Teikyo University Chiba Medical Center

Shimizu N., Mashimo Y., Yokouchi H., Nishio Y., Sawai S., Ichikawa T., Ogi T., Baba T., Onouchi Y.

Abstract Mutations in fibrillin-1 (FBN1) cause various clinical conditions, such as Marfan syndrome (MFS). However, the genotype–phenotype relationships underlying MFS and other conditions relevant to FBN1 mutations have not been fully elucidated. We performed whole-exome sequencing on three participants, including an affected mother–daughter pair, in a three-generation Japanese family with isolated ectopia lentis (IEL). The sequencing identified a novel single-nucleotide variant (c.1327+3A>C) in intron 11 of FBN1 that was shared between the two patients. We confirmed the co-segregation of the variant with IEL in two additional affected relatives in the family. The Combined Annotation-Dependent Depletion score of the variant was 26.1, which was indicated by SpliceAI to influence splicing, with a score of 0.93. Reverse transcription-polymerase chain reaction (RT-PCR) of mRNAs isolated from peripheral blood mononuclear cells revealed aberrant bands in all four affected individuals. Subsequent sequencing revealed that these bands originated from FBN1 transcripts lacking exon 11. The causality of the variant in the skipping of exon 11, which results in an in-frame deletion of 60 amino acids corresponding to the “hinge” region of FBN1 protein, was confirmed in a minigene experiment. Interestingly, the same result was observed for a minigene for c.1327+1G>A, a variant previously identified in two unrelated EL families without MFS manifestations. These results suggest that the c.1327+3A>C mutation in FBN1 likely leads to IEL. The findings expand our knowledge of FBN1 and provide insights into FBN1-related diseases.

Okamoto T., Tamachi S., Iwase T., Niizawa T., Kawamata Y., Yokouchi H., Baba T., Haneishi H.

The choroid is a dense vascular layer that lies between the retina and the sclera and contributes to the blood supply of the outer retina. In recent years, optical coherence tomography (OCT), which enables non-destructive acquisition of cross-sectional images of the choroid, has revealed the relationship between morphological changes in the choroid and eye diseases. In this context, automatic and accurate segmentation of OCT images is critical, but many existing methods face challenges, as they 1) rely on convolutional neural network (CNN)-based architectures, which struggle to capture long-range dependencies, and 2) primarily focus on two-dimensional OCT images and thus have difficulty identifying the complex three-dimensional (3D) structure of the choroid. In this study, we propose an automatic choroid segmentation method, 3DChoroidSwin, which incorporates 3D CNN and 3D Swin Transformer frameworks, achieving both short- and long-distance learning. Furthermore, our method uses a combined loss function that includes the boundary loss, which leverages morphological information, achieving shape-aware training and decreasing unnatural false positives. Experimental results using clinical data demonstrate that the proposed method outperforms comparison methods, delivering performance comparable to ground truth; moreover, it achieves smooth and continuous 3D segmentation with reduced segmentation errors at the choroid margins.

Miyazawa K., Yamaguchi S., Iguchi T., Chikazawa I., Yasui T., Takahashi S., Hinotsu S., Akakura K., Iida S., Ishito N., Inoue T., Kohjimoto Y., Sakamoto S., Sato Y., Takazawa R., et. al.

AbstractThis third edition of the Japanese Clinical Practice Guidelines for Urinary stones (2023) has been developed under the leadership of the Japanese Urological Association, the Japanese Society of Endourology and Robotics, and the Japanese Society on Urolithiasis Research. This revision adheres to the Minds Manual for Guideline Development (2017) and incorporates new findings from a nationwide survey conducted in 2015, which highlighted the epidemiological characteristics of urolithiasis in Japan since the previous guidelines were published in 2013. A significant advancement in this edition is the systematic review (SR) methodology applied to formulate recommendations for 12 clinical questions (CQs). Both quantitative and qualitative SRs were performed, leading to recommendations determined through consensus among 21 members of the guideline development group. Additionally, nine algorithms were created to support clinical decision‐making based on these findings. Topics not addressed by the CQs, considered as foundational knowledge, are outlined in an “Explanation of Related Matters” section, which includes 26 items. This article provides an overview of these guidelines. This section ensures that practitioners have access to comprehensive information, covering aspects of urolithiasis management beyond the scope of the systematic reviews. This article provides an overview of the guidelines, emphasizing their relevance and importance in improving the management and treatment outcomes for patients with urinary stones. The guidelines are designed to be a practical resource for clinicians, facilitating evidence‐based care in the evolving landscape of urolithiasis treatment.

Matsuhashi N., Yamada T., Nagasaka T., Kataoka K., Sakamoto K., Koda K., Hiramatsu K., Matsuoka H., Kuramochi H., Ishida H., Yokomizo H., Kagawa Y., Suenaga M., Matsuda A., Nagata J., et. al.

255 Background: Epidermal growth factor receptor (EGFR) blockade can effectively shrink tumors in metastatic colorectal cancer (CRC) patients without RAS nor BRAF mutations. However, some patients without RAS or BRAF mutations in their primary tumors may develop these mutations in metastatic tumors (heterogeneity). Circulating tumor DNA (ctDNA) can reflect this heterogeneity in metastatic tumors. Here, we evaluated the efficacy of EGFR blockade in patients who had no RAS or BRAF mutations in their primary tumors but did have them in ctDNA. Methods: We prospectively enrolled 100 patients with confirmed metastatic CRC without RAS or BRAF mutations in their primary tumors. Patients were treated with first-line systemic chemotherapy including EGFR blockade. We obtained ctDNA from each patient before they started chemotherapy. RAS, BRAF (V600E), and PIK3CA mutations were detected using digital PCR. Results: One of the 100 cases were excluded due to protocol violation. In the ctDNA obtained before starting chemotherapy, RAS, BRAF, and PIK3CA mutations were detected in 12, 4, and 6 patients, respectively. No patients had both RAS and BRAF mutations in their ctDNA; however, one patient had both BRAF and PIK3CA mutations and one had both RAS and PIK3CA mutations. Eighty-nine patients had measurable tumor lesions. Among these, 3 experienced a complete response (CR), 71 had a partial response (PR), 13 had stable disease (SD), and 2 had progressive disease (PD). The response rates for patients with RAS or BRAF mutations and for patients with neither mutation were 81% and 83%, respectively (P=0.73). Median progression-free survival (PFS) for patients with RAS or BRAF mutations and those without mutations were 251 days and 216.5 days, respectively (P=0.82). The presence or absence of PIK3CA mutations did not affect the response rate or PFS. Conclusions: Previously, we reported that the incidence of RAS and BRAF heterogeneity were 10% (1) and 4% (2). In the present study, RAS and BRAF heterogeneity were 12% and 4%, respectively. The heterogeneity of RAS and BRAF mutations had no effect on the response rate and PFS of EGFR blockade as first line chemotherapy. The effect of heterogeneity on the overall survival is of great interest; however, about half of the patients are still alive. 1. Yamada T, et al. Cancer Science 2016. 2. Ueda K, et al. Eur J Surg Oncol 2022. Clinical trial information: UMIN000031177 .

Saito R., Shimizu T., Kondoh A., Matsuyama T., Hisada A., Yaguchi T., Sato T., Mabuchi T.

Kawamori K., Oguro N., Shimizu K., Kida T., Omura S., Nakagomi D., Abe Y., Kadoya M., Takizawa N., Nomura A., Kukida Y., Kondo N., Yamano Y., Yanagida T., Endo K., et. al.

ABSTRACT Objectives Cytomegalovirus (CMV) reactivation during immunosuppressive therapy poses a risk of severe infections. This study aimed to investigate the risk factors of CMV reactivation in patients with microscopic polyangiitis and granulomatosis with polyangiitis using a nationwide cohort in Japan. Methods This retrospective cohort study used data from the Japan Collaborative Registry of antineutrophil cytoplasmic antibody-associated vasculitis. The outcome was as CMV reactivation up to 48 weeks after treatment initiation. We explored the risk factors for CMV reactivation by comparing the two groups. Results Of the 454 patients, CMV reactivation occurred in 89 (19.6%). The univariate analysis showed that patients with CMV reactivation were older (P < .001), had higher Birmingham Vasculitis Activity Scores (BVAS) (P = .004) and BVAS renal scores (P < .001), and had received glucocorticoid pulse (P = .004). The logistic regression analysis showed that hypoalbuminemia (odds ratio: 0.55, 95% confidence interval: 0.31–0.98), and low serum IgG (OR: 0.94, 95% CI: 0.89–1.00) were risk factors for CMV reactivation. Conclusions Hypoalbuminemia and low serum IgG levels were risk factors for CMV reactivation. It is necessary to accurately identify high-risk patients and closely monitor their condition.

Kagami S., Funahashi K., Kobayashi H., Kotake K., Kawasaki M., Kinugasa Y., Ueno H., Maeda K., Suto T., Itabashi M., Ozawa H., Koyama F., Noura S., Ishida H., Ohue M., et. al.

Fujimoto K., Koyama F., Kobayashi H., Kotake K., Kawasaki M., Kanemitsu Y., Kinugasa Y., Ueno H., Maeda K., Suto T., Itabashi M., Funahashi K., Ozawa H., Noura S., Ishida H., et. al.

AbstractBackgroundChemotherapy is the typical choice for treating colorectal cancer with synchronous peritoneal metastases. Nonetheless, surgical resection may be chosen if the metastases are resectable. Unfortunately, there is no reliable preoperative or intraoperative prognostic indicator. This study aimed to determine the prognostic significance of the preoperative Glasgow prognostic score (GPS) in colorectal cancer patients with synchronous peritoneal metastases.MethodsWe conducted a prospective study on 143 patients with colorectal cancer and concurrent peritoneal metastases. Our analysis included prognostic factors, such as the GPS, using data from the institutional observational study by the Japanese Society for Cancer of the Colon and Rectum.ResultsThe 3‐year survival rates for the GPS0 or 1 and GPS2 groups were 32.7% and 14.3%, respectively, with a significantly worse prognosis in the GPS2 group (p = 0.003). Multivariate analysis identified GPS2 (p = 0.006) and the peritoneal cancer index (PCI) (p = 0.029) or the Japanese surgical peritoneal metastasis grade (p = 0.009) as independent poor prognostic factors. Additionally, the GPS0 or 1 group with total resection of peritoneal metastases had a significantly better prognosis than the non‐resection group (p < 0.001); however, there was no difference between the GPS2 group with total peritoneal resection and the non‐resection group (p = 0.713).ConclusionsPreoperative GPS2 is an independent poor prognostic factor in patients with colorectal cancer and synchronous peritoneal metastases, and surgical resection does not improve prognosis in patients with GPS2. Preoperative GPSs may be used as indicators for surgical resection of synchronous peritoneal metastases.

Ogita C., Noguchi K., Takeuchi J., Azuma N., Omura S., Nakagomi D., Abe Y., Kadoya M., Takizawa N., Nomura A., Kukida Y., Kondo N., Yamano Y., Yanagida T., Endo K., et. al.

Kato H., Goto Y., Kojima S., Onoda Y., Wakai K., Hou K., Araki K., Sakamoto S., Ichikawa T., Naya Y.

ABSTRACTBackgroundRecent clinical trials have shown that patients with metastatic castration‐sensitive prostate cancer in real‐world settings have different overall survival (OS) rates after stratifying for tumor burden or visceral metastasis. However, some patients with a low tumor burden and without visceral metastasis still have a poor survival. Androgen receptor signaling is still a main therapeutic target of prostate cancer treatment even after the achievement of castration resistance. In this regard, we hypothesized that time to castration resistance can be a prognostic factor of metastatic castration‐sensitive prostate cancer even after achieving castration resistance. The current study aimed to assess the novel prognostic factors, particularly time to castration resistance, of prostate cancer in patients at a real‐world single institution.MethodsThe data of 261 patients who were newly diagnosed with metastatic castration‐sensitive prostate cancer from January 2007 to December 2023 were retrospectively analyzed.ResultsThe median OS was 60.7 months, and the median time to castration resistance was 13.1 months. Among 261 patients, 158 developed castration‐resistant prostate cancer. A shorter time to castration resistance, the presence of distant lymph node metastasis, ISUP grade group 5, and older age were associated with a shorter OS in patients who developed castration‐resistant prostate cancer. A shorter time to castration resistance was significantly associated with a shorter OS regardless of the tumor burden. Further, it was associated with a shorter OS even after the achievement of castration resistance.ConclusionsThe study results support the presence of persistent androgen receptor signaling even after achieving castration resistance in prostate cancer, and time to castration resistance can be a biomarker for the activation of androgen receptor signaling regardless of tumor burden.

Kobayashi S., Amano H., Terawaki H., Kawaguchi Y.

Dietary sodium restriction is important in the prognosis of patients with chronic kidney disease (CKD). The association between saltiness perception and sodium intake among CKD patients is unclear, and the factors that influence saltiness are also not fully understood. We evaluated saltiness perception in CKD patients employing a cost-effective saltiness perception test using sodium solutions and evaluated the association between saltiness perception, sodium intake, and the influencing factors.

Takeuchi N., Ohkusu M., Kusuya Y., Takahashi H., Yamaguchi M., Omata Y., Nakazawa T., Ishiwada N.

IntroductionTo understand the in-vivo dynamics in pneumococci, investigation into the carriage in patients with invasive pneumococcal disease (IPD) is extremely important.MethodsTo clarify genomic and morphological differences between pneumococcal strains simultaneously isolated from different sites in a patient with IPD, we conducted comparative analyses of two strains. A capsular strain isolated from the blood and a non-capsular strain isolated from the sputum of a patient with IPD were used.ResultsThe strain isolated from blood was serotype 24B with capsule. The strain isolated from sputum with capsular type 24 genes was non-encapsulated, and genomic analysis revealed an insertion region in the wcxK gene. Its biofilm-forming capacity was higher than that of the capsular strain, as was that of the pspK-positive true non-encapsulated strain. Furthermore, observing the microbe using transmission electron microscopy revealed that the strain isolated from sputum lacked a capsule, like the pspK-positive true non-encapsulated strain.ConclusionsOur analysis of the two strains isolated from the blood and sputum of a patient with IPD showed one possible in-vivo morphological change in Streptococcus pneumoniae.

Nozumi K., Sakamoto S., Zhao X., Pae S., Tamura T., Taguchi K., Yamada Y., Goto Y., Imamura Y., Sazuka T., Awa Y., Yasui T., Nozumi K., Naya Y., Akakura K., et. al.

ObjectivesTo evaluate the success rate of shock wave lithotripsy and identify predictors of stone‐free status after shock wave lithotripsy for ureteral stones, focusing on the impact of stones remaining in the same location for 2 months (SSL2).MethodsA retrospective analysis was conducted on 501 patients with ureteral stones treated with shock wave lithotripsy by expert surgeons (each with over 1000 shock wave lithotripsy operations) at a single Japanese institution in 2020. Logistic regression analysis identified predictors of stone‐free status, including stone length, skin‐to‐stone distance, stone density (Hounsfield Unit), Hounsfield Unit above/below the stone, stone position, and duration of stone at the same location (SSL2).ResultsNinety patients were excluded, resulting in 411 patients undergoing an average of 1.15 ± 0.4 sessions (range: 1–4). 344 patients (83.7%) achieved stone‐free status after a single session. The overall 1‐month stone‐free rate was 71.4%, and the 3‐month stone‐free rate was 88.8%. Stone at the same location ≥2 months (SSL2) was an independent predictor of 1‐month stone‐free status (odds ratio = 2.25, 95%CI: 1.10–4.57, p = 0.025), while mean stone density ≥ 813 HU was an independent predictor of 3‐month stone‐free status (odds ratio = 2.66, 95% CI: 1.10–6.45, p = 0.03).ConclusionStone at the same location ≥2 months (SSL2) was a potent predictor of 1‐month and 3‐month stone‐free status. This condition is associated with impacted stones and can aid in decision‐making for shock wave lithotripsy treatment selection.

Yamada Y., Sato K., Sakamoto S., Tsujino T., Saito S., Nishimura K., Fukushima T., Nakamura K., Yoshikawa Y., Matsunaga T., Maenosono R., Kanesaka M., Arai T., Sazuka T., Imamura Y., et. al.

Abstract Background This study investigated the characteristics of prostate-specific antigen (PSA) dynamics when androgen receptor signaling inhibitor (ARSI), or vintage agent (bicalutamide) was used for patients with metastatic hormone-sensitive prostate cancer (mHSPC). Patients and methods A total of 213 mHSPC patients from each of the ARSI and bicalutamide groups treated between 2015 and 2022 were selected from multiple institutions using propensity score-matched analysis to align backgrounds. PSA progression-free survival (PFS) and overall survival (OS) were assessed. PSA level at 3 months, PSA nadir level, and time to PSA nadir were examined to analyze of PSA kinetics. Results ARSI treatment significantly improved PSA PFS compared to bicalutamide (P = 0.0063), although no significant difference in OS was seen (P = 0.3134). No significant differences were observed between treatment groups in median PSA levels at 3 months (1.47 vs 0.52 ng/ml, P = 0.3042) or PSA nadir levels (0.263 vs 0.1345 ng/ml, P = 0.1228). Bicalutamide treatment demonstrated longer time to nadir than ARSI in progression-free cases (median: 243 vs 213.5 days, P = 0.0003). Survival tree analysis found that PSA nadir ≤ 1.5 ng/ml and time to nadir ≥ 145 days were the optimal cut-offs for best stratifying OS with bicalutamide, while PSA nadir ≤ 0.45 ng/ml and time to nadir ≥ 70 days were optimal with ARSI. Conclusion No significant differences in PSA response was seen between groups; however, distinct optimal cut-offs were demonstrated for PSA nadir and time to nadir. The present findings will be useful for optimal PSA monitoring for mHSPC patients and for early identification of poor-prognosis populations.

Ogata Y., Aita K., Maeda J., Shiragami R., Hagiya M., Shuto K., Nakamura F., Yamaguchi M.

AbstractPulmonary vein thrombosis (PVT) is rarer than pulmonary artery thrombosis (PAT). PVT is potentially fatal but is often overlooked due to its nonspecific symptoms. We present a case with PVT accompanied by paroxysmal atrial fibrillation. The symptoms were limited to transient ischemic attacks. Contrast‐enhanced computed tomography (CT), which showed a thrombus in the right pulmonary vein trunk, was useful in diagnosing PVT. After switching the patient's anticoagulant from dabigatran etexilate to apixaban, the thrombus disappeared within 5 months. Contrast‐enhanced CT is a useful and common tool for diagnosis and follow‐up of PVT.