The incidence rate of colorectal cancer in younger adults has been rising in developed countries. This trend may be attributed to environmental exposures as a result of lifestyle changes. Many of the lifestyle factors that promote colorectal cancer can also affect the gut microbiome, which may be associated with colorectal cancer risks. The role of the microbiome in the ongoing rise of early-onset colorectal cancer is unknown. Here, we aimed to investigate age-related differences in the gut microbiome of patients with colorectal cancer and healthy individuals by examining both the fecal and tumor microbiomes. We utilized the publicly accessible data on fecal shotgun metagenomics from CuratedMetagenomeData and TCGA via the GDC Data Portal. Comparison of 701 colorectal cancer and 693 controls revealed that microbial features were age dependent, with a significant difference in species enrichment between early-onset (65 years) patients with colorectal cancer. Analysis of the tumor-associated microbiome in a separate dataset of 85 patients with colorectal cancer verified age-specific differences in taxon abundance between early- and late-onset patients with colorectal cancer. Finally, using host gene expression data, we found a stronger microbe–host interaction in early- vs. late-onset colorectal cancers. Altogether, these findings indicate that microbial features were age-dependent with stronger microbial–host interactions at the tumor site in early-onset colorectal cancers, suggesting a direct role of microbes in tumorigenesis via interaction with cancer-related pathways in this age group. Prevention Relevance: Early-onset colorectal cancer is on the rise, presumably because of changes in environmental exposures. Lifestyle changes may contribute to colorectal cancer via alterations in gut microbes. Here, we show that microbial association with colorectal cancer is age-dependent, and microbe interactions with tumor pathways are stronger in young versus older colorectal cancers.

Chimeric antigen receptor T (CAR T) cell therapies have emerged as a valuable treatment modality for patients with plasma cell disorders. As the population of patients receiving CAR T therapies grows, identification and management of associated rare toxicities have become increasingly crucial. To identify safety signals associated with commercial anti-B-cell maturation antigen (BCMA) CAR T therapies using the Food and Drug Administration Adverse Event Reporting System (FAERS). This is a cross-sectional analysis of the adverse events (AE) reports associated with ciltacabtagene autoleucel (cilta-cel) and idecabtagene vicleucel (ide-cel), submitted to FAERS between January 2021 and December 2023. AE frequencies were summarized using descriptive statistics, and safety signals were explored by measuring the reporting odds ratio (ROR) compared to control groups. Among 4,472,782 unique FAERS reports, 1,496 involved BCMA-directed CAR-T therapies. AEs reported more frequently included immune associated conditions and neurological disorders. Neurotoxicity associated with cilta-cel predominantly manifested as cranial nerve palsies, parkinsonism, acute and chronic polyneuropathies, while ide-cel neurotoxicity presented as confusion, disorientation, seizures, balance disturbances, and tremors. In cilta-cel reports, other safety signals included Guillain-Barre syndrome (ROR: 17.1, 95% CI 6.1 -47.5), intracranial hemorrhage and cerebrovascular accidents (ROR: 2.9, 95% CI 1.8 -4.8), haemophilus infections (ROR: 34.2, 95% CI 11.8-98.9) and cytomegalovirus infections (ROR: 3.9, 95% CI 1.6 -9.5). For ide-cel, new signals included parkinsonism (ROR: 13.7, 95% CI 5.5-34.5), acute and chronic sarcoidosis (ROR: 197.1, 95% CI 32.9 -1180.1), ventricular arrhythmias, and cardiac arrest (ROR: 3.9, 95% CI 2.1-7.3). This data provides a comprehensive insight into the safety profiles of the commercial BCMA-directed CAR T therapies, underscoring the importance of vigilant post-marketing surveillance to mitigate potential risks.

Background/Aim: The PACIFIC trial demonstrated improved survival in patients with unresectable stage III non-small cell lung cancer (NSCLC) treated with durvalumab following definitive concurrent chemoradiotherapy (CRT). This study sought to explore real-world outcomes with durvalumab consolidation therapy at our institution. Patients and Methods: We retrospectively identified patients diagnosed with stage III NSCLC at our institution from January 2012 to January 2022. We created two cohorts: one who received durvalumab following definitive CRT and a historical one who did not. Primary outcomes of interest included median progression-free survival (PFS) and overall survival (OS). Additionally, we performed subgroup analysis on the durvalumab cohort to explore the associations between survival and time to durvalumab initiation, PD-L1 expression, and neutrophil-to-lymphocyte ratio (NLR). Results: We identified 79 patients with locally advanced NSCLC who were not surgical candidates. Patients treated with durvalumab (n=44) had significantly improved survival compared to the historical cohort (n=35) including a median PFS of 17.4 months versus 8.0 months (p=0.0019) and a median OS of 37.0 months versus 17.0 months (log-rank p-value=0.07, Wilcoxon p-value=0.02). Within the durvalumab group, outcomes did not significantly differ between those who initiated therapy before or after 42 days of finishing CRT, between various PD-L1 expression levels, or between high or low NLR. Conclusion: Patients who received durvalumab as consolidation therapy following definitive CRT demonstrated significantly improved survival compared to a historical cohort who did not receive durvalumab. Furthermore, durvalumab appears to benefit patients regardless of time to initiation, PD-L1 expression, or NLR.

We read with great interest the article by Fallah and colleagues regarding the FDA approval of belzutifan as the first systemic treatment for von Hippel-Lindau disease (VHL; ref. 1). Despite the demonstrated antitumor activity and overall good safety profile in the clinical trial (2), we believe much is still unknown about belzutifan's potential adverse effects given its novelty. Here, we present the first case of hemorrhage from hemangioblastomas resulting in spinal cord compression coincident with initiation of belzutifan treatment.A 54-year-old male with a history of VHL presented to our clinic seeking belzutifan treatment. He had previously undergone left-sided nephrectomy and right-sided partial nephrectomy for multifocal renal cell carcinoma (RCC), had vision loss due to retinal hemangioblastomas, and was undergoing active surveillance for suprasellar and cerebellar hemangioblastomas for which he was otherwise asymptomatic. CT imaging at that time demonstrated multiple 2–2.5 cm lesions in his kidney, slightly increased from prior imaging and radiographically consistent with RCC. Four days after starting belzutifan 120 mg, he presented to the emergency department with acute-onset mid-thoracic back pain, bilateral lower extremity loss of sensation and decreased muscle strength, and urinary retention. MRI revealed contrast-enhancing intramedullary lesions at T1 and T2 and hemorrhage with adjacent spinal cord compression. Belzutifan was held and dexamethasone was administered. A C7-T3 laminectomy with partial T1 lesion resection was performed with resultant pathologic examination demonstrating hemorrhagic blood products and no evidence of malignancy, consistent with bleeding from a hemangioblastoma. Over the next 2 months, he experienced continued neurologic recovery.Belzutifan is the first systemic therapy approved for treatment of VHL-associated RCC, central nervous sysytem hemangioblastomas, and pancreatic neuroendocrine tumors. As Fallah and colleagues note, common side effects include anemia and fatigue (1). The case described here closely associates initiation of belzutifan with the occurrence of hemangioblastoma-associated hemorrhage and damage to the neuroaxis. No such adverse effect was reported in the belzutifan clinical trial (2). Though highly vascular tumors, hemangioblastomas have very low rates of spontaneous hemorrhage, less than 0.01% per person per year (3). The rare nature of VHL serves as a barrier to rigorously determining the causal relationship between belzutifan and damage to the neuroaxis. Given these facts, the low rate of spontaneous hemorrhage, and the close temporal links described in the current case report, we recommend imaging of the complete neuroaxis prior to initiation of belzutifan therapy. In addition, postmarketing studies must be performed to thoroughly evaluate its safety profile.See the Response, p. 685R.C. Bergan reports a patent for 8,481,760, 8,742,141, 9,839,625, 10,231,949 issued to no, a patent for 62/628,243 pending to no, and a patent for 62/801,858 pending to license to a third party imminent. No disclosures were reported by the other authors.

Background: Metastatic adenoid cystic (basal cell) carcinoma of the prostate is an exceedingly rare disease entity. As a result, no current consensus exists for optimal systemic therapy.Methods: We present a patient with metastatic adenoid cystic (basal cell) carcinoma of the prostate who subsequently received systemic treatment, including chemotherapy and immunotherapy. We comprehensively reviewed all published data on therapy outcomes in advanced disease.Results: Our patient benefited from combination chemotherapy (carboplatin and paclitaxel), with objective radiographic response and reduction in cancer‐related pain. However, chemotherapy was stopped due to cumulative neurotoxicity, and subsequent immunotherapy with atezolizumab did not produce any response. Our literature review revealed inconsistent outcomes with various treatments but showed most promise with chemotherapy. Targeted therapy and immunotherapy seem to benefit specific cases, and androgen deprivation therapy had minimal evidence of benefit.Conclusion: Based on the findings of our case report and literature review, we suggest platinum‐based chemotherapy doublets as first‐line treatment for metastatic cases of adenoid cystic (basal cell) carcinoma of the prostate, reserving targeted therapy or immunotherapy for select cases based upon molecular profiles.