Publications by authors named "Yoshiyuki Ishii"

155 Publications

Usefulness of laparoscopic surgery and preoperative examinations for chronic recurrent small bowel obstruction.

Surg Today 2021 May 10;51(5):807-813. Epub 2021 Jan 10.

Department of Surgery, Kitasato University Kitasato Institute Hospital, Shirokane 5-9-1, Minato-ku, Tokyo, 108-8642, Japan.

Purpose: The aim of this study was to investigate the usefulness of laparoscopic surgery for patients with postoperative abdominal symptoms, including chronic recurrent small-bowel obstruction (SBO), and preoperative examinations of barium follow-through and computed tomography (CT) to predict the postoperative outcomes of laparoscopic surgery.

Methods: Between 2016 and 2018, 49 patients with postoperative symptoms were treated by laparoscopic surgery at our institute. The data from two preoperative examinations were available for 42 patients. The patients were divided into 4 groups: CT-positive (CP, n = 18), barium follow-through-positive (BP, n = 1), both positive (AP [all positive] n = 13), and both negative (AN [all negative], n = 10).

Results: Among the 49 patients, 41 received pure laparoscopic surgery, 7 received laparoscopic-assisted surgery with mini-laparotomy, and 1 required conversion. Intra- and postoperative complications occurred in two and seven patients, respectively. Improvement of abdominal symptoms was observed in 40 patients. In terms of the medium-term outcomes, the rate of improvement of symptoms was poorer in the AN group than in the other three groups, but not to a significant degree.

Conclusion: Laparoscopic surgery was safe and feasible for patients with chronic recurrent abdominal symptoms, including SBO. Furthermore, in patients with negative results on both preoperative examinations, laparoscopic surgery may yield only poor improvement of symptoms.
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http://dx.doi.org/10.1007/s00595-020-02197-yDOI Listing
May 2021

Case of cryopyrin-associated periodic syndrome who recovered from growth delay by treatment with canakinumab.

J Dermatol 2021 Feb 8;48(2):e98-e99. Epub 2020 Nov 8.

Department of Dermatology, University of Tsukuba, Tsukuba, Japan.

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http://dx.doi.org/10.1111/1346-8138.15681DOI Listing
February 2021

Establishment and Molecular Phenotyping of Organoids from the Squamocolumnar Junction Region of the Uterine Cervix.

Cancers (Basel) 2020 Mar 15;12(3). Epub 2020 Mar 15.

Department of Molecular Carcinogenesis, Chiba Cancer Center Research Institute, Chiba 260-8717, Japan.

The metaplastic epithelium of the transformation zone (TZ) including the squamocolumnar junction (SCJ) of the uterine cervix is a prime target of human papilloma virus (HPV) infection and subsequent cancer development. Due to the lack of adequate in vitro models for SCJ, however, investigations into its physiological roles and vulnerability to carcinogenesis have been limited. By using Matrigel-based three-dimensional culture techniques, we propagated organoids derived from the normal SCJ region, along with metaplastic squamous cells in the TZ. Consisting predominantly of squamous cells, organoids basically exhibited a dense structure. However, at least in some organoids, a small but discrete population of mucin-producing endocervix cells co-existed adjacent to the squamous cell population, virtually recapitulating the configuration of SCJ in a TZ background. In addition, transcriptome analysis confirmed a higher expression level of many SCJ marker genes in organoids, compared to that in the immortalized cervical cell lines of non-SCJ origin. Thus, the obtained organoids appear to mimic cervical SCJ cells and, in particular, metaplastic squamous cells from the TZ, likely providing a novel platform in which HPV-driven cervical cancer development could be investigated.
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http://dx.doi.org/10.3390/cancers12030694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140077PMC
March 2020

The Transcriptional Cofactor VGLL1 Drives Transcription of Human Papillomavirus Early Genes via TEAD1.

J Virol 2020 05 4;94(10). Epub 2020 May 4.

Pathogen Genomics Center, National Institute of Infectious Diseases, Tokyo, Japan.

The TEAD family of transcription factors requires associating cofactors to induce gene expression. TEAD1 is known to activate the early promoter of human papillomavirus (HPV), but the precise mechanisms of TEAD1-mediated transactivation of the HPV promoter, including its relevant cofactors, remain unexplored. Here, we reveal that VGLL1, a TEAD-interacting cofactor, contributes to HPV early gene expression. Knockdown of VGLL1 and/or TEAD1 led to a decrease in viral early gene expression in human cervical keratinocytes and cervical cancer cell lines. We identified 11 TEAD1 target sites in the HPV16 long control region (LCR) by DNA pulldown assays; 8 of these sites contributed to the transcriptional activation of the early promoter in luciferase reporter assays. VGLL1 bound to the HPV16 LCR via its interaction with TEAD1 both and Furthermore, introducing HPV16 and HPV18 whole genomes into primary human keratinocytes led to increased levels of VGLL1, due in part to the upregulation of TEADs. These results suggest that multiple VGLL1/TEAD1 complexes are recruited to the LCR to support the efficient transcription of HPV early genes. Although a number of transcription factors have been reported to be involved in HPV gene expression, little is known about the cofactors that support HPV transcription. In this study, we demonstrate that the transcriptional cofactor VGLL1 plays a prominent role in HPV early gene expression, dependent on its association with the transcription factor TEAD1. Whereas TEAD1 is ubiquitously expressed in a variety of tissues, VGLL1 displays tissue-specific expression and is implicated in the development and differentiation of epithelial lineage tissues, where HPV gene expression occurs. Our results suggest that VGLL1 may contribute to the epithelial specificity of HPV gene expression, providing new insights into the mechanisms that regulate HPV infection. Further, VGLL1 is also critical for the growth of cervical cancer cells and may represent a novel therapeutic target for HPV-associated cancers.
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http://dx.doi.org/10.1128/JVI.01945-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7199408PMC
May 2020

The homeobox transcription factor HOXC13 upregulates human papillomavirus E1 gene expression and contributes to viral genome maintenance.

FEBS Lett 2020 02 15;594(4):751-762. Epub 2019 Nov 15.

Pathogen Genomics Center, National Institute of Infectious Diseases, Tokyo, Japan.

Human papillomavirus (HPV) infects the basal cells of epithelia and maintains its genome stably as episomes. However, the mechanisms of viral genome maintenance are not fully understood. Here, using normal human immortalized keratinocytes (NIKS), we identified the homeobox transcription factor HOXC13 as a critical host factor for retaining the copy number of HPV genomes in the cell. HOXC13 knockdown in NIKS significantly decreased mRNA levels of the E1 gene, which encodes a DNA helicase required for HPV genome replication, accompanied by a reduction of the viral genome copy number. Chromatin immunoprecipitation assays revealed HOXC13 binding to the long control region that regulates E1 expression. These results indicate that HOXC13 plays invaluable roles in maintaining HPV persistent infection through E1 gene upregulation.
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http://dx.doi.org/10.1002/1873-3468.13646DOI Listing
February 2020

The Efficacy of PTGBD for Acute Cholecystitis Based on the Tokyo Guidelines 2018.

World J Surg 2019 11;43(11):2789-2796

Department of Surgery, Kitasato University, Kitasato Institute Hospital, Tokyo, Japan.

Backgrounds: We usually performed percutaneous transhepatic gallbladder drainage (PTGBD) for moderate and severe acute cholecystitis (AC) prior to cholecystectomy. But, the validity of preoperative drainage for AC is still controversial. The aim of this study is to evaluate the efficacy and safety of PTGBD for moderate and severe AC, based on the Tokyo Guidelines 2018.

Materials: Total of 146 AC patients from 2012 to 2017 were enrolled. Patients were classified in the grade of severity according to TG18, compared with PTGBD and non-PTGBD group. We retrospectively reviewed clinical backgrounds and laboratory data at admission. We evaluated surgical performances as the primary outcomes and recovery periods based on guidelines.

Results: A total of 61 cases were moderate, and 18 cases were severe AC, and PTGBD were performed in 34 cases. For moderate AC, age, DM rate and ASA in PTGBD group were significantly higher than those in non-PTGBD group. Also, serum albumin and hemoglobin at admission were significantly lower in the PTGBD group. However, surgical outcomes were almost the same. For severe AC patients, laparoscopic cholecystectomy was performed safely in all of pre-operating drainage cases, while almost all of non-PTGBD cases underwent open laparotomy and needed transfusion for massive bleeding.

Conclusions: Preoperative PTGBD is a useful and safe procedure for AC patients with comorbidities, especially in severe AC cases. Treatment flowchart in TG18 can be feasible to make accurate prediction for surgically high-risk patients in AC.
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http://dx.doi.org/10.1007/s00268-019-05117-5DOI Listing
November 2019

Laparoscopic surgery to treat leiomyosarcomas of the sigmoid colon:a case report and literature review.

Surg Case Rep 2019 Feb 12;5(1):20. Epub 2019 Feb 12.

Department of Surgery, Kitasato University Kitasato Institute Hospital, 5-9-1 Shirokane, Minato-ku, Tokyo, Japan.

Background: Leiomyosarcomas (LMSs) of the colon are extremely rare and highly aggressive. Although treatment of gastrointestinal LMS is not standardized, surgical resection is generally performed. The fact that the tumors are usually large at the time of diagnosis may explain why no report on laparoscopic resection of a colonic LMS has appeared.

Case Presentation: A 46-year-old male presented with hematochezia 1 month in duration. Abdominal examination including palpation was normal. The levels of several blood tumor markers were normal. Colonoscopy revealed a polypoid lesion approximately 30 mm in diameter in the sigmoid colon 30 cm from the anal verge. Contrast-enhanced computed tomography revealed that the tumor was 28 mm in diameter, and that no lymph node or distant metastasis was apparent. Histopathological examination of a biopsy specimen revealed spindle-shaped cells exhibiting significant nuclear atypia and a trabecular proliferation pattern upon hematoxylin-eosin staining. Immunohistochemically, the sample was positive for SMA and desmin, and negative for c-kit, DOG-1, CD34, and S-100. Furthermore, the Ki-67 index was > 50%. We thus diagnosed a leiomyosarcoma of the sigmoid colon without any metastasis. We performed laparoscopic sigmoid colectomy and regional lymphadenectomy using five trocars. After complete curative resection, a colorectal end-to-end anastomosis was created employing the double-stapling technique. All surgical margins were negative, and no lymph node metastasis was observed. The postoperative course was uneventful, and the patient was discharged 9 days after operation. No recurrence was noted to 1 year after surgery.

Conclusions: We report the first case of a colonic LMS treated via laparoscopic surgery. Although further work is necessary to assess prognosis and to develop the treatment further, laparoscopic surgery to treat small colonic LMSs may be feasible, being both minimally invasive and curative.
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http://dx.doi.org/10.1186/s40792-019-0579-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6372699PMC
February 2019

Short-term and midterm outcomes of single-incision laparoscopic surgery for right-sided colon cancer.

Asian J Endosc Surg 2019 Jul 27;12(3):275-280. Epub 2018 Sep 27.

Department of Surgery, Kitasato University Kitasato Institute Hospital, Tokyo, Japan.

Introduction: The purpose of this study was to clarify the usefulness of SILS for right-sided colon cancer by evaluating the short-term and midterm outcomes.

Methods: Between 2012 and 2017, 65 selected patients with right-sided colon cancer underwent ileocecal resection, right hemicolectomy, or transverse colectomy; all were enrolled in the study. The same well-trained surgeon performed each procedure by using a multi-instrument access port with three channels, which was placed at the umbilicus via an approximately 3-cm skin incision.

Results: The pathological disease stage distribution was stage 0, 4 cases; stage I, 23 cases; stage II, 19 cases; stage III, 17 cases; and stage IV, 2 cases. The surgical procedures performed were ileocecal resection, 23 cases; right hemicolectomy, 35 cases; and transverse colectomy, 7 cases. The median operative time and intraoperative blood loss were 216 min and 10 mL, respectively. Although 18 cases needed additional ports, none required conversion to open surgery. The median number of harvested lymph nodes was 24. No major perioperative morbidities occurred in this patient series. The median postoperative hospital stay was 7 days. The median follow-up period was 30 months, and the 3-year relapse-free and overall survival rates were 100% and 100%, respectively, in the stage 0-I cases and 89% and 96% in the stage II-III cases, respectively.

Conclusion: We concluded that SILS is as feasible as multiport laparoscopic surgery and a reliable surgical option in selected cases of right-sided colon cancer.
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http://dx.doi.org/10.1111/ases.12654DOI Listing
July 2019

Trichostasis spinulosa arising in isolated collagenoma of the scalp.

Eur J Dermatol 2018 Aug;28(4):531-532

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

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http://dx.doi.org/10.1684/ejd.2018.3310DOI Listing
August 2018

Needlescopic versus conventional laparoscopic surgery for colorectal cancer ~a comparative study~.

J Anus Rectum Colon 2017 25;1(2):45-49. Epub 2018 May 25.

Department of Surgery, Keio University School of Medicine.

Objectives: This study set out to determine whether Needlescopic surgery (NS) produces comparable surgical outcomes for patients with colorectal cancer (CRC) compared to conventional multi-port laparoscopic surgery (MPS).

Methods: We used the five-port method with a 3.5 cm umbilical incision for extraction and reconstruction during MPS for CRC. One or two 5 mm ports were exchanged for needle forceps and all surgical procedures were as for previous MPS since July 2012. We investigated the short-term outcomes of 138 consecutive patients who underwent curative resection of CRC by NS (July 2012-August 2014) and 130 consecutive patients with CRC treated with MPS during a previous period (January 2010-June 2012).

Results: Operative time in the NS group was comparable to that of MPS (p=0.467); the NS group had significantly less estimated blood loss (p=0.002) and a shorter postoperative hospital stay (p<0.001). The mean number of dissected lymph nodes was 27 in both groups (p=0.730). No mortality occurred in either group, and similar morbidity rates were observed (p=0.454).

Conclusions: NS using Endo Relief needle forceps is a safe and feasible option compared to conventional MPS for CRC.
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http://dx.doi.org/10.23922/jarc.2016-007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6768669PMC
May 2018

Within-Host Variations of Human Papillomavirus Reveal APOBEC Signature Mutagenesis in the Viral Genome.

J Virol 2018 06 29;92(12). Epub 2018 May 29.

Pathogen Genomics Center, National Institute of Infectious Diseases, Tokyo, Japan

Persistent infection with oncogenic human papillomaviruses (HPVs) causes cervical cancer, accompanied by the accumulation of somatic mutations into the host genome. There are concomitant genetic changes in the HPV genome during viral infection; however, their relevance to cervical carcinogenesis is poorly understood. Here, we explored within-host genetic diversity of HPV by performing deep-sequencing analyses of viral whole-genome sequences in clinical specimens. The whole genomes of HPV types 16, 52, and 58 were amplified by type-specific PCR from total cellular DNA of cervical exfoliated cells collected from patients with cervical intraepithelial neoplasia (CIN) and invasive cervical cancer (ICC) and were deep sequenced. After constructing a reference viral genome sequence for each specimen, nucleotide positions showing changes with >0.5% frequencies compared to the reference sequence were determined for individual samples. In total, 1,052 positions of nucleotide variations were detected in HPV genomes from 151 samples (CIN1, = 56; CIN2/3, = 68; ICC, = 27), with various numbers per sample. Overall, C-to-T and C-to-A substitutions were the dominant changes observed across all histological grades. While C-to-T transitions were predominantly detected in CIN1, their prevalence was decreased in CIN2/3 and fell below that of C-to-A transversions in ICC. Analysis of the trinucleotide context encompassing substituted bases revealed that TpCpN, a preferred target sequence for cellular APOBEC cytosine deaminases, was a primary site for C-to-T substitutions in the HPV genome. These results strongly imply that the APOBEC proteins are drivers of HPV genome mutation, particularly in CIN1 lesions. HPVs exhibit surprisingly high levels of genetic diversity, including a large repertoire of minor genomic variants in each viral genotype. Here, by conducting deep-sequencing analyses, we show for the first time a comprehensive snapshot of the within-host genetic diversity of high-risk HPVs during cervical carcinogenesis. Quasispecies harboring minor nucleotide variations in viral whole-genome sequences were extensively observed across different grades of CIN and cervical cancer. Among the within-host variations, C-to-T transitions, a characteristic change mediated by cellular APOBEC cytosine deaminases, were predominantly detected throughout the whole viral genome, most strikingly in low-grade CIN lesions. The results strongly suggest that within-host variations of the HPV genome are primarily generated through the interaction with host cell DNA-editing enzymes and that such within-host variability is an evolutionary source of the genetic diversity of HPVs.
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http://dx.doi.org/10.1128/JVI.00017-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5974501PMC
June 2018

Congenital peristernal dermal sinus: A case report and published work review.

J Dermatol 2018 Sep 23;45(9):e242-e243. Epub 2018 Mar 23.

Department of Dermatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.

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http://dx.doi.org/10.1111/1346-8138.14299DOI Listing
September 2018

Tufted angioma of the finger: A case of an uncommon location with unique dermoscopic features.

J Dermatol 2018 Aug 6;45(8):e236-e237. Epub 2018 Mar 6.

Department of Dermatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.

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http://dx.doi.org/10.1111/1346-8138.14279DOI Listing
August 2018

Unusual association between digital mucous cyst and acquired ungual fibrokeratoma: A case report.

J Dermatol 2018 Aug 27;45(8):e234-e235. Epub 2018 Feb 27.

Department of Dermatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.

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http://dx.doi.org/10.1111/1346-8138.14275DOI Listing
August 2018

Whole-genome analysis of human papillomavirus genotypes 52 and 58 isolated from Japanese women with cervical intraepithelial neoplasia and invasive cervical cancer.

Infect Agent Cancer 2017 4;12:44. Epub 2017 Aug 4.

Pathogen Genomics Center, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashi-murayama, Tokyo, 208-0011 Japan.

Background: Human papillomavirus genotypes 52 and 58 (HPV52/58) are frequently detected in patients with cervical intraepithelial neoplasia (CIN) and invasive cervical cancer (ICC) in East Asian countries including Japan. As with other HPV genotypes, HPV52/58 consist of multiple lineages of genetic variants harboring less than 10% differences between complete genome sequences of the same HPV genotype. However, site variations of nucleotide and amino acid sequences across the viral whole-genome have not been fully examined for HPV52/58. The aim of this study was to investigate genetic variations of HPV52/58 prevalent among Japanese women by analyzing the viral whole-genome sequences.

Methods: The entire genomic region of HPV52/58 was amplified by long-range PCR with total cellular DNA extracted from cervical exfoliated cells isolated from Japanese patients with CIN or ICC. The amplified DNA was subjected to next generation sequencing to determine the complete viral genome sequences. Phylogenetic analyses were performed with the whole-genome sequences to assign variant lineages/sublineages to the HPV52/58 isolates. The variability in amino acid sequences of viral proteins was assessed by calculating the Shannon entropy scores at individual amino acid positions of HPV proteins.

Results: Among 52 isolates of HPV52 (CIN1,  = 20; CIN2/3,  = 21; ICC,  = 11), 50 isolates belonged to lineage B (sublineage B2) and two isolates belonged to lineage A (sublineage A1). Among 48 isolates of HPV58 (CIN1,  = 21; CIN2/3,  = 19; ICC,  = 8), 47 isolates belonged to lineage A (sublineages A1/A2/A3) and one isolate belonged to lineage C. Single nucleotide polymorphisms specific for individual variant lineages were determined throughout the viral genome based on multiple sequence alignments of the Japanese HPV52/58 isolates and reference HPV52/58 genomes. Entropy analyses revealed that the E1 protein was relatively variable among the HPV52 isolates, whereas the E7, E4, and L2 proteins showed some variations among the HPV58 isolates.

Conclusions: Among the HPV52/58-positive specimens from Japanese women with CIN/ICC, the variant distributions were strongly biased toward lineage B for HPV52 and lineage A for HPV58 across histological categories. Different patterns of amino acid variations were observed in HPV52 and HPV58 across the viral whole-genome.
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http://dx.doi.org/10.1186/s13027-017-0155-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5545048PMC
August 2017

Cetuximab promotes SN38 sensitivity via suppression of heat shock protein 27 in colorectal cancer cells with wild-type RAS.

Oncol Rep 2017 Aug 21;38(2):926-932. Epub 2017 Jun 21.

Department of Surgery, Keio University School of Medicine, Shinanomachi 35, Shinjuku-ku, Tokyo 160-8582, Japan.

Combination treatment with cetuximab and CPT-11 produces beneficial and synergistic effects in wild-type RAS metastatic colorectal cancer (mCRC) patients. However, the mechanism underlying this synergism is not yet understood. We examined whether cetuximab had a synergistic effect with CPT-11 and its active metabolite, SN38, and examined the molecular mechanism of the synergism between cetuximab and SN38 in CRC cells with various mutational status. We hypothesized that cetuximab promotes sensitivity to SN38 via suppression of heat shock protein 27 (HSP27), a protein involved in multidrug resistance through blocking the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway, which is associated with chemosensitivity. Four human CRC cell lines with different RAS and BRAF mutational status were used. Expression levels of HSP27 protein correlated with SN38 sensitivity in these cell lines (R=0.841, p=0.159). Exposure to cetuximab and various concentration of AG490, an inhibitor of JAK2, STAT3 and HSP27 protein levels, except in the KRAS G12V mutant line, SW620. A synergistic effect of cetuximab in combination with SN38 was observed in RAS and BRAF wild-type cells (here, Caco2), but not in the three other RAS- or BRAF-mutated cell lines. These results indicate that cetuximab may promote sensitivity to SN38 via suppression of HSP27 through blocking the JAK/STAT pathway in Caco2 cells. The mutational status of numerous downstream effectors, such as RAS and BRAF, is important in mono- or combination therapy with cetuximab. In conclusion, cetuximab may promote SN38 sensitivity via suppression of HSP27, through blocking the JAK/STAT signaling pathway, and shows synergistic effects when combined with SN38 in wild-type RAS CRC cells.
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http://dx.doi.org/10.3892/or.2017.5734DOI Listing
August 2017

Safety and Indications of Laparoscopic Surgery for Postoperative Small-bowel Obstruction: A Single-center Study of 121 Patients.

Surg Laparosc Endosc Percutan Tech 2017 Aug;27(4):301-305

*Department of Surgery, Kitasato University School of Medicine, Kitasato, Minami-ku, Sagamihara, Kanagawa, Japan †Department of Surgery, Kitasato Institute Hospital, Shirokane, Minato-ku, Tokyo, Japan.

Background/aims: The purpose of this study was to evaluate the safety and effectiveness of laparoscopic surgery for the treatment of small-bowel obstruction.

Materials And Methods: The study group comprised 121 patients who underwent laparoscopic surgery for small-bowel obstruction.

Results: Previous operations were open surgery in 107 patients and laparoscopic surgery in 14. On univariate analysis, 4 risk factors were related to conversion to open surgery: radiotherapy (P=0.0002), previous episode of intestinal obstruction (P=0.0064), bleeding volume of ≥50 mL (P=0.0059), and the presence or absence of previous bowel resection (P=0.0269). On multivariate analysis, only radiotherapy was an independent risk factor for conversion to open surgery (odds ratio, 5.5141; P=0.0091).

Conclusions: Laparoscopic surgery can be safely performed in patients with postoperative small-bowel obstruction and is considered an effective treatment with a low rate of recurrent bowel obstruction.
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http://dx.doi.org/10.1097/SLE.0000000000000430DOI Listing
August 2017

Cutaneous squamous cell carcinoma treated with preoperative intraarterial chemoradiation therapy.

J Dtsch Dermatol Ges 2017 Jul 17;15(7):724-726. Epub 2017 May 17.

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

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http://dx.doi.org/10.1111/ddg.12590DOI Listing
July 2017

Human Papillomavirus 16 E6 Upregulates APOBEC3B via the TEAD Transcription Factor.

J Virol 2017 03 28;91(6). Epub 2017 Feb 28.

Pathogen Genomics Center, National Institute of Infectious Diseases, Tokyo, Japan.

The cytidine deaminase APOBEC3B (A3B) underlies the genetic heterogeneity of several human cancers, including cervical cancer, which is caused by human papillomavirus (HPV) infection. We previously identified a region within the A3B promoter that is activated by the viral protein HPV16 E6 in human keratinocytes. Here, we discovered three sites recognized by the TEAD family of transcription factors within this region of the A3B promoter. Reporter assays in HEK293 cells showed that exogenously expressed TEAD4 induced A3B promoter activation through binding to these sites. Normal immortalized human keratinocytes expressing E6 (NIKS-E6) displayed increased levels of TEAD1/4 protein compared to parental NIKS. A series of E6 mutants revealed that E6-mediated degradation of p53 was important for increasing TEAD4 levels. Knockdown of TEADs in NIKS-E6 significantly reduced A3B mRNA levels, whereas ectopic expression of TEAD4 in NIKS increased A3B mRNA levels. Finally, chromatin immunoprecipitation assays demonstrated increased levels of TEAD4 binding to the A3B promoter in NIKS-E6 compared to NIKS. Collectively, these results indicate that E6 induces upregulation of A3B through increased levels of TEADs, highlighting the importance of the TEAD-A3B axis in carcinogenesis. The expression of APOBEC3B (A3B), a cellular DNA cytidine deaminase, is upregulated in various human cancers and leaves characteristic, signature mutations in cancer genomes, suggesting that it plays a prominent role in carcinogenesis. Viral oncoproteins encoded by human papillomavirus (HPV) and polyomavirus have been reported to induce A3B expression, implying the involvement of A3B upregulation in virus-associated carcinogenesis. However, the molecular mechanisms causing A3B upregulation remain unclear. Here, we demonstrate that exogenous expression of the cellular transcription factor TEAD activates the A3B promoter. Further, the HPV oncoprotein E6 increases the levels of endogenous TEAD1/4 protein, thereby leading to A3B upregulation. Since increased levels of TEAD4 are frequently observed in many cancers, an understanding of the direct link between TEAD and A3B upregulation is of broad oncological interest.
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http://dx.doi.org/10.1128/JVI.02413-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5331809PMC
March 2017

[A Case of Glycogen-Rich Clear Cell Carcinoma of the Breast with Extensive Intraductal Components and Micrometastases to the Axillary Lymph Node].

Gan To Kagaku Ryoho 2016 Feb;43(2):239-41

Breast Center, Kitasato University Kitasato Institute Hospital.

A 48-year-old woman had a left breast mass identified during routine breast cancer screening. The mammogram showed pleomorphic-segmental microcalcifications in the mediolateral-oblique view of the left breast. Ultrasonography showed a hypoechoic mass approximately 3.7 cm in diameter with multiple calcifications. Contrast-enhanced magnetic resonance imaging of the breast showed non-mass like enhancement of approximately 4 cm in diameter in the C area of the left breast. She was diagnosed with glycogen-rich clear cell carcinoma (GRCC) by ultrasound-guided vacuum-assisted biopsy. Nipplesparing mastectomy was performed along with sentinel lymph node biopsy. The intraoperative consultation suggested sentinel lymph node metastasis and we therefore performed axillary lymph node dissection. Pathological examination reported microinvasive carcinomas, 0.4 cm in maximum diameter, and extensive intraductal components, 5 cm in size. The tumor cells were stained on PAS staining, but the stains were digested with diastase. The cells were negative for adipophilin. GRCC was first reported by Hull et al. This is a rare type of breast carcinoma. There is no standard therapy for this disease or any data on the prognosis of breast cancer patients with GRCC.
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February 2016

Randomized phase II trial of TEGAFIRI (tegafur/uracil, oral leucovorin, irinotecan) compared with FOLFIRI (folinic acid, 5-fluorouracil, irinotecan) in patients with unresectable/recurrent colorectal cancer.

Int J Cancer 2016 Aug 23;139(4):946-54. Epub 2016 Apr 23.

Department of Surgery, Keio University School of Medicine, 35 Shinano-Machi, Shinjuku-Ku, Tokyo, 160-8582, Japan.

Irinotecan-based chemotherapy with bevacizumab is one of the first-line standard therapies for metastatic colorectal cancer (mCRC). TEGAFIRI (UFT/LV + irinotecan) is an irinotecan-based chemotherapy regimen. Currently, few clinical data regarding TEGAFIRI are available. This study evaluated the efficacy and safety of TEGAFIRI in Japanese patients with mCRC. This is a multicenter, randomized, phase II study. The major inclusion criteria were previously untreated patients with mCRC (age: 20-75 years, Eastern Cooperative Oncology Group performance status: 0-1). Eligible patients were randomly assigned (1:1) to receive either FOLFIRI ± bevacizumab or TEGAFIRI ± bevacizumab. The primary endpoint was progression-free survival (PFS). The secondary endpoints were response rate, overall survival, dose intensity and toxicity. From November 2007 to October 2011, 36 and 35 patients assigned to the FOLFIRI and TEGAFIRI groups were included in the primary analysis. No significant difference in PFS was observed between the groups {median PFS: TEGAFIRI 9.9 months [95% confidence interval (CI), 6.5-14.7], FOLFIRI 10.6 months [95% CI, 7.7-16.5]; Hazard ratio, 0.98, 95% CI, 0.57-1.66, p = 0.930}. The response rates in the FOLFIRI and TEGAFIRI groups were 56% and 66%, respectively. Relative dose intensity was similar between the groups. The most common Grade 3/4 adverse event was diarrhea (26%) in TEGAFIRI group and neutropenia (39%) in the FOLFIRI group. The results of the present study indicate that TEGAFIRI ± bevacizumab is an effective and tolerable first-line treatment regimen for mCRC.
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http://dx.doi.org/10.1002/ijc.30127DOI Listing
August 2016

Risk of major bleeding at different PT-INR ranges in elderly Japanese patients with non-valvular atrial fibrillation receiving warfarin: a nested case-control study.

J Pharm Health Care Sci 2016 11;2. Epub 2016 Jan 11.

Department of Pharmacotherapy, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose Tokyo, 204-8588 Japan.

Background: Debate continues about the optimal anticoagulation level for elderly Japanese patients with non-valvular atrial fibrillation (NVAF) receiving warfarin. The Japanese Circulation Society guideline has recommended prothrombin time-international normalized ratios (PT-INR) of 1.6 - 2.6 for elderly patients and 2.0 - 3.0 for non-elderly patients, because previous observational studies indicated increased risk of bleeding when the ratio exceeded 2.6. We aimed to reappraise the relationship between PT-INR and the risk of major bleeding in elderly Japanese patients.

Methods: From the electronic medical records, we selected a cohort of elderly (age ≥ 70 years) Japanese patients with NVAF who were prescribed warfarin for the prevention of thromboembolic diseases between November 2010 and March 2014 at Kanto Rosai Hospital. We identified those who developed major bleeding (cases). For each case, we randomly selected two matched controls by adopting a risk-set sampling method defined by calendar date, age, gender, length of warfarin administration, and the prescriber of warfarin. The risk of major bleeding in patients having PT-INR ≤ 1.49, 1.50 - 1.99, 2.00 - 2.49 (the reference), 2.50 - 2.99, and ≥ 3.00 were compared using the conditional logistic regression method. The study protocol was approved by the IRB before the study was begun.

Results: Among the cohort of 806 elderly patients, we identified 32 cases and selected 64 matched controls. The overall incidence of major bleeding was 3.5 per 100 patient-years. The odds ratios (95 % confidence intervals) for the risk of developing major bleeding in patients with PT-INR ≤ 1.49 (n = 20), 1.50 - 1.99 (n = 32), 2.00 - 2.49 (n = 18), 2.50 - 2.99 (n = 10), and ≥ 3.00 (n = 16) were 1.0 (0.2, 5.9), 0.3 (0.1, 1.9), 1.0 (reference), 1.2 (0.2, 8.4), and 19.8 (2.0, 198.9), respectively, with a significant difference between ≥ 3.00 and reference.

Conclusions: Among elderly Japanese patients with NVAF, PT-INR 2.0 - 3.0 may be associated with a clinically permissible risk of major bleeding while PT-INR ≥ 3.00 a significant risk. Further studies are warranted to determine whether the risk of major bleeding is significantly lower for PT-INR 2.50 - 2.99 than for PT-INR ≥ 3.00.
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http://dx.doi.org/10.1186/s40780-015-0036-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4729034PMC
January 2016

Superior Mesenteric Artery Syndrome Caused by Massive Lumbar Osteophytes: A Case Report.

Spine (Phila Pa 1976) 2015 Aug;40(15):E909-12

*Department of Surgery †Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo, Japan; and ‡Department of Digestive Surgery, Kitasato University Kitasato Institute Hospital, Tokyo, Japan.

Study Design: Case report.

Objective: To present a rare case of superior mesenteric artery (SMA) syndrome caused by massive lumbar osteophytes.

Summary Of Background Data: SMA syndrome is a relatively rare condition thought to be secondary to functional obstruction. Although several risk factors for SMA syndrome have been reported, no other previous reports have suggested that lumbar osteophytes caused SMA syndrome.

Methods: A rare case of SMA syndrome caused by massive lumbar osteophytes was treated by resecting the osteophytes.

Results: An 82-year-old man, with a history of polysurgery, presented with frequent vomiting. He was diagnosed with SMA syndrome after endoscopic and several radiological examinations, and was successfully treated by the resection of the osteophytes.

Conclusion: To the best of our knowledge, a case of SMA syndrome secondary to lumbar osteophytes has not been reported in the literature. The possibility of SMA syndrome caused by massive lumbar osteophytes should be taken into consideration when the cause of SMA syndrome is unknown. In addition, the resection of osteophytes could be a less invasive treatment in such cases.

Level Of Evidence: 5.
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http://dx.doi.org/10.1097/BRS.0000000000000933DOI Listing
August 2015

Identification of APOBEC3B promoter elements responsible for activation by human papillomavirus type 16 E6.

Biochem Biophys Res Commun 2015 May 20;460(3):555-60. Epub 2015 Mar 20.

Pathogen Genomics Center, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashi-murayama, Tokyo 208-0011, Japan.

Recent cancer genomics studies have identified mutation patterns characteristic of APOBEC3B (A3B) in multiple cancers, including cervical cancer, which is caused by human papillomavirus (HPV) infection. A3B expression is upregulated by HPV E6/E7 oncoproteins, implying a crucial role for A3B upregulation in HPV-induced carcinogenesis. Here, we explored the molecular mechanisms underlying the activation of the A3B promoter by E6. Luciferase reporter assays with a series of deleted fragments of the human A3B promoter in normal immortalized human keratinocytes (NIKS) identified two functional regions in the promoter: the distal region (from -200 to -51), which is required for basal promoter activity, and the proximal region (from +1 to +45), which exerts an inhibitory effect on gene expression. Each promoter region was found to contain an E6-responsive element(s). Disruption of an AT-rich motif located between +10 and +16 abrogated the proximal-region-mediated activation of the A3B promoter by E6. DNA pull-down assays revealed that a cellular zinc-finger protein, ZNF384, binds to the AT-rich motif in the A3B promoter, and chromatin immunoprecipitation assays confirmed that ZNF384 binds to the A3B promoter in cells. ZNF384 knockdown reduced the A3B mRNA levels in NIKS expressing E6, but not in the parental NIKS, indicating that ZNF384 contributes to A3B upregulation by E6, but not to basal A3B expression. The exogenous expression of ZNF384 led to the activation of the A3B promoter in NIKS. Collectively, these results indicate that E6 activates the A3B promoter through the distal and proximal regions, and that ZNF384 is required for the proximal-region-mediated activation of A3B.
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http://dx.doi.org/10.1016/j.bbrc.2015.03.068DOI Listing
May 2015