Tonan Hospital

Metastatic colorectal cancer (mCRC) differs clinically based on RAS and BRAF mutations or DNA methylation. However, in mCRC, the prognostic value and biological characteristics of genome-wide DNA methylation status (GWMS) in each RAS/BRAF genotype is unknown. To clarify this, primary tumor samples from patients with informed consent in the phase III TRICOLORE study were collected, and RAS and BRAF mutations, immunohistochemical staining of mismatch repair-related proteins, comprehensive gene expression, and genome-wide DNA methylation were analyzed. The tumor samples were classified into high-methylated colorectal cancer (HMCC) and low-methylated colorectal cancer (LMCC). Gene set enrichment analysis (GSEA) was conducted using microarray data. A total of 226 patients were included and classified into the RAS/BRAF wild-type (wt) (n = 125), RAS mutant (mt) (n = 87), and BRAF mt (n = 14), of whom 22 (17.6%), 30 (34.5%), and 14 (100%) had HMCC. HMCC exhibited significantly worse overall survival (OS) than that of LMCC in the RAS/BRAF wt group but not in the RAS mt group. In GSEA, RAS/BRAF wt HMCC was associated with microsatellite instability and BRAF V600E mutation. The poor prognosis of RAS/BRAF wt HMCC may be attributed to gene expression patterns associated with microsatellite instability and BRAF V600E mutation.

Background: Immune thrombocytopenia (ITP) is an acquired autoimmune disorder characterized by isolated thrombocytopenia, most commonly mediated by pathogenic immunoglobulin G (IgG) autoantibodies. Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with incompletely understood etiology, in which immune dysregulation has been implicated. Efgartigimod, the neonatal Fc receptor (FcRn) inhibitor approved for chronic/persistent ITP, accelerates IgG degradation by blocking IgG recycling via FcRn. We describe a patient with ITP and comorbid ALS in whom FcRn inhibition was temporally associated with transient improvement in both conditions. Case Description: A 66-year-old Japanese man with ALS diagnosed in March 2023 developed severe thrombocytopenia in September 2024, with a platelet count of 1.0×109/L and an elevated immature platelet fraction (18.1%). After differential diagnosis, ITP was diagnosed. Prednisolone and eltrombopag were ineffective. Intravenous efgartigimod (10 mg/kg) was initiated in October 2024 (day 0), resulting in a prompt platelet increase. Total IgG decreased from 1,643 to 858 mg/dL, and platelet-associated IgG normalized. During efgartigimod therapy, the revised ALS Functional Rating Scale (ALSFRS-R) score showed a subtle increase from 40 to 41 in January 2025 (day 83). After nine doses, efgartigimod was discontinued in January 2025 (day 91) and romiplostim was titrated with the goal of treatment cessation, but platelet counts remained unstable without remission. Unexpectedly, vital capacity increased from 81% to 93.9% in February 2025 (day 109). Thereafter ALS progressed and frequent clinic visits became difficult, romiplostim was replaced with eltrombopag and fostamatinib was added in June 2025 (day 238), resulting in stable platelet counts. In December 2025 (day 422, eleven months after efgartigimod discontinuation) total IgG increased to 1,499 mg/dL; platelet-associated IgG remained normal, however, ALSFRS-R declined to 31 and gastrostomy was required. Conclusions: This case documents concurrent ITP and ALS with transient improvement in platelet counts and ALS functional measures during FcRn inhibition with efgartigimod, followed by deterioration after discontinuation. Although causality cannot be inferred from a single case and neurologic changes may be coincidental, the temporal association raises the possibility that IgG-mediated immune mechanisms contribute to disease activity in a subset of ALS patients with autoimmune comorbidities. Further clinical and translational studies are warranted.

Vascular malformations originate from congenital abnormalities in vascular differentiation and formation, and their subtypes exhibit diverse overlapping phenotypes that make differential diagnosis challenging. Recent advances in next-generation sequencing (NGS) technology for tissue specimens have enabled the identification of somatic variants in genes that are associated with vascular malformations, such as those in the RAS/MEK/ERK and phosphoinositide 3-kinase/AKT/mTOR pathways. Liquid biopsy using cell-free DNA (cfDNA) is a minimally invasive alternative method that has recently been applied to vascular malformations. This study aimed to apply ultra-deep targeted NGS using liquid biopsy to detect somatic variants in vascular malformations. A total of 10 mL peripheral blood was collected from 40 patients with vascular malformations, and cfDNA was extracted for liquid biopsy. Ultra-deep NGS (mean coverage: 104,000×) with unique molecular identifier error correction was performed using a custom panel of five genes: BRAF, KRAS, MAP2K1, PIK3CA, and TEK/TIE2. The diagnoses included arteriovenous malformation (AVM, n = 11), PIK3CA-related overgrowth spectrum (PROS, n = 9), and venous malformation (VM, n = 20). Somatic variants were identified in 23 patients, even at a low variant allele frequency of 0.05%. Hotspot BRAF and KRAS variants and a non-hotspot MAP2K1 variant were detected in patients with AVM. Fifteen variants were detected in seven patients with PROS, including hotspot PIK3CA variants in helical domains. Three novel PIK3CA and four novel TEK variants were identified in patients with VM. Liquid biopsy of cfDNA from the peripheral blood enables safe, outpatient-compatible molecular diagnosis, to potentially guide tailored treatment.

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, particularly PDAC with peritoneal metastases. The present report describes a case of distal pancreatectomy (DP) following ip and iv chemotherapy for PDAC with peritoneal metastases, with long-term survival after CS. A 62-year-old man was referred to Tonan Hospital (Sapporo, Japan) for ip and iv chemotherapy after being diagnosed with unresectable pancreatic body adenocarcinoma with peritoneal dissemination at another hospital. The patient was administered four cycles of ip paclitaxel (ipPTX) plus ivPTX plus S-1, followed by four cycles of ipPTX plus fluorouracil plus leucovorin, irinotecan and oxaliplatin. After 9 months of preoperative treatment, the disappearance of peritoneal dissemination was confirmed; thus, the patient underwent DP. The histopathological diagnosis was ypT2, ypN0, ypM0 and ypStage IB, and the histologic response to chemotherapy was grade IIb, according to the Evans classification. Postoperative adjuvant chemotherapy including ipPTX was administered for 12 months. The patient survived without recurrence for 7 years after the CS.

Objectives: To investigate whether preservation of the posterior elements protects the spine from degeneration and improves postoperative symptoms in lumbar spine laminoplasty. Methods: Eighty-five consecutive patients who underwent lumbar spine laminoplasty were retrospectively reviewed. They were non-randomly stratified into two groups, the posterior elements resection (R) group and the preservation (P) group, and they were followed for two years after surgery. We radiographically analyzed the conditions of the spine and intervertebral disc (IVD) two years after surgery. The Japanese Orthopaedic Association Back Pain Evaluation Questionnaire (JOABPEQ) was used for symptom assessments. Logistic regression analysis was performed to determine whether the kissing spine was a significant factor for the outcomes in group R. Results: The 2-year D score increment and 2-year IVD height decrement was lower in group P. No difference was found in the flexion–extension angles or incidence of instability between groups. The JOABPEQ revealed higher scores in walking ability, social life function, and mental health in group P one year after surgery. Walking ability was the only score that remained higher two years after surgery. The visual analog scale of pain in the buttocks and lower limbs was lower in group P only one year after surgery. Finally, the kissing spine was not a significant factor in any outcome. Conclusions: The preserved posterior elements were considered to protect the IVD in lumbar spine laminoplasty. In addition, they positively affected postoperative health status from multiple aspects.

The Japanese Society for Sentinel Node Navigation Surgery conducted a multi-institutional prospective cohort study to compare sentinel node biopsy (SNB) with SNB followed by axillary lymph node dissection (ALND) in breast cancer patients with positive sentinel lymph node (SLN). Female patients with breast cancer with cT1-3N0-1M0 were eligible. In cases of one to three positive micro- or macrometastases in the SLN confirmed by histological or molecular diagnosis, SNB alone (SNB group) or additional ALND (ALND group) was performed under physician's discretion. The primary endpoint was the 5-year regional node (RN) recurrence rate in the SNB group. Propensity score matching (PSM) was performed to compare the prognosis between the two groups. Of the 871 eligible cases registered between 2013 and 2016, 308 underwent SNB alone. At the median follow-up of 6.3years, 5-year RN recurrence rate was 2.7%. After PSM, 209 cases were matched in each group. Breast-conserving surgery and mastectomy were performed in 225 (54%) and 193 cases (46%), respectively. One-positive SLN was recorded in 366 cases (88%), two in 48 (11%), and three in 4 (1%). Macro- and micrometastases in SLN were diagnosed in 271 (65%) and 147 cases (35%), respectively. Regional nodal irradiation (RNI) was performed in 42 (20%) and 13 (6%) cases of the SNB and ALND group. The 5-year RN recurrence rate was 2.1% and 2.0%, respectively. ALND is not necessary for early breast cancer patients with one-positive SLN despite type of breast surgery.

Programmed death ligand 1 (PD-L1) serves as a crucial biomarker for predicting the efficacy of immune checkpoint inhibitors in patients with non-small cell lung cancer (NSCLC). This study aimed to identify the most suitable first-line treatment regimen for patients with PD-L1 expression <1% (PD-L1-negative) NSCLC by comparing nivolumab plus ipilimumab (NI), NI combined with chemotherapy (NICT), and pembrolizumab and chemotherapy (PCT). We analyzed data from 141 patients with PD-L1-negative NSCLC treated with NI, NICT, or PCT at 14 Japanese institutions between December 2020 and November 2022. Propensity score analysis was employed to minimize selection bias, and Kaplan-Meier analysis and Cox proportional hazards regression were used to evaluate progression-free survival (PFS) and overall survival (OS). Neither NI nor NICT demonstrated superior PFS or OS than PCT. Subgroup analyses revealed no significant differences between treatment groups across age, histological subtypes, or clinical features. Results from propensity score matching and inverse probability of treatment weighting were consistent with those observed in the overall cohort. Moreover, safety profiles showed that PCT was associated with the lowest rates of treatment discontinuation and immune-related adverse events requiring systemic corticosteroid therapy. In patients with PD-L1-negative NSCLC, the efficacy of NI and NICT was not superior to that of PCT. Thus, we concluded that PCT could be a favorable treatment option for this patient population.

ObjectivesIn gastroenterology, sedation demand is increasing, although elderly patients are more prone to experiencing adverse events. Remimazolam, a novel ultra‐short‐acting benzodiazepine, may reduce recovery time after endoscopic procedures.MethodsThis study was a secondary analysis of the investigator‐initiated trial, which investigated the efficacy and safety of remimazolam in gastrointestinal endoscopy (REM‐IICT JP01). Remimazolam sedation was administered during upper gastrointestinal endoscopy. Patients were divided into two groups: 45 non‐elderly and 11 elderly patients (aged ≥65 years). The primary outcome was sedation success. Secondary outcomes included the dose required for sedation, time to awakening, time to regain the ability to walk, and occurrence of adverse events.ResultsEndoscopic sedation was successful in 95.6% of the non‐elderly group and 100% of the elderly group. The total dose of remimazolam was significantly higher in the non‐elderly group (4.0 [3.0–8.0] mg) than in the elderly group (3.0 [2.0–3.0] mg; p < 0.01). The time to awakening was 0.0 (0.0–10.0) min in the non‐elderly group compared to 0.0 (0.0–30.0) min (p = 0.98) in the elderly group. The time to regain the ability to walk was significantly longer in the elderly group (5.0 [0.0–60.0] min) than in the non‐elderly group (5.0 [0.0–30.0] min; p = 0.03). During the procedure, adverse events included hypotension in two cases (4.4%) in the non‐elderly group and hypoxemia in one case (9.0%) in the elderly group.ConclusionsUpper gastrointestinal endoscopy with remimazolam was effective and safe, regardless of age.

症例は62歳，男性．便秘を主訴に近医を受診し，直腸診で肛門管直上に腫瘤を認め，生検でGISTと診断された．50mm大の腫瘍は前立腺，肛門挙筋に接しており，イマチニブによる術前治療後の手術を計画した．6カ月間のイマチニブ投与により腫瘍は39mmに縮小し，前立腺および肛門挙筋との境界も明瞭となったため，taTMEを併用した腹腔鏡下低位前方切除術を施行した．腫瘍は被膜損傷なく完全切除され，病理学的には生検検体と比較し著明な細胞密度の低下を認めた．術後1年3カ月，局所再発および遠隔転移を認めていない．直腸GISTは比較的腫瘍径が大きく，狭い骨盤腔内での手術は非常に難度が高いため，拡大手術が行われる場合も多い．術前イマチニブ治療とtaTMEにより，合併症および後遺症なく完全切除しえた直腸GISTの1例を経験したので報告する．

Acute myeloid leukemia (AML) is an aggressive hematological malignancy with genetic alterations. The FMS-like tyrosine kinase 3 (FLT3) gene is frequently mutated in adult de novo AML, with two types of mutations: internal tandem duplication (ITD) and point mutations in the tyrosine kinase domain. This study aimed to investigate the impact of FLT3 inhibitors and hematopoietic cell transplantation (HCT) on survival outcomes in patients with FLT3-ITD AML in a real-world setting. We retrospectively analyzed 139 patients with FLT3-ITD-positive AML between 2012 and 2021. The median age was 63 years. In the propensity score-matched cohort, FLT3 inhibitors improved overall survival (OS) compared with patients treated without FLT3 inhibitors (3-year OS: 33.7% vs. 25.8%, p = 0.021). Patients who underwent HCT had superior outcomes to those without HCT (3-year OS: 45.3% vs. 2.2%, p < 0.0001). The combination of FLT3 inhibitors and HCT resulted in the highest OS and relapse-free survival (RFS) rates (3-year OS: 62.4%; 3-year RFS: 44.4%). Disease status before transplantation did not predict the prognosis, but use of FLT3 inhibitors increased survival in patients without complete remission before HCT. These results demonstrate the clinical impact of FLT3 inhibitors on survival outcomes in patients with FLT3-ITD-positive AML, particularly when combined with HCT. FLT3 inhibitors can improve the prognosis of AML with FLT3 mutations, especially in patients who undergo HCT.