Publications by authors named "Yusuke Sato"

462 Publications

Clinical significance and risk factors of International Society of Urological Pathology (ISUP) grade upgrading in prostate cancer patients undergoing robot-assisted radical prostatectomy.

BMC Cancer 2021 May 4;21(1):501. Epub 2021 May 4.

Department of Urology, Graduate School of Medicine, The University of Tokyo, Hongo7-3-1, Bunkyo-Ku, Tokyo, Japan.

Background: The objective of this study is to investigate the clinical significance and risk factors of upgrading in the International Society of Urological Pathology (ISUP) Grade Group System in men undergoing robot-assisted radical prostatectomy (RARP) for prostate cancer.

Methods: A total of 583 patients diagnosed with prostate cancer by systematic biopsy were treated with RARP without neoadjuvant therapy from November 2011 to December 2018. Clinicopathological data were obtained from our clinical records. ISUP grade upgrading (IGU) was defined as 'ISUP grade in prostatectomy specimen determined to be higher than that in the biopsy specimen'. Clinicopathological factors, including age, PSA, prostate volume at biopsy (PV), PSA density, clinical stage, body mass index (BMI), interval from biopsy to prostatectomy, maximum percentage of cancer involvement per core (%CI), total number of biopsy cores, percentage of cancer positive biopsy cores (%PC), and sampling density were analyzed to detect potential risk factors of IGU. Biochemical recurrence (BCR) rates were calculated to analyze the effect of IGU on cancer prognosis.

Results: In univariate analysis, BMI was a positive predictor of IGU, while %CI, %PC, and sampling density were negative predictors of IGU. BMI and %PC were statistically significant predictors of IGU in multivariate analysis. For cases diagnosed as ISUP grade group 2 or higher at biopsy, there was a significant difference in BCR rates between cases with and without IGU.

Conclusions: The results from our cohort showed that elements of both high-grade cancer risk (such as BMI) and sampling efficiency (such as %PC) contribute to IGU. Excluding cases diagnosed as ISUP grade group 1 at biopsy, BCR-free rates were significantly worse in cases with IGU, highlighting the need for more accurate pathological diagnosis at biopsy.
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http://dx.doi.org/10.1186/s12885-021-08248-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097801PMC
May 2021

Clinical significance and risk factors of urethrovesical anastomotic urinary leakage following robot-assisted radical prostatectomy: a multi-institutional study.

BMC Urol 2021 May 3;21(1):75. Epub 2021 May 3.

Department of Urology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-8655, Japan.

Background: There has been a limited number of reports on the significance and risk factors of urethrovesical anastomotic urinary leakage (AUL) following robot-assisted radical prostatectomy (RARP). We aimed to analyze the clinical significance of AUL and evaluated its risk factors.

Methods: We conducted a multi-institutional study to review patients with prostate cancer undergoing RARP in three centers (The University of Tokyo Hospital, Mitsui Memorial Hospital, and Chiba Tokushukai Hospital). "Positive AUL" was defined as urinary extravasation at the anastomosis detected by post-operative cystogram and was further categorized into minor or major AUL. Univariate and multivariate analyses were performed to identify predictors of AUL. Postoperative continence rates and time to achieve continence were also analyzed.

Results: A total of 942 patients underwent RARP for prostate cancer in 3 centers. Of these patients, a cystogram after the RARP procedure was not performed in 26 patients leaving 916 patients for the final analysis. AUL was observed in 56 patients (6.1%); 34 patients (3.7%) with minor AUL and 22 patients (2.4%) with major AUL. Patients with major AUL exhibited a significantly longer time to achieve continence than those without major AUL. Multivariate analysis demonstrated that longer console time (≥ 184 min) was significantly associated with overall AUL, and higher body mass index (≥ 25 g/kg) was a significant predictor of both major and overall AUL.

Conclusions: The presence of major AUL was associated with the achievement of urinary continence, suggesting clinical relevance of its diagnosis by postoperative cystogram. A selective cystogram has been proposed for high-risk cases. Furthermore, identification of the risk factors of AUL will lead to optimal application.
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http://dx.doi.org/10.1186/s12894-021-00844-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8091677PMC
May 2021

Axitinib Induces and Aggravates Hypertension Regardless of Prior Treatment With Tyrosine Kinase Inhibitors.

Circ Rep 2021 Mar 10;3(4):234-240. Epub 2021 Mar 10.

Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo Tokyo Japan.

Axitinib is a tyrosine kinase inhibitor (TKI) that inhibits vascular endothelial growth factor receptor signaling and is approved for second-line treatment of advanced renal cell carcinoma (RCC). Although the occurrence of hypertension with axitinib use has been documented, it is unclear whether a first-line TKI regimen can significantly affect the development of hypertension when axitinib is used as second-line therapy. In this single-center retrospective study, advanced RCC patients treated with axitinib after first-line chemotherapy were divided into 2 groups according to the use of TKIs as part of first-line treatment before the initiation of axitinib. Clinical outcomes were compared between patients who were treated with (TKI(+); n=11) or without (TKI(-); n=11) a TKI. Although 63.6% of all patients had hypertension at baseline, axitinib-induced hypertension developed in 81.8% of patients, and 36.4% of patients experienced Grade 3 hypertension. After initiation of axitinib, both systolic and diastolic blood pressures and the hypertension grade were significantly elevated both in the TKI(+) and TKI(-) groups, and the number of antihypertensive drugs was significantly increased among all patients. This study suggests the need for proper monitoring and management of blood pressure in RCC patients treated with axitinib, regardless of a prior regimen with or without TKIs.
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http://dx.doi.org/10.1253/circrep.CR-21-0008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024013PMC
March 2021

The carcinoembryonic antigen ratio is a potential predictor of survival in recurrent colorectal cancer.

Int J Clin Oncol 2021 Apr 11. Epub 2021 Apr 11.

Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.

Background: The carcinoembryonic antigen (CEA) "value" itself is often useless in patients with a normal CEA level at initial presentation and those with tumor-irrelevant elevated CEA. Although the unified marker using CEA has been desirable for recurrent tumor staging as well as for primary tumor staging, little is known concerning its relationship with the survival of patients with recurrent colorectal cancer in particular.

Methods: This retrospective historical study included patients who experienced disease relapse after curative surgery for stage I-III colorectal cancer between 2006 and 2018. A total of 129 patients with recurrent disease after curative surgery for colorectal cancer were included. We focused on the CEA "ratio" (CEA-R: the ratio of the CEA level at the time of recurrence to that measured 3 months before recurrence) and aimed to evaluate the correlation between CEA-R and survival in recurrent colorectal cancer.

Results: Patients with a high CEA-R (≥ 2) exhibited significantly worse 2 year survival than those with a low CEA-R (< 2) (88.1% vs. 44.9%, P < 0.001), irrespective of the CEA value before primary resection. Multivariate analyses demonstrated that the CEA-R (HR; 3.270, 95% CI 1.646-6.497, P = 0.001) was a significant prognostic factor.

Conclusion: The CEA-R is a potential marker stratifying the survival of patients with disease relapse who exhibit aggressive biology at recurrent disease foci. As a novel marker, the CEA-R would serve as a clinical guide for tailoring treatment strategies at the time of disease relapse in patients with colorectal cancer.
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http://dx.doi.org/10.1007/s10147-021-01919-7DOI Listing
April 2021

SUV reduction predicts long-term survival in patients of non-pCR both in the tumor and lymph nodes after neoadjuvant chemoradiotherapy in esophageal squamous cell carcinoma.

World J Surg Oncol 2021 Apr 9;19(1):105. Epub 2021 Apr 9.

Department of Thoracic Surgery, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan.

Background: A pathological complete response (pCR) after neoadjuvant chemoradiotherapy (NACRT) ensures long-term survival in esophageal squamous cell carcinoma (ESCC) patients following esophagectomy, but pCR patients are a minority. The aim here was to identify prognostic factors in patients with non-pCR ESCC after NACRT.

Methods: This is a retrospective study. Investigated were 5-year overall survival (OS), disease-specific survival (DSS), and relapse-free survival (RFS) among non-pCR ESCC patients divided into pT0N0, primary site pCR (pT0N+), lymph node pCR (pT+N0), and non-pCR in both the tumor and lymph node (pT+N+) subgroups after NACRT and esophagectomy. Focusing on the SUV reduction rate in the primary tumor in 88 patients who underwent FDG-PET before and after NACRT, we used univariate and multivariate Cox proportional hazard models to identify prognostic factors.

Results: Although there were no significant survival differences among non-pCR ESCC patients with pT0N+, pT+N0, or pT+N+, survival rate among pT+N+patients was the poorest. After setting a 60% cutoff for the SUV reduction rate in the tumor, RFS curves for non-pCR patients significantly differed between patients above the cutoff and those below it. For pT+N+ patients, the SUV reduction rate (<60% vs ≥ 60%) was an independent prognostic factor of OS, DSS, and RFS.

Conclusion: Because ESCC patients with SUV reduction rates of <60% in the tumor after NACRT and categorized as pT+N+ after NACRT had significantly poorer prognoses, even after esophagectomy, a change in treatment strategy may be an option to improve survival.
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http://dx.doi.org/10.1186/s12957-021-02208-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035772PMC
April 2021

Novel PEGylated Lipid Nanoparticles Have a High Encapsulation Efficiency and Effectively Deliver MRTF-B siRNA in Conjunctival Fibroblasts.

Pharmaceutics 2021 Mar 13;13(3). Epub 2021 Mar 13.

Faculty of Life Sciences & Medicine, King's College London, London SE1 7EH, UK.

The master regulator of the fibrosis cascade is the myocardin-related transcription factor/serum response factor (MRTF/SRF) pathway, making it a key target for anti-fibrotic therapeutics. In the past, inhibitors and small interfering RNAs (siRNAs) targeting the gene have been deployed to counter fibrosis in the eye, with the latter showing promising results. However, the biggest challenge in implementing siRNA therapeutics is the method of delivery. In this study, we utilised the novel, pH-sensitive, cationic lipid CL4H6, which has previously demonstrated potent targeting of hepatocytes and endosomal escape, to safely and efficiently deliver an MRTF-B siRNA into human conjunctival fibroblasts. We prepared two lipid nanoparticle (LNP) formulations, incorporating targeting cleavable peptide cY in one of them, and measured their physicochemical properties and silencing effect in human conjunctival fibroblasts. Both proved to be non-cytotoxic at a concentration of 50 nM and effectively silenced the gene in vitro, with the targeting cleavable peptide not affecting the silencing efficiency [LNP with cY: 62.1% and 81.5% versus LNP without cY: 77.7% and 80.2%, at siRNA concentrations of 50 nM ( = 0.06) and 100 nM ( = 0.09), respectively]. On the other hand, the addition of the targeting cleavable peptide significantly increased the encapsulation efficiency of the LNPs from 92.5% to 99.3% ( = 0.0005). In a 3D fibroblast-populated collagen matrix model, both LNP formulations significantly decreased fibroblast contraction after a single transfection. We conclude that the novel PEGylated CL4H6-MRTF-B siRNA-loaded LNPs represent a promising therapeutic approach to prevent conjunctival fibrosis after glaucoma filtration surgery.
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http://dx.doi.org/10.3390/pharmaceutics13030382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998417PMC
March 2021

A male with primary accessory breast carcinoma in an axilla is strongly suspected of having hereditary breast cancer.

Int Cancer Conf J 2021 Apr 10;10(2):107-111. Epub 2021 Jan 10.

Department of Thoracic Surgery, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543 Japan.

We herein report on a male with primary accessory breast cancer in an axilla. A 75-year-old man first noticed a subcutaneous nodule about 2 cm in diameter in the area of his right axilla. The patient underwent extirpation of the mass in a public hospital. Histological examination revealed invasive breast carcinoma of no special type associated with mucinous carcinoma, invasive micropapillary carcinoma and intraductal components. Immunohistochemical analysis showed that the tumor cells were positive for Gross cystic disease fluid protein (GCDFP)-15, mammaglobin and GATA3. Staining for estrogen receptor (ER) and progesterone receptor (PR) was positive, and human epidermal growth factor receptor 2 (HER2) was negative. The Ki67 labeling index (LI) was 33.6%. Imaging revealed no evidence of a primary tumor in any other organ or in the bilateral mammary gland. We performed radical resection of the right axilla, including the scar, and axillary lymph node dissection. The final pathological examination of the surgical specimen showed normal mammary gland tissue that was not connected to the proper mammary gland, and no residual cancer or metastatic lymph nodes. Based on our clinical and pathological findings, this tumor was diagnosed as breast cancer originating from the accessory mammary gland in the right axilla. After surgery, tamoxifen was administered as adjuvant therapy. Since the surgery, 2 years ago, there has been no evidence of recurrence. Hereditary Breast and Ovarian Cancer syndrome was suspected in this case because the patient was a male with breast cancer, and he had two first-degree relatives with breast cancer. This patient had no BRCA mutations on genetic testing. Nonetheless, in cases of male breast cancer, it is necessary to obtain genetic information due to the possibility of hereditary breast cancer, including cancers associated with BRCA gene mutation.
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http://dx.doi.org/10.1007/s13691-020-00466-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947143PMC
April 2021

Novel operative technique of advancement urethral meatoplasty utilizing buccal mucosa for Vulvar Paget's disease with urethral invasion: two case reports.

J Med Case Rep 2021 Mar 28;15(1):136. Epub 2021 Mar 28.

Department of Urology, The Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Background: Vulvar Paget's disease (VPD) is a rare malignant disorder originating in the external genitalia. It occasionally invades into urethral or vaginal mucosa of female, making surgical treatment more complicating. In case of urethral invasion of Paget's cells, systematic mapping biopsy of urethral mucosa is the standard of care to determine the range of surgical resection. Resection of urethral mucosa and simple skin grafting often result in urethral stricture after surgery, which severely deteriorates patient's quality of life.

Case Presentation: We applied a new technique of advancement urethral meatoplasty using buccal mucosa, in two Japanese cases of VPD with urethral invasion. After broad resection of vulvar skin together with the urethral mucosa, buccal mucosa was implanted between advanced urethral mucosa and skin graft. In both cases, we could prevent urethral stricture one year and two years after surgery, respectively.

Conclusion: This technique prevented urethral stricture after surgery and could be a useful technique as part of urethroplasty for VPD.
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http://dx.doi.org/10.1186/s13256-021-02729-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005229PMC
March 2021

Lower local recurrence rate after robot-assisted thoracoscopic esophagectomy than conventional thoracoscopic surgery for esophageal cancer.

Sci Rep 2021 Mar 24;11(1):6774. Epub 2021 Mar 24.

Thoracic Surgery, Akita University Graduate School of Medicine, Akita, Japan.

The oncological advantages of robot-assisted thoracoscopic esophagectomy (RATE) over conventional thoracoscopic esophagectomy (TE) for thoracic esophageal cancer have yet to be verified. In this study, we retrospectively analyzed clinical data to compare the incidences of recurrence within the surgical field after RATE and TE as an indicator of local oncological control. Among 121 consecutive patients with thoracic esophageal or esophagogastric junction cancers for which thoracoscopic surgery was indicated, 51 were treated with RATE while 70 received TE. The number of lymph nodes dissected from the mediastinum, duration of the thoracic portion of the surgery, and morbidity due to postoperative complications did not differ between the two groups. However, the rate of overall local recurrence within the surgical field was significantly (P = 0.039) higher in the TE (9%) than the RATE (0%) group. Lymph node recurrence within the surgical field occurred in left recurrent nerve, left tracheobronchial, left main bronchus and thoracic paraaortic lymph nodes, which were all difficult to approach to dissect. The other two local failures occurred around the anastomotic site. This study indicates that using RATE enabled the incidence of recurrence within the surgical field to be reduced, though there were some limitations.
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http://dx.doi.org/10.1038/s41598-021-86420-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990925PMC
March 2021

Neoadjuvant Chemoradiotherapy Followed by Esophagectomy with Three-Field Lymph Node Dissection for Thoracic Esophageal Squamous Cell Carcinoma Patients with Clinical Stage III and with Supraclavicular Lymph Node Metastasis.

Cancers (Basel) 2021 Feb 26;13(5). Epub 2021 Feb 26.

Esophageal Surgery, Akita University Hospital, Akita 010-8543, Japan.

Background: Neoadjuvant chemoradiotherapy (NACRT) followed by esophagectomy is now the standard treatment for patients with resectable advanced thoracic esophageal squamous cell carcinoma (ESCC) worldwide. However, the efficacy of NACRT followed by esophagectomy with three-field lymph node dissection for clinical Stage III patients and for clinical Stage IVB patients with supraclavicular LN metastasis has not yet been determined.

Methods: Between 2008 and 2018, 94 ESCC patients diagnosed as clinical Stage III and 18 patients diagnosed as clinical Stage IVB with supraclavicular LN metastasis as the only distant metastatic factor were treated with NACRT followed by esophagectomy with extended lymph node dissection at Akita University Hospital. Long-term survival and the patterns of recurrence in these 112 patients were analyzed.

Results: The median follow-up period of censored cases was 60 months. The five-year OS and DSS rates among the clinical Stage III patients were 57.6% and 66.6%, respectively. The five-year OS and DSS rates among the clinical Stage IVB patients were 41.3% and 51.6%, respectively. The most frequent recurrence pattern was distant metastasis (69.2%) in the Stage III patients and LN metastasis (75.0%) in the Stage IVB patients.

Conclusion: NACRT followed by esophagectomy with three-field LN dissection is feasible and offers the potential for long-term survival of clinical Stage III ESCC patients and even clinical Stage IVB patients with supraclavicular LN metastasis as the only distant metastatic factor. At least in patients with upper and middle thoracic ESCC, treating supraclavicular LNs as regional LNs seems to be appropriate.
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http://dx.doi.org/10.3390/cancers13050983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956374PMC
February 2021

Harmonization across programmed death ligand 1 (PD-L1) assays for lung cancer by immunohistochemistry using noncontact alternating current electric field mixing.

Thorac Cancer 2021 04 2;12(8):1187-1194. Epub 2021 Mar 2.

Department of Thoracic Surgery, Akita University Graduate School of Medicine, Akita, Japan.

Background: Immune checkpoint inhibitors (ICIs) are a promising advance in the treatment of patients with lung cancer. However, each ICI has been tested with an independently designed companion diagnostic assay that is based on a unique antibody. Consequently, the different trial-validated programmed death ligand 1 (PD-L1) immunohistochemistry (IHC) assays should not be considered interchangeable. Our aim was to compare the performance of each available PD-L1 antibody for its ability to accurately measure PD-L1 expression and to investigate the possibility of harmonization across antibodies through the use of a new rapid IHC system, which uses noncontact alternating current (AC) mixing to achieve more stable staining.

Methods: First, 58 resected non-small cell lung cancer (NSCLC) specimens were stained using three PD-L1 IHC assays (28-8, SP142, and SP263) to assess the harmonization achieved with AC mixing IHC. Second, specimens from 27 patients receiving ICIs for postoperative recurrent NSCLC were stained using the same IHC method to compare the clinical performance of ICIs to PD-L1 scores. All patients received a tumor proportion score (TPS) with the 22C3 companion diagnostic test.

Results: Better staining was achieved with the new AC mixing IHC method than the conventional IHC in PD-L1-positive cases, and the interchangeability of some combinations of assays was increased in PD-L1-positive. In addition, AC mixing IHC provided more appropriate overall response rates for ICIs in all assays.

Conclusions: Stable PD-L1 IHC driven by AC mixing helped to improve TPS scoring and patient selection for ICIs through interchangeable assays.
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http://dx.doi.org/10.1111/1759-7714.13893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046066PMC
April 2021

Does Esophagectomy Provide a Survival Advantage to Patients Aged 80 Years or Older? Analyzing 5,066 Patients in the National Database of Hospital-Based Cancer Registries in Japan.

Ann Surg 2020 Dec 29. Epub 2020 Dec 29.

*Division of Esophageal Surgery, Akita University Hospital. Akita, Japan †Department of Comprehensive Cancer Control ‡Environmental Health Science and Public Health §Gastroenterology ¶Thoracic Surgery, Akita University Graduate School of Medicine, Akita, Japan ||Division of Health Services Research, Center for Cancer Control and Information Services, National Cancer Center, Tokyo, Japan.

Objective: To determine whether esophagectomy provides a survival advantage in octogenarians with resectable thoracic esophageal cancer.

Summary Background Data: Elderly patients with thoracic esophageal cancer do not always receive the full standard treatment; however, advanced age alone should not preclude the use of effective treatment that could meaningfully improve survival.

Methods: We retrieved the 2008-2011 data from the National Database of Hospital-based Cancer Registries from the National Cancer Center in Japan, divided the patients into a ≥75 group (75-79 years; n = 2,935) and a ≥80 group (80 years or older; n = 2,131), and then compared the patient backgrounds and survival curves. A multivariable Cox proportional hazards regression model was developed to compare the effects of esophagectomy and chemoradiotherapy in the two groups.

Results: A significantly greater percentage of patients were treated with esophagectomy in the ≥75 group (34.6%) than the ≥80 group (18.4%). Among patients who received esophagectomy, the 3-year survival rate was 51.1% in the ≥75 group and 39.0% in the ≥80 group (P < 0.001). However, among patients who received chemoradiotherapy, there was no difference in survival curve between the two groups (P = 0.17). Multivariable Cox proportional hazard analysis revealed that esophagectomy for clinical Stage II-III patients was significantly associated to better survival (adjusted HR: 0.731) (95%CI: 0.645-0.829, p < 0.001) in the ≥75 group but not the ≥80 group when compared with CRT.

Conclusions: Many octogenarians do not necessarily get a survival benefit from esophagectomy. However, patients should be evaluated based on their overall health before ruling out surgery based on age alone.
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http://dx.doi.org/10.1097/SLA.0000000000004437DOI Listing
December 2020

Prediction of successful guidewire crossing of below-the-knee chronic total occlusions using a Japanese scoring system.

J Vasc Surg 2021 Feb 16. Epub 2021 Feb 16.

Cardiovascular Center, Tokeidai Memorial Hospital, Sapporo, Japan.

Objective: To develop a scoring system that can adequately predict a successful guidewire crossing (S-GC) of below-the-knee (BTK) chronic total occlusions (CTOs) in angiographic evaluation.

Methods: A retrospective, multicenter, nonrandomized study examined 448 consecutive BTK CTOs in 299 patients treated with endovascular therapy in seven Japanese medical centers from April 2012 to April 2020. The cohort was classified into two groups: an S-GC group and a failed guidewire crossing group.

Results: The final logistic regression model created by a backward stepwise multivariate logistic regression model included five variables: "No outflow of the target vessel," "CTO length ≥200 mm," "Reference vessel diameter <2.0 mm," "Calcification at the proximal entry point," and "Blunt type at entry point." Optimisms were adjusted using 1000 bootstrap samples with replacement and candidate's risk score models developed according to optimism-adjusted correlation coefficients of risk factors. Choosing the best model as the Japanese-BTK (J-BTK) CTO score by comparing the optimism-adjusted area under receiver-operating characteristic curves it was decided to assign one point to "Blunt type at the proximal entry point," one point to "Calcification at the proximal entry point," one point to "Reference vessel diameter <2.0 mm," one point to "CTO length ≥200 mm," and two points to "No outflow of the target vessel." This rule was then used to categorize BTK CTOs into four grades with varying probabilities of S-GC: grade A (J-BTK CTO score of 0 and 1), grade B (score of 2 and 3), grade C (score of 4 and 5), and grade D (score of 6). Rates of S-GC in each grade (grades A, B, C, and D) were 97.3%, 76.8%, 19.3%, and 0%, respectively. Lesions categorized as grade C or D have a lower chance of S-GC. Internal validation was performed using the Hosmer-Lemeshow test (P = .99).

Conclusions: The J-BTK CTO score predicts the probability of an S-GC of BTK CTOs and stratifies the difficulty of endovascular therapy for BTK CTOs in angiographic evaluation.
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http://dx.doi.org/10.1016/j.jvs.2021.01.059DOI Listing
February 2021

Multiple Osteochondritis Dissecans in Multiple Joints.

Case Rep Orthop 2021 28;2021:8828687. Epub 2021 Jan 28.

Department of Orthopedic Surgery, Graduate School of Medicine, Chiba University, Japan.

Background: Osteochondritis dissecans (OCD) rarely occurs in multiple joints. Furthermore, the existence of left-right asymmetric OCDs in different joints of the contralateral side of the body and lesions occurring with a temporal difference is rare. Here, we report a rare case with multiple OCDs sequentially detected in various joints. . The 15-year-old male patient was referred to our hospital for an OCD in the medial femoral condyle of the left knee. He had a history of an OCD in his right elbow, and his father had a history of surgically treated OCDs in both knees. One year and five months after, surgery was performed to the lesion in his left medial femoral condyle, a new OCD lesion occurred in the femoral trochlea of the same knee, which was again treated surgically. Five months after the second surgery, the patient returned with pain in the right knee, and an OCD on the right femoral trochlea was detected by an MRI scan. This lesion remained stable without any further restriction in physical activities for 17 months until detachment occurred and was again treated surgically.

Conclusion: In cases with history and a family history of multiple OCDs, in particular, with a short stature, an MRI scan should be performed for the symptomatic joint to detect and treat the lesion before progression.
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http://dx.doi.org/10.1155/2021/8828687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864730PMC
January 2021

Influence of Spondylolysis on Clinical Presentations in Patients With Lumbar Degenerative Disease.

Cureus 2021 Jan 8;13(1):e12570. Epub 2021 Jan 8.

Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, Chiba, JPN.

Background: There is insufficient current information regarding the prognosis of patients with lumbar spondylolysis when bone union is not achieved. To examine the number, age, and surgically treated levels of patients with lumbar degenerative disease who underwent lumbar spine surgery, and to compare the results between patients with spondylolysis and without spondylolysis, a cross-sectional study was performed.

Methods: Patients with degenerative lumbar disease who underwent lumbar spine surgery were retrospectively reviewed (n=354). The prevalence of spondylolysis was determined using CT images. Patients were divided into a spondylolysis group and a non-spondylolysis group, and the patients' age, sex, and surgically treated levels were compared between the two groups.

Results: The prevalence of lumbar spondylolysis in the 354 patients was 6.50% (23/354). The patients' age was significantly lower in the spondylolysis group (54.2 ± 13.5 years) than in the non-spondylolysis group (63.8 ± 14.2). The number of surgically treated levels was significantly lower in the spondylolysis group (1.33 ± 0.56 levels) than in the non-spondylolysis group (1.70 ± 0.87). The percentage of patients who underwent surgery at L5-S1 was significantly higher in the spondylolysis group; whereas the percentage of patients who underwent surgery at L3-L4 or L4-L5 was significantly higher in the non-spondylolysis group.

Conclusions: Our results suggest that the presence of spondylolysis may not increase the incidence of degenerative lumbar spinal disorders requiring spinal surgery. However, spondylolysis patients frequently have severe degenerative disease at one level caudal to the spondylolysis, and infrequently have multilevel lumbar degenerative disease requiring spinal surgery.
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http://dx.doi.org/10.7759/cureus.12570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863028PMC
January 2021

Nose size indicates maximum penile length.

Basic Clin Androl 2021 Feb 4;31(1). Epub 2021 Feb 4.

Department of Urology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

Background: In a previous report, we investigated whether the size of male genitalia similarly exposed to serum testosterone during aging could change with age and found that penile length almost stopped increasing during adolescence and decreased in older males. In this report, to determine what factors other than age are related to penile length, we performed a multivariate analysis of the relationships between stretched penile length (SPL) and other measurements of genital organs, nose size, height and body weight in 126 adults in their 30s-50s.

Results: The most highly correlated factor with SPL was flaccid penile length (r = 0.565, P < 0.0001). The next highest correlation was nose size (r = 0.564, P < 0.0001). The penile stretched rate correlated with FPL (r = - 0.690, P < 0.0001) but not with SPL or penile circumference.

Conclusions: The fact that nose size is related to SPL indicates that penile length may not be determined by age, height or body weight but has already been determined before birth.
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http://dx.doi.org/10.1186/s12610-021-00121-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7860195PMC
February 2021

Direct puncture technique efficacy for the treatment of cystic adventitial degeneration of the popliteal artery.

Cardiovasc Interv Ther 2021 Jan 29. Epub 2021 Jan 29.

Cardiovascular Center, Tokeidai Memorial Hospital, 2-3 North-1, East1, Chuo-Ku Sapporo, Hokkaido, 060-0031, Japan.

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http://dx.doi.org/10.1007/s12928-020-00743-6DOI Listing
January 2021

Impact of Initial Computed Tomography Findings on Management of Atypical Urinary Cytology of the Upper Urinary Tract.

Urol Int 2021 Jan 28:1-5. Epub 2021 Jan 28.

Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Introduction: Management of patients with atypical urinary cytology (class III) of the upper urinary tract is often complicated because some patients develop upper urinary tract urothelial carcinoma (UTUC). Here, we aimed to help define the optimal management of these patients.

Methods: We investigated 31 patients who underwent retrograde ureteropyelography (RP) and were diagnosed with atypical findings of upper urinary tract cytology.

Results: UTUC was revealed in 17 of 31 patients during the follow-up period of 1 year or longer. Tumor-like lesions and wall thickening in the upper urinary tract on initial computed tomography (CT) were significant predictors of UTUC (p = 0.0002 and p = 0.012, respectively). All 11 patients with tumor-like lesions and 3 of 8 patients with wall thickening on initial CT underwent nephroureterectomy, and UTUC was confirmed histologically. Moreover, 3 of 12 patients with hydronephrosis only or with normal findings later went on to develop UTUC. Repeated RP performed within 6 months from the initial RP was able to distinguish patients with UTUC from those without, even in individuals with normal CT findings.

Discussion/conclusion: Repeated RP based on initial CT findings is recommended in patients with atypical urinary cytology of the upper urinary tract. Nephroureterectomy without repeated RP may be warranted in patients with tumor-like lesions on initial CT findings.
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http://dx.doi.org/10.1159/000512978DOI Listing
January 2021

Influence of Preoperative Difference in Lumbar Lordosis Between the Standing and Supine Positions on Clinical Outcomes After Single-Level Transforaminal Lumbar Interbody Fusion: Minimum 2-Year Follow-Up.

Spine (Phila Pa 1976) 2021 Jan 22. Epub 2021 Jan 22.

Department of Orthopaedic Surgery, Eastern Chiba Medical Center, Togane, Chiba, Japan Department of General Medical Science, Graduate School of Medicine, Chiba University, Chiba-city, Chiba, Japan Department of Orthopaedic Surgery, Sawara Prefectural Hospital, Katori, Chiba, Japan Department of Orthopaedic Surgery, University of Tsukuba, Tsukuba, Ibaraki, Japan Department of Orthopaedic Surgery, Toho University Sakura Medical Center, Sakura, Chiba, Japan Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, Chiba-city, Chiba, Japan.

Study Design: Retrospective cohort study.

Objective: To investigate whether a preoperative difference in lumbar lordosis (D-LL) between the standing and supine positions is associated with clinical outcomes after transforaminal lumbar interbody fusion (TLIF).

Summary Of Background Data: Several factors have been reported to be associated with surgical outcomes after TLIF. However, the association between preoperative D-LL and clinical outcomes after TLIF is unknown.

Methods: We enrolled 45 lumbar degenerative disease patients (mean age: 65.7 ± 11.3 years old; 24 male) treated with single-level TLIF. Surgical outcomes were assessed using Oswestry disability index, visual analog scale (VAS; low back pain (LBP), lower-extremity pain, numbness, LBP in motion, in standing, and in sitting), Japanese Orthopaedic Association Back Pain Evaluation Questionnaire, Japanese Orthopaedic Association score for intermittent claudication (JOA score), and Nakai's scoring system. The preoperative D-LL between the standing radiograph and computed tomography (CT) in the supine position was defined as LL in supine CT-standing radiograph. Patients were divided into two groups according to D-LL value (D-LL > -4°, and D-LL ≤ -4°). Clinical outcomes were compared between the groups, and correlations between preoperative D-LL and clinical outcomes were analyzed.

Results: There were no significant differences in preoperative clinical parameters between the two groups. Postoperative VASs for lower extremity pain, numbness, LBP in standing, and JOA score in D-LL > -4° group were significantly worse than in the D-LL ≤ -4° group (P < 0.05). Preoperative D-LL showed a weak correlation with postoperative lower extremity pain and numbness (P < 0.05).

Conclusions: This study revealed that lumbar degenerative disease patients, who have greater preoperative kyphotic lumbar alignment in the standing versus supine position, tend to have postoperative residual symptoms after TLIF. A preoperative comparison of lateral radiographs between the standing and supine positions is useful to predict patients' postoperative residual symptoms.Level of Evidence: 3.
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http://dx.doi.org/10.1097/BRS.0000000000003955DOI Listing
January 2021

Mortality risk after use of a paclitaxel-coated stent in femoropopliteal peripheral artery disease.

Cardiovasc Interv Ther 2021 Jan 22. Epub 2021 Jan 22.

Cardiovascular Center Tokeidai Memorial Hospital, 2-3 North-1, East1, Chuo-Ku, Sapporo, Hokkaido, 060-0031, Japan.

Although paclitaxel-based devices which demonstrated improved outcomes in the treatment of lower-extremity peripheral artery disease (PAD) have been used worldwide, Katsanos et al. reported a systematic review and summary-level meta-analysis of RCTs in which application of paclitaxel-based devices in the femoropopliteal artery was associated with an increased mortality risk. The purpose of this study was to describe the safety of endovascular therapy (EVT) using paclitaxel-coated stents for femoropopliteal disease by evaluating the mortality risk compared with patients treated with paclitaxel-free devices. A retrospective, multicenter, non-randomized study examined 481 de-novo symptomatic PAD patients treated in 13 Japanese medical centers from January 2011 to December 2015. The risk of all-cause mortality was analyzed between the 65 patients treated with a paclitaxel-coated stent (PTX-coated group) and 416 patients treated with an uncoated balloon or bare nitinol stent (PTX-free group). Overall survival of the PTX-coated group and the PTX-free group were compared after propensity score matching. The 2-year overall survival estimates were 87.7% in the PTX-coated group vs 88.7% in the PTX-free group. There were no significant differences in the mortality risk between the groups through a full follow-up of 2 years (p = 0.80). The multivariate cox proportional hazards model identified three significant predictors of mortality; age (HR, 1.08; 95% CI, 1.03-1.13; p = 0.002), hemodialysis (HR, 3.16; 95% CI, 1.34-7.42; p = 0.008), and albumin (g/dl) (HR, 0.46; 95% CI, 0.25-0.85; p = 0.01).
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http://dx.doi.org/10.1007/s12928-020-00744-5DOI Listing
January 2021

Discovery of Functional Alternatively Spliced Transcripts in Human Cancers.

Cancers (Basel) 2021 Jan 19;13(2). Epub 2021 Jan 19.

Science for Life Laboratory, KTH-Royal Institute of Technology, SE-17165 Stockholm, Sweden.

Pyruvate kinase muscle type () is a key enzyme in glycolysis and plays an important oncological role in cancer. However, the association of expression and the survival outcome of patients with different cancers is controversial. We employed systems biology methods to reveal prognostic value and potential biological functions of transcripts in different human cancers. Protein products of transcripts were shown and detected by western blot and mass spectrometry analysis. We focused on different transcripts of and investigated the associations between their mRNA expression and the clinical survival of the patients in 25 different cancers. We find that the transcripts encoding PKM2 and three previously unstudied transcripts, namely ENST00000389093, ENST00000568883, and ENST00000561609, exhibited opposite prognostic indications in different cancers. Moreover, we validated the prognostic effect of these transcripts in an independent kidney cancer cohort. Finally, we revealed that ENST00000389093 and ENST00000568883 possess pyruvate kinase enzymatic activity and may have functional roles in metabolism, cell invasion, and hypoxia response in cancer cells. Our study provided a potential explanation to the controversial prognostic indication of , and could invoke future studies focusing on revealing the biological and oncological roles of these alternative spliced variants of .
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http://dx.doi.org/10.3390/cancers13020348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835739PMC
January 2021

Impact of age, body mass index, and renal function for severe hypotension caused by oral 5-aminolevulinic acid administration in patients undergoing transurethral resection of bladder tumor.

Photodiagnosis Photodyn Ther 2021 Mar 8;33:102179. Epub 2021 Jan 8.

Department of Urology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

Background: Severe hypotension is a notable adverse event caused by administration of 5-aminolevulinic acid (5-ALA) during photodynamic diagnosis-assisted transurethral resection of bladder tumor (PDD-TURBT). Hypotension can be prolonged following induction of anesthesia and may require continuous administration of a vasopressor. Here, we investigated the risk factors for severe hypotension caused by oral administration of 5-ALA.

Methods: A total of 128 patients with bladder tumors who underwent PDD-TURBT using 5-ALA were included in this study. Clinicopathological data were collected retrospectively and the correlations between the incidence of severe hypotension and clinicopathological factors were analyzed.

Results: Severe hypotension developed in 8 cases (6.3 %). Age ≥ 80 years, body mass index (BMI) ≥ 25 (kg/m), and estimated glomerular filtration rate (eGFR) < 45 (mL/min/1.73 m) were significantly correlated with severe hypotension (P = 0.003, 0.017, and 0.027, respectively). Severe hypotension developed in 1 of 89 cases (1.1 %) which have 0 or 1 risk factor, and in 3 of 31 cases (9.7 %) which have 2 risk factors, whereas it developed in 4 of 8 cases (50 %) which have all risk factors. Patients with all risk factors developed severe hypotension significantly more frequently compared with patients with 1 or fewer risk factors (P < 0.001).

Conclusion: Age ≥ 80 years, BMI ≥ 25, and eGFR < 45 are risk factors for severe hypotension in PDD-TURBT using 5-ALA. The risk of developing severe hypotension is extremely high in patients who have all factors. Adjustment of the 5-ALA dose may be desirable in those patients.
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http://dx.doi.org/10.1016/j.pdpdt.2021.102179DOI Listing
March 2021

Relationship between the frequency of electrocautery of Hunner lesions and changes in bladder capacity in patients with Hunner type interstitial cystitis.

Sci Rep 2021 Jan 8;11(1):105. Epub 2021 Jan 8.

Japanese Red Cross Medical Center, Tokyo, Japan.

Electrocautery is a promising treatment option for patients with Hunner type interstitial cystitis (HIC), but frequently requires multiple sessions due to recurrence of the lesions. In the present study, we assessed the relationship between the frequency of electrocautery of Hunner lesions and changes in maximum bladder capacity (MBC) at hydrodistension in a large cohort of 118 HIC patients. Three mixed-effect linear regression analyses were conducted for MBC against (1) the number of sessions; (2) the number of sessions and the time between each session and the first session; and (3) other relevant clinical parameters in addition to the Model (2). The mean number of sessions was 2.8 times. MBC decreased approximately 50 mL for each additional electrocautery session, but this loss was offset by 10 mL for each year the subsequent session was postponed. MBC of < 400 mL at the first session was a significant risk factor for MBC loss with further sessions. No other clinical parameters were associated with MBC over time. This study demonstrates a significant relationship between the frequency of electrocautery of Hunner lesions and MBC changes in HIC patients. Low MBC at the first session is a poor prognostic marker for MBC loss over multiple sessions.
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http://dx.doi.org/10.1038/s41598-020-80589-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794499PMC
January 2021

Dermatomyositis associated with prostate adenocarcinoma with neuroendocrine differentiation.

BMC Urol 2021 Jan 7;21(1). Epub 2021 Jan 7.

Department of Urology, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 1138655, Japan.

Background: Although it is known that malignancies can be associated with dermatomyositis, there are few reports on dermatomyositis associated with prostate cancer with neuroendocrine differentiation.

Case Presentation: A 63-year-old man visited our hospital due to pollakiuria. High levels of PSA and NSE were observed, and prostate biopsy revealed an adenocarcinoma with neuroendocrine differentiation. Multiple metastases to the lymph nodes, bones, and liver were identified, and androgen deprivation therapy (ADT) was started immediately. Following 2 weeks of treatment, erythema on the skin, and muscle weakness with severe dysphagia appeared. The patient was diagnosed with dermatomyositis, and high-dose glucocorticoid therapy was initiated. ADT and subsequent chemotherapy with etoposide and cisplatin (EP) were performed for prostate cancer, which resulted in decreased PSA and NSE and reduction of all metastases. After the initiation of EP therapy, dermatomyositis improved, and the patient regained oral intake function. Although EP therapy was replaced by docetaxel, abiraterone, and enzalutamide because of adverse events, no cancer progression was consistently observed. Dermatomyositis worsened temporarily during the administration of abiraterone, but it improved upon switching from abiraterone to enzalutamide and dose escalation of glucocorticoid.

Conclusions: We successfully treated a rare case of dermatomyositis associated with prostate adenocarcinoma with neuroendocrine differentiation.
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http://dx.doi.org/10.1186/s12894-020-00779-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791876PMC
January 2021

Effects of SLC31A1 and ATP7B polymorphisms on platinum resistance in patients with esophageal squamous cell carcinoma receiving neoadjuvant chemoradiotherapy.

Med Oncol 2021 Jan 7;38(1). Epub 2021 Jan 7.

Department of Pharmacy, Akita University Hospital, 1-1-1 Hondo, Akita, 010-8543, Japan.

The relationship between the SLC31A1 (protein: copper transporter 1) rs10981694 A > C and ATP7B (protein: P-type adenosine triphosphatase 7B) rs9535828 A > G polymorphisms on the overall survival and disease-free survival of 104 Japanese patients with esophageal squamous cell carcinoma (ESCC) receiving neoadjuvant chemoradiotherapy (CRT) was investigated. Chemotherapy consisted of protracted infusion of 5-fluoracil (800 mg/m/day) on days 1-5 and cisplatin or nedaplatin (80 mg/m/day) on day 1. The median (range) follow-up was 47 (6-127) months. The 5-year overall and disease-free survival rates were 71.2% and 60.6%, respectively. The 5-year overall survival rate was significantly higher in patients with the SLC31A1 rs10981694 C allele compared with the rs10981694 A/A genotype (91.7% vs. 65.0%, P = 0.018). The 5-year disease-free survival rate was significantly higher in patients with the SLC31A1 rs10981694 C allele compared with the rs10981694 A/A genotype (79.2% vs. 55.0%, P = 0.043). In addition, univariate and multivariate analyses showed the SLC31A1 rs10981694 A > C polymorphism to be a significant prognostic factor affecting 5-year overall survival after neoadjuvant CRT. However, the overall and disease-free survival rates after surgery did not differ significantly among the ATP7B rs9535828 genotypes. In conclusion, only the SLC31A1 rs10981694 A/A genotype was an independent predictor of a poorer 5-year overall survival. Therefore, in neoadjuvant CRT for ESCC patients, the effect of platinum was affected by the SLC31A1 rs10981694 A > C polymorphism. The presence of this polymorphism should be considered when devising neoadjuvant CRT regimens or treatment strategies for ESCC.
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http://dx.doi.org/10.1007/s12032-020-01450-1DOI Listing
January 2021

Age-Specific Characteristics of Lumbopelvic Alignment in Patients with Spondylolysis: How Bilateral L5 Spondylolysis Influences Lumbopelvic Alignment During the Aging Process.

World Neurosurg 2021 Mar 29;147:e524-e532. Epub 2020 Dec 29.

Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, Chiba-city, Japan.

Background: To elucidate the influence of spondylolysis on age-related lumbar degenerative changes, age-specific lumbopelvic alignment in patients with or without spondylolysis was examined.

Methods: Sagittal reconstructed computed tomography images of the lumbar spine in consecutive patients (n = 581) undergoing computed tomography scans of abdominal or lumbar regions for reasons other than low back disorders were obtained. Lumbar lordosis (LL), L5-S1 angle, and sacral slope (SS) were measured. Lumbopelvic parameters in patients with or without spondylolysis were evaluated in 3 age groups (<50, 50-69, and ≥70). The influence of bilateral L5 spondylolysis (L5-lysis) and L5 vertebral slip on each lumbopelvic parameter, as well as correlation between cross-sectional area (CSA) of paraspinal muscles and the degree of vertebral slip, were examined by multiple regression analysis.

Results: Patients with bilateral spondylolysis showed greater LL and SS than patients without spondylolysis. When analyzing the influence of L5-lysis, only elderly patients (≥70) with L5-lysis showed significantly greater LL and SS than nonspondylolysis (nonlysis) patients. L5-lysis patients more frequently showed L5 vertebral slip than nonlysis patients, and a smaller L5-S1 angle was observed when L5 vertebral slip accompanied L5-lysis. The degree of vertebral slip was significantly correlated with CSA of psoas muscles, but not with CSA of paraspinal extensor muscles.

Conclusions: When patients have L5-lysis, lumbar lordosis and pelvic anteversion occurred age dependently. In elderly patients with L5-lysis, L5 vertebral slip with decrease of the L5-S1 angle occurs frequently. The progression of vertebral slip was correlated with atrophy of psoas muscles, but not that of paraspinal extensor muscles.
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http://dx.doi.org/10.1016/j.wneu.2020.12.097DOI Listing
March 2021

Outcomes of Definitive Chemoradiotherapy for Stage IVa (T4b vs. N4) Esophageal Squamous Cell Carcinoma Based on the Japanese Classification System: A Retrospective Single-Center Study.

Cancers (Basel) 2020 Dec 22;13(1). Epub 2020 Dec 22.

Department of Radiology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita 010-8545, Japan.

The differences in prognoses or progression patterns between T4b non-N4 and non-T4b N4 esophageal squamous cell carcinoma post chemoradiotherapy (CRT) is unclear. This study compared the outcomes of CRT for stage IVa esophageal squamous cell carcinoma according to T/N factors. We retrospectively identified 66 patients with stage IVa esophageal squamous cell carcinoma who underwent definitive CRT at our center between January 2009 and March 2013. The treatment outcomes, i.e., progression patterns, prognostic factors, and toxicities based on version 5.0 of the National Cancer Institute Common Terminology Criteria for Adverse Events, were studied. The patients (56 men and 10 women) had a median age of 67 (range: 37-87) years. The T/N classifications were T4b non-N4 (28/66), non-T4b N4 (24/66), and T4b N4 (14/66). Objective response was achieved in 57 patients (86.4%, (95% confidence interval, 74.6-94.1%)). There were no significant differences between the T/N groups in terms of overall survival, progression-free survival, and progression pattern. We found no significant differences in prognoses or progression patterns among patients with T4b non-N4, non-T4b N4, and T4b N4 esophageal squamous cell carcinoma. Thus, it seems impractical to modify CRT regimens based on T/N factors.
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http://dx.doi.org/10.3390/cancers13010008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792968PMC
December 2020

The nanomedicine rush: New strategies for unmet medical needs based on innovative nano DDS.

J Control Release 2021 02 20;330:305-316. Epub 2020 Dec 20.

Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan; Laboratory for Biological Drug Development based on DDS Technology, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan. Electronic address:

The era of Nanomedicine has arrived with the approval of ONPATTRO™ by the FDA in 2018. Lipid nanoparticle (LNP) technology has succeeded in delivering siRNA to the human liver in genetic diseases and has also been applied to mRNA vaccinations for COVID-19 using a similar LNP technology. In this review, we focus on the current status of new lipids for use in LNP formulations including our original lipids (CL4H6/CL4C6/CL4D6) as well as mechanisms of targeting without a ligand. Clinical applications of nano DDS are moving forward rapidly in the field of cancer immunology since the successful introduction of OPDIVO™ in 2014. Antigen presentation and the maturation of immune cells can be controlled by nano DDS for cancer immunotherapy. YSK12-C4, a newly designed ionizable amino lipid can induce successful immune activation by silencing mRNA in DC and NK cells, which are expected to be evaluated for clinical use. Finally, new cancer therapy by targeting mitochondria involving the use of a MITO-Porter, a membrane fusion-type mitochondrial delivery system, has been introduced. The importance of delivering a photo sensitizer to mitochondria was clearly demonstrated in photodynamic cancer therapy. Clinical applications of MITO-Porters started in collaborative efforts with LUCA Science Co., Ltd. And was established in 2018. The future direction of Nanomedicine is discussed.
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http://dx.doi.org/10.1016/j.jconrel.2020.12.032DOI Listing
February 2021

Randomised phase II trial of capecitabine plus oxaliplatin with continuous versus intermittent use of oxaliplatin as adjuvant chemotherapy for stage II/III colon cancer (CCOG-1302 study).

Eur J Cancer 2021 Feb 16;144:61-71. Epub 2020 Dec 16.

Department of Gastroenterological Surgery, Nagoya University Hospital, Nagoya, Japan.

Background: Peripheral sensory neuropathy (PSN) caused by oxaliplatin-based adjuvant chemotherapy adversely affects patients' quality of life. This study evaluated the efficacy and safety of capecitabine plus oxaliplatin (CAPOX) with intermittent oxaliplatin use compared with the standard CAPOX in adjuvant therapy for colon cancer.

Patients And Methods: Patients with curative resection for stage II/III colon cancer were randomly assigned to receive either CAPOX with continuous oxaliplatin (eight cycles of CAPOX) or CAPOX with intermittent oxaliplatin (two cycles of CAPOX, four cycles of capecitabine and two cycles of CAPOX). The primary end-point was the 1-year PSN rate, and the key secondary end-point was disease-free survival (DFS).

Results: Two hundred patients were enrolled in the intent-to-treat population. After 4 patients withdrew, 196 patients were included in the safety analysis. The overall treatment completion rate was 65% for continuous vs. 89% for intermittent treatment (p < 0.001). The 1-year PSN rate was 60% (95% confidence interval [CI], 50%-70%) for continuous and 16% (95% CI, 10%-25%) for intermittent treatment (p < 0.001). After a median follow-up of 52 months, 40 events (20%) were observed. The 3-year DFS was 81% (95% CI, 71%-87%) for continuous and 84% (95% CI, 75%-90%) for intermittent treatment (hazard ratio [HR], 0.87; 95% CI, 0.47-1.63). Among patients with high-risk disease (T4 or N2-3), the 3-year DFS was 57% for continuous vs. 74% for intermittent treatment (HR, 0.66).

Conclusion: CAPOX with planned intermittent oxaliplatin may be feasible as an adjuvant therapy for colon cancer and substantially reduce the duration of long-lasting PSN.

Trial Identifier: UMIN000012535.
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http://dx.doi.org/10.1016/j.ejca.2020.11.007DOI Listing
February 2021