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Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy with poorly characterized molecular features. To identify disease-specific mutational profiles, we performed targeted next-generation sequencing (NGS) on a cohort of 21 BPDCN patients. Our study revealed that TET2 (57%) and ASXL1 (33%) were the most frequently mutated genes, followed by NRAS (29%), SRSF2 (14%), ZRSR2 (14%), and KMT2D (14%). Further analysis demonstrated that poor prognosis was associated with older age (≥65 years), the presence of three or more mutations, TET2 mutations, TET2 truncating mutations, and mutations involving DNA methylation pathways. In contrast, patients who underwent hematopoietic stem cell transplantation (HSCT) exhibited more favorable clinical outcomes. Moreover, our study indicated that CCDC50 expression was significantly elevated in BPDCN cases compared to those with acute myeloid leukemia (AML) or chronic monomyelocytic leukemia (CMML), suggesting that CCDC50 may serve as a reliable diagnostic marker for distinguishing BPDCN from AML, as well as a potential biomarker for disease monitoring. Finally, our investigation of mutational profiles in sequentially paired specimens revealed a high prevalence of bone marrow clonal hematopoiesis in patients with BPDCN. In conclusion, the genetic landscape of BPDCN identified in this study provides valuable insights that may improve diagnostic accuracy and guide prognostic evaluation and therapeutic strategies. However, validation in larger, independent cohorts are warranted.

Heavily pretreated metastatic colorectal cancer (mCRC) poses significant therapeutic challenges. Advances in molecular profiling enables personalized strategies. We present a 62-year-old male with mCRC harboring BRAF, MET, APC, TP53 and NRAS alterations, following FOLFOX and FOLFIRI, dabrafenib plus panitumumab, and a BRAF inhibitor clinical trial, each leading to initial responses followed by disease progression. WIN Consortium International Molecular Tumor Board (MTB), included experts from institutions across 13 countries. Enrollment in suitable clinical trials was explored but limited by availability. Personalized combinations suggested included amivantamab-vmjw (anti-MET/EGFR antibody) (one-third standard dose) (for MET amplification and due to prior response to anti-EGFR antibody), trametinib, 1 mg po daily (MEK inhibitor for BRAF V600E mutation), and regorafenib (may have WNT inhibitor activity relevant to APC mutation; VEGFR activity relevant since TP53 alterations upregulate VEGF/VEGFR axis) starting at 40 mg po daily three weeks on, one week off. Another option was trametinib at 1 mg daily, cetuximab (EGFR antibody), 250 mg/m² IV every two-weeks, and cabozantinib (MET and VEGFR inhibitor), 40 mg po daily. FOLFOXFIRI combined with bevacizumab, or liver-directed therapies for hepatic metastases, or regorafenib with 5FU, or crizotinib (MET inhibitor) combined with regorafenib or dabrafenib, was also suggested. This case emphasizes the critical role of comprehensive molecular profiling and personalized therapeutic approaches in managing complex mCRC. The WIN International MTB aims to provide treatment and biomarker analysis discussion with the ultimate goal of optimizing treatment efficacy by targeting specific molecular alterations, though final treatment decisions remain at the discretion of the treating physician.

The CHEK2 gene serves a canonical role in the DNA damage response (DDR) pathway encoding the regulatory kinase CHK2 in the homologous recombination (HR) repair of double-strand breaks (DSB). Although CHEK2 is traditionally considered a tumor suppressor gene, recent studies suggest additional functions. Across several cohort studies, CHEK2 expression was negatively correlated with the efficacy of immune checkpoint inhibitors (ICI), which target the interaction between effector immune and tumor cells. This review explores two possible explanations for this observed phenomenon: the first relating to the canonical role of CHEK2, and the second introducing a novel role of the CHEK2 gene in immunomodulation of the tumor microenvironment (TME). DDR mutations have been implicated in increased levels of tumor mutation burden (TMB), often manifesting as neoepitope expression on the tumor cell surface recognized by effector immune cells. As a result, impaired DNA repair due to CHEK2 loss of function, either from germline deleterious variants or acquired mutations, results in the recruitment of CD8+ cytotoxic T-cells and subsequent efficacy of ICI treatment. However, functional loss of CHEK2 may be directly involved in potentiating the immune response through canonical inflammatory and anti-tumor pathways, acting through the cGAS-STING pathway. Although the exact mechanism by which CHEK2 modulates immune responses is still under investigation, combination therapy with CHEK1/2 inhibition and ICI immunotherapy has shown benefit in preclinical studies of several solid tumors.

Introduction: Immunotherapy has emerged as a standard treatment option for multiple solid tumors. However, most patients with pancreatic cancer (PC) do not derive a significant benefit. Identification and analyses of exceptional responders could eventually offer hints as to why PC is resistant to immunotherapy.

Methods: Oncologists from cancer centers in the United States were contacted to identify patients with PC who responded to immunotherapy. Exceptional responders were defined as those having either partial (PR) or complete response (CR) based on Response Evaluation Criteria in Solid Tumors, or biochemical response (CA 19-9 levels) after starting immunotherapy. Patients receiving concurrent chemotherapy were excluded.

Results: 14 patients met inclusion criteria. Immunotherapy drugs included checkpoint inhibitors and macrophage inhibitors. Eight patients (42%) were MSI (microsatellite instability)-high. Radiologically, 82% had PR. Four patients (28%) had marked reduction in CA 19-9. The median progression-free survival was 12 months from the start of immunotherapy. Median survival was not reached. The 1- and 2-year survival probabilities were 80%, 70% respectively.

Conclusion: Majority of clinical trials evaluating immunotherapy in PC have yielded disappointing response rates compared to other solid tumors. Our case series adds to published data from early-phase trials supporting the promise of immunotherapy in some patients with PC.

The unattainable triangle, also known as the iron triangle or triple constraint, traditionally applied in business as a model for balancing time, cost, and quality, offers valuable insight into the field of cardio-oncology. Cardio-oncology merges cardiovascular care with cancer treatment, addressing the growing risk of cardiovascular complications in cancer patients. Similar to the business model, this specialty faces the challenge of providing timely, high-quality, and cost-effective care. The urgency of cancer treatment often strains cardiovascular assessments, while comprehensive care increases costs due to advanced diagnostics and specialized teams. Establishing a cardio-oncology center of excellence, where oncologists and cardiologists collaborate in real-time, can help balance these demands, enhance care coordination, and manage resource utilization effectively. This article explores how the specialty of cardio-oncology could deliver comprehensive, timely, and affordable patient care by applying the unattainable triangle method.

Patients with NSCLC harboring uncommon EGFR mutations have limited therapeutic options and often poor outcomes, especially following progression on standard EGFR tyrosine kinase inhibitors (TKIs). Amivantamab, an anti-EGFR/MET bispecific antibody, shows efficacy in EGFR-mutated NSCLC, but its role in rare EGFR alterations and CNS involvement, including leptomeningeal disease (LMD), remains insufficiently characterized. We report a 67-year-old male with stage IVB NSCLC harboring EGFR G719A and A289V mutations who developed LMD while on osimertinib. After progression on immunotherapy and chemotherapy, amivantamab monotherapy was initiated. Treatment produced a durable response over 19 months, including a 32.2% reduction in tumor size at six weeks, and complete resolution of brain metastases and LMD by six months. Circulating tumor DNA analyses showed EGFR variant allele fractions decreasing from 25.6% to undetectable. This case challenges current paradigms, demonstrating that amivantamab monotherapy can effectively target rare EGFR mutations, achieve durable extracranial and CNS disease control, and potentially overcome blood-brain barrier limitations. These findings suggest that amivantamab's utility may extend beyond established combination regimens and well-characterized EGFR mutations, offering an effective option for patients with atypical molecular profiles who lack standard therapies. Amivantamab monotherapy may represent a viable strategy for patients with uncommon EGFR mutations and CNS involvement, including LMD. Further research is warranted to elucidate underlying mechanisms, refine treatment strategies, and assess amivantamab's broader applicability in similarly challenging NSCLC scenarios.