Structure-Activity Relationship Study of Splicing Modulators on Hsh155/SF3B1 through Chemical Synthesis and Yeast Genetics.

Meayamycins are synthetic analogs of the natural product FR901464 and exhibit potent anticancer activity against human cancers. They bind SF3B1 and PHF5A, components of the human spliceosome, and they alter pre-mRNA splicing. Detailed analysis of the active site led us to investigate a narrow pocket within the binding site that surrounds the α,β-unsaturated amide portion of meayamycin.

Matched three-dimensional organoids and two-dimensional cell lines of melanoma brain metastases mirror response to targeted molecular therapy.

Despite advances in the treatment paradigm for patients with metastatic melanoma, melanoma brain metastasis (MBM) continues to represent a significant treatment challenge. The study of MBM is limited, in part, by shortcomings in existing preclinical models. Surgically eXplanted Organoids (SXOs) are ex vivo, three-dimensional cultures prepared from primary tissue samples with minimal processing that recapitulate genotypic and phenotypic features of parent tumors without an artificial extracellular scaffold.

High-Throughput Empirical and Virtual Screening to Discover Novel Inhibitors of Polyploid Giant Cancer Cells in Breast Cancer.

Therapy resistance in breast cancer is increasingly attributed to polyploid giant cancer cells (PGCCs), which arise through whole-genome doubling and exhibit heightened resilience to standard treatments. Characterized by enlarged nuclei and increased DNA content, these cells tend to be dormant under therapeutic stress, driving disease relapse. Despite their critical role in resistance, strategies to effectively target PGCCs are limited, largely due to the lack of high-throughput methods for assessing their viability.

Soft Tissue Fine-Needle Aspiration: Current and Future Impact on Patient Care.

Soft tissue neoplasms pose many diagnostic challenges on fine-needle aspiration (FNA), owing largely to their rarity, large number of entities, and histologic diversity. Advances in ancillary testing now allow detection of the characteristic immunophenotypes and molecular alterations for many neoplasms and include reliable surrogate immunohistochemical markers for underlying molecular events that are highly efficient in small biopsies. A morphology-based framework is recommended to guide appropriate differentials and judicious selection of ancillary tests for small biopsies.

Safety of pembrolizumab as adjuvant therapy in a pooled analysis of phase 3 clinical trials of melanoma, non-small cell lung cancer, and renal cell carcinoma.

Background: The safety profile of adjuvant pembrolizumab was evaluated in a pooled analysis of 4 phase 3 clinical trials.

Methods: Patients had completely resected stage IIIA, IIIB, or IIIC melanoma per American Joint Committee on Cancer, 7th edition, criteria (AJCC-7; KEYNOTE-054); stage IIB or IIC melanoma per AJCC-8 (KEYNOTE-716); stage IB, II, or IIIA non-small cell lung cancer per AJCC-7 (PEARLS/KEYNOTE-091); or postnephrectomy/metastasectomy clear cell renal cell carcinoma at increased risk of recurrence (KEYNOTE-564). Patients received adjuvant pembrolizumab 200 mg (2 mg/kg up to 200 mg for pediatric patients) or placebo every 3 weeks for approximately 1 year.

Synthesis and antiproliferative activity of a tetrahydrofuran analog of FR901464.

FR901464 is a natural product that exhibits antiproliferative activity at single-digit nanomolar concentrations in cancer cells. Its tetrahydropyran-spiroepoxide covalently binds the spliceosome. Through our medicinal chemistry campaign, we serendipitously discovered that a bromoetherification formed a tetrahydrofuran.

INDUCE-2: A Phase I/II, open-label, two-part study of feladilimab in combination with tremelimumab in patients with advanced solid tumors.

Combining immunotherapies with distinct mechanisms of action has the potential to overcome treatment resistance and improve outcomes. The inducible T-cell co-stimulator (ICOS) agonist feladilimab is directed at enhancing T-cell activation and function, thereby promoting an antitumor response. INDUCE-2 (NCT03693612) was a Phase I/II, open-label, two-part study evaluating the anti-ICOS agonist feladilimab in combination with the anti-CTLA-4 antibody tremelimumab in patients with select advanced solid tumors.

US physician perspective on the use of biomarker and ctDNA testing in patients with melanoma.

New treatments have increased survival of patients with melanoma, and methods to monitor patients throughout the disease process are needed. Circulating tumor DNA (ctDNA) is a predictive and prognostic biomarker that may allow routine, real-time monitoring of disease status. We surveyed 44 US physicians to understand their preferences and practice patterns for biomarker and ctDNA testing in their patients with melanoma.

A phase II clinical trial evaluating the safety and efficacy of durvalumab as first line therapy in advanced and metastatic non-small cell lung cancer patients with Eastern Cooperative Oncology Group performance status of 2.

Background: Approximately 30-40% of patients with advanced and metastatic non-small cell lung cancer (NSCLC) present with an impaired performance status (PS). There are limited prospective data on the safety and efficacy of durvalumab in these patients.

Methods: In this single-arm phase II clinical trial (NCT02879617), patients with previously untreated Stage IIIB/IV NSCLC and ECOG PS of 2 received durvalumab 1500 mg every 28 days until progression or unacceptable toxicity.

Synthesis and Conformational Analysis of FR901464-Based RNA Splicing Modulators and Their Synergism in Drug-Resistant Cancers.

FR901464 is a cytotoxic natural product that binds splicing factor 3B subunit 1 (SF3B1) and PHD finger protein 5A (PHF5A), the components of the human spliceosome. The amide-containing tetrahydropyran ring binds SF3B1, and it remains unclear how the substituents on the ring contribute to the binding. Here, we synthesized meayamycin D, an analogue of FR901464, and three additional analogues to probe the conformation through methyl scanning.

Artificial Intelligence-Enabled Gastric Cancer Interpretations: Are We There yet?

The integration of digital pathology and artificial intelligence (AI) is revolutionizing pathology by providing pathologists with new tools to improve workflow, enhance diagnostic accuracy, and undertake novel discovery. The capability of AI to recognize patterns and features in digital images beyond human perception is particularly valuable, thereby providing additional information for prognostic and predictive purposes. AI-based tools diagnose gastric carcinoma in digital images, detect gastric carcinoma metastases in lymph nodes, automate Ki-67 scoring in gastric neuroendocrine tumors, and quantify tumor-infiltrating lymphocytes.

Phase II study of border zone stereotactic radiosurgery with bevacizumab in patients with recurrent or progressive glioblastoma multiforme.

Purpose: Recurrent glioblastoma is universally fatal with limited effective treatment options. The aim of this phase 2 study of Border Zone SRS plus bevacizumab was to evaluate OS in patients with recurrent GBM.

Methods: Patients with histologically confirmed GBM with recurrent disease who had received prior first-line treatment with fractionated radiotherapy and chemotherapy and eligible for SRS were enrolled.

Advances in the Surgical Treatment of Pancreatic Cancer.

Three recent advances in the surgical approach to pancreatic cancer over the past decade have improved both short- and long-term outcomes for patients with nonmetastatic, operable pancreatic cancer. These include (1) minimally invasive pancreatectomy to reduce operative morbidity while adhering to principles of open oncologic resections, (2) neoadjuvant chemotherapy to treat radiographically occult metastatic disease and improve locoregional control, and (3) applying irreversible electroporation as an adjunct to surgery, allowing a fraction of locally advanced pancreatic cancer to be resected.

Concurrent Androgen Deprivation Therapy for Prostate Cancer Improves Survival for Synchronous or Metachronous Non-Small Cell Lung Cancer: A SEER-Medicare Database Analysis.

Introduction: The crosstalk between receptor kinase signaling, such as EGFR and androgen receptor signaling, suggests a potential interaction between androgen deprivation therapy (ADT) and lung cancer outcome. Methods: We employed the SEER−Medicare data of lung cancer patients diagnosed between 1988 and 2005 to test for an association between ADT for prostate cancer and lung cancer outcome. We employed the Kaplan−Meier method and Cox proportional hazard with log-rank test model to assess any significant impact of ADT on survival.

The Association between Serum Serine and Glycine and Related-Metabolites with Pancreatic Cancer in a Prospective Cohort Study.

Background. Serine and glycine play an important role in the folate-dependent one-carbon metabolism. The metabolism of serine and glycine has been shown to be associated with cancer cell proliferation.

Pembrolizumab plus azacitidine in patients with chemotherapy refractory metastatic colorectal cancer: a single-arm phase 2 trial and correlative biomarker analysis.

Background: DNA mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC) is not responsive to pembrolizumab monotherapy. DNA methyltransferase inhibitors can promote antitumor immune responses. This clinical trial investigated whether concurrent treatment with azacitidine enhances the antitumor activity of pembrolizumab in mCRC.

Advances in Treatment of Recurrent Small Cell Lung Cancer (SCLC): Insights for Optimizing Patient Outcomes from an Expert Roundtable Discussion.

Second-line treatment options for patients with relapsed, extensive-stage small cell lung cancer (ES-SCLC) are limited, and even with currently available treatments, prognosis remains poor. Until recently, topotecan (a topoisomerase I inhibitor) was the only drug approved by the United States (US) Food and Drug Administration (FDA) for the management of ES-SCLC following progression after first-line treatment with etoposide plus a platinum derivative (EP; carboplatin preferred). With the most recent approval of EP plus a programmed death ligand 1 (PD-L1) inhibitor, there are now more therapeutic options for managing ES-SCLC.

Phase 1 study of safety, pharmacokinetics, and pharmacodynamics of tivantinib in combination with bevacizumab in adult patients with advanced solid tumors.

Purpose: We investigated the combination of tivantinib, a c-MET tyrosine kinase inhibitor (TKI), and bevacizumab, an anti-VEGF-A antibody.

Methods: Patients with advanced solid tumors received bevacizumab (10 mg/kg intravenously every 2 weeks) and escalating doses of tivantinib (120-360 mg orally twice daily). In addition to safety and preliminary efficacy, we evaluated pharmacokinetics of tivantinib and its metabolites, as well as pharmacodynamic biomarkers in peripheral blood and skin.

Rare Presentation of Metastatic Lobular Breast Carcinoma Involving Clear Cell Renal Cell Carcinoma.

Although the first case of tumor-to-tumor metastasis was reported over a century ago, it remains a rare occurrence. We report a rare case of metastatic infiltrating lobular carcinoma involving clear cell renal cell carcinoma, as well as offer a brief literature review.

Synergistic apoptosis following endoplasmic reticulum stress aggravation in mucinous colon cancer.

Background: Mucinous colon cancers (MCC) are characterized by abundant production of mucin 2 (MUC2) protein and are less sensitive to standard systemic chemotherapy. We postulated that severe/persistent endoplasmic reticulum stress (ERS) aggravation in MCC would overwhelm compensatory cytoprotective pathways and induce apoptosis.

Results: Basal levels of ERS markers were higher in MCC and dnTCF-LS174T cells than non-mucinous tumors and these levels were significantly increased by combinatorial treatment with ERS aggravators celecoxib + orlistat.

The Role of Neoadjuvant Therapy in Melanoma.

Purpose Of Review: Neoadjuvant therapy in melanoma is an area of active investigation with numerous completed and ongoing trials studying a variety of therapeutic interventions utilizing diverse designs. Here, we review completed and ongoing neoadjuvant trials in melanoma, discuss endpoint assessment, and highlight biomarker development in this context.

Recent Findings: High-risk resectable melanoma with clinically detectable lymph node (LN) with or without in-transit and/or satellite metastases represent ~ 20% of melanoma patients and have a high risk of relapse despite definitive surgery.

Publisher Correction: Shared heritability and functional enrichment across six solid cancers.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Central Nervous System Involvement by Waldenstrom Macroglobulinemia: A Case Report of the Bing-Neel Syndrome.

Bing-Neel syndrome (BNS) is a rare complication of Waldenstrom macroglobulinemia (WM) defined by a lymphoplasmacytic infiltration of the central nervous system (CNS). Patients present with a range of neurologic symptoms of variable severity. Diagnosis requires a low threshold of suspicion and is considered in WM patients with unexplained neurologic symptoms.