Publications by authors named "Hiroshi Miyamoto"

419 Publications

Time-dependent efficacy of combination of silver-containing hydroxyapatite coating and vancomycin on methicillin-resistant Staphylococcus aureus biofilm formation in vitro.

BMC Res Notes 2021 Mar 2;14(1):81. Epub 2021 Mar 2.

Department of Orthopaedic Surgery, Faculty of Medicine, Saga University, Nabeshima 5-1-1, Saga, 849-8501, Japan.

Objective: We developed a silver-containing hydroxyapatite (Ag-HA) coating to prevent periprosthetic joint infection (PJI). Methicillin-resistant Staphylococcus aureus (MRSA) is the main PJI-causing bacteria. Previously, we had reported the combined effect of Ag-HA coating and vancomycin (VCM) on MRSA biofilm formation 24 h after MRSA inoculation. In this study, we investigated the time-dependent efficacy of Ag-HA coating and VCM on MRSA biofilm formation on Ti discs in vitro by three-dimensional confocal laser scanning microscopic analysis.

Results: For the Ti VCM and HA VCM groups, the total biofilm volumes per area at 96 h after MRSA inoculation were significantly larger than those at 48 h after MRSA inoculation, respectively (p < 0.001). In contrast, for the Ag-HA VCM group, the total biofilm volume per area at 96 h was significantly smaller than that at 48 h (p < 0.0001). Moreover, 96 h after MRSA inoculation, the total biofilm volume per area of the Ag-HA VCM groups was significantly smaller than those of the Ti VCM and HA VCM groups (p < 0.0001). Thus, the combination of Ag-HA and VCM might be useful for the prevention of MRSA-associated PJI.
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http://dx.doi.org/10.1186/s13104-021-05499-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927400PMC
March 2021

Identification of BXDC2 as a Key Downstream Effector of the Androgen Receptor in Modulating Cisplatin Sensitivity in Bladder Cancer.

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

Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA.

Underlying mechanisms for resistance to cisplatin-based chemotherapy in bladder cancer patients are largely unknown, although androgen receptor (AR) activity, as well as extracellular signal-regulated kinase (ERK) signaling, has been indicated to correlate with chemosensitivity. We also previously showed ERK activation by androgen treatment in AR-positive bladder cancer cells. Because our DNA microarray analysis in control vs. AR-knockdown bladder cancer lines identified BXDC2 as a potential downstream target of AR, we herein assessed its functional role in cisplatin sensitivity, using bladder cancer lines and surgical specimens. BXDC2 protein expression was considerably downregulated in AR-positive or cisplatin-resistant cells. BXDC2-knockdown sublines were significantly more resistant to cisplatin, compared with respective controls. Without cisplatin treatment, BXDC2-knockdown resulted in significant increases/decreases in cell proliferation/apoptosis, respectively. An ERK activator was also found to reduce BXDC2 expression. Immunohistochemistry showed downregulation of BXDC2 expression in tumor (vs. non-neoplastic urothelium), higher grade/stage tumor (vs. lower grade/stage), and AR-positive tumor (vs. AR-negative). Patients with BXDC2-positive/AR-negative muscle-invasive bladder cancer had a significantly lower risk of disease-specific mortality, compared to those with a BXDC2-negative/AR-positive tumor. Additionally, in those undergoing cisplatin-based chemotherapy, BXDC2 positivity alone ( = 0.083) or together with AR negativity ( = 0.047) was associated with favorable response. We identified BXDC2 as a key molecule in enhancing cisplatin sensitivity. AR-ERK activation may thus be associated with chemoresistance via downregulating BXDC2 expression in bladder cancer.
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http://dx.doi.org/10.3390/cancers13050975DOI Listing
February 2021

Comparison of Converse Ω Anastomosis and Extracorporeal Anastomosis After Laparoscopic Distal Gastrectomy for Gastric Cancer.

Surg Laparosc Endosc Percutan Tech 2021 Feb 3. Epub 2021 Feb 3.

Department of Surgery, Gastroenterological Center, Yokohama City University Medical Center Departments of Gastroenterological Surgery Biostatistics, Graduate School of Medicine, Yokohama City University, Yokohama, Kanagawa Prefecture, Japan.

Background: Converse Ω anastomosis is a recently developed technique of delta-shaped anastomosis for intracorporeal gastroduodenostomy to simplify the anastomotic procedures and reduce their potential risks. This study aimed to evaluate the safety and effectiveness of converse Ω anastomosis, comparing it with conventional extracorporeal Billroth-I anastomosis after laparoscopic distal gastrectomy (LDG) for gastric cancer.

Patients And Methods: Among 169 gastric cancer patients who underwent LDG with Billroth-I anastomosis anastomosis between April 2013 and March 2018, we selected 100 patients by propensity score matching (50 in the converse Ω anastomosis group and 50 in the extracorporeal anastomosis group). Patients' characteristics, intraoperative outcomes, postoperative complications, and survival time were compared between the 2 groups.

Results: Median anastomosis time was significantly longer in the converse Ω group than in the extracorporeal group (40.0 vs. 30.5 min, P=0.005). However, the total procedure time did not differ significantly between the groups. Intraoperative blood loss volume was significantly lower in the converse Ω group than in the extracorporeal anastomosis group (40 vs. 120 mL, P<0.001). There were no significant differences in the number of dissected lymph nodes, postoperative morbidity, mortality, or length of hospital stay. The postoperative body mass index and the prognostic nutritional index did not differ between the groups 1 year after surgery. There were no significant differences in overall survival and relapse-free survival between the 2 groups.

Conclusions: Converse Ω anastomosis is feasible and safe. This novel technique can be adopted as a treatment option for reconstruction after LDG in patients with early-stage gastric cancer. Therefore, the risks and benefits of converse Ω anastomosis after LDG should be confirmed in larger cohorts.
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http://dx.doi.org/10.1097/SLE.0000000000000906DOI Listing
February 2021

PMEPA1 and NEDD4 control the proton production of osteoclasts by regulating vesicular trafficking.

FASEB J 2021 Feb;35(2):e21281

Department of Pathology and Microbiology, Faculty of Medicine, Saga University, Saga, Japan.

Osteoclast bone resorption activity is critically regulated to maintain bone homeostasis. Osteoclasts resorb bone by producing protons and acid hydrolase via lysosomal secretion, however, a detailed mechanism remains elusive. PMEPA1 is a vesicular membrane protein, which binds to the NEDD4 family member of ubiquitin ligases. We have previously reported that Pmepa1 is highly expressed in bone resorbing osteoclasts, and regulates bone resorption. Here, we investigated the mechanism of bone resorption regulated by PMEPA1. Mutant mice lacking NEDD4-binding domains of PMEPA1 displayed enhanced bone volume, and reduced bone resorption activity in comparison with those of WT mice. Analysis with pH-sensitive fluorescence probe revealed that proton secretion from osteoclasts significantly decreased in Pmepa1 mutant osteoclasts. Immunofluorescence analysis revealed that PMEPA1 was colocalized with NEDD4, V0A3, and V0D2 subunits of vacuolar ATPase, which regulate the proton production of osteoclasts. In addition, Nedd4 knockdown reduced bone resorption and proton secretion of osteoclasts. Furthermore, Pmepa1 mutation and Nedd4 knockdown altered the cytoplasmic distribution of components of V-ATPase and expression of autophagy-related proteins, suggesting that lysosomal secretion is affected. Collectively, these findings indicate that PMEPA1 controls proton secretion from osteoclasts via NEDD4 by regulating vesicular trafficking, and NEDD4 is an important regulator of bone resorption.
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http://dx.doi.org/10.1096/fj.202001795RDOI Listing
February 2021

An Adult Case of Congenital Extrahepatic Portosystemic Shunt Successfully Treated with Balloon-occluded Retrograde Transvenous Obliteration.

Intern Med 2021 Jan 15. Epub 2021 Jan 15.

Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Japan.

A 42-year-old woman visited our hospital due to syncope. Contrast-enhanced CT revealed portosystemic shunt, portal vein hypoplasia, and multiple liver nodules. The histological examination of a liver biopsy specimen exhibited portal vein hypoplasia and revealed that the liver tumor was positive for glutamine synthetase. The patient was therefore diagnosed with congenital extrahepatic portosystemic shunt type II, and with focal nodular hyperplasia (FNH)-like nodules. She had the complication of severe portopulmonary hypertension and underwent complete shunt closure by balloon-occluded retrograde transvenous obliteration (B-RTO). The intrahepatic portal vein was well developed at 1 year after B-RTO, and multiple liver nodules completely regressed. Her pulmonary hypertension also improved.
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http://dx.doi.org/10.2169/internalmedicine.5914-20DOI Listing
January 2021

Effects of α-adrenergic receptor antagonists on the development and progression of urothelial cancer.

Am J Cancer Res 2020 1;10(12):4386-4398. Epub 2020 Dec 1.

Department of Pathology & Laboratory Medicine, University of Rochester Medical Center Rochester, NY, USA.

We recently demonstrated that silodosin, a selective α-blocker often prescribed for the symptomatic treatment of benign prostatic hyperplasia (BPH), could inactivate a proto-oncogene regulator ELK1 in bladder cancer cells possessing a functional androgen receptor (AR). However, the clinical impact of α-blockers on the development and progression of bladder cancer remained poorly understood. In the present study, we investigated if α-blockers clinically used, including silodosin, tamsulosin, and naftopidil, could prevent the neoplastic/malignant transformation and cell growth, using non-neoplastic urothelial SVHUC sublines with carcinogen/MCA challenge and bladder cancer lines, respectively. Bladder cancers in men treated with silodosin, tamsulosin, or naftopidil for their BPH were then compared. Silodosin at 1-10 µM significantly inhibited the neoplastic transformation of MCA-SVHUC-AR cells, but not that of AR-negative MCA-SVHUC-control cells. In MCA-SVHUC-AR, silodosin significantly reduced the expression levels of oncogenes () and induced those of tumor suppressors (). However, tamsulosin (up to 1 µM) or naftopidil (up to 10 µM) failed to significantly inhibit the neoplastic transformation of AR-positive or AR-negative urothelial cells. Similarly, cell proliferation/migration of AR-positive bladder cancer lines was considerably inhibited only by silodosin. Meanwhile, the incidence of bladder cancer in patients with silodosin [49/540 (9.1%)] was marginally lower, compared to those with tamsulosin [64/523 (12.2%); =0.094] or tamsulosin or naftopidil [64+28/523+236 (12.1%); =0.082]. There were no significant differences in tumor grade/stage among the 3 cohorts. Outcome analysis revealed lower risks for disease progression of non-muscle-invasive bladder tumors in the silodosin group than in the naftopidil group (=0.011) or tamsulosin+naftopidil groups (=0.035). Similarly, silodosin patients with muscle-invasive tumor had lower risks for disease progression, compared with tamsulosin (=0.006) or tamsulosin+naftopidil (=0.028) patients. Multivariate analysis further showed that silodosin treatment in those with non-muscle-invasive tumor was associated with improved progression-free survival, compared with naftopidil (hazard ratio=0.086; 95% confidence interval=0.008-0.905; =0.041) or tamsulosin/naftopidil (hazard ratio=0.128; 95% confidence interval=0.016-1.036; =0.054) treatment. Our studies thus indicate that both urothelial tumorigenesis and tumor growth are inhibited by silodosin, but not by tamsulosin or naftopidil. Clinical data further suggest that even pharmacological doses ( 0.1 µM) of silodosin contribute to preventing bladder cancer progression.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783756PMC
December 2020

S100P Expression via DNA Hypomethylation Promotes Cell Growth in the Sessile Serrated Adenoma/Polyp-Cancer Sequence.

Digestion 2021 Jan 4:1-14. Epub 2021 Jan 4.

Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan,

Background/aims: Sessile serrated adenomas/polyps (SSA/Ps) are a putative precursor lesion of colon cancer. Although the relevance of DNA hypermethylation in the SSA/P-cancer sequence is well documented, the role of DNA hypomethylation is unknown. We investigated the biological relevance of DNA hypomethylation in the SSA/P-cancer sequence by using 3-dimensional organoids of SSA/P.

Methods: We first analyzed hypomethylated genes using datasets from our previous DNA methylation array analysis on 7 SSA/P and 2 cancer in SSA/P specimens. Expression levels of hypomethylated genes in SSA/P specimens were determined by RT-PCR and immunohistochemistry. We established 3-dimensional SSA/P organoids and performed knockdown experiments using a lentiviral shRNA vector. DNA hypomethylation at CpG sites of the gene was quantitated by MassARRAY analysis.

Results: The mean number of hypomethylated genes in SSA/P and cancer in SSA/P was 41.6 ± 27.5 and 214 ± 19.8, respectively, showing a stepwise increment in hypomethylation during the SSA/P-cancer sequence. S100P, S100α2, PKP3, and MUC2 were most commonly hypomethylated in SSA/P specimens. The mRNA and protein expression levels of S100P, S100α2, and MUC2 were significantly elevated in SSA/P compared with normal colon tissues, as revealed by RT-PCR and immunohistochemistry, respectively. Among these, mRNA and protein levels were highest for S100P. Knockdown of the S100P gene using a lentiviral shRNA vector in 3-dimensional SSA/P organoids inhibited cell growth by >50% (p < 0.01). The mean diameter of SSA/P organoids with S100P gene knockdown was significantly smaller compared with control organoids. MassARRAY analysis of DNA hypomethylation in the S100P gene revealed significant hypomethylation at specific CpG sites in intron 1, exon 1, and the 5'-flanking promoter region.

Conclusion: These results suggest that DNA hypomethylation, including S100P hypomethylation, is supposedly associated with the SSA/P-cancer sequence. S100P overexpression via DNA hypomethylation plays an important role in promoting cell growth in the SSA/P-cancer sequence.
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http://dx.doi.org/10.1159/000512575DOI Listing
January 2021

Sorafenib as second-line treatment option after failure of lenvatinib in patients with unresectable hepatocellular carcinoma.

JGH Open 2020 Dec 15;4(6):1135-1139. Epub 2020 Aug 15.

Department of Gastroenterology and Oncology, Institute of Biomedical Sciences Tokushima University Graduate School Tokushima Japan.

Background And Aim: Currently, there is no molecular-targeted agent that has demonstrated evidence of efficacy in patients with unresectable hepatocellular carcinoma (u-HCC) who have developed resistance to treatment with lenvatinib (LEN). In this real-world study, we aimed to investigate the therapeutic effect and safety of sorafenib (SOR) in patients with u-HCC after progression on treatment with LEN.

Methods Patients And Results: A total of 13 patients with u-HCC (12 males and 1 female), who were treated with SOR after progression on LEN, were enrolled in this retrospective study. Therapeutic efficacy was evaluated via contrast-enhanced computerized tomography at 8 weeks after the initiation of SOR therapy according to modified response evaluation criteria in solid tumors (mRECIST) and RECIST. According to mRECIST, the objective response rate (ORR) and disease control rate (DCR) were 15.3% (2/13) and 69.2% (9/13), respectively. According to RECIST, the ORR and DCR were 0% (0/13) and 69.2% (9/13), respectively. The median progression-free survival was 4.1 months. The median albumin-bilirubin scores did not deteriorate significantly at 4, 6, and 8 weeks after initiation of SOR, compared with the scores at the baseline. The most frequent grade 1 or 2 adverse events (AEs) were palmar-plantar erythrodysesthesia, fatigue, diarrhea, and hypertension. There was no incidence of grade 3 AEs.

Conclusion: Treatment with SOR may be effective for u-HCC after failure on LEN and may not worsen the liver reserve.
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http://dx.doi.org/10.1002/jgh3.12408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731817PMC
December 2020

Comparison of therapeutic outcomes of sorafenib and lenvatinib as primary treatments for hepatocellular carcinoma with a focus on molecular-targeted agent sequential therapy: A propensity score-matched analysis.

Hepatol Res 2020 Nov 25. Epub 2020 Nov 25.

Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School of Medicine, Tokushima, Tokushima, Japan.

Aim: The optimal choice between sorafenib (SOR) or lenvatinib (LEN) as the first-line treatment for unresectable hepatocellular carcinoma (u-HCC) remains debatable. Using propensity score matching, this study compares the outcomes of SOR and LEN in the molecular-targeted agent (MTA) sequential treatment of u-HCC patients.

Methods: This retrospective, multicenter, observational study recruited 137 u-HCC patients who underwent primary treatment with LEN (n = 52) or SOR (n = 85) between June 2017 and June 2020 after regorafenib was approved as the secondary treatment for u-HCC. Propensity score matching was used to reduce confounding, resulting in the selection of 104 patients (n = 52 for the SOR and LEN cohorts).

Results: The median overall survival was 21.8 months for LEN and 20.4 months for SOR. LEN exhibited significantly greater therapeutic efficacy as compared to SOR (objective response rate: 3.8% [SOR] vs. 42.3% [LEN], p < 0.01; progression-free survival: 10 months [LEN] vs. 5.1 months [SOR], p < 0.01). No significant intergroup differences were noted in the rate of transition to secondary MTA treatments (SOR: 58.7%; LEN: 48.4%), adverse events (SOR: 86%; LEN: 95%), and maintenance of the Child-Pugh (CP) score during treatment. Compared to non-MTA treatments, secondary MTA treatment achieved a greater improvement in survival (4.3  vs. 2.8 months, p = 0.0047). Multivariate analysis demonstrated that the CP score (p < 0.01) and alpha-fetoprotein level (p < 0.01) were independent prognostic factors.

Conclusions: Both SOR and LEN treatments showed a clinically comparable therapeutic efficacy as the first-line treatments for u-HCC patients in an MTA sequential therapy.
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http://dx.doi.org/10.1111/hepr.13597DOI Listing
November 2020

Radiation-Induced Osteosarcoma in the Cervical Spine after Definitive Radiotherapy for Esophageal Cancer: A Case Report.

Spine Surg Relat Res 2020 28;4(4):374-376. Epub 2020 May 28.

Department of Orthopaedic Surgery, Kindai University Hospital, Sayama, Japan.

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http://dx.doi.org/10.22603/ssrr.2019-0127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7661033PMC
May 2020

Clinical impact of primary tumour location, early tumour shrinkage, and depth of response in the treatment of metastatic colorectal cancer with first-line chemotherapy plus cetuximab or bevacizumab.

Sci Rep 2020 11 13;10(1):19815. Epub 2020 Nov 13.

Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan.

The primary tumour location is an important prognostic factor for previously untreated metastatic colorectal cancer (mCRC). However, the predictive efficacies of primary tumour location, early tumour shrinkage (ETS), and depth of response (DpR) on mCRC treatment has not been fully evaluated. This study aimed to investigate the predictive efficacies of these traits in mCRC patients treated with first-line 5-fluorouracil-based chemotherapy plus biologic agents, namely, cetuximab and bevacizumab. This was a retrospective analysis of the medical records of 110 patients with pathology-documented unresectable mCRC. Patients with left-sided mCRC receiving any first-line regimen showed better overall survival (OS) than those with right-sided mCRC [33.3 vs 16.3 months; hazard ratio (HR) 0.44; 95% confidence interval (CI) 0.27-0.74; p < 0.001]. In patients with left-sided tumours, treatment with chemotherapy plus cetuximab yielded longer OS than chemotherapy plus bevacizumab (50.6 vs 27.8 months, HR 0.55; 95% CI 0.32-0.97; p = 0.0378). mCRC patients with ETS and high DpR showed better OS than those lacking ETS and with low DpR (33.5 vs 19.6 months, HR 0.50, 95% CI 0.32-0.79, p = 0.023 and 38.3 vs 19.0 months, HR 0.43, 95% CI 0.28-0.68, p < 0.001, respectively). Moreover, ETS and/or high DpR achieved in patients with right-sided mCRC receiving chemotherapy plus cetuximab were associated with significantly better OS than in those lacking ETS and with low DpR (34.3 vs 10.4 months, HR 0.19, 95% CI 0.04-0.94, p = 0.025 and 34.3 vs 10.4 months, HR 0.19, 95% CI 0.04-0.94, p = 0.0257, respectively). Taken together, our study demonstrates that primary tumour location is not only a well-known prognostic factor but also a relevant predictive factor in patients with mCRC receiving chemotherapy plus cetuximab. Additionally, both ETS and DpR could predict treatment outcomes and also potentially guide cetuximab treatment even in right-sided mCRCs.
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http://dx.doi.org/10.1038/s41598-020-76756-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666202PMC
November 2020

Conversion therapy for unresectable hepatocellular carcinoma after lenvatinib: Three case reports.

Medicine (Baltimore) 2020 Oct;99(42):e22782

Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School.

Introduction: Lenvatinib (LEN) is a novel potent multi-tyrosine kinase inhibitor, approved as first-line treatment for unresectable hepatocellular carcinoma (HCC). Considering its high objective response rate, LEN therapy could be expected to achieve downstaging of tumors and lead to conversion therapy with hepatectomy or ablation. However, the feasibility of conversion therapy after LEN treatment in unresectable HCC remains largely unknown.

Patient Concerns: Here, we reported 3 cases of unresectable HCC: case 1, a 69-year-old man diagnosed with ruptured HCC; case 2, a 72-year-old woman with nonalcoholic steatohepatitis-based HCC; and case 3, a 73-year-old man with a history of alcoholic cirrhosis-based HCC.

Diagnosis: In all cases, cirrhosis was classified as Child-Pugh 5 and modified albumin-bilirubin grade 1 or 2a. HCC was diagnosed as Barcelona Clinic Liver Cancer (BCLC) stage B.

Interventions: In all cases, LEN was initiated after conventional-transcatheter arterial embolization enforcement, while maintaining liver function.

Outcomes: In all cases, the main tumor size decreased after 6 months of LEN treatment and no satellite nodes were detected, indicating downstaging of HCC to BCLC stage A. Subsequently, conversion hepatectomy or ablation was performed. After successful conversion therapy, the general condition of the patients was good, without tumor recurrence during the observation period (median 10 months).

Lessons: This study demonstrated that LEN enables downstaging of HCC and thus represents a bridge to successful surgery or ablation therapy. In particular, LEN treatment may facilitate the possibility for conversion therapy of initially unresectable HCC, while maintaining the hepatic functional reserve.
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http://dx.doi.org/10.1097/MD.0000000000022782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571946PMC
October 2020

2-Methacryloyloxyethyl Phosphorylcholine Polymer Coating Inhibits Bacterial Adhesion and Biofilm Formation on a Suture: An and Study.

Biomed Res Int 2020 1;2020:5639651. Epub 2020 Oct 1.

Sensory & Motor System Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.

Initial bacterial adhesion to medical devices and subsequent biofilm formation are known as the leading causes of surgical site infection (SSI). Therefore, inhibition of bacterial adhesion and biofilm formation on the surface of medical devices can reduce the risk of SSIs. In this study, a highly hydrophilic, antibiofouling surface was prepared by coating the bioabsorbable suture surface with poly(2-methacryloyloxyethyl phosphorylcholine (MPC)-co-n-butyl methacrylate) (PMB). The PMB-coated and noncoated sutures exhibited similar mechanical strength and surface morphology. The effectiveness of the PMB coating on the suture to suppress adhesion and biofilm formation of methicillin-resistant and methicillin-susceptible was investigated both and . The bacterial adhesion test revealed that PMB coating significantly reduced the number of adherent bacteria, with no difference in the number of planktonic bacteria. Moreover, fluorescence microscopy and scanning electron microscopy observations of adherent bacteria on the suture surface after contact with bacterial suspension confirmed PMB coating-mediated inhibition of biofilm formation. Additionally, we found that the PMB-coated sutures exhibited significant antibiofouling effects . In conclusion, PMB-coated sutures demonstrated bacteriostatic effects associated with a highly hydrophilic, antibiofouling surface and inhibited bacterial adhesion and biofilm formation. Therefore, PMB-coated sutures could be a new alternative to reduce the risk of SSIs.
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http://dx.doi.org/10.1155/2020/5639651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547360PMC
October 2020

Rapid detection method of carbapenemase-producing Enterobacteriaceae by MALDI-TOF MS with imipenem/cilastatin (KB) disc and zinc sulfate solution.

J Infect Chemother 2021 Feb 29;27(2):205-210. Epub 2020 Sep 29.

Department of Clinical Laboratory, Saga University Hospital, 5-1-1 Nabeshima, Saga, 849-8501, Japan; Department of Laboratory Medicine, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan.

Introduction: Carbapenemase-producing Enterobacteriaceae (CPE) is a major global health threat, and development of rapid detection methods is desired. Here, we established a cost-effective and relatively rapid CPE detection method using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS).

Methods: We examined 134 CPE strains (IMP-type, NDM-type, VIM-type, KPC-type, OXA-48-like-type, and GES-type) and 107 non-CPE strains, previously confirmed by genetic tests. The proposed MALDI-TOF MS method involves mixing of a carbapenem drug [here, the commercially available imipenem (IPM) KB disc] and the bacterial strains to be tested, and the consequent drug hydrolysis owing to bacterial carbapenemase activity is confirmed by a waveform spectrum before and after 2 h of the mixing. As metallo-beta-lactamases require zinc in their active site, the false-negatives obtained from our method were cultured in presence of zinc sulfate solution and tested again.

Results: Based on the presence or absence of the IPM (+cyano-4-hydroxy-cinnamic acid)-specific waveform peak near 489.45 m/z (±500 ppm), the detection sensitivity and specificity of our method for CPE were determined to be 94.8% and 91.6%, respectively. Seven false-negatives of IMP-type (4), VIM-type (2), and GES-type (1) were found, of which the IMP- and VIM-types tested positive as CPE after culture with zinc sulfate solution. Thus, the overall detection sensitivity improved to 99.3%.

Conclusion: Our study proposes a new approach for CPE detection using MALDI-TOF MS. Moreover, we propose cultivation of test strains with zinc sulfate solution for efficient detection of IMP-type CPE, not only for MALDI-TOF MS, but also for other detection methods.
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http://dx.doi.org/10.1016/j.jiac.2020.09.013DOI Listing
February 2021

Practice patterns related to prostate cancer grading: results of a 2019 Genitourinary Pathology Society clinician survey.

Urol Oncol 2020 Sep 15. Epub 2020 Sep 15.

Departments of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD; Departments of Urology and Oncology, The Johns Hopkins Medical Institutions, Baltimore, MD.

Purpose: To survey urologic clinicians regarding interpretation of and practice patterns in relation to emerging aspects of prostate cancer grading, including quantification of high-grade disease, cribriform/intraductal carcinoma, and impact of magnetic resonance imaging-targeted needle biopsy.

Materials And Methods: The Genitourinary Pathology Society distributed a survey to urology and urologic oncology-focused societies and hospital departments. Eight hundred and thirty four responses were collected and analyzed using descriptive statistics.

Results: Eighty percent of survey participants use quantity of Gleason pattern 4 on needle biopsy for clinical decisions, less frequently with higher Grade Groups. Fifty percent interpret "tertiary" grade as a minor/<5% component. Seventy percent of respondents would prefer per core grading as well as a global/overall score per set of biopsies, but 70% would consider highest Gleason score in any single core as the grade for management. Seventy five percent utilize Grade Group terminology in patient discussions. For 45%, cribriform pattern would affect management, while for 70% the presence of intraductal carcinoma would preclude active surveillance.

Conclusion: This survey of practice patterns in relationship to prostate cancer grading highlights similarities and differences between contemporary pathology reporting and its clinical application. As utilization of Gleason pattern 4 quantification, minor tertiary pattern, cribriform/intraductal carcinoma, and the incorporation of magnetic resonance imaging-based strategies evolve, these findings may serve as a basis for more nuanced communication and guide research efforts involving pathologists and clinicians.
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http://dx.doi.org/10.1016/j.urolonc.2020.08.027DOI Listing
September 2020

Implants in the distal radius unlikely to induce a new niche for microbiomes.

APMIS 2020 11 29;128(11):603-604. Epub 2020 Sep 29.

Department of Orthopaedic Surgery, Faculty of Medicine, Saga University, Saga, Japan.

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http://dx.doi.org/10.1111/apm.13079DOI Listing
November 2020

Estrogen receptor-β signaling induces cisplatin resistance in bladder cancer.

Am J Cancer Res 2020 1;10(8):2523-2534. Epub 2020 Aug 1.

Department of Pathology & Laboratory Medicine, University of Rochester Medical Center Rochester, NY, USA.

The efficacy of cisplatin-based chemotherapy in patients with bladder cancer is often limited due to the development of therapeutic resistance. Our recent findings in bladder cancer suggested that activation of prostaglandin receptors ( EP2, EP4) or cyclooxygenase (COX)-2 induced cisplatin resistance. Meanwhile, emerging evidence indicates the involvement of estrogen receptor-β (ERβ) signals in urothelial cancer progression. In this study, we aimed to investigate whether ERβ activity was associated with cisplatin sensitivity in bladder cancer. Immunohistochemistry in muscle-invasive bladder cancer specimens from 55 patients who had subsequently received at least 3 cycles of cisplatin + gemcitabine neoadjuvant chemotherapy showed that ERβ was positive in 38% of responders vs. 71% of non-responders ( = 0.016), including 42% of male responders vs. 65% of male non-responders ( = 0.142) and 20% of female responders vs. 100% of female non-responders ( = 0.048). Then, cisplatin cytotoxicity was compared in human bladder cancer cell lines. Control sublines endogenously expressing ERβ were significantly more resistant to cisplatin treatment at its pharmacological concentrations, compared with ERβ knockdown sublines via short hairpin RNA virus infection. An ER modulator tamoxifen increased sensitivity to cisplatin in ERα-negative/ERβ-positive cell lines, while, in an estrogen-depleted condition, 17β-estradiol reduced it. Additionally, western blot showed considerable elevation in ERβ expression in cisplatin-resistant bladder cancer sublines, compared with respective controls. Moreover, treatment with tamoxifen or a COX-2 inhibitor celecoxib increased cisplatin sensitivity even in resistant cells, while COX-2/EP2/EP4 inhibitor treatment resulted in reduced expression of ERβ. The expression and activity of β-catenin known to involve cisplatin resistance was also up-regulated in cisplatin-resistant cells, which was further induced by 17β-estradiol treatment. The present results suggest that estrogen-mediated ERβ signaling plays an important role in modulating cisplatin sensitivity in bladder cancer cells. Targeting ERβ during chemotherapy may thus be a useful strategy to overcome cisplatin resistance especially in female patients with ERβ-positive bladder cancer.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471368PMC
August 2020

Activation of Glucocorticoid Receptor Inhibits the Stem-Like Properties of Bladder Cancer via Inactivating the β-Catenin Pathway.

Front Oncol 2020 5;10:1332. Epub 2020 Aug 5.

Department of Urology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.

Glucocorticoid receptor (GR) signaling pathway has been shown to involve epithelial -to- mesenchymal transition which was implicated in the regulation of bladder cancer stem cells (CSCs) in our previous study. Herein, we aim to figure out how GR affects the stem-like properties of bladder cancer cells. We used dexamethasone (DEX) treatment or gene-knockdown/-knockout techniques to activate or silence the GR pathway, respectively. Then we applied immunohistochemical staining and flow cytometry to assess the associations between the expression levels of GR and a stem cell surface marker CD44. Stem-like properties were assessed by reactive oxygen species (ROS), sphere-formation and side population assays. The expression levels of cancer stem cell-associated molecules were assessed by quantitative PCR and Western blotting. Tumor growth was compared using mouse xenograft models. In GR-positive bladder cancer cells, DEX significantly reduced the expression of CD44 as well as pluripotency transcription factors including β-catenin and its downstream target (C-MYC, Snail, and OCT-4), the rate of sphere formation, and the proportion of side populations, and induced the intracellular levels of ROS. By contrast, GR silencing in bladder cancer cells showed the opposite effects. In xenograft-bearing mice, GR silencing resulted in the enhancement of tumor growth. These data suggested that GR activity was inversely associated with the stem-like properties of bladder cancer cells, potentially via inactivating the β-catenin pathway.
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http://dx.doi.org/10.3389/fonc.2020.01332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419687PMC
August 2020

Impact of Vasectomy on the Development and Progression of Prostate Cancer: Preclinical Evidence.

Cancers (Basel) 2020 Aug 15;12(8). Epub 2020 Aug 15.

Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA.

Some observational studies have implied a link between vasectomy and an elevated risk of prostate cancer. We investigated the impact of vasectomy on prostate cancer outgrowth, mainly using preclinical models. Neoplastic changes in the prostate were compared in transgenic TRAMP mice that underwent vasectomy vs. sham surgery performed at 4 weeks of age. One of the molecules identified by DNA microarray (i.e., ZKSCAN3) was then assessed in radical prostatectomy specimens and human prostate cancer lines. At 24 weeks, gross tumor ( = 0.089) and poorly differentiated adenocarcinoma ( = 0.036) occurred more often in vasectomized mice. Vasectomy significantly induced expression in prostate tissues from C57BL/6 mice and prostate cancers from TRAMP mice. Immunohistochemistry showed increased ZKSCAN3 expression in adenocarcinoma vs. prostatic intraepithelial neoplasia (PIN), PIN vs. non-neoplastic prostate, Grade Group ≥3 vs. ≤2 tumors, pT3 vs. pT2 tumors, pN1 vs. pN0 tumors, and prostate cancer from patients with a history of vasectomy. Additionally, strong (2+/3+) ZKSCAN3 expression ( = 0.002), as an independent prognosticator, or vasectomy ( = 0.072) was associated with the risk of tumor recurrence. In prostate cancer lines, ZKSCAN3 silencing resulted in significant decreases in cell proliferation/migration/invasion. These findings suggest that there might be an association between vasectomy and the development and progression of prostate cancer, with up-regulation of ZKSCAN3 expression as a potential underlying mechanism.
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http://dx.doi.org/10.3390/cancers12082295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464827PMC
August 2020

The incidences of metachronous multiple gastric cancer after various types of gastrectomy: analysis of data from a nationwide Japanese survey.

Gastric Cancer 2021 Jan 12;24(1):22-30. Epub 2020 Jul 12.

Department of Surgical Oncology, Kanazawa Medical University, 1-1 Daigaku, Uchinada-machi, Kahoku-gun, Ishikawa, 920-0293, Japan.

Background: The incidence of metachronous multiple gastric cancer (MMGC) after gastrectomy remains unclear. This study evaluated the incidences of MMGC according to specific gastrectomy types, including pylorus-preserving gastrectomy (PPG), proximal gastrectomy (PG), and function-preserving gastrectomy (FPG), which was categorized as segmental gastrectomy and local resection.

Methods: We conducted a questionnaire survey of the Japanese Society for Gastro-Surgical Pathophysiology members, who were asked to report their institutional numbers of radical gastrectomy cases for cancer between 2003 and 2012. The cases were categorized according to whether the remnant stomach's status was followed for > 5 years, confirmation of MMGC, time to diagnosis, and treatment for MMGC. We calculated the "precise incidence" of MMGC by dividing the number of MMGC cases by the number of cases in which the status of remnant stomach was followed up for > 5 years.

Results: The responses identified 33,731 cases of gastrectomy. The precise incidences of MMGC were 2.35% after distal gastrectomy (DG), 3.01% after PPG, 6.28% after PG (p < 0.001), and 8.21% after FPG (p < 0.001). A substantial proportion of MMGCs (36.4%) was found at 5 years after the initial surgery. The rates of MMGC treatment using endoscopic submucosal dissection were 31% after DG, 28.6% after PPG, 50.8% after PG (p < 0.001), and 67.9% after FPG (p < 0.001).

Conclusions: The incidence of MMGC was 2.4% after DG, and higher incidences were observed for larger stomach remnants. However, the proportion of cases in which MMGC could be treated using endoscopic submucosal dissection was significantly higher after PG and FPG than after DG.
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http://dx.doi.org/10.1007/s10120-020-01104-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790780PMC
January 2021

The Role of Steroid Hormone Receptors in Urothelial Tumorigenesis.

Cancers (Basel) 2020 Aug 4;12(8). Epub 2020 Aug 4.

Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA.

Preclinical and/or clinical evidence has indicated a potential role of steroid hormone-mediated signaling pathways in the development of various neoplastic diseases, while precise mechanisms for the functions of specific receptors remain poorly understood. Specifically, in urothelial cancer where sex-related differences particularly in its incidence are noted, activation of sex hormone receptors, such as androgen receptor and estrogen receptor-β, has been associated with the induction of tumor development. More recently, glucocorticoid receptor has been implied to function as a suppressor of urothelial tumorigenesis. This article summarizes and discusses available data suggesting that steroid hormone receptors, including androgen receptor, estrogen receptor-α, estrogen receptor-β, glucocorticoid receptor, progesterone receptor and vitamin D receptor, as well as their related signals, contribute to modulating urothelial tumorigenesis.
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http://dx.doi.org/10.3390/cancers12082155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465876PMC
August 2020

Androgen Receptor Signaling Reduces the Efficacy of Bacillus Calmette-Guérin Therapy for Bladder Cancer via Modulating Rab27b-Induced Exocytosis.

Mol Cancer Ther 2020 09 31;19(9):1930-1942. Epub 2020 Jul 31.

Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, New York.

Although intravesical bacillus Calmette-Guérin (BCG) immunotherapy has been the gold standard for nonsurgical management of non-muscle-invasive bladder cancer, a considerable number of patients exhibit resistance to the adjuvant treatment with unexplained mechanisms. This study aimed to investigate whether and how androgen receptor (AR) signals modulate BCG cytotoxicity in bladder cancer. AR knockdown or overexpression in bladder cancer lines resulted in induction or reduction, respectively, in intracellular BCG quantity and its cytotoxic activity. Microarray screening identified Rab27b, a small GTPase known to mediate bacterial exocytosis, which was upregulated in BCG-resistant cells and downregulated in AR-shRNA cells. Knockdown of Rab27b, or its effector SYTL3, or overexpression of Rab27b also induced or reduced, respectively, BCG quantity and cytotoxicity. In addition, treatment with GW4869, which was previously shown to inhibit Rab27b-dependent secretion, induced them and reduced Rab27b expression in bladder cancer cells. Meanwhile, AR expression was upregulated in BCG-resistant lines, compared with respective controls. In a mouse orthotopic xenograft model, Rab27b/SYTL3 knockdown or GW4869 treatment enhanced the amount of BCG within tumors and its suppressive effect on tumor growth. Moreover, in non-muscle-invasive bladder cancer specimens from patients subsequently undergoing BCG therapy, positivity of AR/Rab27b expression was associated with significantly higher risks of tumor recurrence. AR activation thus correlates with resistance to BCG treatment, presumably via upregulating Rab27b expression. Mechanistically, it is suggested that BCG elimination from urothelial cells is induced by Rab27b/SYTL3-mediated exocytosis. Accordingly, Rab27b inactivation, potentially via antiandrogenic drugs and/or exocytosis inhibition are anticipated to sensitize the efficacy of BCG therapy, especially in patients with BCG-refractory AR/Rab27b-positive bladder cancer.
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http://dx.doi.org/10.1158/1535-7163.MCT-20-0050DOI Listing
September 2020

Histopathological distinction of non-invasive and invasive bladder cancers using machine learning approaches.

BMC Med Inform Decis Mak 2020 07 17;20(1):162. Epub 2020 Jul 17.

Thomas H. Gosnell School of Life Sciences, Rochester Institute of Technology, 1 Lomb Memorial Drive, Rochester, NY, 14623, USA.

Background: One of the most challenging tasks for bladder cancer diagnosis is to histologically differentiate two early stages, non-invasive Ta and superficially invasive T1, the latter of which is associated with a significantly higher risk of disease progression. Indeed, in a considerable number of cases, Ta and T1 tumors look very similar under microscope, making the distinction very difficult even for experienced pathologists. Thus, there is an urgent need for a favoring system based on machine learning (ML) to distinguish between the two stages of bladder cancer.

Methods: A total of 1177 images of bladder tumor tissues stained by hematoxylin and eosin were collected by pathologists at University of Rochester Medical Center, which included 460 non-invasive (stage Ta) and 717 invasive (stage T1) tumors. Automatic pipelines were developed to extract features for three invasive patterns characteristic to the T1 stage bladder cancer (i.e., desmoplastic reaction, retraction artifact, and abundant pinker cytoplasm), using imaging processing software ImageJ and CellProfiler. Features extracted from the images were analyzed by a suite of machine learning approaches.

Results: We extracted nearly 700 features from the Ta and T1 tumor images. Unsupervised clustering analysis failed to distinguish hematoxylin and eosin images of Ta vs. T1 tumors. With a reduced set of features, we successfully distinguished 1177 Ta or T1 images with an accuracy of 91-96% by six supervised learning methods. By contrast, convolutional neural network (CNN) models that automatically extract features from images produced an accuracy of 84%, indicating that feature extraction driven by domain knowledge outperforms CNN-based automatic feature extraction. Further analysis revealed that desmoplastic reaction was more important than the other two patterns, and the number and size of nuclei of tumor cells were the most predictive features.

Conclusions: We provide a ML-empowered, feature-centered, and interpretable diagnostic system to facilitate the accurate staging of Ta and T1 diseases, which has a potential to apply to other types of cancer.
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http://dx.doi.org/10.1186/s12911-020-01185-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367328PMC
July 2020

FOXO1 inactivation induces cisplatin resistance in bladder cancer.

Cancer Sci 2020 Sep 17;111(9):3397-3400. Epub 2020 Jul 17.

Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

We found that FOXO1-shRNA sublines or FOXO1-positive cells co-treated with a FOXO1 inhibitor were significantly more resistant to cisplatin treatment at pharmacological concentrations, compared with respective control sublines or those with mock treatment. Western blot demonstrated considerable increases in the expression levels of a phosphorylated inactive form of FOXO1 (p-FOXO1) in cisplatin-resistant sublines established by long-term culture with low/increasing doses of cisplatin, compared with respective controls. Immunohistochemistry in surgical specimens from patients with muscle-invasive bladder cancer undergoing cisplatin-based neoadjuvant therapy further showed a strong trend to associate between p-FOXO1 positivity and unfavorable response to chemotherapy.
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http://dx.doi.org/10.1111/cas.14557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469822PMC
September 2020

Synergistic anti-tumor activity of miriplatin and radiation through PUMA-mediated apoptosis in hepatocellular carcinoma.

J Gastroenterol 2020 Nov 14;55(11):1072-1086. Epub 2020 Jul 14.

Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.

Background: The prognosis for patients with unresectable advanced hepatocellular carcinoma (HCC) is poor. Miriplatin is a hydrophobic platinum compound that has a long retention time in lesions after transarterial chemoembolization (TACE). We investigated anti-tumor activity of miriplatin combined with irradiation on HCC cells, and its underlying mechanism of apoptosis. We also analyzed the effectiveness of miriplatin-TACE and radiotherapy for locally advanced HCC.

Methods: Human HCC cell lines HepG2 and HuH-7 were treated with DPC (active form of miriplatin) and radiation, and synergy was evaluated using a combination index (CI). Apoptosis-related proteins and cell cycles were analyzed by western blotting and flowcytometry. We retrospectively analyzed treatment outcomes in 10 unresectable HCC patients with vascular/bile duct invasion treated with miriplatin-TACE and radiotherapy.

Results: DPC or X-ray irradiation decreased cell viability dose-dependently. DPC plus irradiation decreased cell viability synergistically in both cell lines (CI < 1, respectively). Cleaved PARP expression was induced much more strongly by DPC plus irradiation than by each treatment alone. Expression of p53 up-regulated modulator of apoptosis (PUMA) was significantly induced by the combination, and knockdown of PUMA with siRNA significantly decreased apoptosis in both cell lines. DPC plus irradiation caused sub-G1, G2/M, and S phase cell arrest in those cells. The combination of miriplatin-TACE and radiotherapy showed a high response rate for patients with locally advanced HCC despite small number of patients.

Conclusions: Miriplatin plus irradiation had synergistic anti-tumor activity on HCC cells through PUMA-mediated apoptosis and cell cycle arrest. This combination may possibly be effective in treating locally advanced HCC.
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http://dx.doi.org/10.1007/s00535-020-01705-8DOI Listing
November 2020

Potential use of lenvatinib for patients with unresectable hepatocellular carcinoma including after treatment with sorafenib: Real-world evidence and assessment via protein phosphorylation array.

Oncotarget 2020 Jun 30;11(26):2531-2542. Epub 2020 Jun 30.

Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.

The efficacy and safety of lenvatinib (LEN) as a second/third-line treatment for unresectable hepatocellular carcinoma (HCC) after sorafenib (SOR) therapy remains unknown. We evaluated the outcomes of second/third-line LEN treatment, investigated the sensitivity of a SOR-resistant HCC cell line (PLC/PRF5-R2) to LEN, and assessed their signal transduction pathways by protein array analysis. We retrospectively enrolled 57 patients with unresectable HCC. Fifty-three radiologically evaluated patients comprised 34 molecular-targeted agent (MTA)-naive (first-line), nine intolerant to SOR (second-line), and 10 resistant to regorafenib (third-line). The objective response rates (ORRs) were 61.8% in first-line, 33.3% in second-line, and 20.0% in third-line groups. The overall survival (OS) in the first-line was significantly longer than that in the third-line group ( < 0.05). Patients with better liver functional reserves (child score, ALBI grade) exhibited higher ORR and longer OS. The IC of LEN against PLC/PRF5-R2 was significantly higher than that against PLC/PRF5. LEN significantly inhibited more LEN-related signal transduction pathways in PLC/PRF5 than in PLC/PRF5-R2 cells. This suggests that LEN is active and safe as a second/third-line treatment for unresectable HCC. LEN seems more effective for patients with HCC with better hepatic reserve functions or before MTA-resistance is acquired because of the partial cross-resistance to SOR.
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http://dx.doi.org/10.18632/oncotarget.27640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335665PMC
June 2020

The role of adipocytokines and their receptors in bladder cancer: expression of adiponectin or leptin is an independent prognosticator.

Am J Transl Res 2020 15;12(6):3033-3045. Epub 2020 Jun 15.

Department of Pathology and James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine Baltimore, MD 21287, USA.

Adipocytokines such as leptin and adiponectin have functions in metabolism as well as the development and progression of various types of malignancies. However, little is known about their role in bladder cancer. In this study, we investigated whether leptin, adiponectin, and their receptors have an impact on bladder cancer outgrowth and the mechanisms involved. We performed immunohistochemistry for leptin, leptin receptor (Ob-R), adiponectin, and adiponectin receptors (AdipoR1, AdipoR2) in bladder cancer tissue microarrays. Wound healing assay and western blot were then performed in human bladder cancer lines. The positive rates (0 vs 1+/2+/3+) of Ob-R (P=0.004), adiponectin (P<0.001), AdipoR1 (P=0.016), and AdipoR2 (P<0.001) expression were significantly higher in bladder tumors than in benign urothelial tissues. Strong (3+) leptin expression tended to be present more often in tumors (10.2%; P=0.079) than in benign tissues (3.2%). Multivariate analysis revealed a lower risk of recurrence (hazard ratio [HR]=0.432; 95% confidence interval [CI]=0.198-0.942; P=0.034) in patients with an adiponectin-positive non-muscle-invasive tumor and a higher risk of progression (HR=5.148, 95% CI=1.190-22.273; P=0.028) in patients with a leptin-positive muscle-invasive tumor. Treatment of two bladder cancer cell lines with a synthetic adiponectin inhibited their migration and the expressions of phospho-NF-κB, NF-κB, snail, slug, Y-box-binding protein 1, and COX-2, whereas leptin showed reverse effects. Downregulation of adiponectin expression and upregulation of leptin expression were independent predictors for the recurrence of non-muscle-invasive bladder tumors and progression of muscle-invasive bladder tumors, respectively. In summary, synthetic adiponectin might exhibit antitumor activity against bladder cancer.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7344091PMC
June 2020

A two-stage reconstruction for aortoesophageal fistula after replacement of thoracic aorta for Stanford Type B dissecting aortic aneurysm: esophagectomy and a double-tract reconstruction using the pedicled jejunum: a case report and literature review.

Clin J Gastroenterol 2020 Oct 26;13(5):722-727. Epub 2020 Jun 26.

Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

An aortoesophageal fistula (AEF) is a rare, potentially fatal condition, and esophagectomy is usually performed simultaneously with aortic surgery. However, esophageal reconstruction method has not been established. This case report describes a two-stage operation for AEF after replacement of thoracic aorta for Stanford Type B dissecting aortic aneurysm. A 61-year-old man who had underwent total arch replacement with frozen elephant trunk for Stanford Type B dissecting aortic aneurysm 3 years ago admitted to the hospital with high fever. Based on the computed tomography and endoscopic findings, he was diagnosed with having aortoesophageal fistula (AEF). After administration of antibiotics with fasting foods and drinks for a month, he underwent the second aortic replacement, thoracic esophagectomy, cervical esophagostomy, gastrostomy and omental wrapping. After 3 months, he underwent double-tract reconstruction using the pedicled jejunal transfer with supercharge and superdrainage via the subcutaneous route. After reconstruction surgery, the patient was doing well. Two-stage reconstruction was a safe procedure for AEF case who underwent aortic replacement, esophagectomy and omental wrapping. The pedicled jejunum reconstruction via subcutaneous route is an optional procedure for second reconstruction surgery.
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http://dx.doi.org/10.1007/s12328-020-01158-9DOI Listing
October 2020

The 2019 Genitourinary Pathology Society (GUPS) White Paper on Contemporary Grading of Prostate Cancer.

Arch Pathol Lab Med 2020 Jun 26. Epub 2020 Jun 26.

From the Departments of Pathology (Drs Epstein, DeMarzo, and Lotan), Urology (Dr Epstein), and Oncology (Dr Epstein), The Johns Hopkins Medical Institutions, Baltimore, Maryland; Department of Pathology and Laboratory Medicine and Urology, University of Tennessee Health Science, Memphis (Dr Amin); Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York (Dr Fine); Department of Pathology, Fundacio Puigvert, Barcelona, Spain (Dr Algaba); Department of Pathology, University of Southern California, Los Angeles (Dr Aron); Department of Pathology, Faculty of Medicine, Koç University, İstanbul, Turkey (Dr Baydar); Department of Pathology, Champalimaud Centre for the Unknown, Lisbon, Portugal (Dr Beltran); Department of Pathology, McGill University Health Center, Montréal, QC, Canada (Dr Brimo); Department of Pathology, Mayo Clinic, Rochester, Minnesota (Drs Cheville and Jimenez); Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy (Dr Colecchia); Department of Pathology, Hôpital Tenon, Sorbonne University, Paris, France (Dr Comperat); Pathology Department, Rede D'OR-Sao Luiz, Sao Paulo, SP, Brazil (Dr da Cunha); Douglass Hanly Moir Pathology, Sydney, Australia (Dr Delprado); Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee (Drs Giannico and Gordetsky); Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston (Dr Guo); Department of Pathology, Oregon Health and Science University, Portland (Dr Hansel); Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts (Dr Hirsch); Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California (Dr Huang); Department of Pathology, Yale School of Medicine, New Haven, Connecticut (Dr Humphrey); Department of Pathology and Laboratory Medicine and Urology, Weill Cornell Medicine, New York, New York (Drs Khani and Robinson); Department of Pathology, Qingdao Municipal Hospital, Qingdao, Shandong, China (Dr Kong); Departments of Pathology and Laboratory Medicine and Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida (Dr Kryvenko); Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan (Drs Kunju and Mehra); Perelman School of Medicine, University of Pennsylvania, Philadelphia (Dr Lal); Department of Pathology, CHUM, Université de Montréal, Montréal, QC, Canada (Dr Latour); Douglass Hanly Moir Pathology, Faculty of Medicine and Health Sciences Macquarie University, North Ryde, Australia (Dr Maclean); Department of Pathology, The University of Alabama at Birmingham, Birmingham (Drs Magi-Galluzzi and Netto); Department of Surgical Pathology, Tata Memorial Hospital, Parel, Mumbai, India (Dr Menon); Departments of Pathology and Laboratory Medicine and Urology, University of Rochester Medical Center, Rochester, New York (Dr Miyamoto); Section of Pathological Anatomy, School of Medicine, Polytechnic University of the Marche Region, United Hospitals, Ancona, Italy (Dr Montironi); Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio (Dr Nguyen); Department of Pathology, Emory University School of Medicine, Atlanta, Georgia (Dr Osunkoya); Department of Pathology, Ohio State University, Columbus (Drs Parwani and Zynger); Department for BioMedical Research, University of Bern, Bern, Switzerland (Dr Rubin); Department of Pathology, The University of Texas Southwestern Medical Center, Dallas (Dr Shah); Institute of Pathology, St Luke's Medical Center, Quezon City and Global City, Philippines (Dr So); Department of Pathology, The Jikei University School of Medicine, Tokyo, Japan (Dr Takahashi); Argos Laboratory, Federal University of Ceara, Fortaleza, Brazil (Dr Tavora); Department of Pathology, University of Washington School of Medicine, Seattle (Drs Tretiakova and True); Departments of Pathology and Laboratory Medicine and Urology, University of North Carolina, Chapel Hill (Dr Wobker); Department of Pathology, Northwestern University, Chicago, Illinois (Dr Yang); Department of Pathology, Tufts Medical Center, Boston, Massachusetts (Dr Zhou); and Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB, Canada (Dr Trpkov). Dr Kong is currently located at Kaiser Permanente Sacramento Medical Center, Sacramento, California.

Context.—: Controversies and uncertainty persist in prostate cancer grading.

Objective.—: To update grading recommendations.

Data Sources.—: Critical review of the literature along with pathology and clinician surveys.

Conclusions.—: Percent Gleason pattern 4 (%GP4) is as follows: (1) report %GP4 in needle biopsy with Grade Groups (GrGp) 2 and 3, and in needle biopsy on other parts (jars) of lower grade in cases with at least 1 part showing Gleason score (GS) 4 + 4 = 8; and (2) report %GP4: less than 5% or less than 10% and 10% increments thereafter. Tertiary grade patterns are as follows: (1) replace "tertiary grade pattern" in radical prostatectomy (RP) with "minor tertiary pattern 5 (TP5)," and only use in RP with GrGp 2 or 3 with less than 5% Gleason pattern 5; and (2) minor TP5 is noted along with the GS, with the GrGp based on the GS. Global score and magnetic resonance imaging (MRI)-targeted biopsies are as follows: (1) when multiple undesignated cores are taken from a single MRI-targeted lesion, an overall grade for that lesion is given as if all the involved cores were one long core; and (2) if providing a global score, when different scores are found in the standard and the MRI-targeted biopsy, give a single global score (factoring both the systematic standard and the MRI-targeted positive cores). Grade Groups are as follows: (1) Grade Groups (GrGp) is the terminology adopted by major world organizations; and (2) retain GS 3 + 5 = 8 in GrGp 4. Cribriform carcinoma is as follows: (1) report the presence or absence of cribriform glands in biopsy and RP with Gleason pattern 4 carcinoma. Intraductal carcinoma (IDC-P) is as follows: (1) report IDC-P in biopsy and RP; (2) use criteria based on dense cribriform glands (>50% of the gland is composed of epithelium relative to luminal spaces) and/or solid nests and/or marked pleomorphism/necrosis; (3) it is not necessary to perform basal cell immunostains on biopsy and RP to identify IDC-P if the results would not change the overall (highest) GS/GrGp part per case; (4) do not include IDC-P in determining the final GS/GrGp on biopsy and/or RP; and (5) "atypical intraductal proliferation (AIP)" is preferred for an intraductal proliferation of prostatic secretory cells which shows a greater degree of architectural complexity and/or cytological atypia than typical high-grade prostatic intraepithelial neoplasia, yet falling short of the strict diagnostic threshold for IDC-P. Molecular testing is as follows: (1) Ki67 is not ready for routine clinical use; (2) additional studies of active surveillance cohorts are needed to establish the utility of PTEN in this setting; and (3) dedicated studies of RNA-based assays in active surveillance populations are needed to substantiate the utility of these expensive tests in this setting. Artificial intelligence and novel grading schema are as follows: (1) incorporating reactive stromal grade, percent GP4, minor tertiary GP5, and cribriform/intraductal carcinoma are not ready for adoption in current practice.
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http://dx.doi.org/10.5858/arpa.2020-0015-RADOI Listing
June 2020

The combination of silver-containing hydroxyapatite coating and vancomycin has a synergistic antibacterial effect on methicillin-resistant biofilm formation.

Bone Joint Res 2020 May 8;9(5):211-218. Epub 2020 Jun 8.

Department of Orthopaedic Surgery, Faculty of Medicine, Saga University, Saga, Japan.

Aims: Biofilm formation is intrinsic to prosthetic joint infection (PJI). In the current study, we evaluated the effects of silver-containing hydroxyapatite (Ag-HA) coating and vancomycin (VCM) on methicillin-resistant (MRSA) biofilm formation.

Methods: Pure titanium discs (Ti discs), Ti discs coated with HA (HA discs), and 3% Ag-HA discs developed using a thermal spraying were inoculated with MRSA suspensions containing a mean in vitro 4.3 (SD 0.8) x 10 or 43.0 (SD 8.4) x 10 colony-forming units (CFUs). Immediately after MRSA inoculation, sterile phosphate-buffered saline or VCM (20 µg/ml) was added, and the discs were incubated for 24 hours at 37°C. Viable cell counting, 3D confocal laser scanning microscopy with Airyscan, and scanning electron microscopy were then performed. HA discs and Ag HA discs were implanted subcutaneously in vivo in the dorsum of rats, and MRSA suspensions containing a mean in vivo 7.2 (SD 0.4) x 10  or 72.0 (SD 4.2) x 10  CFUs were inoculated on the discs. VCM was injected subcutaneously daily every 12 hours followed by viable cell counting.

Results: Biofilms that formed on HA discs were thicker and larger than those on Ti discs, whereas those on Ag-HA discs were thinner and smaller than those on Ti discs. Viable bacterial counts in vivo revealed that Ag-HA combined with VCM was the most effective treatment.

Conclusion: Ag-HA with VCM has a potential synergistic effect in reducing MRSA biofilm formation and can thus be useful for preventing and treating PJI. 2020;9(5):211-218.
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http://dx.doi.org/10.1302/2046-3758.95.BJR-2019-0326.R1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7284291PMC
May 2020