Naoki Fukuda

Purpose: Thyroid cancer (TC) incidence has increased rapidly worldwide since the 1980s. Although often indolent, TC poses substantial clinical and socioeconomic burdens on working-age populations. Antibiotic exposure has been implicated in cancer development through microbiota-mediated mechanisms; however, its relationship with TC risk remains unclear.,Methods: We conducted a nested case-control study using the JMDC Claims Database. Individuals diagnosed with TC were identified and matched 1:4 with controls according to age, sex, and follow-up duration by using risk-set sampling. Antibiotic exposure was defined as a prescription recorded 1 to 10 years before the index date. Multivariable conditional logistic regression models were used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) after adjusting for body mass index and hepatitis C virus infection. Missing data were handled using multiple imputation.,Results: Overall, 37,240 cases and 148,909 matched controls were included. Antibiotic exposure was associated with an increased TC risk (adjusted OR, 1.22; 95% CI, 1.17–1.28). A dose-response relationship was observed, with adjusted ORs of 1.10 (95% CI, 1.04–1.16), 1.28 (95% CI, 1.21–1.35), and 1.54 (95% CI, 1.43–1.66) for 1, 2–5, and ≥6 antibiotic courses, respectively. Class-specific analyses showed modest associations for penicillins, cephalosporins, macrolides, quinolones, and sulphonamides, and no significant associations for tetracyclines, nitroimidazoles, or antifungal agents.,Conclusions: Antibiotic exposure was associated with a moderately increased dose-dependent TC risk. However, given the potential for residual confounding and detection bias, particularly those related to healthcare utilisation, these findings should be interpreted with caution.

Purpose Weight loss is common in patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) and is associated with poor prognosis. However, its prognostic significance in patients receiving nutritional support from surgery through postoperative chemoradiotherapy (CRT) remains unclear. We evaluated the impact of treatment-related weight loss on clinical outcomes in this setting. Methods This retrospective study included patients with high-risk LA-HNSCC treated with surgery, postoperative CRT, and nutritional intervention. Pre-CRT weight loss was defined as the percentage weight loss between surgery and CRT initiation and analyzed using a 5% cutoff. Associations with recurrence-free survival (RFS), overall survival (OS), and adverse events (AEs) were evaluated. Results A total of 105 patients were included. Median pre-CRT and overall weight loss were 4.8% and 7.9%, respectively. Patients with recurrence experienced greater pre-CRT weight loss than those without recurrence (6.1% vs. 4.0%, p = 0.004). Patients with ≥ 5% pre-CRT weight loss had significantly worse RFS and OS (log-rank p = 0.001 and p < 0.001). In multivariable analysis, ≥ 5% pre-CRT weight loss remained independently associated with poorer RFS (hazard ratio 2.54, 95% confidence interval 1.35–4.80). The incidence of grade ≥ 3 AEs was comparable between groups (81.8% vs. 86.0%, p = 0.75). Conclusion Pre-CRT weight loss of ≥ 5% was independently associated with poorer RFS in patients with high-risk LA-HNSCC undergoing surgery followed by postoperative CRT despite nutritional intervention. Pre-CRT weight loss may be a simple and clinically useful prognostic marker in this setting.

PURPOSE: Adolescents and young adults (AYAs) with cancer are a biologically heterogeneous population with both pediatric- and adult-type malignancies. Tumor lineage rather than patient age often determines genomic architecture and therapeutic targetability, and understanding lineage-specific differences is essential to evaluate the clinical utility of comprehensive genomic profiling (CGP) in this population. This study aimed to compare genomic alterations and access to genome-matched therapies between pediatric-type and adult-type tumors among AYAs in Japan, using nationwide CGP data. PATIENTS AND METHODS: We analyzed data from 2,325 AYAs with cancer who underwent CGP in a routine clinical practice in Japan. Tumors were classified as pediatric or adult type using established tumor lineage frameworks. Genomic alterations were annotated using OncoKB, and the prevalence of pathogenic variants, actionable alterations, and genome-matched therapies was evaluated at the patient level. RESULTS: Among 2,325 AYAs, 35.4% had pediatric-type and 64.6% had adult-type tumors. At least one pathogenic genomic alteration was identified in 67.8% of pediatric-type tumors and 76.3% of adult-type tumors with actionable alterations detected in 49.4% and 59.6%, respectively. Access to genome-matched therapies differed substantially between the two groups, with markedly lower treatment rates in pediatric-type tumors than in adult-type tumors (2.9% v 9.7%). This disparity reflects both differences in the genomic landscapes of pediatric- and adult-type tumors and historical limitations in drug availability in Japan. CONCLUSION: Overall access to genome-matched therapies among AYAs with tumors in Japan was comparable with that reported for the general cancer population, but there are substantial lineage-specific disparities. Patients with pediatric-type tumors remain underserved, highlighting a genome-to-therapy gap driven by both tumor lineage–specific differences in therapeutic targetability and regulatory constraints.

The KEYNOTE-048 trial established pembrolizumab plus platinum and 5-fluorouracil (5-FU) as the standard first-line treatment for recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC). In the present study, the efficacy and safety of cisplatin and carboplatin in combination with pembrolizumab were compared using real-world data. In this retrospective study, 76 patients with R/M HNSCC treated with pembrolizumab plus 5-FU and either cisplatin (n = 41) or carboplatin (n = 35) were analysed. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and the incidence of grade ≥ 3 haematological and grade ≥ 2 non-haematological adverse events. The median PFS was 4.1 months with cisplatin and 7.1 months with carboplatin (p = 0.58). The median OS values were 14.8 and 20.7 months, respectively (p = 0.88). The ORR values were similar (34.1% vs. 34.3%, p = 0.99). Grade ≥ 3 haematological adverse events were more frequent with cisplatin than with carboplatin (87.8% vs. 48.6%, p < 0.01), as were grade ≥ 2 non-haematological adverse events (97.6% vs. 54.3%, p < 0.01). Cisplatin did not demonstrate a significant advantage over carboplatin in terms of OS, PFS, and ORR, but was associated with higher toxicity pembrolizumab-based therapy for R/M HNSCC. These findings suggest that carboplatin may represent a reasonable alternative in combination with pembrolizumab.

Objectives: To evaluate the efficacy of glucocorticoid-sparing management in patients with G-CSF-associated large-vessel vasculitis (LVV). Methods: Patients with cancer diagnosed with LVV following G-CSF administration between April 2020 and December 2024 were included. Patients received non-glucocorticoid treatment, mainly NSAIDs, whereas those with an inadequate response to or intolerance of NSAIDs were treated with glucocorticoids. The primary outcome was the remission rate in patients treated without glucocorticoids. Results: G-CSF-associated LVV occurred in 19 of 4708 patients (0.4%). The median age was 64 years (range: 53–79), and 73.7% were females. Breast cancer was the most common cancer type (36.8%). Pegfilgrastim was the most frequently used agent (94.7%). Of the 19 patients, 18 (94.7%) received non-glucocorticoid treatment: 15 (78.9%) with NSAIDs, one (5.3%) with acetaminophen and two (10.5%) under observation, all achieving remission (100%). NSAIDs were discontinued in one patient owing to liver dysfunction; however, no serious adverse events were observed. Another patient (5.3%) with renal dysfunction received glucocorticoids for 2 weeks. The median intervals from the last G-CSF administration to LVV onset, peak inflammation, remission and imaging remission were 7 (range: 2–15), 14 (10–19), 30 (14–49) and 51 (27–346) days, respectively. Filgrastim was subsequently administered to five patients (26.3%) who developed LVV following pegfilgrastim administration. All patients achieved remission and experienced no recurrence regardless of treatment. Conclusion: Glucocorticoid-sparing management of G-CSF-associated LVV may be a safe and effective approach.

Soft-tissue sarcoma (STS) is a rare malignancy that accounts for less than 1% of all cancers, and recent advances in molecular biology have led to its classification based on genomic information. Some RET-rearranged neoplasms have been reported to present pathological features similar to Neurotrophic Tyrosine Kinase Receptor-rearranged spindle cell neoplasms. Here, we report the first case of head and neck spindle cell sarcoma with a GOLGA5–RET fusion that demonstrated a sustained clinical response to selpercatinib, identified through targeted next-generation sequencing (NGS). The patient was a 43 year-old man with a tumor in the arytenoid region that was resected and diagnosed as a malignant spindle cell tumor. Despite initial treatment with surgical resection alone, local recurrence was confirmed, requiring salvage therapy with total laryngectomy and bilateral cervical dissection. Surgical specimen revealed a spindle tumor with a patternless pattern and collagenous stroma. Immunohistochemistry (IHC) with positivity for CD34, bcl-2 (focally), S100, and weak nuclear staining for STAT6, with absence of expression of CK AE1/3, desmin, c-kit, smooth muscle actin, myogenin, synaptophysin, and SOX10. Trk A/B/C were also negative on IHC. Following confirmation of multiple lung metastases, the patient was treated with doxorubicin monotherapy. Targeted NGS identified GOLGA5–RET rearrangement, FGF14 amplification (equivocal), CDKN2B loss, and CDKN2A loss. GOLGA5–RET rearrangements were validated through fluorescence in situ hybridization. The patient subsequently was enrolled in a phase 1/2 trial for the selective RET inhibitor selpercatinib, resulting in a sustained partial response over 5 years. Although solitary fibrous tumor (SFT) was initially considered as a differential diagnosis based on immunohistochemical findings, the lack of strong and diffuse STAT6 expression made this diagnosis unlikely. Subsequent next-generation sequencing (NGS) revealed a RET fusion, leading to the diagnosis of an RET-rearranged spindle cell neoplasm. This case highlights the importance of genomic testing for certain spindle cell sarcomas and the potential benefit of RET-specific inhibitors against RET-altered sarcomas.

Medullary thyroid carcinoma is a rare thyroid malignancy derived from parafollicular C cells that is frequently driven by activating mutations in the REarranged during Transfection (RET) proto-oncogene. While most actionable RET mutations are located in the extracellular cysteine-rich or intracellular tyrosine kinase domains, mutations in the transmembrane domain are exceedingly rare and their oncogenic significance remains unclear. We report a case of a 59-year-old male with sporadic medullary thyroid carcinoma harboring a rare RET A641R mutation in the transmembrane domain. The patient experienced multiple locoregional recurrences after four surgical resections. While the companion diagnostic test did not identify RET mutations, comprehensive genomic profiling using a next-generation sequencing panel revealed the RET A641R mutation. Following administration of selpercatinib, a selective RET inhibitor, a rapid biochemical response with decreased serum carcinoembryonic antigen and calcitonin levels was observed, and radiological assessment showed partial response. This is the first report demonstrating the clinical efficacy of selpercatinib in a patient with medullary thyroid carcinoma harboring a RET A641R mutation, supporting the oncogenic potential of this rare variant. This case also emphasizes the importance of comprehensive genomic profiling in identifying rare but actionable RET alterations that are undetectable by targeted sequencing companion diagnostic tests. Selpercatinib may represent an effective therapeutic option for patients with medullary thyroid carcinoma driven by uncommon RET mutations, including mutations in the transmembrane domain.

Background: Existing circulating cell-free DNA (cfDNA) assays are primarily centralized, requiring specialized sample handling and transportation. Implementing a flexible, decentralized sequencing system at point of care, with minimal technical oversight, can enhance turnaround times and patient access to genomic profiling. In this study, we aimed to evaluate the clinical feasibility of an automated and decentralized cfDNA next-generation sequencing (NGS) assay for identifying actionable alterations in advanced solid tumors. Methods: Genomic profiling of plasma cfDNA from 298 patients with advanced solid tumors was conducted using an automated NGS assay. We assessed concordance of tumor mutations detected in plasma cfDNA and patient-matched tumor tissues analyzed by an FDA-approved assay, investigating clinical factors influencing circulating tumor DNA (ctDNA) aberration (mut-ctDNA) detection sensitivity. Results: Sequencing success rates for cfDNA genomic profiling was significantly higher than archived tumor tissue (99% vs 96%). Mut-ctDNA detection rates ranged from 20% to 67% across different solid tumors. Targetable or resistance alterations were found in 18% of the patients. About 72% of the patients showed concordant alterations from tissue and plasma. The level of concordance was associated with the cancer type, tumor burden, and metastatic location. Notably, 63 plasma-only alterations were identified in 18% of patients and were more frequently observed in those with prior targeted treatments (24%) compared to chemotherapy (10%). Conclusions: This study underscores the clinical feasibility of an automated, decentralized cfDNA genomic profiling approach. It emphasizes the importance of considering confounding clinical factors when selecting plasma- or tissue-based profiling assay. Such an approach holds promise for enhancing patient access to timely genomic profiling and targeted therapy selection.

Proteinuria has been described as a major on-target adverse event of lenvatinib, although its long-term impact on renal function and clinical outcomes remains unclear. We conducted a retrospective observational study to assess renal function and prognosis in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC) receiving lenvatinib. Overall, 70 patients with RR-DTC treated with lenvatinib were enrolled. When proteinuria was observed, the dose and schedule of lenvatinib were adjusted to achieve a urine protein-to-creatinine ratio (UPCR) of less than 3.5 g/gCre according to the study protocols of recent pivotal trials. In total, 50 (71%) and 25 (36%) patients presented with any-grade and grade 3 proteinuria, respectively. Multivariate analysis revealed that age [>65; odds ratio (OR) 8.24, 95% confidence interval (CI) 1.74–39.00, p < 0.01], history of diabetes mellitus (OR 7.79, 95% CI 1.31–46.20, p = 0.02), and hypertension (OR 4.07, 95% CI 1.22–13.60, p = 0.02) were significantly associated with the development of grade 3 proteinuria. Overall, the median estimating glomerular filtration rate (eGFR) gradually decreased every 3 months during treatment. However, no significant deterioration in eGFR was observed in patients with grade 3 proteinuria compared with patients with grades 0–2 proteinuria until 48 months. Patients who developed proteinuria had better survival outcomes than those without proteinuria. In conclusion, the proteinuria grade was not significantly associated with decreased eGFR under UPCR monitoring in our study. Therefore, lenvatinib can carefully be continued targeting UPCR of less than 3.5 g/gCre.