to potentiate T cell responses for robust ICB combination immunotherapy of melanoma.

Hepatocyte-derived extracellular vesicles regulate liver regeneration through a negative feedback mechanism.

While significant progress has been made in understanding various aspects of liver regeneration, the molecular mechanisms responsible for the initiation and termination of cell proliferation in the liver following massive tissue loss or injury of liver remain unknown. As it was previously shown, the loss of liver mass affects putative hepatocyte-specific mitogenic inhibitors in the blood. Although the presence of these putative inhibitors regulating precise liver regeneration has been described in numerous publications, they have never been identified.

Obesity Paradox and the Effect of NT-proBNP on All-Cause and Cause-Specific Mortality.

Background: In heart failure patients, obesity is associated with better outcomes as compared to normal weight, a phenomenon called the obesity paradox.

Objective: To examine if obesity modifies the relationship between NT-proBNP and all-cause and cause-specific mortality in adults without coronary artery disease or heart failure history.

Methods: We used the National Health and Nutrition Examination Survey (NHANES) data from 1999 to 2004 and linked it with mortality through December 31, 2019.

Design and Synthesis of Small Molecule Probes of MDA-9/Syntenin.

MDA-9/Syntenin, a key scaffolding protein and a molecular hub involved in a diverse range of cell signaling responses, has proved to be a challenging target for the design and discovery of small molecule probes. In this paper, we report on the design and synthesis of small molecule ligands of this key protein. Genetic algorithm-based computational design and the five-eight step synthesis of three molecules led to ligands with affinities in the range of 1-3 µM, a 20-60-fold improvement over literature reports.

Improving Patient Understanding and Outcomes in Lung Cancer Using an Animated Patient's Guide with Visual Formats of Learning.

Lung cancer patient education resources that address barriers to health literacy, improve understanding, and demonstrate improved patient outcomes are limited. Our study aim was to evaluate and report on learner knowledge improvement and intent to implement behavior change, and validate the benefits of the You and Lung Cancer website and YouTube resources. Our study occurred from November 2017 to December 2023.

Fibroblasts Regulate the Transformation Potential of Human Papillomavirus-positive Keratinocytes.

Persistent human papillomavirus (HPV) infection is necessary but insufficient for viral oncogenesis. Additional contributing co-factors, such as immune evasion and viral integration have been implicated in HPV-induced cancer progression. It is widely accepted that HPV+ keratinocytes require co-culture with fibroblasts to maintain viral episome expression, yet the exact mechanisms for this have yet to be elucidated.