Publications by authors named "Takashi Kobayashi"

831 Publications

[A Case of Pelvic Unicentric Castleman Disease Treated by Preoperative Transcatheter Arterial Embolization and Tumor Complete Resection with Combined Lower Abdominal and Posterior Approach].

Hinyokika Kiyo 2021 Apr;67(4):157-162

The Department of Urology, Kyoto University Hospital.

A 22-year-old woman was referred to our hospital for further examination of an incidentally discovered hypervascular pelvic tumor with a maximum diameter of 10 cm. Although Castleman disease was suspected based on the imaging findings and pathologic findings of the needle biopsy, a definitive diagnosis was not made. Preoperative transcatheter arterial embolization was performed to decrease intraoperative bleeding, and tumor resection was performed on the following day. As for posterior approach prior to anterior approach, the patient was placed in a prone position, and the dorsal aspect of tumor was approached through the dissection of gluteal muscles. Then, dilated branches of the internal iliac vein was found on the tumor capsule, which were safely ligated under direct vision with favorable visual field. Then, the patient was placed in a supine position, the tumor was completely resected by anterior approach without transfusion. Histopathological diagnosis was Castleman disease hyaline vascular type. The patient was discharged without complication and has been free from recurrence for 6 months after surgery.
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http://dx.doi.org/10.14989/ActaUrolJap_67_4_157DOI Listing
April 2021

[Promotion of Diversity in the Academic Field of Urology : Analysis of 10,000 Articles Published in Acta Urologica Japonica during a 65-Year Period].

Hinyokika Kiyo 2021 Apr;67(4):125-132

The Department of Urology, Kyoto University Graduate School of Medicine.

Gender equality is one of the most important issues in the promotion of diversity. The participation status of female urologists in academic activities has not been clarified. In the present study, we analyzed a total of 10,288 articles published by 58,914 authors in Acta Urologica Japonica since the first issue in 1955 to the present. The author's gender was determined by an application program interface for gender estimation in combination with independent manual confirmation by two researchers. The increasing rate (⊿person/⊿year) of female authors was as low as 0.067 in 1955-79, but increased to 0.400 in 1980-2000 and 0.814 in 2001-20. Over the time periods, the annual total numbers of female authors (person/year) showed an increasing trend from 3.2 in 1955-79 to 16.3 in 1980-2000 and 26.0 in 2001-20. The numbers of female author individuals, the ratio of female authors to all authors and the ratio of publications by female first author to all publications also showed similar trends. These results suggest that gender equality is becoming more prevalent in the academic field of urology. The methods and data of this study are considered to be useful for the promotion of gender equality in the academic field of urology for the future.
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http://dx.doi.org/10.14989/ActaUrolJap_67_4_125DOI Listing
April 2021

Quantum tomography of an entangled three-qubit state in silicon.

Nat Nanotechnol 2021 Jun 7. Epub 2021 Jun 7.

Center for Emergent Matter Science (CEMS), RIKEN, Wako-shi, Saitama, Japan.

Quantum entanglement is a fundamental property of coherent quantum states and an essential resource for quantum computing. In large-scale quantum systems, the error accumulation requires concepts for quantum error correction. A first step toward error correction is the creation of genuinely multipartite entanglement, which has served as a performance benchmark for quantum computing platforms such as superconducting circuits, trapped ions and nitrogen-vacancy centres in diamond. Among the candidates for large-scale quantum computing devices, silicon-based spin qubits offer an outstanding nanofabrication capability for scaling-up. Recent studies demonstrated improved coherence times, high-fidelity all-electrical control, high-temperature operation and quantum entanglement of two spin qubits. Here we generated a three-qubit Greenberger-Horne-Zeilinger state using a low-disorder, fully controllable array of three spin qubits in silicon. We performed quantum state tomography and obtained a state fidelity of 88.0%. The measurements witness a genuine Greenberger-Horne-Zeilinger class quantum entanglement that cannot be separated into any biseparable state. Our results showcase the potential of silicon-based spin qubit platforms for multiqubit quantum algorithms.
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http://dx.doi.org/10.1038/s41565-021-00925-0DOI Listing
June 2021

Evaluation of Weighted Diffusion Subtraction for Detection of Clinically Significant Prostate Cancer.

J Magn Reson Imaging 2021 Jun 4. Epub 2021 Jun 4.

Department of Diagnostic Imaging and Nuclear Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Background: Diffusion-weighted imaging (DWI) is an important method for clinically significant prostate cancer (csPCa) diagnosis; however, the Prostate Imaging-Reporting and Data System (PI-RADS) requires the subjective assessment of "markedly hypointense or not" on apparent diffusion coefficient (ADC) map. We hypothesize that weighted diffusion subtraction (WDS) images, created by weighted subtraction of high and low b-value DWIs, might better show areas of ADC values below a set threshold, thus decreasing the subjectivity of the assessment.

Purpose: To evaluate the diagnostic ability of WDS for csPCa by comparing scores based on WDS images (DWI/WDS) with those based on PI-RADS DWI (DWI/ADC).

Study Type: Retrospective.

Subjects: Eighty-six PCa patients.

Field Strength/sequences: 3.0 T; DWI.

Assessment: Four readers assessed the probability of csPCa in lesions (overall, in the peripheral zone [PZ] and transitional zone [TZ]) using 5-point DWI/ADC and DWI/WDS scores. Prostatectomy specimens were the reference standard. ADC values and contrast between csPCa and normal prostate tissue on ADC maps and WDS images were calculated with reference to the pathological map.

Statistical Tests: Diagnostic ability was evaluated by Jackknife alternative free-response receiver-operating characteristic curve. Figure of merit (FOM), sensitivity, and positive predictive value (PPV) between the DWI/ADC and DWI/WDS scores were compared using paired t-test. Inter-reader agreement was analyzed using κ statistics, and the significance probability was calculated using the Z statistic. Wilcoxon signed-rank test was used to compare contrast between csPCa and normal prostate tissue on ADC maps and WDS images. A P value <0.05 was considered statistically significant.

Results: FOM and sensitivity of the DWI/WDS scores were significantly better than those of the DWI/ADC scores overall, in the PZ and TZ (FOM: overall, 0.715 vs. 0.783; PZ, 0.756 vs. 0.815; TZ, 0.653 vs. 0.738. Sensitivity: overall, 0.512 vs. 0.607; PZ, 0.485 vs. 0.573; TZ, 0.636 vs. 0.761). For PPV, a statistically significant difference was observed overall (0.727 vs. 0.777). The κ value of DWI/WDS score was significantly higher than that of DWI/ADC score overall and in the PZ (overall, 0.614 vs. 0.792; PZ, 0.609 vs. 0.797). Contrast was significantly higher overall in the PZ and TZ in WDS images (median, 1.26, 1.19, and 1.61) than in ADC maps (0.46, 0.47, and 0.41).

Data Conclusion: WDS images performed better than ADC maps in the diagnosis of csPCa and in inter-reader agreement of the diagnosis.

Level Of Evidence: 4 Technical Efficacy Stage: 2.
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http://dx.doi.org/10.1002/jmri.27771DOI Listing
June 2021

Intravesical Bacillus Calmette-Guérin Treatment for T1 High-Grade Non-Muscle Invasive Bladder Cancer with Divergent Differentiation or Variant Morphologies.

Cancers (Basel) 2021 May 26;13(11). Epub 2021 May 26.

Department of Urology, Nara Medical University, Kashihara, Nara 634-8522, Japan.

The 2016 World Health Organization classification newly described infiltrating urothelial carcinoma (UC) with divergent differentiation (DD) or variant morphologies (VMs). Data comparing oncological outcomes after bladder-preservation therapy using intravesical Bacillus Calmette-Guérin (BCG) treatment among T1 bladder pure UC (pUC), UC with DD (UC-DD), and UC with VMs (UC-VM) are limited. We evaluated 1490 patients with T1 high-grade bladder UC who received intravesical BCG during 2000-2019. They were classified into three groups: 93.6% with pUC, 4.4% with UC-DD, and 2.0% with UC-VM. Recurrence-free, progression-free, and cancer-specific survival following intravesical BCG were compared among the groups using multivariate Cox regression analysis, also used to estimate inverse probability of treatment weighting-adjusted hazard ratio and 95% confidence interval for the outcomes. Glandular differentiation and micropapillary variant were the most common forms in the UC-DD and UC-VM groups, respectively. Of 1490 patients, 31% and 13% experienced recurrence and progression, respectively, and 5.0% died of bladder cancer. Survival analyses revealed the impact of concomitant VMs was significant for cancer-specific survival, but not recurrence-free and progression-free survival compared with that of pUC. Our analysis clearly demonstrated that concomitant VMs were associated with aggressive behavior in contrast to concomitant DD in patients treated with intravesical BCG.
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http://dx.doi.org/10.3390/cancers13112615DOI Listing
May 2021

Efficacy of G9-1 in improving quality of life in patients with chronic constipation: a prospective intervention study.

Biosci Microbiota Food Health 2021 19;40(2):105-114. Epub 2021 Jan 19.

Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine, 3-9 Fuku-ura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan.

Chronic constipation is a functional disorder that decreases a patient's quality of life (QOL). Because dysbiosis has been associated with constipation, we aimed to investigate the efficacy of G9-1 (BBG9-1) in improving QOL in patients with constipation. This was a prospective, single-center, non-blinded, single-arm feasibility trial. A total of 31 patients with constipation and decreased QOL received BBG9-1 treatment for 8 weeks, followed by a 2-week washout period. The primary endpoint was change in the overall Japanese version of the patient assessment of constipation of QOL (JPAC-QOL) score after probiotic administration relative to that at baseline. Secondary endpoints included changes in gut microbiota, stool consistency, frequency of bowel movement, degree of straining, sensation of incomplete evacuation, and frequency of rescue drug use. The overall JPAC-QOL scores and frequency of bowel movement significantly improved after BBG9-1 administration from those at baseline (p<0.01 and p<0.01, respectively). There were no statistically significant changes in other clinical symptoms. Subset analysis revealed that patients with initial Bristol Stool Form Scale stool types of <4 had improvements in stool consistency, a significant increase in the frequency of bowel movements, and a significant alleviation in the degree of straining, following BBG9-1 administration. At the genus and species levels, and were significantly increased. Functional analysis showed that butanoate metabolism increased significantly, whereas methane metabolism decreased significantly. We concluded that BBG9-1 is safe and improves QOL in patients with constipation. The underlying improvements may be due to changes in stool consistency.
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http://dx.doi.org/10.12938/bmfh.2020-073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099630PMC
January 2021

Thymic epithelial tumor with superior vena cava syndrome diagnosed by percutaneous endovascular tumor biopsy: A report of two cases.

Respir Investig 2021 May 8. Epub 2021 May 8.

Department of Comprehensive Cancer Therapy, Shinshu University School of Medicine, Matsumoto, Japan.

Thymic epithelial tumor is a rare, potentially progressive disease that commonly infiltrates mediastinal structures. In rare cases, it may cause superior vena cava syndrome. Pretreatment histopathological diagnosis is essential to determine the most effective treatment strategy. Percutaneous endovascular biopsy is a rarely reported non-surgical diagnostic option for large vessel tumoral involvement. We report two cases of thymic epithelial tumor with superior vena cava syndrome diagnosed by percutaneous endovascular biopsy. No procedural complications occurred, and subsequent systemic treatment was promptly administered. This procedure may have potential as a useful diagnostic method for patients with mediastinal tumors involving large vessels.
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http://dx.doi.org/10.1016/j.resinv.2021.04.003DOI Listing
May 2021

A narrative review of urinary phospholipids: from biochemical aspect towards clinical application.

Transl Androl Urol 2021 Apr;10(4):1829-1849

Department of Nephro-Urologic Surgery and Andrology, Mie University Graduate School of Medicine, Tsu, Japan.

As a newly emerged discipline, lipidomic studies have focused on the comprehensive characterization and quantification of lipids in a given biological system, which has remarkably advanced in recent years owing to the rapid development of analytical techniques, especially mass spectrometry. Among diverse lipid classes, phospholipids, which have fundamental roles in the formation of cellular membranes, signaling processes, and bioenergetics have gained momentum in several fields of research. The altered composition, concentration, spatial distribution, and metabolism of phospholipids in cells, tissues, and body fluids have been elucidated in various human diseases such as cancer, inflammation, as well as cardiovascular and metabolic disorders. Among the different kinds of phospholipid sources in the human body, urine has not been extensively investigated in recent years owing to the extremely low concentrations of phospholipids and high levels of salts and other contaminants, which can interfere with precise detection. However, with profound advances and rapid expansion in analytical methods, urinary phospholipids have attracted increasing attention in current biomedical research as urine is an easily available source for the discovery of noninvasive biomarkers. In this review, we provide an overview of urinary phospholipids, including their biochemical aspects and clinical applications, aimed at promoting this field of research.
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http://dx.doi.org/10.21037/tau-20-1263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100843PMC
April 2021

Establishment and characterization of a novel treatment-related neuroendocrine prostate cancer cell line KUCaP13.

Cancer Sci 2021 May 7. Epub 2021 May 7.

Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

The prevalence of neuroendocrine prostate cancer (NEPC) arising from adenocarcinoma (AC) upon potent androgen receptor (AR) pathway inhibition is increasing. Deeper understanding of NEPC biology and development of novel therapeutic agents are needed. However, research is hindered by the paucity of research models, especially cell lines developed from NEPC patients. We established a novel NEPC cell line, KUCaP13, from tissue of a patient initially diagnosed with AC which later recurred as NEPC. The cell line has been maintained permanently in vitro under regular cell culture conditions and is amenable to gene engineering with lentivirus. KUCaP13 cells lack the expression of AR and overexpress NEPC-associated genes, including SOX2, EZH2, AURKA, PEG10, POU3F2, ENO2, and FOXA2. Importantly, the cell line maintains the homozygous deletion of CHD1, which was confirmed in the primary AC of the index patient. Loss of heterozygosity of TP53 and PTEN, and an allelic loss of RB1 with a transcriptomic signature compatible with Rb pathway aberration were revealed. Knockdown of PEG10 using shRNA significantly suppressed growth in vivo. Introduction of luciferase allowed serial monitoring of cells implanted orthotopically or in the renal subcapsule. Although H3K27me was reduced by EZH2 inhibition, reversion to AC was not observed. KUCaP13 is the first patient-derived, treatment-related NEPC cell line with triple loss of tumor suppressors critical for NEPC development through lineage plasticity. It could be valuable in research to deepen the understanding of NEPC.
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http://dx.doi.org/10.1111/cas.14935DOI Listing
May 2021

Usefulness of the Monti-Malone procedure as a reconstruction of the antegrade continence enema procedure: a case report.

Surg Case Rep 2021 May 6;7(1):112. Epub 2021 May 6.

Department of Pediatric Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, Niigata, Japan.

Background: The antegrade continence enema (ACE) procedure is effective for severe constipation in patients with spina bifida and can improve quality of life (QOL). The Monti-Malone procedure (MM), which is a method of creating an enema tract from the colon, has been reported as an alternative to the ACE procedure when the appendix cannot be used. We report the usefulness of MM as a reconstruction of the antegrade continence enema procedure.

Case Presentation: Our patient was a 22-year-old man with congenital spina bifida and hydrocephalus. Ventriculoperitoneal (VP) shunt surgery was performed immediately after birth, and preventative appendectomy was carried out during VP shunt repair when 4 months old. At 5 years of age, the ACE procedure using a balloon-button gastrostomy tube was performed for intractable chronic constipation. Simple management was expected, but after 17 years of age, he experienced increased stool leakage around the gastrostomy tube and his QOL declined due to difficulty in managing the ACE. Therefore, reconstruction of the ACE procedure by MM was performed. After reconstruction, the ACE performed well without any complications. The patient is currently satisfied because management of the ACE is easier than before, and his QOL has markedly improved without stool leakage and dermatitis.

Conclusions: MM is less likely to cause complications and is useful as a reconstruction of the ACE procedure.
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http://dx.doi.org/10.1186/s40792-021-01197-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102661PMC
May 2021

Pembrolizumab for treating advanced urothelial carcinoma in patients with impaired performance status: Analysis of a Japanese nationwide cohort.

Cancer Med 2021 May 1;10(10):3188-3196. Epub 2021 May 1.

Department of Urology, University of Tsukuba, Ibaraki, Japan.

Background: The benefits of pembrolizumab in patients with advanced urothelial carcinoma (UC) and impaired performance status (PS) remain unknown. This study assessed the safety and efficacy of pembrolizumab in patients with platinum-refractory UC and Eastern Cooperative Oncology Group PS ≥2 to identify which subgroups may benefit from this drug.

Methods: This retrospective nationwide cohort study collected clinicopathological information for 755 patients from 59 institutions. The overall response rate (ORR) and overall survival (OS) were compared among the patients with PS 0-1, 2, and 3-4. Multivariate analysis was conducted to identify factors predicting OS in patients with PS ≥2.

Results: The numbers of patients with PS 0-1, 2, and 3-4 were 602, 98, and 55, respectively; the ORRs in these groups were 29.5, 15.3, and 9.1%, respectively, and the median OS times were 14.3, 3.1, and 2.4 months, respectively. In multivariate Cox regression analysis, a neutrophil-lymphocyte ratio (NLR) ≥3.5 (hazard ratio [HR] = 1.897) and liver metastasis (HR = 2.072) were associated with OS in the PS ≥2 subgroup. The median OS of patients with PS ≥2 without either risk factor was 6.8 months, compared with 3.1 months for patients with one risk factor and 2.3 months for patients with both risk factors.

Conclusions: PS ≥2 portended worse ORR and OS than PS ≤1 despite a comparable safety profile. Among the patients with impaired PS, patients with NLR <3.5 and no liver metastasis may most greatly benefit from pembrolizumab therapy.
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http://dx.doi.org/10.1002/cam4.3863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8124127PMC
May 2021

The Roles of IL-17, IL-21, and IL-23 in the Infection and Gastrointestinal Inflammation: A Review.

Toxins (Basel) 2021 04 28;13(5). Epub 2021 Apr 28.

Institute of Tropical Disease, Universitas Airlangga, Surabaya 60115, Indonesia.

Although millions of people have been infected by (), only a small proportion of infected individuals will develop adverse outcomes, ranging from chronic gastritis to gastric cancer. Advanced development of the disease has been well-linked with chronic inflammation, which is significantly impacted by the adaptive and humoral immunity response. From the perspective of cellular immunity, this review aims to clarify the intricate axis between IL-17, IL-21, and IL-23 in -related diseases and the pathogenesis of inflammatory gastrointestinal diseases. CD4 helper T (Th)-17 cells, with the hallmark pleiotropic cytokine IL-17, can affect antimicrobial activity and the pathogenic immune response in the gut environment. These circumstances cannot be separated, as the existence of affiliated cytokines, including IL-21 and IL-23, help maintain Th17 and accommodate humoral immune cells. Comprehensive understanding of the dynamic interaction between molecular host responses in -related diseases and the inflammation process may facilitate further development of immune-based therapy.
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http://dx.doi.org/10.3390/toxins13050315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8147029PMC
April 2021

Vitamin B6 efficacy in the treatment of nonalcoholic fatty liver disease: an open-label, single-arm, single-center trial.

J Clin Biochem Nutr 2021 Mar 16;68(2):181-186. Epub 2021 Jan 16.

Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan.

Vitamin B6 is an important cofactor in fat metabolism and its deficiency has been correlated with nonalcoholic fatty liver disease. However, no study has investigated the efficacy of vitamin B6 supplementation in these patients. The aim of this open-label, single-arm, single-center study was to examine the therapeutic effect of vitamin B6 in patients with nonalcoholic fatty liver disease. Twenty-two patients with nonalcoholic fatty liver disease received vitamin B6 (90 mg/day) orally for 12 weeks. Clinical parameters were evaluated, and liver fat and fibrosis were quantified before and after treatment using magnetic resonance imaging-based proton density fat fraction and magnetic resonance elastography. Serum alanine aminotransferase levels, the primary endpoint, did not change significantly after vitamin B6 treatment (93.6 ± 46.9 to 93.9 ± 46.6,  = 0.976). On the other hand, magnetic resonance imaging-based proton density fat fraction, a parameter of hepatic lipid accumulation, was significantly reduced (18.7 ± 6.1 to 16.4 ± 6.4, <0.001) despite no significant changes in body mass index, even in those not taking vitamin E ( = 17, 18.8 ± 6.9 to 16.7 ± 7.3,  = 0.0012). Vitamin B6 administration significantly ameliorated hepatic fat accumulation. As an inexpensive agent with few side effects, vitamin B6 could be a novel therapeutic agent for the treatment of nonalcoholic fatty liver disease.
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http://dx.doi.org/10.3164/jcbn.20-142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046002PMC
March 2021

Anatomic location of residual disease after initial cholecystectomy independently determines outcomes after re-resection for incidental gallbladder cancer.

Langenbecks Arch Surg 2021 Apr 10. Epub 2021 Apr 10.

Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata City, Niigata, 951-8510, Japan.

Purpose: This study aimed to elucidate the impact of anatomic location of residual disease (RD) after initial cholecystectomy on survival following re-resection of incidental gallbladder cancer (IGBC).

Methods: Patients with pT2 or pT3 gallbladder cancer (36 with IGBC and 171 with non-IGBC) who underwent resection were analyzed. Patients with IGBC were classified as follows according to the anatomic location of RD after initial cholecystectomy: no RD (group 1); RD in the gallbladder bed, stump of the cystic duct, and/or regional lymph nodes (group 2); and RD in the extrahepatic bile duct and/or distant sites (group 3).

Results: Timing of resection (IGBC vs. non-IGBC) did not affect survival in either multivariate or propensity score matching analysis. RD was found in 16 (44.4%) of the 36 patients with IGBC; R0 resection following re-resection was achieved in 32 patients (88.9%). Overall survival (OS) following re-resection was worse in group 3 (n = 7; 5-year OS, 14.3%) than in group 2 (n = 9; 5-year OS, 55.6%) (p = 0.035) or in group 1 (n = 20; 5-year OS, 88.7%) (p < 0.001). There was no survival difference between groups 1 and 2 (p = 0.256). Anatomic location of RD was independently associated with OS (group 2, HR 2.425, p = 0.223; group 3, HR 9.627, p = 0.024).

Conclusion: The anatomic location of RD independently predicts survival following re-resection, which is effective for locoregional disease control in IGBC, similar to resection for non-IGBC. Not all patients with RD have poor survival following re-resection for IGBC.
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http://dx.doi.org/10.1007/s00423-021-02165-1DOI Listing
April 2021

Antigen analysis of patients with gastrointestinal symptoms resulting from immediate allergic reactions to mushrooms.

Allergol Int 2021 Apr 5. Epub 2021 Apr 5.

Department of Integrative Medical Science for Allergic Disease, Fujita Health University School of Medicine, Aichi, Japan; Department of Allergology, Fujita Health University School of Medicine, Aichi, Japan. Electronic address:

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http://dx.doi.org/10.1016/j.alit.2021.02.005DOI Listing
April 2021

Long-term clinical outcomes of external beam radiation therapy for oligometastatic prostate cancer: A combination of prostate-targeted treatment and metastasis-directed therapy.

Int J Urol 2021 Apr 2. Epub 2021 Apr 2.

Department of Radiation Oncology and Image-applied Therapy, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Objective: To assess the efficacy of combination of prostate-targeted treatment and metastasis-directed therapy for oligometastatic prostate cancer.

Methods: We retrospectively evaluated the clinical outcomes of synchronously diagnosed oligometastatic prostate cancer patients treated with external beam radiation therapy for the prostate and all metastatic lesions (≤3 lesions) at Kyoto University Hospital between January 2004 and April 2019. The prescribed dose was basically ≥70 Gy for the prostate with or without whole pelvic irradiation, and ≥45 Gy for the metastatic lesions. Clinical outcomes were compared with a contemporary cohort of 55 synchronous oligometastatic prostate cancer patients treated with the standard of care.

Results: In total, 16 consecutive patients with synchronous oligometastatic prostate cancer were analyzed. The median follow-up period was 7.4 years. The 8-year overall survival, prostate cancer-specific survival, biochemical failure-free, clinical failure-free and castration-resistant prostate cancer-free rates were 64.8%, 71.3%, 38.5%, 47.3% and 67.3%, respectively. No grade 3 or higher radiation-induced late toxicities occurred. Patients with prostate-targeted treatment plus metastasis-directed therapy had a significantly higher castration-resistant prostate cancer-free rate than those without prostate-targeted treatment plus metastasis-directed therapy (P = 0.00741).

Conclusions: Prostate-targeted treatment plus metastasis-directed therapy through external beam radiation therapy can result in favorable long-term disease-free and survival outcomes with acceptable morbidities among synchronous oligometastatic prostate cancer patients. Therefore, this approach may represent a promising treatment strategy for this population. Further investigation is required.
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http://dx.doi.org/10.1111/iju.14567DOI Listing
April 2021

Downregulation of ZNF395 Drives Progression of Pancreatic Ductal Adenocarcinoma through Enhancement of Growth Potential.

Pathobiology 2021 Apr 1:1-9. Epub 2021 Apr 1.

Department of Molecular Pathology, Faculty of Medicine, Oita University, Yufu, Japan.

Background: Progression of pancreatic intraepithelial neoplasia (PanIN) to invasive carcinoma is a critical factor impacting the prognosis of patients with pancreatic tumors. However, the molecular mechanisms involved are not fully understood. We have reported that the process frequently involves loss of chromosome 8p, causing downregulation of DUSP4, thus conferring invasive ability on cancer cells. Here, we focus on ZNF395, whose expression was also found to be decreased by 8p loss and was predicted to be a growth suppressor gene.

Methods: Pancreatic cancer cell lines inducibly expressing ZNF395 were established to assess the functional significance of ZNF395 in pancreatic carcinogenesis. Immunohistochemistry was also performed to analyze the expression levels of ZNF395 in pancreatic cancer tissues.

Results: Induction of ZNF395 in pancreatic cancer cells resulted in marked activation of JNK and suppression of their proliferation through a delay in cell cycle progression. Immunohistochemistry revealed that ZNF395 was expressed ubiquitously in both normal pancreatic ducts and PanINs but was significantly reduced in invasive cancers, especially those showing poor differentiation.

Conclusion: ZNF395 acts as a novel tumor suppressor gene. Its downregulation caused by 8p loss in intraepithelial cells accelerates their proliferation through dysregulation of the cell cycle, leading to progression to invasive cancer.
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http://dx.doi.org/10.1159/000514593DOI Listing
April 2021

NQO1 as a Marker of Chemosensitivity and Prognosis for Colorectal Liver Metastasis.

Anticancer Res 2021 Mar;41(3):1563-1570

Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.

Background/aim: This study aimed to evaluate how NAD(P)H: quinone oxidoreductase-1 (NQO1) affects survival after hepatectomy in patients with colorectal liver metastasis (CRLM).

Patients And Methods: A retrospective analysis was conducted of 88 consecutive patients who underwent hepatectomy for CRLM. Of the 88 patients, preoperative chemotherapy was administered to 30 patients. Immunohistochemistry of the resected specimens was conducted using monoclonal anti-NQO1 antibody.

Results: NQO1-positive expression in tumor cells of CRLM was associated with worse overall survival (p=0.026) and was an independent adverse prognostic factor in multivariate analysis (hazard ratio=5.296, p=0.007). Among 30 patients who received preoperative chemotherapy, patients with loss of NQO1 expression in non-neoplastic epithelial cells of the bile ducts (NQO1 polymorphism: n=19) showed significantly better response to preoperative chemotherapy for CRLM (p=0.004).

Conclusion: NQO1-positive expression in tumor cells of CRLM may be an adverse prognostic factor after hepatectomy for CRLM.
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http://dx.doi.org/10.21873/anticanres.14916DOI Listing
March 2021

Postoperative laxity of the lateral soft tissue is largely negligible in total knee arthroplasty for varus osteoarthritis.

J Orthop Surg (Hong Kong) 2021 Jan-Apr;29(1):23094990211002002

Department of Orthopaedic Surgery, 13094Teikyo University School of Medicine, Tokyo, Japan.

Purpose: To evaluate the integrity of lateral soft tissue in varus osteoarthritis knee by comparing the mechanical axis under varus stress during navigation-assisted total knee arthroplasty before and after compensating for a bone defect with the implant.

Methods: Sixty-six knees that underwent total knee arthroplasty were investigated. The mechanical axis of the operated knee was evaluated under manual varus stress immediately after knee exposure and after navigation-assisted implantation. The correlation between each value of the mechanical axis and degree of preoperative varus deformity was compared by regression analysis.

Results: The maximum mechanical axis under varus stress immediately after knee exposure increased in proportion to the degree of preoperative varus deformity. Moreover, the maximum mechanical axis under varus stress after implantation increased in proportion to the degree of preoperative varus deformity. Therefore, the severity of varus knee deformity leads to a progressive laxity of the lateral soft tissue. However, regression coefficients after implantation were much smaller than those measured immediately after knee exposure (0.99 vs 0.20). Based on the results of the regression formula, the postoperative laxity of the lateral soft tissue was negligible, provided that an appropriate thickness of the implant was compensated for the bone and cartilage defect in the medial compartment without changing the joint line.

Conclusion: The severity of varus knee deformity leads to a progressive laxity of the lateral soft tissue. However, even if the degree of preoperative varus deformity is severe, most cases may not require additional procedures to address the residual lateral laxity.
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http://dx.doi.org/10.1177/23094990211002002DOI Listing
March 2021

EUS-guided cholecystoduodenostomy using novel dumbbell-shaped fully covered metal stent (with video).

J Hepatobiliary Pancreat Sci 2021 May 9;28(5):e19-e20. Epub 2021 Apr 9.

Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.

Highlight Atalla and colleagues present a novel dumbbell-shaped fully covered self-expandable metal stent which, with its anti-migration property and relatively lower cost, is a feasible and cost-effective option as an alternative to lumen-apposing metal stents for endoscopic ultrasound-guided transduodenal gallbladder drainage for acute cholecystitis in patients who are ineligible for surgery.
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http://dx.doi.org/10.1002/jhbp.942DOI Listing
May 2021

Gut microbiota composition associated with hepatic fibrosis in non-obese patients with non-alcoholic fatty liver disease.

J Gastroenterol Hepatol 2021 Mar 11. Epub 2021 Mar 11.

Department of Gastroenterology and Hepatology, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.

Background And Aim: Gut microbiota composition is associated with the pathogenesis of non-alcoholic fatty liver disease. However, the association between gut microbiota composition and non-alcoholic fatty liver disease in non-obese patients remains unclear. We compared clinical parameters and gut microbiota profiles of healthy controls and non-obese and obese patients with non-alcoholic fatty liver disease.

Methods: We examined the clinical parameters and gut microbiota profiles by 16S rRNA sequences and short-chain fatty acid levels in fecal samples from 51 non-obese patients with non-alcoholic fatty liver disease (body mass index <25 kg/m ) and 51 obese patients with non-alcoholic fatty liver disease (body mass index ≥30 kg/m ) who underwent pathological examination and 87 controls at five hospitals in Japan.

Results: Although no significant differences between the non-obese and other groups were observed in alpha diversity, a significant difference was found in beta diversity. We observed a significant decrease in serum alanine aminotransferase levels, Eubacterium population, and butyric acid levels in non-obese patients with non-alcoholic fatty liver disease compared with those in obese patients with non-alcoholic fatty liver disease. A significant negative correlation was found between the stage of hepatic fibrosis and Eubacterium abundance in non-obese patients with non-alcoholic fatty liver disease.

Conclusions: The decrease in the abundance of Eubacterium that produces butyric acid may play an important role in the development of non-alcoholic fatty liver disease in non-obese individuals. This study was registered at the University Hospital Medical Information Network clinical trial registration system (UMIN000020917).
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http://dx.doi.org/10.1111/jgh.15487DOI Listing
March 2021

Non-maintenance intravesical Bacillus Calmette-Guérin induction therapy with eight doses in patients with high- or highest-risk non-muscle invasive bladder cancer: a retrospective non-randomized comparative study.

BMC Cancer 2021 Mar 11;21(1):266. Epub 2021 Mar 11.

Department of Urology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.

Background: To explore possible solutions to overcome chronic Bacillus Calmette-Guérin (BCG) shortage affecting seriously the management of non-muscle invasive bladder cancer (NMIBC) in Europe and throughout the world, we investigated whether non-maintenance eight-dose induction BCG (iBCG) was comparable to six-dose iBCG plus maintenance BCG (mBCG).

Methods: This observational study evaluated 2669 patients with high- or highest-risk NMIBC who treated with iBCG with or without mBCG during 2000-2019. The patients were classified into five groups according to treatment pattern: 874 (33%) received non-maintenance six-dose iBCG (Group A), 405 (15%) received six-dose iBCG plus mBCG (Group B), 1189 (44%) received non-maintenance seven-/eight-dose iBCG (Group C), 60 (2.2%) received seven-/eight-dose iBCG plus mBCG, and 141 (5.3%) received only ≤5-dose iBCG. Recurrence-free survival (RFS), progression-free survival, and cancer-specific survival were estimated and compared using Kaplan-Meier analysis and the log-rank test, respectively. Propensity score-based one-to-one matching was performed using a multivariable logistic regression model based on covariates to obtain balanced groups. To eliminate possible immortal bias, 6-, 12-, 18-, and 24-month conditional landmark analyses of RFS were performed.

Results: RFS comparison confirmed that mBCG yielded significant benefit following six-dose iBCG (Group B) in recurrence risk reduction compared to iBCG alone (groups A and C) before (P < 0.001 and P = 0.0016, respectively) and after propensity score matching (P = 0.001 and P = 0.0074, respectively). Propensity score-matched sequential landmark analyses revealed no significant differences between groups B and C at 12, 18, and 24 months, whereas landmark analyses at 6 and 12 months showed a benefit of mBCG following six-dose iBCG compared to non-maintenance six-dose iBCG (P = 0.0055 and P = 0.032, respectively). There were no significant differences in the risks of progression and cancer-specific death in all comparisons of the matched cohorts.

Conclusions: Although non-maintenance eight-dose iBCG was inferior to six-dose iBCG plus mBCG, the former might be an alternative remedy in the BCG shortage era. To overcome this challenge, further investigation is warranted to confirm the real clinical value of non-maintenance eight-dose iBCG.
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http://dx.doi.org/10.1186/s12885-021-07966-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948348PMC
March 2021

Effect of optimal neoadjuvant chemotherapy on oncological outcomes of locally advanced bladder cancer with laparoscopic radical cystectomy: A matched-pair analysis in a multicenter cohort.

Int J Urol 2021 Jun 7;28(6):656-664. Epub 2021 Mar 7.

Department of Urology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Objectives: To assess the effect of optimal neoadjuvant chemotherapy of at least three cycles of cisplatin-based regimen on oncological outcomes of clinical stage T3 or higher bladder cancer treated with laparoscopic radical cystectomy.

Methods: Laparoscopic radical cystectomies carried out at 10 institutions were included in this retrospective study. The outcomes of patients who received optimal neoadjuvant chemotherapy and those who did not receive neoadjuvant chemotherapy were compared using propensity score matching in clinical stage T3-4 or T2 cohorts, separately.

Results: Of the 455 patients screened, matched pairs of 54 patients in the clinical T3-4 cohort and 68 patients in the clinical T2 cohort were finally analyzed. In the cT3-4 cohort, the 5-year overall survival (78% vs 41%; P = 0.014), cancer-specific survival (81% vs 44%; P = 0.008) and recurrence-free survival (71% vs 53%; P = 0.049) were significantly higher in the optimal neoadjuvant chemotherapy group than in the no neoadjuvant chemotherapy group; no significant survival difference was shown between the two groups in the cT2 cohort. In the cT3-4 cohort, the incidence of local recurrence (4% vs 26%; P = 0.025) and abdominal or intrapelvic recurrence, including peritoneal carcinomatosis (7% vs 30%; P = 0.038), was significantly lower in the optimal neoadjuvant chemotherapy group.

Conclusions: Administration of optimal neoadjuvant chemotherapy has a significant survival benefit. It decreases the incidence of local and atypical recurrence patterns in patients with clinical stage T3 or higher locally advanced bladder cancer undergoing laparoscopic radical cystectomy.
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http://dx.doi.org/10.1111/iju.14533DOI Listing
June 2021

Pancreatic metastasis of renal cell carcinoma filling into the duct of Santorini.

Clin J Gastroenterol 2021 Jun 6;14(3):905-909. Epub 2021 Mar 6.

Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.

A 78-year-old man who underwent right nephrectomy for renal cell carcinoma (RCC) 18 years ago visited our hospital complaining of abdominal pain. Imaging revealed that the pancreatic head tumor obstructed the Santorini duct. We suspected a pancreatic intraductal tumor, such as an intraductal tubulopapillary neoplasm or intraductal papillary mucinous neoplasm. Thus, the patient underwent subtotal stomach-preserving pancreaticoduodenectomy. Pathological findings confirmed the diagnosis of metastatic RCC. Herein, we report a case of pancreatic metastasis of an RCC that presented with a tumor in the pancreatic duct.
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http://dx.doi.org/10.1007/s12328-021-01369-8DOI Listing
June 2021

CCR4-positive peripheral T-cell lymphoma presenting as eosinophilic pneumonia and developing from prolonged pustular psoriasis.

J Int Med Res 2021 Feb;49(2):300060521996165

Department of Comprehensive Cancer Therapy, Shinshu University School of Medicine, Matsumoto, Japan.

A 29-year-old woman with chronic, prolonged pustular psoriasis was admitted to our hospital because of high-grade fever and a systemic skin rash. General examination revealed a whole-body skin rash and superficial lymphadenopathy. Peripheral blood examination showed unclassified cells positive for CD3, CD4, and T-cell receptor αβ, and negative for CD20 and CD56. Soon after administration, she developed acute respiratory failure and required artificial ventilation. Bronchoalveolar lavage fluid showed increased numbers of eosinophils and abnormal lymphocytes of the same phenotype in peripheral blood and skin. She was diagnosed with eosinophilic pneumonia, and her respiratory failure was improved by corticosteroid therapy. Based on the histological findings of skin, lymph node, and bone marrow biopsies, a diagnosis of peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), with positivity for CC chemokine receptor 4 was made. She received chemotherapy followed by allogeneic stem cell transplantation, which resulted in complete remission of her PTCL-NOS. She remained alive and disease-free 6 years later. This is the first reported case of PTCL-NOS developing during the clinical course of pustular psoriasis. The clinical manifestations of PTCL-NOS are complex, but an accurate diagnosis and appropriate therapy may produce a good clinical outcome in patients with PTCL-NOS.
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http://dx.doi.org/10.1177/0300060521996165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917889PMC
February 2021

Comparing the effects of tofogliflozin and pioglitazone in non-alcoholic fatty liver disease patients with type 2 diabetes mellitus (ToPiND study): a randomized prospective open-label controlled trial.

BMJ Open Diabetes Res Care 2021 Feb;9(1)

Department of Gastroenterology and Hepatology, Yokohama City University, Yokohama, Japan.

Introduction: The treatment of diabetes has a significant impact on the pathogenesis of non-alcoholic fatty liver disease (NAFLD). We compared the effectiveness of tofogliflozin, a selective sodium-glucose cotransporter 2 inhibitor, and pioglitazone for the treatment of NAFLD patients with type 2 diabetes mellitus.

Research Design And Methods: This open-label, prospective, single-center, randomized clinical trial recruited NAFLD patients with type 2 diabetes mellitus and a hepatic fat fraction of at least 10% as assessed based on the MRI-proton density fat fraction (MRI-PDFF). Eligible patients were stratified according to hemoglobin A1c (HbA1c), alanine transaminase, and MRI-PDFF levels and randomly assigned (1:1) to receive either 20 mg tofogliflozin or 15-30 mg pioglitazone, orally, once daily for 24 weeks. The primary endpoint was an absolute change in MRI-PDFF at 24 weeks. Efficacy and safety was assessed in all treated patients. This trial was registered in the Japan Registry of Clinical Trials.

Results: Overall, 40 eligible patients were randomly assigned to receive tofogliflozin (n=21) or pioglitazone (n=19). Changes in hepatic steatosis after 24 weeks of treatment were evaluated by MRI-PDFF, which showed a significant decrease in both groups (-7.54% (p<0.0001) and -4.12% (p=0.0042) in the pioglitazone and tofogliflozin groups, respectively). Compared with baseline, the body weight decreased by 2.83±2.86 kg (-3.6%, p=0.0443) in the tofogliflozin group and increased by 1.39±2.62 kg (1.7%, p=0.0002) in the pioglitazone group after 24 weeks. No life-threatening events or treatment-related deaths occurred.

Conclusions: Tofogliflozin was well tolerated, and it reduced the MRI-PDFF levels in NAFLD patients with type 2 diabetes mellitus.

Trial Registration Number: jRCTs031180159.
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http://dx.doi.org/10.1136/bmjdrc-2020-001990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7888333PMC
February 2021

Dysregulation of sphingolipid metabolic enzymes leads to high levels of sphingosine-1-phosphate and ceramide in human hepatocellular carcinoma.

Hepatol Res 2021 May 9;51(5):614-626. Epub 2021 Mar 9.

Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Niigata, Japan.

Aim: Sphingosine-1-phosphate (S1P) and ceramide are bioactive sphingolipids known to be important in regulating numerous processes involved in cancer progression. The aim of this study was to determine the absolute levels of sphingolipids in hepatocellular carcinoma (HCC) utilizing data obtained from surgical specimens. In addition, we explored the clinical significance of S1P in patients with HCC and the biological role of S1P in HCC cells.

Methods: Tumors and normal liver tissues were collected from 20 patients with HCC, and sphingolipids were measured by mass spectrometry. The Cancer Genome Atlas (TCGA) cohort was utilized to evaluate gene expression of enzymes related to sphingolipid metabolism. Immunohistochemistry of phospho-sphingosine kinase 1 (SphK1), an S1P-producing enzyme, was performed for 61 surgical specimens. CRISPR/Cas9-mediated SphK1 knockout cells were used to examine HCC cell biology.

Results: S1P levels were substantially higher in HCC tissue compared with normal liver tissue. Levels of other sphingolipids upstream of S1P in the metabolic cascade, such as sphingomyelin, monohexosylceramide and ceramide, were also considerably higher in HCC tissue. Enzymes involved in generating S1P and its precursor, ceramide, were found in higher levels in HCC compared with normal liver tissue. Immunohistochemical analysis found that phospho-SphK1 expression was associated with tumor size. Finally, in vitro assays indicated that S1P is involved in the aggressiveness of HCC cells.

Conclusions: Sphingolipid levels, including S1P and ceramide, were elevated in HCC compared with surrounding normal liver tissue. Our findings suggest S1P plays an important role in HCC tumor progression, and further examination is warranted.
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http://dx.doi.org/10.1111/hepr.13625DOI Listing
May 2021

Solubility and mass transfer coefficient of oxygen through gas- and water-lipid interfaces.

J Food Sci 2021 Mar 13;86(3):867-873. Epub 2021 Feb 13.

Faculty of Bio-environmental Science, Kyoto University of Advanced Science, Kameoka, Kyoto, 621-8555, Japan.

The solubility of oxygen and its transfer rate to the lipid phase play important roles in lipid oxidation, which affects the taste and safety of lipid-containing foods. In this study, we measured the Henry's constants (solubility) of oxygen for fatty acids, fatty acid esters, and triacylglycerols (TAGs; vegetable oils), as well as the mass transfer coefficients of oxygen at the gas- and water-lipid interfaces. The constants and coefficients were estimated by analyzing the change over time in the oxygen partial pressure or concentration in the closed container based on the mass balance equations of oxygen in the gas and liquid phases. The constant for water obtained by the method used in this study was in agreement with the previously reported value to confirm the validity of the method. The constants for lipids depended on the lipid type, and were higher in the order of fatty acid ester, fatty acid, and TAG. That is, the solubility of oxygen decreased in this order. For all lipids, the constant increased as the number of carbon atoms in the fatty acid chain increased. The constants for fatty acids and their esters were linearly correlated with the enthalpies of evaporation of the lipids. The mass transfer coefficients of oxygen at the gas-liquid interface were on the order of 10 m/s for water and methyl dodecanoate and of 10 m/s for TAG (rapeseed oil). The coefficient at the water-lipid interface was on the order of 10 m/s. PRACTICAL APPLICATION: The Henry's constants (solubility) and transfer rate of oxygen to the lipid phase, fatty acids, fatty acid esters, and triacylglycerols (TAG) were measured. The lipids solubilized three to five times more oxygen than water, and mass transfer rate of oxygen at gas- and water-lipid interfaces were almost same. The constants for fatty acids and fatty acid esters were linearly correlated to their enthalpies of evaporation, and this correlation is expected to be useful for estimating the Henry's constants for other fatty acids and their esters.
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http://dx.doi.org/10.1111/1750-3841.15641DOI Listing
March 2021

Clinicopathological Characteristics and Surgical Outcomes of Primary Cystic Duct Carcinoma: A Multi-institutional Study.

World J Surg 2021 May 11;45(5):1613-1615. Epub 2021 Feb 11.

Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan.

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http://dx.doi.org/10.1007/s00268-021-05991-yDOI Listing
May 2021

Oncological outcomes of surgery for recurrent biliary tract cancer: who are the best candidates?

HPB (Oxford) 2021 Jan 22. Epub 2021 Jan 22.

Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. Electronic address:

Background: This study aimed to investigate the impact of surgery on outcomes in patients with recurrent biliary tract cancer (BTC) and elucidate factors affecting survival after surgery for this disease.

Methods: A single-center study was undertaken in 178 patients with recurrent BTC, of whom 24 underwent surgery for recurrence, 85 received chemotherapy, and 69 received best supportive care. Then, we carried out a multicenter study in 52 patients undergoing surgery for recurrent BTC (gallbladder cancer, 39%; distal cholangiocarcinoma, 27%; perihilar cholangiocarcinoma, 21%; intrahepatic cholangiocarcinoma, 13%).

Results: In the single-center study, 3-year survival after recurrence was 53% in patients who underwent surgery, 4% in those who received chemotherapy, and 0% in those who received best supportive care (p < 0.001). Surgery was an independently prognostic factor (p < 0.001). In the multicenter series, the respective 3-year and 5-year survival after surgery for recurrence was 50% and 29% in the 52 patients. Initial site of recurrence was the only independent prognostic factor (p = 0.019). Five-year survival after surgery for recurrence in patients with single distant, multifocal distant, and locoregional recurrence was 51%, 0%, and 0%, respectively (p = 0.002). Sites of single distant recurrence included the liver (n = 13, 54%), distant lymph nodes (all from gallbladder cancer, n = 7, 29%), lung (n = 2, 9%), peritoneum (n = 1, 4%), and abdominal wall (n = 1, 4%).

Conclusion: Surgery may be an effective option for patients with less aggressive tumor biology characterized by single distant recurrence in recurrent BTC.
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http://dx.doi.org/10.1016/j.hpb.2021.01.007DOI Listing
January 2021