Publications by authors named "Toshiaki Tanaka"

625 Publications

Efficacy and Safety of Once-Weekly Somatrogon Compared With Once-Daily Somatropin (Genotropin®) in Japanese Children With Pediatric Growth Hormone Deficiency: Results From a Randomized Phase 3 Study.

Horm Res Paediatr 2022 Apr 13. Epub 2022 Apr 13.

Introduction Somatrogon is a long-acting recombinant human growth hormone being developed as a once weekly treatment for children with growth hormone deficiency (GHD). The objective of this Phase 3 study (NCT03874013) was to compare the efficacy and safety of once-weekly somatrogon with once-daily Genotropin in Japanese children with GHD. Methods In this open-label, randomized, active-controlled study, 44 prepubertal Japanese children with GHD (boys: 3 to <11 years; girls: 3 to <10 years) were randomized 1:1 to receive once weekly somatrogon or once daily Genotropin (0.025 mg/kg/day) for 12 months. Dose escalation for somatrogon-treated subjects occurred in the first 6 weeks (0.25, 0.48, and 0.66 mg/kg/week; 2 weeks each) with the remaining 46 weeks at a dose of 0.66 mg/kg/week. The study's primary endpoint was annualized height velocity (HV) at 12 months. Results Baseline characteristics were similar between treatment groups. Compared with Genotropin-treated subjects, somatrogon-treated subjects had higher least-squares (LS) mean HV at 12 months (9.65 cm/year vs 7.87 cm/year). Once weekly somatrogon was concluded as being comparable to once daily Genotropin as the mean treatment difference (somatrogon-Genotropin) in HV was +1.79 cm/year (95% CI, 0.97-2.60), which was greater than the pre-established margin (-1.8 cm/year). For both treatment groups, most adverse events were mild to moderate in severity and a similar proportion of subjects reported injection-site pain, although the somatrogon group reported more painful injections. Conclusion In prepubertal Japanese children with GHD, once-weekly somatrogon was comparable to once-daily Genotropin in terms of annualized (12-month) HV. Both treatments had similar safety and tolerability profiles. ClinicalTrials.gov:NCT03874013.
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http://dx.doi.org/10.1159/000524600DOI Listing
April 2022

A case of metastatic Xp11.2 translocation renal cell carcinoma showing a prolonged response to nivolumab as 6th-line treatment.

Int Cancer Conf J 2022 Apr 21;11(2):134-137. Epub 2022 Feb 21.

Department of Urology, Sapporo Medical University, South-1, West-16, Chuo-ku, Sapporo, Hokkaido 060-8543 Japan.

A female patient with Xp11.2 translocation renal cell carcinoma developed lung metastasis 24 months after partial nephrectomy that was performed at the age of 32. Sunitinib, everolimus, axitinib, temsirolimus and pazopanib were sequentially administered for 55 months and disease progression was observed. Then nivolumab was started as 6th-line treatment. After a transient increase in tumor size, metastatic tumors started to shrink. Eventually, nivolumab provided a partial response with a 35% reduction of tumor size at 50 months and freedom from progression for 60 months. The present case suggests that immune checkpoint inhibitors are effective in selected cases with Xp11.2 translocation renal cell carcinoma.
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http://dx.doi.org/10.1007/s13691-022-00536-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8938562PMC
April 2022

Heat shock protein 90 is a new potential target of anti-rejection therapy in allotransplantation.

Cell Stress Chaperones 2022 Apr 9. Epub 2022 Apr 9.

Department of Urology, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan.

The critical roles of heat shock protein 90 (HSP90) in immune reactions associated with viral infection and autoimmune disease are well known. To date, however, its roles in the alloimmune response and the immunosuppressive effect of HSP90 inhibitors in allotransplantation have remained unknown. The purpose of this study was to examine the therapeutic efficacy of the HSP90 inhibitor 17-DMAG in allotransplantation models. C57BL/6 (H-2b) and BALB/c (H-2d) mice were used as donors for and recipients of skin and heart transplantation, respectively. Treatment with 17-DMAG (daily i.p.) or a vehicle was initiated 3 days before transplantation. Immunological outcomes were assessed by histopathological examinations, flow cytometric analysis, quantitative RT-PCR, ELISA, ELISPOT assay, and MLR. 17-DMAG treatment significantly prolonged the survival of both skin and heart allografts. In 17-DMAG-treated mice, donor-reactive splenocytes producing IFN-γ were significantly reduced along with the intragraft mRNA expression level and serum concentration of IFN-γ. Intragraft mRNA expression of cytokines and chemokines associated with both innate and adaptive immunity was suppressed in 17-DMAG-treated group. MLR showed suppression of the donor-specific proliferation of CD4 + T and CD19 + B cells in the spleens of 17-DMAG-treated mice. 17-DMAG treatment also reduced the number of activated NK cells. Furthermore, the treatment lowered the titers of donor-specific antibodies in the serum and prolonged a second skin allograft in mice sensitized by previous skin transplantation. HSP90 inhibition by 17-DMAG can affect various immune responses, including innate immunity, adaptive immunity, and humoral immunity, suggesting its therapeutic potential against acute rejection in allotransplantation.
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http://dx.doi.org/10.1007/s12192-022-01272-2DOI Listing
April 2022

Treatment Adherence to Injectable Treatments in Pediatric Growth Hormone Deficiency Compared With Injectable Treatments in Other Chronic Pediatric Conditions: A Systematic Literature Review.

Front Endocrinol (Lausanne) 2022 1;13:795224. Epub 2022 Mar 1.

Pediatric Endocrinology Division, University of Minnesota Masonic Children's Hospital, Minneapolis, MN, United States.

Background: Pediatric patients with growth hormone deficiency (GHD) are currently treated with daily injections of recombinant human growth hormone (rhGH) to promote linear growth and enable attainment of normal adult height. One of the main reasons for suboptimal growth during rhGH therapy is non-adherence to treatment. The objective of this systematic literature review was to examine the recent literature on pediatric adherence to injectable treatments for chronic conditions (focusing on rhGH) to characterize levels of adherence and identify the factors/barriers associated with adherence.

Methods: The Embase and MEDLINE databases (January 2015-October 2020) were searched to identify publications describing studies of pediatric patients (aged ≤17 years) with GHD and other chronic conditions requiring daily or weekly injectable treatments; a similar targeted search of Chinese literature was also performed. Adherence data were extracted from the included studies and summarized. Risk of bias was determined using the Cochrane Risk of Bias tool 2 or the Newcastle-Ottawa Scale.

Results: A total of 23 publications were included, with all publications except for one (multiple sclerosis) focused on pediatric GHD studies: there were two clinical trials, 18 observational studies and three survey studies. Study sample sizes ranged from 30 to 13,553 patients (median: 95 patients). The definition of adherence varied between studies and included mean adherence rate, median adherence rate, and the percentage of patients within pre-specified adherence categories. Of the publications assessing adherence to daily rhGH, 11 studies reported 12-month mean adherence rate (range: 73.3%- 95.3%) and eight studies reported median adherence (range: 91%- 99.2%). The barriers to treatment adherence identified included self-administration, increased administration frequency, age (adolescence), longer treatment duration, device design, and insufficient family education, awareness, and/or engagement. Recommendations for increasing adherence included using adherence reminder tools, increasing patient engagement/education, and improving injection device design and drug product.

Conclusions: Adherence to rhGH treatment was high (>80%) for many studies, though comparability between studies was limited given the substantial heterogeneity in the way adherence was defined, measured, and reported. To address this heterogeneity, we recommend standardizing how adherence is defined and reported and encourage the use of standardized study designs and outcome measures.
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http://dx.doi.org/10.3389/fendo.2022.795224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8921265PMC
April 2022

Demographic characteristics of children with growth hormone deficiency from 1996 to 2015 in Japan: 20 years of data from the foundation for growth science in Japan.

Endocr J 2022 Mar 3. Epub 2022 Mar 3.

Growth Hormone (GH) and its related Factors Study Committee and GH Treatment Study Committee, The Foundation for Growth Science in Japan, Tokyo, Japan.

Growth hormone (GH) deficiency (GHD) in children is a heterogeneous condition that includes several entities of various severities. GH treatment has been affected by various factors. Because comprehensive analyses for Japanese children with GHD over time are scarce, we investigated the baseline characteristics of patients with GHD at the start of GH treatment between 1996 and 2015 using data from the Foundation for Growth Science in Japan. During the registration period, 19,717 subjects were determined to be eligible for GH treatment as GHD. Overall analyses revealed that there were twice the number of male patients as female patients, and the etiology was idiopathic in 91.1%, central nervous system (CNS) tumor at the hypothalamus-pituitary area in 1.7%, CNS tumor distant from the hypothalamus-pituitary area in 0.68%, other tumors in 0.91%, congenital CNS malformations in 0.83%, and other diseases in 1.1% with their specific characteristics. The latest average age, height standard deviation score (SDS), insulin-like growth factor-1 SDS, and proportion of severe GHD at GH treatment initiation were 8.8 years, -2.76, -1.42, and 19.5%, respectively. The proportions of breech delivery and asphyxia gradually decreased, whereas that of caesarean section gradually increased during the registration period with the latest values of 2.2%, 4.9%, and 14.0%, respectively (all analyses: p < 0.0001). In contrast, the proportion of idiopathic GHD with breech delivery seemed to reach the lowest level among those with a birth year before 2000. This study identified the characteristics and changes of patients with GHD over 20 years.
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http://dx.doi.org/10.1507/endocrj.EJ21-0520DOI Listing
March 2022

Visualized procollagen Iα1 demonstrates the intracellular processing of propeptides.

Life Sci Alliance 2022 05 18;5(5). Epub 2022 Feb 18.

School of Materials and Chemical Technology, Tokyo Institute of Technology, Tokyo, Japan.

The processing of type I procollagen is essential for fibril formation; however, the steps involved remain controversial. We constructed a live cell imaging system by inserting fluorescent proteins into type I pre-procollagen α1. Based on live imaging and immunostaining, the C-propeptide is intracellularly cleaved at the perinuclear region, including the endoplasmic reticulum, and subsequently accumulates at the upside of the cell. The N-propeptide is also intracellularly cleaved, but is transported with the repeating structure domain of collagen into the extracellular region. This system makes it possible to detect relative increases and decreases in collagen secretion in a high-throughput manner by assaying fluorescence in the culture medium, and revealed that the rate-limiting step for collagen secretion occurs after the synthesis of procollagen. In the present study, we identified a defect in procollagen processing in activated hepatic stellate cells, which secrete aberrant collagen fibrils. The results obtained demonstrated the intracellular processing of type I procollagen, and revealed a link between dysfunctional processing and diseases such as hepatic fibrosis.
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http://dx.doi.org/10.26508/lsa.202101060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8860094PMC
May 2022

Outcomes of open partial nephrectomy for renal cell carcinoma in the minimally invasive approach era.

Curr Urol 2021 Dec 8;15(4):198-203. Epub 2021 Oct 8.

Department of Urology, Sapporo Medical University School of Medicine, Sapporo, Japan.

Background: We investigated the characteristics and outcomes of patients who underwent open partial nephrectomy (OPN) in the minimally invasive approach era.

Materials And Methods: We retrospectively reviewed 52 patients (55 cases) who underwent OPN from May 2009 to March 2016. We assessed perioperative change in estimated glomerular filtration rate (eGFR), complications, and oncological outcomes. Tumor complexity was evaluated using the R.E.N.A.L nephrometry score (NS) and the modified NS.

Results: Fifteen cases (27%) had imperative indications and 40 (73%) had elective indications. The elective cases were more likely to have adverse tumor complexity based on NS. The perioperative complication rate defined as a Clavien-Dindo grade ≥IIIa was 11%. The rate of postoperative decline in eGFR at 1 month, 1 year, and 2 years was 22%, 20%, and 21%, respectively. Multivariate analysis revealed that male gender (odds ratio [OR] 11.8,  = 0.03), NS ≥9 (OR 13.9,  = 0.02), modified NS ≥11 (OR 13.5,  = 0.01), and cold ischemic time ≥40 minutes (OR 7.9,  = 0.04) were significantly associated with worsening eGFR at 1 year after surgery. During a median follow-up period of 52 months, the 5-year overall survival and recurrence-free survival rates were 93% and 84%, respectively.

Conclusions: OPN is acceptable with regard to oncological outcomes and complications in the minimally invasive surgery era. We propose that OPN should be the preferred approach in cases in which it is technically difficult to preserve maximum renal function via a minimally invasive approach.
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http://dx.doi.org/10.1097/CU9.0000000000000046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8772638PMC
December 2021

History of GH treatment in Japan.

Authors:
Toshiaki Tanaka

Clin Pediatr Endocrinol 2022 1;31(1):1-9. Epub 2021 Nov 1.

Tanaka Growth Clinic, Tokyo, Japan.

In Japan, a pituitary-extracted human GH (phGH), Crescormon®, was approved for the treatment of pituitary dwarfism in 1975. The Study Group of Pituitary Dysfunction was organized by the Ministry of Health and Welfare (MHW) in 1973 and prepared the "Diagnostic Handbook: Pituitary Dwarfism" guidelines in 1974. Eligibility assessments for phGH treatment were conducted by the research group on pituitary dwarfism (later the Foundation for Growth Science [FGS] GH Treatment Eligibility Assessment Committee); however, there were 200-300 patients on the waiting list. GH treatment has been financially supported by the Grant-in-Aid Program for Chronic Diseases in Childhood, MHW, since 1974. In 1984, phGH was discontinued in the United States due to reports of the onset of Creutzfeldt-Jakob disease in patients treated with phGH. Japan approved the use of methionyl hGH in 1986 and recombinant hGH in 1988. As a result, the phGH disappeared from the market. The role of the Eligibility Assessment Committee of the FGS shifted to the provision of second opinions about diagnoses and treatment appropriateness. Since then, the indications for GH treatment of pediatric growth disorders have expanded to include other pediatric growth disorders such as Turner syndrome, achondroplasia/hypochondroplasia, etc.
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http://dx.doi.org/10.1297/cpe.2021-0044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8713065PMC
November 2021

Sonographically Measured Adipose Tissue Thickness Correlates with Laboratory Test Abnormalities Reflecting Metabolic State in Elderly Women.

Metab Syndr Relat Disord 2022 Apr 28;20(3):148-155. Epub 2021 Dec 28.

Dean, Kyorin University School of Medicine, Mitaka, Tokyo, Japan.

Accumulation of adipose tissue progresses to metabolic diseases. Sonography is a convenient modality for measuring the thickness of adipose tissue. The present study aimed to clarify the site of adipose tissue thickness that correlated best with laboratory test values reflecting metabolic abnormalities. Subjects comprised 37 elderly women with metabolic diseases or an almost healthy state (median age, 71 years; interquartile range, 62-78 years). Abdominal visceral adipose tissue (VAT), subcutaneous adipose tissue, peritoneal adipose tissue, perirenal adipose tissue, and epicardial adipose tissue (EAT) thicknesses were measured. Correlations were evaluated between laboratory test values and these adipose tissue thicknesses. VAT thickness measured at the level of the umbilicus correlated positively with values of triglycerides (TGs) ( = 0.593,  = 0.0009) and hemoglobin A1c ( = 0.490,  = 0.0081) and negatively with the value of high-density lipoprotein cholesterol ( = -0.521,  = 0.0045), even after adjusting for body mass index. Significant positive correlations were also found between EAT thickness and TGs ( = 0.542,  = 0.0029). Among the adipose tissue thicknesses measured at several sites by sonography, VAT thickness correlated most closely with laboratory test values representing metabolic abnormalities in elderly women.
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http://dx.doi.org/10.1089/met.2021.0082DOI Listing
April 2022

Immunocytochemical Analysis of DGKη in Cultured Cells Using a Monoclonal Antibody DhMab-4.

Monoclon Antib Immunodiagn Immunother 2021 Dec;40(6):261-265

Department of Anatomy and Cell Biology, Yamagata University Faculty of Medicine, Yamagata, Japan.

Diacylglycerol kinase (DGK) is a lipid kinase that converts diacylglycerol (DG) to phosphatidic acid (PA). Since both DG and PA serve as intracellular second messenger molecules, DGK plays a pivotal role in balancing these two signaling pathways. Of the DGK family, DGKη is classified as a type II DGK. Reportedly, DGKη is expressed ubiquitously through mammalian tissues and cells. Previous studies using cDNA transfection methods reported cytoplasmic localization of DGKη in cultured human cells. However, subcellular localization of native protein is still unknown. Recently, we established a human DGKη-specific monoclonal antibody, DhMab-4. In this study, we examined subcellular localization of native protein of DGKη using DhMab-4 by immunocytochemistry in human cultured cells.
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http://dx.doi.org/10.1089/mab.2021.0034DOI Listing
December 2021

Improvement in Surgical Outcomes Using 3-Dimensional Printed Models for Lateral Pelvic Lymph Node Dissection in Rectal Cancer.

Dis Colon Rectum 2022 Apr;65(4):566-573

Department of Surgical Oncology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.

Background: Lateral pelvic lymph node dissection for rectal cancer is challenging due to the complexity of the pelvic wall anatomy, and incomplete lateral pelvic lymph node dissection may result in local recurrence in the lateral pelvis. Although 3-dimensional printed organ models are useful for understanding spatial anatomy, it is currently unclear whether they improve surgical outcomes.

Objective: We aimed to assess whether the surgical effectiveness of lateral pelvic lymph node dissection is increased by the use of individualized 3-dimensional printed pelvic models.

Design: This was a retrospective study using a propensity matching analysis.

Settings: This study was conducted at a university hospital in Japan.

Patients: In total, 115 patients comprising 184 pelvic sides (right, 85 sides; left, 99 sides) who underwent lateral pelvic lymph node dissection for colorectal adenocarcinoma between January 2012 and December 2019 were enrolled.

Interventions: We compared surgical outcomes using 3-dimensional printed pelvic models with control outcomes.

Main Outcome Measures: The primary outcome was the number of harvested lateral pelvic lymph nodes on 1 pelvic side after the propensity matching analysis.

Results: After matching, 35 pelvic sides each were allocated to the 3-dimensional model and control groups, and no significant differences were observed in patient characteristics between the 2 groups. The number of harvested lateral pelvic lymph nodes was significantly higher in the 3-dimensional model group (median, 9; range, 3-16) than in the control group (median, 6; range, 0-22; p = 0.047).

Limitations: This was a retrospective study using propensity score matching. However, historical backgrounds were not matched, and the majority of lateral pelvic lymph node dissection procedures in the 3-dimensional model group were recently performed. This limitation may have influenced surgical outcomes.

Conclusion: The present study demonstrated that, by referring to individualized 3-dimensional printed pelvic models, colorectal surgeons harvested a larger number of lateral pelvic lymph nodes during lateral pelvic lymph node dissection. This result suggests that 3-dimensional printed models help surgeons to complete more detailed procedures. See Video Abstract at http://links.lww.com/DCR/B776.

Mejora De Los Resultados Quirrgicos Mediante El Uso De Modelos Impresos En D Para La Diseccin Lateral De Los Ganglios Linfticos Plvicos En El Cncer De Recto: ANTECEDENTES:La disección lateral de los ganglios linfáticos de la pelvis en el cáncer de recto es un desafío debido a la complejidad de la anatomía de la pared pélvica; la disección incompleta de las mismas puede resultar en una recidiva local en dicha zona. Aunque la impresión tridimensional de modelos de órganos es útil para comprender la estructura anatómica espacial, actualmente no está claro si mejoran los resultados quirúrgicos.OBJETIVO:Nuestro objetivo fue evaluar si la efectividad quirúrgica de la disección de los ganglios linfáticos laterales de la pelvis aumenta mediante el uso individualizado de modelos pélvicos impresos en 3D.DISEÑO:Este fue un estudio retrospectivo que utilizó un análisis de coincidencia de propensión.AJUSTE:Este estudio se realizó en un hospital universitario de Japón.PACIENTES:En total, se enrolaron 115 pacientes que comprendían 184 lados pélvicos (85 de lado derecho; 99 de lado izquierdo) que fueron sometidas a disección lateral de ganglios linfáticos de la pelvis por adenocarcinoma colorrectal entre enero de 2012 y diciembre de 2019.INTERVENCIONES:Comparamos los resultados quirúrgicos mediante modelos pélvicos tridimensionales impresos con los resultados de control.PRINCIPALES MEDIDAS DE RESULTADO:El resultado primario fue el número de ganglios linfáticos laterales pélvicos extraídos en un lado pélvico después del análisis de coincidencia de propensión.RESULTADOS:Después del emparejamiento, se asignaron 35 lados pélvicos cada uno, tanto al modelo tridimensional como al grupo de control; no se observaron diferencias significativas con respecto a las características de los pacientes entre los dos grupos. El número de ganglios linfáticos pélvicos laterales extraídos fue significativamente mayor en el grupo del modelo tridimensional (mediana, 9; rango 3-16) que en el grupo de control (mediana, 6; rango, 0-22) (p = 0.047).LIMITACIONES:Este fue un estudio retrospectivo que utilizó el emparejamiento por puntuación de propensión. Sin embargo, antecedentes históricos no fueron encontrados y la mayoría de los procedimientos de disección de los ganglios linfáticos laterales pélvicos en el grupo del modelo tridimensional se realizaron recientemente. Esta limitación pudo haber influido en los resultados quirúrgicos.CONCLUSIONES:El presente estudio demostró que al referirse a modelos pélvicos individualizados impresos en 3D, los cirujanos colorrectales recolectaron un mayor número de ganglios linfáticos laterales de la pelvis durante la disección lateral. Este resultado sugiere que los modelos tridimensionales impresos ayudan a los cirujanos a completar procedimientos más detallados. Consulte Video Resumen en http://links.lww.com/DCR/B776.
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http://dx.doi.org/10.1097/DCR.0000000000002327DOI Listing
April 2022

Early growth hormone treatment accelerates delayed onset of puberty in patients with growth hormone deficiency.

Endocr J 2022 Feb 29;69(2):199-207. Epub 2021 Sep 29.

Tanaka Growth Clinic, Setagaya, Tokyo 158-0097, Japan.

We investigated whether growth hormone (GH) treatment could accelerate the onset of puberty in patients with isolated GH deficiency (GHD). Of the 135 boys and 89 girls who started GH treatment before the onset of puberty and were followed up at Tanaka Growth Clinic, 83 boys and 51 girls who started GH treatment sufficiently earlier than the average age at onset of puberty of GHD patients (<10 years vs. 11.7 years for boys; <9.5 years vs. 11.4 years for girls) were analyzed. Age at onset of puberty significantly positively correlated to age at the start of GH treatment (boys: r = 0.427, p < 0.0001; girls: r = 0.302, p < 0.05). When the subjects were divided into two groups each: for boys, Groups A (n = 45) and B (n = 39), treatment was started at age <8 and 8 to <10 years, respectively; for girls, Groups A (n = 26) and B (n = 21), treatment was started at age <7 and 7 to <9.5 years, respectively, age at the onset of puberty was significantly lower in Groups A than in Groups B by the Mann-Whitney U test (boys: p < 0.01; girls: p < 0.05) and Kaplan-Meier log-rank test (boys: p < 0.01; girls: p < 0.05). These results indicate that GH treatment accelerates the delayed onset of puberty in patients with GHD. Heights at the onset of puberty in Groups A and B were not significantly different, suggesting that early treatment does not increase adult height.
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http://dx.doi.org/10.1507/endocrj.EJ21-0209DOI Listing
February 2022

What sexual symptoms are most related to testosterone deficiency among older Japanese men?

Int J Urol 2021 Dec 15;28(12):1306-1307. Epub 2021 Sep 15.

Department of Urology, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan.

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http://dx.doi.org/10.1111/iju.14697DOI Listing
December 2021

Tumor-infiltrating CD8 T cells recognize a heterogeneously expressed functional neoantigen in clear cell renal cell carcinoma.

Cancer Immunol Immunother 2022 Apr 7;71(4):905-918. Epub 2021 Sep 7.

Department of Pathology, Sapporo Medical University School of Medicine, South-1 West-17, Chuo-Ku, Sapporo, 060-8556, Japan.

Immune checkpoint inhibitors (ICIs) are used in cancer immunotherapy to block programmed death-1 and cytotoxic T-lymphocyte antigen 4, but the response rate for ICIs is still low and tumor cell heterogeneity is considered to be responsible for resistance to immunotherapy. Tumor-infiltrating lymphocytes (TILs) have an essential role in the anti-tumor effect of cancer immunotherapy; however, the specificity of TILs in renal cell carcinoma (RCC) is elusive. In this study, we analyzed a 58-year-old case with clear cell RCC (ccRCC) with the tumor showing macroscopic and microscopic heterogeneity. The tumor was composed of low-grade and high-grade ccRCC. A tumor cell line (1226 RCC cells) and TILs were isolated from the high-grade ccRCC lesion, and a TIL clone recognized a novel neoantigen peptide (YVVPGSPCL) encoded by a missense mutation of the tensin 1 (TNS1) gene in a human leukocyte antigen-C*03:03-restricted fashion. The TNS1 gene mutation was not detected in the low-grade ccRCC lesion and the TIL clone did not recognized low-grade ccRCC cells. The missense mutation of TNS1 encoding the S1309Y mutation was found to be related to cell migration by gene over-expression. These findings suggest that macroscopically and microscopically heterogenous tumors might show heterogenous gene mutations and reactivity to TILs.
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http://dx.doi.org/10.1007/s00262-021-03048-6DOI Listing
April 2022

The Boy:Girl Ratio of Children Diagnosed with Growth Hormone Deficiency-Induced Short Stature Is Associated with the Boy:Girl Ratio of Children Visiting Short Stature Clinics.

Horm Res Paediatr 2021 23;94(5-6):211-218. Epub 2021 Aug 23.

Miyagawa Kid's Clinic, Hatsukaichi, Japan.

Background: About twice as many boys as girls undergo growth hormone (GH) therapy in GH deficiency (GHD). However, this sex difference may not correctly reflect a real incidence.

Objectives: We analyzed the evidence of a selection bias whereby more boys seek treatment at short stature clinics.

Subjects And Methods: The present study included 3,902 children who visited 17 short stature clinics with a height SD score of -2 SD or less. The percentage of children who underwent the GH stimulation test was compared between boys and girls, as was the percentage of children ultimately diagnosed with GHD.

Results: The children comprised 2,390 boys (61.3%) and 1,512 girls (38.7%), with a boy:girl ratio of 1.58:1. The percentage of children who underwent the GH stimulation test did not differ between boys (45.7%) and girls (49.8%). Among the children who underwent the GH stimulation test, the percentage diagnosed with GHD did not differ significantly between boys (22.0%) and girls (20.1%). The boy:girl ratio of children diagnosed with GHD was 1.59:1.

Conclusions: The boy:girl ratio of children with short stature (1.58:1) did not differ significantly from that of children diagnosed with GHD (1.59:1). These results indicate that the predominance of boys in GHD does not reflect a real incidence, but rather a selection bias whereby a higher proportion of boys with short stature seek treatment at clinics. This difference arises because parents are more concerned about boys' height, and because boys reach adult height at an older age.
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http://dx.doi.org/10.1159/000518995DOI Listing
March 2022

Therapeutic options to reduce intravesical recurrence in newly diagnosed Ta high-grade bladder cancer according to risk stratification: A multicenter retrospective study.

Int J Urol 2021 Nov 3;28(11):1136-1142. Epub 2021 Aug 3.

Department of Urology, Sapporo Medical University School of Medicine, Sapporo, Japan.

Objectives: To evaluate the risk factors for intravesical recurrence in patients with newly diagnosed Ta high-grade non-muscle-invasive bladder cancer and the optimal management to reduce the risk of recurrence.

Methods: We retrospectively evaluated Ta high-grade bladder cancer in patients who were newly diagnosed by transurethral resection from January 2007 through October 2018. Using multivariate analyses, we evaluated the risk factors and therapeutic options affecting intravesical recurrence and stratified the patients according to the risk numbers.

Results: We included 390 patients and the median follow-up period was 31 months after the initial transurethral resection. According to multivariate analysis, having a previous history of upper urinary tract carcinoma, and multiple and sessile tumors were risk factors for intravesical recurrence (P = 0.001, P = 0.02 and P = 0.01, respectively). Risk groups were stratified according to these risk factors into favorable, intermediate and poor. In the entire cohort, induction and immediate intravesical instillation therapy were treatment options to reduce intravesical recurrence (P < 0.01 and P = 0.02, respectively). Analyses in each risk group showed that a second transurethral resection was the only therapeutic option to reduce intravesical recurrence in the favorable group (P = 0.048), whereas induction intravesical instillation therapy was effective in the intermediate and poor risk groups (P = 0.01 and P < 0.01, respectively), as was immediate intravesical instillation for the poor risk group (P < 0.001).

Conclusions: Sessile, multiple tumors and a history of upper urinary tract carcinoma are risk factors for intravesical recurrence in Ta high-grade bladder cancer patients.
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http://dx.doi.org/10.1111/iju.14657DOI Listing
November 2021

Necessity of salt intake reduction education beginning in youth: a cross-sectional survey of sodium-to-potassium ratios in mothers and their preschool children.

Hypertens Res 2021 10 20;44(10):1307-1315. Epub 2021 Jul 20.

Health Care Center, Fukuoka University, Fukuoka, Japan.

Urinary sodium-to-potassium ratios are known to be high in preschoolers, but there are no reports comparing these ratios with those of the children's mothers. The aim of this study was to investigate the association between the urinary sodium-to-potassium ratios of mothers and their preschool children under the hypothesis that the ratio is equivalent between the two. We evaluated 297 preschoolers aged four to five attending six kindergartens (four in northern Japan, two in southern Japan), and we also evaluated the children's mothers. We asked the participants to take morning first urine samples for 2 consecutive days in the spring and autumn of the same year (four samples per participant) and to fill out a dietary questionnaire. There was a correlation between the urinary sodium-to-potassium ratios of preschoolers and those of their mothers. However, in a comparison between the preschoolers and their mothers overall, higher values were found in the preschoolers [preschoolers: 4.6 (3.5-6.3) mmol/L/g·Cr; mothers: 4.3 (3.9-4.7) mmol/L/g·Cr, p = 0.003]. These results correlated with the urinary sodium-to-potassium ratios estimated from the dietary questionnaire. The preschoolers showed high sodium and low potassium intake consumption compared to the mothers. Interestingly, these were found to differ by region and gender. In conclusion, the urinary sodium-to-potassium ratio in Japanese preschoolers is related to and higher than that of their mothers. It is important to educate children, their parents, childcare professionals, and society as a whole about proper salt restriction and potassium supplementation, as well as to improve the food environment.
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http://dx.doi.org/10.1038/s41440-021-00705-2DOI Listing
October 2021

[Two Cases of Palliative Radiation Therapy for Prostate Cancer Patients in the Terminal Phase].

Hinyokika Kiyo 2021 Jun;67(6):245-248

The Department of Urology, Sapporo Medical University School of Medicine.

Herein we report two cases of palliative radiation therapy for retroperitoneal lymph node metastasis (RLNM) causing annoying leg edema in castration-resistant prostate cancer (CRPC) patients in the terminal phase. [Case 1] A 53-year-oldman with T3bN0M1a prostate cancer was treated with androgen deprivation therapy (ADT). After 9 months, he developed CRPC with local progression that required local radiation therapy (75.6 Gy/36 fr). Disease progression after life-prolonging therapies was followed only by best supportive care (BSC). Radiation therapy (40 Gy/20 fr) was performed for the RLNM due to which he suffered from painful leg edema. Although the painful leg edema was alleviated, he died of prostate cancer after 2 months. [Case 2] A 71-year-oldman with T4N1M1a prostate cancer was treated with ADT plus bicalutamide. After 10 months, he developed CRPC. He was treated with only BSC for disease progression after life-prolonging therapies. He had RLNM that caused painful leg edema, making it difficult for him to stretch and lie on his back. Radiation therapy (16 Gy/2 fr) was performed for the RLNM. His condition improved enough that he was able to move to a wheelchair and lie on his back. However, he died of prostate cancer without recurrence of the painful leg edema after one month. Our experience with these two CRPC patients with severe leg edema due to the RLNM indicates that radiation therapy for lymph node metastasis may be included as one of the treatment options even for terminal disease.
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http://dx.doi.org/10.14989/ActaUrolJap_67_6_245DOI Listing
June 2021

[A Case of Diagnosed Lynch Syndrome in a Patient with Ureteral Cancer].

Hinyokika Kiyo 2021 Jun;67(6):229-232

The Department of Urology, Sapporo Medical University School of Medicine.

Lynch syndrome (LS) is an autosomal dominant genetic disorder in which tumors are known to develop at an early age. Upper tract urothelial carcinoma is one of the tumors related to Lynch syndrome. A 49-year-old woman visited a urologic clinic due to left abdominal pain. She had a history of ovarian cancer. Her mother had a history of colorectal cancer and renal pelvic cancer, and her grandmother had had colorectal cancer. After detailed examination, she received laparoscopic left nephroureterectomy and she was pathologically diagnosed with left ureteral cancer. LS was suspected based on her past history, family history, and age. A microsatellite instability (MSI) test gave a positive result, and genetic analysis confirmed a mutation in the MSH2 gene, leading to the diagnosis of Lynch syndrome. Although LS has a high frequency of carcinogenesis, it is thought that an improved prognosis can be achieved by early discovery and treatment of cancer in LS patients. From our case report, we recommend screening of LS in patients with a past/family history, who have had an upper tract urothelial carcinoma. Once LS is diagnosed, the patient should be followed by a planned surveillance of cancer development.
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http://dx.doi.org/10.14989/ActaUrolJap_67_6_229DOI Listing
June 2021

Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2020 for the Clinical Practice of Hereditary Colorectal Cancer.

Int J Clin Oncol 2021 Aug 29;26(8):1353-1419. Epub 2021 Jun 29.

Tokyo Medical and Dental University, Tokyo, Japan.

Hereditary colorectal cancer (HCRC) accounts for < 5% of all colorectal cancer cases. Some of the unique characteristics commonly encountered in HCRC cases include early age of onset, synchronous/metachronous cancer occurrence, and multiple cancers in other organs. These characteristics necessitate different management approaches, including diagnosis, treatment or surveillance, from sporadic colorectal cancer management. There are two representative HCRC, named familial adenomatous polyposis and Lynch syndrome. Other than these two HCRC syndromes, related disorders have also been reported. Several guidelines for hereditary disorders have already been published worldwide. In Japan, the first guideline for HCRC was prepared by the Japanese Society for Cancer of the Colon and Rectum (JSCCR), published in 2012 and revised in 2016. This revised version of the guideline was immediately translated into English and published in 2017. Since then, several new findings and novel disease concepts related to HCRC have been discovered. The currently diagnosed HCRC rate in daily clinical practice is relatively low; however, this is predicted to increase in the era of cancer genomic medicine, with the advancement of cancer multi-gene panel testing or whole genome testing, among others. Under these circumstances, the JSCCR guidelines 2020 for HCRC were prepared by consensus among members of the JSCCR HCRC Guideline Committee, based on a careful review of the evidence retrieved from literature searches, and considering the medical health insurance system and actual clinical practice settings in Japan. Herein, we present the English version of the JSCCR guidelines 2020 for HCRC.
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http://dx.doi.org/10.1007/s10147-021-01881-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8286959PMC
August 2021

[Fever after Gemcitabine Administration is a Poor Prognostic Factor in Patients with Metastatic Urothelial Carcinoma : Multicenter Retrospective Study].

Hinyokika Kiyo 2021 May;67(5):181-185

The Department of Urology, Sapporo Medical University School of Medicine.

Gemcitabine (GEM) is currently a standard chemotherapeutic agent for metastatic urothelial carcinoma (mUC). Fever isknown to be an adverse effect of GEM ; however, itsincidence, etiology and clinical significance have not been evaluated. The objective of this study was to elucidate the characteristics and clinical significance of fever associated with GEM in patients with mUC receiving GEM plus cisplatin (GC) chemotherapy. Between 2005 and 2014, 184 patientswith mUC who received first-line GC therapy at 10 institutions were enrolled. GEM-associated fever (GEMAF) was defined as a body temperature ≥37.5ºC within 96 hours after administration of GEM with no evidence of specific conditions causing fever including infection. Clinical parametersbefore GC therapy were evaluated to determine predictorsof GEMAF. Furthermore, the impact of GEMAF on clinical outcomeswasals o evaluated. The median age was70 years and median follow-up was14.2 months. GEMAF wasobs erved in 44 patients (23.9%). In multivariate analysis, elevated C-reactive protein (CRP) before chemotherapy was an independent predictive factor for GEMAF (oddsratio 2.450, p=0.041). There was a significant difference in progression-free survival (median 6.7 vs 8.0 months, p=0.031) and cancer-specific survival (median 12.0 vs 15.8 months, p=0.045) between patients with and without GEMAF. Results of this study suggest that GEMAF is a common adverse event of GC therapy for mUC and can be a poor prognostic factor. GEMAF may be associated with systemic inflammatory response induced by the tumor in patients with mUC.
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http://dx.doi.org/10.14989/ActaUrolJap_67_5_181DOI Listing
May 2021

Significance of urinary liver-type fatty acid-binding protein in patients with normal renal function after undergoing intestinal urinary diversion: a preliminary study.

Clin Exp Nephrol 2021 Oct 7;25(10):1151-1157. Epub 2021 Jun 7.

Department of Urology, Sapporo Medical University School of Medicine, South 1, West 16, Chuo-ku, Sapporo, 060-8543, Japan.

Background: Liver-type fatty acid-binding protein (L-FABP) in urine is one of the early diagnostic biomarkers for acute and chronic kidney injuries. Although this protein is also identified in the intestine, there is no verified reference value for patients with intestinal urinary diversion (UD). The aim of the present study was to measure L-FABP values in such patients and compare them with the results for patients without UD.

Methods: Spot urine specimens were collected from 41 patients with UD and 50 subjects without UD with estimated glomerular filtration rates of over 60 ml/min/1.73 m, and the L-FABP values were measured. The normal upper cutoff value in healthy subjects without UD is considered to be 7.24 μg/g Cr. First, the median values of the two groups were compared. Next, the subjects with negative proteinuria and without comorbidities associated with renal function were further selected and the median values of the groups were compared.

Results: The mean age was significantly higher in the UD group. The types of UD were ileal conduit (38 patients) and ileal neobladder (three patients). The median L-FABP value in the UD group was significantly higher than that in the non-diversion group (89.1 μg/g Cr vs. 2.0 μg/g Cr, p < 0.0001). After adjustment for their backgrounds, the median value remained higher in the UD group.

Conclusions: L-FABP values in subjects with UD are higher than in those without UD. By this result, to develop a reference value in patients with intestinal UD population, further studies are required.
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http://dx.doi.org/10.1007/s10157-021-02088-7DOI Listing
October 2021

[A Case of Detrusor Hyperactivity with Impaired Contractility (DHIC) after Transverse Myelitis].

Hinyokika Kiyo 2021 Mar;67(3):109-112

The Department of Urology, Sapporo Medical University School of Medicine.

A 44-year-old man was carried to the hospital in an ambulance because of dyspnea, paralysis and dysuria after signs of the flu. Acute encephalomyelitis was diagnosed by examination of magnetic resonance imaging. Antimicrobial treatment and respirator management was carried out with indwelling of urethral catheter for urinary retention. After improvement of encephalitis, the urethral catheter was removed. However, he still needed medical care because of persistent lower urinary tract symptoms. He complained of urge incontinence and urination frequency. Decrease of functional bladder capacity was noticed in a frequency volume chart. After consulting with our neurologist, acute transverse myelitis was diagnosed from imaging and neurological findings. Pressure flow study (PFS)demonstrated detrusor overactive during the filling phase and insufficient contractility during the voiding phase. We reached the diagnosis of detrusor hyperactivity with impaired contractility (DHIC). We did not introduce clean intermittent catheterization but used the mirabegron instead. Although storage symptoms did not improve on the mirabegron monotherapy, the symptoms improved by solifenacin added. There is a possibility that combination therapy with mirabegron and solifenacin is effective for DHIC.
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http://dx.doi.org/10.14989/ActaUrolJap_67_3_109DOI Listing
March 2021

Patient preferences for growth hormone treatment in Japanese children.

Pediatr Int 2021 Oct 25;63(10):1185-1191. Epub 2021 Aug 25.

RWE & HEOR, IQVIA Solutions Japan K.K, Tokyo, Japan.

Background: There are not clear evidence to date evaluating patients' and caregivers' preferences for the recombinant-human growth hormone (r-hGH) injection in children in Japan. This study aimed to quantitatively evaluated the factors driving preferences for daily r-hGH injections among Japanese children with growth hormone deficiency (GHD) or their caregivers and to determine the relative importance of treatment delivery factors.

Methods: This study was performed among Japanese children with GHD or their caregivers who visited a specialized clinic in Japan as part of their routine care. The participants were asked to complete a web-based discrete choice experiment (DCE) questionnaire.

Results: Choice-based conjoint analysis was used to evaluate the relative importance of the attributes of the choice predictors and determine utility scores for each attribute. Of the 47 respondents who participated in this study, 41 were caregivers who responded on behalf of the patients, the remaining six were patients who completed the DCE themselves. The injection schedule was found to be the most important factor for both patients and caregivers; a once-weekly injection schedule was preferred over a daily injection schedule. Storage and preparation was deemed more important to patients than it was to caregivers, with patients preferring storage at room temperature even if it required additional mixing (reconstitution). Both patients and caregivers showed a clear preference for devices that offered a dose-setting memory.

Conclusions: A less frequent injection schedule may enhance adherence to r-hGH treatment and expected improve quality of life for GHD patients over the long term.
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http://dx.doi.org/10.1111/ped.14760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8596999PMC
October 2021

The current status of 492 adult women with Turner syndrome: a questionnaire survey by the Foundation for Growth Science.

Endocr J 2021 Sep 28;68(9):1081-1089. Epub 2021 Apr 28.

Growth Hormone Therapy Research Committee, Foundation for Growth Science, Tokyo 113-0033, Japan.

Current status and its background of Adult Turner Syndrome (TS) are not clarified well. Via a questionnaire survey of 492 adult women with TS, this study investigated the association between menstruation, Kaufmann therapy (menstrual induction therapy), social status (education, employment & marriage), complications, transition from pediatric to adult care, and sex chromosome karyotype using statistical methods. Spontaneous menarche occurred in 22.0% and more frequently among patients with the 45,X/46,XX karyotype. Over 60% of these subjects, menstruation did not persist regularly. Kauffmann therapy was performed in 69.4%; the most common formulation was a conjugated estrogen and progesterone combination. Marriage and higher education advancement rates were low in adults with TS, whereas their employment rate was similar to that of the age-matched general female population. Patients receiving Kauffmann therapy had higher complication rates, greater education length, and higher employment rates. The higher-education advancement rate was observed among patients with 45,X/46,X,Xi and 46,X,Xi karyotypes. Transition from pediatrician to adult specialist was not smooth, subjects were treated in pediatric departments (60.7%), gynecological department (21.4%), internal medicine departments (13.3%), and others. While reason is not clear, the largest number of TS patients are treated in general pediatrics and the percentage of receiving Kauffmann therapy and having complication were significantly lower than in pediatric and adult department of endocrinology (& metabolism). This Study revealed many novel findings of adult TS.
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http://dx.doi.org/10.1507/endocrj.EJ20-0617DOI Listing
September 2021

Risk factors for non-reaching of ileal pouch to the anus in laparoscopic restorative proctocolectomy with handsewn anastomosis for ulcerative colitis.

Intest Res 2021 Mar 12. Epub 2021 Mar 12.

Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan.

Background/aims: Restorative proctocolectomy (RPC) with ileal pouch-anal anastomosis and handsewn anastomosis for ulcerative colitis requires pulling down of the ileal pouch into the pelvis, which can be technically challenging. We examined risk factors for the pouch not reaching the anus.

Methods: Clinical records of 62 consecutive patients who were scheduled to undergo RPC with handsewn anastomosis at the University of Tokyo Hospital during 1989-2019 were reviewed. Risk factors for non-reaching were analyzed in patients in whom hand sewing was abandoned for stapled anastomosis because of nonreaching. Risk factors for non-reaching in laparoscopic RPC were separately analyzed. Anatomical indicators obtained from presurgical computed tomography (CT) were also evaluated.

Results: Thirty-seven of 62 cases underwent laparoscopic procedures. In 6 cases (9.7%), handsewn anastomosis was changed to stapled anastomosis because of non-reaching. Male sex and a laparoscopic approach were independent risk factors of non-reaching. Distance between the terminal of the superior mesenteric artery (SMA) ileal branch and the anus > 11 cm was a risk factor for non-reaching.

Conclusions: Laparoscopic RPC with handsewn anastomosis may limit extension and induction of the ileal pouch into the anus. Preoperative CT measurement from the terminal SMA to the anus may be useful for predicting non-reaching.
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http://dx.doi.org/10.5217/ir.2020.00158DOI Listing
March 2021

The Effect of Walking Backward on a Treadmill on Balance, Speed of Walking and Cardiopulmonary Fitness for Patients with Chronic Stroke: A Pilot Study.

Int J Environ Res Public Health 2021 03 1;18(5). Epub 2021 Mar 1.

Department of Sports Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.

This study determines the effect of walking backward on a treadmill on balance, speed of walking and cardiopulmonary fitness for patients with chronic stroke. Subjects with chronic stroke for more than six months, whose level of Brunnstrom stage is greater than IV and who are able to walk more than eleven meters with or without assistive devices were recruited. After grouping for a single-blind clinical randomized controlled trial, the subjects were divided into two groups: eight in the control group and eight in the experimental group. All subjects were subjected to 30 min traditional physical therapy, three times a week for four weeks. The experimental group was subjected to an additional 30 min of walking backward on a treadmill. The Berg Balance Scale (BBS) and the Timed Up and Go test (TUG) were used to determine the functional balance and walking ability. The walking speed was evaluated using a timed 10-Meter Walk Test (10MWT), and the cardiopulmonary fitness was determined using a 6-Minute Walk Test (6MWT) and a pulmonary function test (PFT). All assessments were made at baseline before training commenced (pre-training) and at the end of the four-week training period (post-training). A paired -test and an independent -test were used to determine the effect on balance, speed of walking and cardiopulmonary fitness before and after training. The level of significance α was 0.05. After four weeks of training, the experimental group showed significant differences ( < 0.05) on TUG, BBS, 10MWT, 6MWT, forced vital capacity (FVC) and forced expiratory volume in one second (FEV1). This pilot study shows that the 30 min of walking backward on a treadmill three times a week for four weeks increased balance, speed of walking and cardiopulmonary fitness. Trial registration: Current Controlled Trials NCT02619110.
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http://dx.doi.org/10.3390/ijerph18052376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7967772PMC
March 2021

Clinical significance of CD8 and FoxP3 tumor-infiltrating lymphocytes and MFG-E8 expression in lower rectal cancer with preoperative chemoradiotherapy.

Mol Clin Oncol 2021 May 5;14(5):87. Epub 2021 Mar 5.

Division of Surgical Oncology, Department of Surgery, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.

Preoperative chemoradiotherapy (CRT) for rectal cancer contributes to tumor down-staging and decreases locoregional recurrence. However, each patient shows a significantly different response to CRT. Therefore, the identification of predictive factors to CRT response would be beneficial to avoid unnecessary treatment. Cancer immunity in patients has been suggested to play an important role in the eradication of the tumor by CRT. In the present study, the utility of CD8 and forkhead box P3 (FoxP3) tumor-infiltrating lymphocytes (TILs) and the expression of a novel immuno-regulatory factor, lactadherin (MFG-E8), in predicting CRT effectiveness in patients with rectal cancer was examined. A total of 61 patients with rectal cancer, who underwent curative resection following CRT were included in the study. The numbers of CD8 and FoxP3 TILs in a biopsy taken before CRT and MFG-E8 expression level in the specimens obtained at the time of the surgery after CRT were examined using immunohistochemical staining, and their association with clinicopathological characteristics, including patient survival, was determined. The tumors with more CD8 TILs in the biopsy samples before CRT showed a significantly more favorable CRT response. The patients with tumors and a higher number of CD8 TILs before CRT also exhibited significantly longer disease-free and overall survival times. Higher MFG-E8 expression level in post-CRT specimens was significantly associated with favorable CRT response; however, no significant association was found with any other clinicopathological characteristics, including survival time. The number of CD8 TILs before CRT was a valuable predictor for CRT response and was associated with favorable prognosis in patients with lower rectal cancer and who were treated with CRT. High MFG-E8 expression level after CRT was also associated with a favorable CRT response.
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http://dx.doi.org/10.3892/mco.2021.2249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7976375PMC
May 2021

Neuregulin-1-β1 and γ-secretase play a critical role in sphere-formation and cell survival of urothelial carcinoma cancer stem-like cells.

Biochem Biophys Res Commun 2021 05 19;552:128-135. Epub 2021 Mar 19.

Department of Pathology, School of Medicine, Sapporo Medical University, Sapporo, 060-8556, Japan. Electronic address:

Previously, we investigated gene expression in a high aldehyde dehydrogenase 1 expression (ALDH1) population of urothelial carcinoma (UC) cells as UC cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) and found that NRG1 expression was upregulated in ALDH1 cells. NRG1 is a trophic factor that contains an epidermal growth factor (EGF)-like domain that signals by stimulating ERBB receptor tyrosine kinases and the cytoplasmic domain. NRG1 has been determined to be involved in frequent gene fusions with other partners in several malignancies and has a role in carcinogenesis through the NRG1 EGF-like domain and its cognitive receptor ERBBs. We thus aimed to elucidate the function of NRG1 in UC CSCs/CICs in this study. Both NRG1α and NRG1-β1 were preferentially expressed in ALDH1 cells compared with ALDH1 cells; however, siRNA experiments revealed that NRG1-β1 but not NRG1-α has a role in sphere formation. The EGF-like domain of NRG1 had a role in sphere formation of UC cells to some extent but was not essential. The intracellular domain of NRG1 did not have a role in sphere-formation. Inhibition of γ-secretase suppressed sphere formation. These findings indicate that cleavage of NRG1-β1 by γ-secretase plays an important role in UC CSC/CIC proliferation; however, the downstream targets of NRG1-β1 remain elusive.
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http://dx.doi.org/10.1016/j.bbrc.2021.03.038DOI Listing
May 2021
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