Publications by authors named "Kazuhiko Yamada"

289 Publications

Current status of doublet combinations of platinum and fluoropyrimidines using oxaliplatin for advanced gastric cancer.

Glob Health Med 2021 Feb;3(1):31-36

Department of Surgery, National Center for Global Health and Medicine, Tokyo, Japan.

The most common treatment for advanced gastric cancer (AGC) is systemic chemotherapy. The standard treatment for advanced gastric cancer differs worldwide. In Japan, two phase III clinical trials demonstrated the non-inferiority of S-1 compared with 5-fluorouracil (5-FU) and superiority of cisplatin plus S-1 (CS), compared with S-1, with respect to overall survival (SPIRITS trial). Oxaliplatin (L-OHP) has a favorable toxicity profile compared with cisplatin; hence, a phase III clinical trial (G-SOX trial) demonstrated the progression-free survival (PFS) and overall survival in CS was 5.4 and 13.1 months and those in SOX was 5.5 and 14.1 months, respectively. Serious adverse events were more frequently seen in CS than in SOX. So, SOX is as effective as CS for advanced gastric cancer with favorable safety profile. After the publication of this G-SOX trial, the combination of oral or intravenous 5-FU and various doses of L-OHP have been reported. And FOLFOX6 regimen (FOLFOX: a combination of 1-LV and FU with L-OHP) was approved for the treatment of AGC in Japan in 2017. FOLFOX was promising for patients with severe peritoneal metastasis from AGC, because the FOLFOX regimen does not require hydration and does not include oral agents. This review summarizes the efficacy and safety of doublet combinations of platinum and fluoropyrimidines using L-OHP for advanced gastric cancer.
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http://dx.doi.org/10.35772/ghm.2020.01075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936367PMC
February 2021

Phase I study of afatinib plus bevacizumab in patients with advanced non-squamous non-small cell lung cancer harboring mutations.

Transl Lung Cancer Res 2021 Jan;10(1):183-192

Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.

Background: Afatinib is a second-generation epidermal growth factor receptor () tyrosine kinase inhibitor (TKI). Combination therapies with first-generation EGFR-TKIs and bevacizumab have been reported to prolong progression-free survival (PFS). However, there are few data on the combination of afatinib and bevacizumab.

Methods: In this phase I trial, we evaluated the safety of afatinib plus bevacizumab in patients with advanced non-squamous non-small cell lung cancer (NSCLC) harboring mutations. This study consisted of two cohorts. In the dose-finding cohort, enrolled patients were treated with afatinib at a dose of 20, 30, or 40 mg/day (days 1-21) plus bevacizumab at a dose of 15 mg/kg (day 1) in 21-day cycles. This cohort was performed according to a 3 + 3 manner. In the expansion cohort, enrolled patients received the recommended dose (RD) based on the results of the dose-finding cohort. The serum trough concentration of afatinib was determined at the steady state.

Results: Seventeen patients were enrolled in this study (6 patients in the dose-finding cohort and 11 patients in the expansion cohort). There were no dose-limiting toxicities (DLTs) with afatinib at a dose of 30 mg/day. With afatinib at a dose of 40 mg/day, two of two patients experienced DLTs (grade 3 diarrhea) in cycle 1. With these results, afatinib at a dose of 30 mg/day plus bevacizumab at a dose of 15 mg/kg was determined as the RD. Eleven patients in the expansion cohort were treated with the RD. Common treatment-related adverse events (AEs) with the RD were diarrhea (79%), rash (71%), perionychia (64%), and stomatitis (50%). Grade 3 AEs with the RD were diarrhea (7%), perionychia (7%), and hypertension (7%). There were no grade 4/5 AEs or cases of interstitial lung disease. Dose-proportional increases in serum afatinib trough concentrations at steady state were not observed. The response rates (RRs) and disease control rates were 55% and 100% in EGFR-TKI-naïve patients. Re-biopsy was performed in eight patients after progressive disease following the study treatment, and three patients acquired a T790M mutation.

Conclusions: Afatinib at a dose of 30 mg/day plus bevacizumab at a dose of 15 mg/kg q3w is well tolerated.
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http://dx.doi.org/10.21037/tlcr-20-824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867760PMC
January 2021

Comparative incidence of immune-related adverse events and hyperprogressive disease in patients with non-small cell lung cancer receiving immune checkpoint inhibitors with and without chemotherapy.

Invest New Drugs 2021 Jan 22. Epub 2021 Jan 22.

Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan.

Immune-related adverse events (irAEs) and hyperprogressive disease (HPD) are serious problems arising in the early period of monotherapy (MT) with programmed cell death protein 1 (PD-1) and programmed cell death ligand1 (PD-L1) inhibitors. However, the frequency and clinical features of these problems in patients receiving combination therapy (CT) with cytotoxic chemotherapy in addition to these agents remain unclear. We retrospectively screened patients with pathologically confirmed advanced or recurrent non-small cell lung cancer (NSCLC) who had received PD-1/PD-L1 inhibitors at Kurume University Hospital between February 2016 and March 2020. We recruited 210 patients, of whom 172 (81.9%) had received PD-1/PD-L1 inhibitor MT and 38 (18.1%) had received CT. The incidence of irAE during the 3 months after treatment initiation was significantly higher in the MT group (57 of 172, 33.1%) than in the CT group (6 of 38, 15.8%) (p = 0.049). During the same period, the incidence of pneumonitis was also higher in the MT group (18 of 172, 10.9%) than in the CT group (0 of 38) (p = 0.049). A similar trend was observed in patients who had received these treatments on a first line basis. The HPD rate was significantly lower in the CT group (1 of 34, 2.9%) than in the MT group (25 of 142, 17.6%) (p = 0.031). The incidences of HPD and irAE, especially pneumonitis, during 3 months after treatment initiation were relatively lower in the CT group than in the MT group. The mechanisms underlying these differences warrant further study.
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http://dx.doi.org/10.1007/s10637-021-01069-7DOI Listing
January 2021

ASO Author Reflections: Serine Protease 27 is a Novel Prognostic Indicator for Esophageal Squamous Cell Carcinoma with Preoperative Treatment.

Ann Surg Oncol 2021 Jan 16. Epub 2021 Jan 16.

Department of Gastroenterology, The Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, Chiba, Japan.

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http://dx.doi.org/10.1245/s10434-020-09580-6DOI Listing
January 2021

Expression Status of Serine Protease 27: A Prognostic Marker for Esophageal Squamous Cell Carcinoma Treated with Preoperative Chemotherapy/Chemoradiotherapy.

Ann Surg Oncol 2021 Jan 15. Epub 2021 Jan 15.

Department of Gastroenterology, The Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, Chiba, Japan.

Background: A previous study conducted a transcriptome analysis of paired normal and esophageal squamous cell carcinoma (ESCC) tissue samples. The results showed that the expression of serine protease 27 (PRSS27) was perturbed in tumor samples. Hence, this retrospective study aimed to validate the prognostic significance of PRSS27 in patients with preoperative treatment for ESCC.

Methods: We enrolled 86 patients who received preoperative treatment before esophagectomy for ESCC. The expression of PRSS27 in resected ESCC and biopsy tissue samples obtained before preoperative treatment was evaluated via immunostaining, and its relationship with clinicopathological features and prognosis was analyzed.

Results: In normal esophageal mucosa tissue samples, PRSS27 was expressed in the cytoplasm of spinous cells in the suprabasal layer and basal cells in the basal layer. Of 64 resected ESCC tissue samples, 35 (54.7%) expressed PRSS27 and 29 (45.3%) did not. Moreover, ectopic nuclear expression of PRSS27 was observed. Based on multivariate analysis, PRSS27 expression in resected tumor samples was a predictor of poor prognosis. In cases in which PRSS27 expression was observed in biopsy samples, patients with PRSS27-negative resected tumors had a better postoperative prognosis than those with PRSS27-positive resected tumors.

Conclusions: PRSS27 expression in resected ESCC tissue samples is a poor prognostic factor in ESCC patients with preoperative treatment. Furthermore, conversion of PRSS27 expression from positive in biopsy samples to negative in resected tumor samples is a predictor of good prognosis in these patients. Hence, PRSS27 status is an effective tool for decision making regarding adjuvant treatment in ESCC patients.
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http://dx.doi.org/10.1245/s10434-020-09550-yDOI Listing
January 2021

Efficacy of cell proliferation imaging with 4DST PET/CT for predicting the prognosis of patients with esophageal cancer: a comparison study with FDG PET/CT.

Eur J Nucl Med Mol Imaging 2021 Jan 12. Epub 2021 Jan 12.

Department of Surgery, National Center for Global Health and Medicine, 1-21-1, Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan.

Purpose: 4'-[Methyl-11C] thiothymidine (4DST) incorporates into DNA directly and is a PET tracer used for cell proliferation imaging. The aim of this study was to evaluate the prediction of prognosis with pretreatment 4DST PET/CT compared to fluorodeoxyglucose (FDG) PET/CT in patients with esophageal cancer.

Methods: In this prospective study, we analyzed 46 patients (68.2 ± 10.0 years old) with pathologically proven esophageal squamous cell cancer who underwent pretreatment 4DST and FDG PET/CT. The maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), total lesion glycolysis (TLG), and total lesion proliferation (TLP) were measured for FDG and 4DST PET. The study endpoints were progression-free survival (PFS) and overall survival (OS). Patients' clinical backgrounds, including age, histological type, clinical stage, and surgical treatment, were adjusted using the Cox proportional-hazards model.

Results: In the follow-up period (median 18.8 (interquartile range: 10.1-29.0) months), 26 and 19 patients showed disease progression and cancer-related death, respectively. After adjusting for clinical variables, only the 4DST parameters (SUVmax (p = 0.001) and TLP (p = 0.022)) were statistically significant for predicting PFS. FDG MTV (p = 0.031), 4DST SUVmax (p = 0.022), and TLP (p = 0.023) were statistically significant for predicting OS. Of the PET parameters, 4DST SUVmax yielded the highest adjusted hazard ratio for both PFS (4.88, 95% confidence intervals (CI): 1.83-12.97) and OS (4.19, 95% CI: 1.23-14.20).

Conclusion: Higher accumulation of 4DST in the primary tumor may lead to shorter OS and PFS. 4DST PET/CT is useful for predicting prognosis and may outperform FDG PET/CT.
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http://dx.doi.org/10.1007/s00259-020-05179-xDOI Listing
January 2021

E7386, a Selective Inhibitor of the Interaction between β-Catenin and CBP, Exerts Antitumor Activity in Tumor Models with Activated Canonical Wnt Signaling.

Cancer Res 2021 Feb 6;81(4):1052-1062. Epub 2021 Jan 6.

Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba, Ibaraki, Japan.

The Wnt/β-catenin signaling pathway plays crucial roles in embryonic development and the development of multiple types of cancer, and its aberrant activation provides cancer cells with escape mechanisms from immune checkpoint inhibitors. E7386, an orally active selective inhibitor of the interaction between β-catenin and CREB binding protein, which is part of the Wnt/β-catenin signaling pathway, disrupts the Wnt/β-catenin signaling pathway in HEK293 and adenomatous polyposis coli ()-mutated human gastric cancer ECC10 cells. It also inhibited tumor growth in an ECC10 xenograft model and suppressed polyp formation in the intestinal tract of mice, in which mutation of activates the Wnt/β-catenin signaling pathway. E7386 demonstrated antitumor activity against mouse mammary tumors developed in mouse mammary tumor virus (MMTV)-Wnt1 transgenic mice. Gene expression profiling using RNA sequencing data of MMTV-Wnt1 tumor tissue from mice treated with E7386 showed that E7386 downregulated genes in the hypoxia signaling pathway and immune responses related to the CCL2, and IHC analysis showed that E7386 induced infiltration of CD8 cells into tumor tissues. Furthermore, E7386 showed synergistic antitumor activity against MMTV-Wnt1 tumor in combination with anti-PD-1 antibody. In conclusion, E7386 demonstrates clear antitumor activity via modulation of the Wnt/β-catenin signaling pathway and alteration of the tumor and immune microenvironments, and its antitumor activity can be enhanced in combination with anti-PD-1 antibody. SIGNIFICANCE: These findings demonstrate that the novel anticancer agent, E7386, modulates Wnt/β-catenin signaling, altering the tumor immune microenvironment and exhibiting synergistic antitumor activity in combination with anti-PD-1 antibody.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-0782DOI Listing
February 2021

Randomized phase II trial of S-1 plus cisplatin or docetaxel plus cisplatin with concurrent thoracic radiotherapy for inoperable stage III non-small cell lung cancer.

Cancer Med 2021 Jan 14;10(2):626-633. Epub 2020 Dec 14.

Department of Respiratory Medicine, Yokohama Municipal Citizen's Hospital, Kanagawa, Japan.

Cisplatin-based chemoradiotherapy is considered standard treatment for unresectable locally advanced non-small-cell lung cancer (LA-NSCLC). This study examined two regimens of chemotherapy in concurrent chemoradiation. Eligible patients with unresectable, radically irradible LA-NSCLC were randomized to either the SP (S-1 and cisplatin) or DP (docetaxel and cisplatin) arms with concurrent thoracic radiotherapy of 60 Gy, comprising 2 Gy per daily fraction. The primary endpoint was the overall survival (OS) rate at 2 years (the 2-year OS rate). From May 2011 to August 2014, 110 patients were enrolled. Of 106 eligible patients, the 2-year OS rates were 79% (95% CI: 66%-88%) and 69% (95% CI: 55%-80%) the SP and DP arms, respectively. The median progression-free survival was 11.6 months for the SP arm and 19.9 months for the DP arm, while the median survival time was 55.2 months for the SP arm and 50.8 months for the DP arm. Grade 3/4 leukopenia were more frequent in DP arm. The incidences of febrile neutropenia and pneumonitis tended to be higher in DP arm. There were no treatment-related deaths in either arm. The primary endpoint was met in both arms. The SP arm as a future reference regimen will be chosen due to fewer toxicities and better OS.
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http://dx.doi.org/10.1002/cam4.3641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877366PMC
January 2021

Improved Diagnostic Accuracy of Bone Metastasis Detection by Water-HAP Associated to Non-contrast CT.

Diagnostics (Basel) 2020 Oct 20;10(10). Epub 2020 Oct 20.

Department of Radiology, Yokohama City University Hospital, 3-9 Fukuura, Kanazawa-ward, Yokohama City 2360004, Japan.

We examined whether water-hydroxyapatite (HAP) images improve the diagnostic accuracy of bone metastasis compared with non-contrast CT alone. We retrospectively evaluated dual-energy computed tomography (DECT) images of 83 cancer patients (bone metastasis, 31; without bone metastasis, 52) from May 2018 to June 2019. Initially, two evaluators examined for bone metastasis on conventional CT images. In the second session, both CT and CT images plus water-HAP images on DECT. The confidence of bone metastasis was scored from 1 (benign) to 5 (malignant). The sensitivity, specificity, positive predictive values, and negative predictive values for both modalities were calculated based on true positive and negative findings. The intra-observer area under curve (AUC) for detecting bone metastasis was compared by receiver operating characteristic analysis. Kappa coefficient calculated the inter-observer agreement. In conventional CT images, sensitivity, specificity, positive predictive value, and negative predictive value of raters 1 and 2 for the identification of bone metastases were 0.742 and 0.710, 0.981 and 0.981, 0.958 and 0.957, and 0.864 and 0.850, respectively. In water-HAP, they were 1.00 and 1.00, 0.981 and 1.00, 0.969 and 1.00, and 1.00 and 1.00, respectively. In CT, AUCs were 0.861 and 0.845 in each observer. On water-HAP images, AUCs were 0.990 and 1.00. Kappa coefficient was 0.964 for CT and 0.976 for water-HAP images. The combination of CT and water-HAP images significantly increased diagnostic accuracy for detecting bone metastasis. Water-HAP images on DECT may enable accurate initial staging, reduced radiation exposure, and cost.
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http://dx.doi.org/10.3390/diagnostics10100853DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589875PMC
October 2020

Occupational exposure of platinum-based anti-cancer drugs: five-year monitoring of hair and environmental samples in a single hospital.

J Occup Med Toxicol 2020 29;15:29. Epub 2020 Sep 29.

Division of Hematology, Internal Medicine, Hospital, NCGM, Tokyo, Japan.

Background: Occupational exposure to chemotherapeutic agents in hospitals is a critical issue. Here, we focused on occupational exposure to platinum-based anti-cancer drugs (PDs) by evaluating platinum concentrations in hair and environmental workplace samples to monitor the risk among workers.

Methods: Hospital workers who dealt with or without PDs, patients treated with PDs, and non-medical office workers outside the hospital donated hair samples and completed a questionnaire regarding their history of handling PDs, including any incidents. Hair samples were collected and surface wipe sampling was performed in July 2010 and April 2015, before and after moving to a new building and introducing a revised safety program in August 2010. Samples were analyzed by inductively coupled plasma-mass spectrometry.

Results: Platinum concentrations in hair from PDs-handling workers was significantly higher than in non-PDs-handling workers ( = 0.045), although 50 times lower than that from PDs-treated patients. Platinum concentrations in the hospital environment had decreased at the second survey 5 years later but had not changed significantly in the hair samples from hospital workers.

Conclusion: Platinum concentrations in hair are likely dependent on the frequency of handling PDs. Reduced environmental contamination from PDs did not influence platinum levels in hospital workers' hair. Continuous monitoring by measuring platinum concentrations in the environment and in hair would provide information regarding these issues.
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http://dx.doi.org/10.1186/s12995-020-00280-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523399PMC
September 2020

Field-stepwise-swept QCPMG solid-state In NMR of indium oxide.

Solid State Nucl Magn Reson 2020 Oct 8;109:101688. Epub 2020 Sep 8.

National Institute for Materials Science, 3-13 Sakura, Tsukuba, Ibaraki 305-0003, Japan.

Experimental and theoretical investigations of indium-115 electric-field-gradient (EFG) tensors of indium(III) oxide, InO, have been presented. Field-stepwise-swept QCPMG solid-state In NMR experiments are carried out at T ​= ​120 ​K, observed at 52.695 ​MHz, and in the range of external magnetic fields between 4.0 and 6.5 ​T. The spectral simulations yield the quadrupolar coupling constant, C value, of 183(2) MHz and the asymmetry parameter, η, of 0.05(5), for In(1), and that of 126(2) MHz and η of 0.86(5) for In(2). Quantum chemical calculations are carried out to provide In EFG tensor orientations with respect to the molecular structure. A relationship between operative frequencies and variable ranges of external magnetic fields is briefly discussed for field-swept solid-state In NMR.
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http://dx.doi.org/10.1016/j.ssnmr.2020.101688DOI Listing
October 2020

Antibody reactivity with new antigens revealed in multi-transgenic triple knockout pigs may cause early loss of pig kidneys in baboons.

Xenotransplantation 2021 01 9;28(1):e12642. Epub 2020 Sep 9.

Columbia Center for Translational Immunology, Department of Medicine, Columbia University, New York, NY, USA.

Background: Recent advances in gene editing technology have enabled the production of multi-knockout (KO) and transgenic pigs in order to overcome immunologic barriers in xenotransplantation (XTx). However, the genetic manipulations required to produce these changes may have the unintended consequence of producing or revealing neoantigens reactive with natural antibodies present in baboons. In this study, we examined whether the neoantigens that develop in multi-transgenic (mTg) GalT, Cytidine monophospho-N-acetylneuraminic acid hydroxylase (CMAH), β-1,4-N-acetyl-galactosaminyl transferase 2 (B4) KO pigs can cause rejection of xenografts in baboons.

Methods: Five baboons that had <35% cytotoxicity against GalT-KO peripheral blood mononuclear cells (PBMCs) in a pre-screening assay received pig kidneys and vascularized thymic grafts (VT + K) from multi-transgenic hCD47, human thrombomodulin (hTBM), human endothelial protein C receptor (EPCR) with/without hCD46 and hCD55 with GalT-KO/NeuGC-KO/B4-KO (mTg Tri-KO) swine. In order to further examine the effects of anti-donor non-Gal natural antibody (nAb), anti-pig preformed IgM and IgG nAb binding against the GalT-KO PBMCs was compared with the donor-type PBMCs using donor pretransplant sera as well as 5 additional naïve baboon sera by flow cytometric analysis.

Results: Five baboons that received VT + K grafts had stable renal function in the first 11 days (serum creatinine < 1.5 mg/dL). Two of the five baboons had higher binding of preformed IgG to mTg Tri-KO PBMCs than to GalT-KO PBMCs (mTg Tri-KO > GalT-KO), and they rejected their grafts at POD 20. In contrast, the other three baboons demonstrated either mTg Tri-KO = GalT-KO or mTg Tri-KO < GalT-KO, and they maintained renal function 43, 52, and 154 days without rejection. Among 10 baboon sera, two had less antibody binding against PBMCs that were syngeneic to the mTg Tri-KO than against GalT-KO PBMCs (mTg Tri-KO < GalT-KO); three had similar binding to mTg Tri-KO and GalT-KO PBMCs (mTg Tri-KO = GalT-KO); and five had higher binding to m Tg Tri-KO than to GalT-KO PBMCs (mTg Tri-KO > GalT-KO).

Conclusions: These data suggest that neoantigens associated with mTg Tri-KO promote acute xenograft rejection in a pig-to-baboon VT + K XTx model. The screening assays may be useful to select "safe" recipients to receive mTg Tri-KO kidneys.
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http://dx.doi.org/10.1111/xen.12642DOI Listing
January 2021

Protection of Pancreatic Islets Using Theranostic Silencing Nanoparticles in a Baboon Model of Islet Transplantation.

Diabetes 2020 11 27;69(11):2414-2422. Epub 2020 Aug 27.

Precision Health Program, Michigan State University, East Lansing, MI

The long-term success of pancreatic islet transplantation (Tx) as a cure for type 1 diabetes remains limited. Islet loss after Tx related to apoptosis, inflammation, and other factors continues to limit Tx efficacy. In this project, we demonstrate a novel approach aimed at protecting islets before Tx in nonhuman primates (NHPs) (baboons) by silencing a gene (caspase-3) responsible for induction of apoptosis. This was done using siRNA (siCas-3) conjugated to magnetic nanoparticles (MNs). In addition to serving as carriers for siCas-3, these nanoparticles also act as reporters for MRI, so islets labeled with MN-siCas-3 can be monitored in vivo after Tx. In vitro studies showed the antiapoptotic effect of MN-siCas-3 on islets in culture, resulting in minimal islet loss. For in vivo studies, donor baboon islets were labeled with MN-siCas-3 and infused into recipient diabetic subjects. A dramatic reduction in insulin requirements was observed in animals transplanted with even a marginal number of labeled islets compared with controls. By demonstrating the protective effect of MN-siCas-3 in the challenging NHP model, this study proposes a novel strategy to minimize the number of donor islets required from either cadaveric or living donors.
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http://dx.doi.org/10.2337/db20-0517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576559PMC
November 2020

Immunohistochemical staining as supportive diagnostic tool for pseudomyxoma peritonei arising from intraductal papillary mucinous neoplasm: A report of two cases and literature review.

Pancreatology 2020 Sep 7;20(6):1226-1233. Epub 2020 Jul 7.

Department of Surgery, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan.

Background/objectives: Pseudomyxoma peritonei (PMP) arising from an intraductal papillary mucinous neoplasm of the pancreas (IPMN) is a rare condition. The diagnosis of IPMN as the origin of PMP is mainly inferred from the clinical course and the exclusion of PMP from other organs. The pathological diagnosis has not yet been established. To evaluate the usefulness of immunohistochemical staining for the diagnosis of the primary lesion of PMP as IPMN.

Methods: There are 2 cases of PMP arising from IPMN between March 2010 and December 2019 at National Center for Global Health and Medicine. A PubMed search that reported PMP arising from IPMN identified 16 additional cases. Diagnostic methods and clinicopathological features of 18 cases were compared.

Results: Four cases including our two cases used immunohistochemical staining for the diagnosis of PMP arising from IPMN. The correspondence of the immunohistochemical staining between PMP and IPMN was shown in the three cases including previously reported two cases and one of our two cases to identify the primary lesion of PMP as IPMN. In addition, we revealed that the comparison of the immunostaining pattern of PMP with the representative immunostaining pattern of the candidate primary lesions is helpful for the diagnosis of the primary lesion of PMP.

Conclusions: Immunohistochemical staining is helpful to identify the primary lesion of PMP as IPMN.
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http://dx.doi.org/10.1016/j.pan.2020.06.008DOI Listing
September 2020

Clinical impact of preoperative serum p53 antibody titers in 1487 patients with surgically treated esophageal squamous cell carcinoma: a multi-institutional study.

Esophagus 2021 Jan 26;18(1):65-71. Epub 2020 Jul 26.

Japan Esophageal Society Promotion Research: p53 Antibody Multicenter Research Group, Tokyo, Japan.

Background: Although the clinicopathological significance of serum p53 antibodies (s-p53-Abs) in esophageal cancer have been evaluated previously, previous reports only analyzed around 100-200 patients. This study was a multi-institutional study promoted by the Japan Esophageal Society to evaluate the clinical significance of preoperative s-p53-Ab status and antibody titers in 1487 esophageal cancer patients without neoadjuvant therapy.

Methods: A total of 1487 patients with esophageal squamous cell carcinoma surgically treated between 2008 and 2016 in 15 hospitals in Japan were enrolled. The cut-off value to classify the patients into s-p53-Ab positive and negative groups was 1.30 U/ml. A receiver operating characteristic curve was constructed to assess the s-p53-Abs cut-off levels to differentiate poor prognosis among the s-p53-Ab positive group. Univariate and multivariate analyses were used to evaluate the clinicopathological and prognostic significance of s-p53-Ab status and titers.

Results: Although s-p53-Ab status was significantly associated with tumor depth (P = 0.002), nodal status (P = 0.027), and pathological stage (P = 0.002). The s-p53-Ab positive status was not significantly associated with poor overall survival (P = 0.699). Using 9.82 U/ml as a cut-off, the high s-p53-Ab titer group showed a significantly worse overall survival than the low s-p53-Ab titer group (P = 0.038). However, the difference was not significant in the multivariate analysis.

Conclusion: The presence of s-p53-Abs was associated with tumor progression. Although high s-p53-Ab titers more than 9.82 U/ml, might be associated with poor prognosis for patients with esophageal squamous cell carcinoma, it was not an independent risk factor.
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http://dx.doi.org/10.1007/s10388-020-00761-6DOI Listing
January 2021

Low-Dose Erlotinib Treatment in Elderly or Frail Patients With EGFR Mutation-Positive Non-Small Cell Lung Cancer: A Multicenter Phase 2 Trial.

JAMA Oncol 2020 07 9;6(7):e201250. Epub 2020 Jul 9.

Department of Respiratory Medicine and Medical Oncology, Yokohama Municipal Citizen's Hospital, Yokohama, Japan.

Importance: Although the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors for EGFR gene mutation-positive non-small cell lung cancer is well established, optimal dosing remains to be established, especially in elderly or frail patients.

Objective: To investigate the efficacy and safety of low-dose erlotinib in elderly or frail patients with EGFR mutation-positive non-small cell lung cancer.

Design, Setting, And Participants: Single-arm phase 2 trial with the Southwest Oncology Group (SWOG) 2-stage design that enrolled frail patients from 21 Japanese institutions after meeting the inclusion criteria. Chemotherapy-naive patients with EGFR-activating mutation-positive non-small cell lung cancer who were considered frail based on age, the Charlson Comorbidity Index, and Eastern Cooperative Oncology Group performance status were eligible for the study.

Interventions: Patients were initially administered 50 mg/d erlotinib for 4 weeks, which was modified based on response or adverse events. Dose increase was permitted for patients with stable disease after 4 weeks.

Main Outcomes And Measures: The primary end point was the independent review committee-confirmed objective response rate (ORR) at the dose of 50 mg/d. The study also evaluated the pharmacokinetics of low-dose erlotinib and influence of ABCB1 gene polymorphisms.

Results: Eighty patients were enrolled, with a median (range) age of 80 (49-90) years; 54 (68%) were men. An independent review committee confirmed a significant ORR of 60.0% (90% CI, 50.2%-69.2%). The disease control rate was 90.0% (90% CI, 82.7%-94.9%), median progression-free survival was 9.3 months (95% CI, 7.2-11.4 months), and median overall survival was 26.2 months (95% CI, 21.9-30.4 months). Mild adverse events were observed in some participants, with few patients exhibiting grade 3 or greater adverse events. Low-dose erlotinib treatment was temporarily suspended for 10 patients owing to adverse events. Five of 80 patients (6%) had their erlotinib dose reduced to 25 mg because of oral mucositis, paronychia, erythema multiforme, diarrhea, and anorexia. Two patients discontinued treatment because of adverse events (cutaneous ulcer and bone infection, and oral mucositis, respectively). There were no cases of interstitial lung disease or treatment-related deaths. The median (range) erlotinib plasma concentration was measured at 685 (153-1950) ng/mL. Seventy-three patients discontinued study treatment owing to disease progression (n = 60), death (n = 3), AEs (n = 4), and patient requests (n = 6). No clear association was observed between the pharmacokinetics of low-dose erlotinib and the treatment outcome.

Conclusions And Relevance: Low-dose erlotinib appears to be safe and effective in elderly or frail patients with EGFR mutation-positive non-small cell lung cancer and can be a valid treatment option.

Trial Registration: UMIN-CTR Identifier: UMIN000015949.
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http://dx.doi.org/10.1001/jamaoncol.2020.1250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226294PMC
July 2020

Development of an error-detection examination for conservative dentistry education.

Clin Exp Dent Res 2020 02 22;6(1):69-74. Epub 2019 Nov 22.

Section of General Dentistry, Department of General Dentistry, Fukuoka Dental College, Fukuoka, Japan.

Objective: For dental students, textbooks and lectures provide basic knowledge, and simulated and actual clinical training provide learning in technical and communication skills. At our college, conservative dentistry is taught in the third and fourth years of a 6-year undergraduate degree. Clinical training is undertaken subsequently in the fifth year and includes cavity preparation and composite resin filling tasks. However, despite the clinical importance of a full understanding surrounding these procedures, sixth-year students occasionally provide incorrect answers regarding these procedures in assessments. Although they demonstrated a basic understanding of the procedures, they may have forgotten the acquired knowledge during their clinical training. Therefore, we developed an error-detection examination to evaluate and improve fifth-year students' knowledge.

Methods: Written detailed treatment procedures for standardized, typical, cases were presented to students. Some critical steps were intentionally written incorrectly, and students had to identify and correct these. After correcting the steps, students gave a presentation to their peers on their corrections. This was followed by a summary of the correct answers and a short lecture by the teacher. Students then completed a questionnaire investigating their experience of the examination.

Results: Students misunderstood some key treatment steps, such as pretreatment of composite resin filling, amalgam removal, and ceramic inlay fitting. The questionnaire revealed that this method of testing applied knowledge was new to students and helped them to identify knowledge gaps. The test also increased their motivation to study conservative dentistry. Students were open to taking similar tests in different areas.

Conclusion: Although conservative dentistry is a basic field of dental treatment, mistakes in treatment can lead to early treatment failure or reduce the lifetime of a restored tooth. Therefore, students need to have a deep understanding of procedures. Error-detection examinations may help students identify knowledge gaps and provide useful feedback to teachers to identify areas that they should stress in earlier years.
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http://dx.doi.org/10.1002/cre2.250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7025997PMC
February 2020

Predictive value of CD73 expression for the efficacy of immune checkpoint inhibitors in NSCLC.

Thorac Cancer 2020 04 15;11(4):950-955. Epub 2020 Feb 15.

Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan.

Background: CD73 induces the dephosphorylation of adenosine monophosphate converting it to adenosine, enabling malignancies to escape from immune surveillance. Although CD73 overexpression has been reported to be a poor prognostic factor in several malignancies including non-small cell lung cancer (NSCLC), its predictive relevance in NSCLC patients receiving immune checkpoint inhibitors is unknown. The present research was conducted to investigate the prognostic significance of CD73 expression in NSCLC patients receiving immune checkpoint inhibitors (ICIs).

Methods: We screened 91 patients with advanced or recurrent NSCLC who received immune checkpoint inhibitors. CD73 expression was evaluated immunohistochemically using tissue specimens obtained just before treatment with ICIs.

Results: Analysis of progression-free survival (PFS) and overall survival (OS) in relation to several levels of CD73 expression (1%, 10%, 30%, and 50%) showed that both tended to be more favorable as expression of CD73 increased. PFS and OS were longer for patients in whom at least 50% of the tumor cells expressed CD73 than for those in whom <50% of the tumor cells did so. In patients who were positive for EGFR mutation, immune checkpoint inhibitors were significantly more effective in those with high CD73 expression, whereas CD73 expression did not significantly affect the efficacy in patients with EGFR mutation-negative NSCLC. Furthermore, CD73 expression was predictive factor for the PFS independent of PD-L1 expression in patients with EGFR mutation.

Conclusions: High CD73 expression may predict a favorable response to ICIs in NSCLC patients, especially those harboring EGFR mutations.

Key Points: Significant findings of the study: In patients who were positive for EGFR mutation, immune checkpoint inhibitors (ICIs) were significantly more effective in those with high CD73 expression, whereas CD73 expression did not significantly affect the efficacy in patients with EGFR mutation-negative NSCLC.

What This Study Adds: High CD73 expression may predict a favorable response to immune checkpoint inhibitors in NSCLC patients, especially those harboring EGFR mutations.
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http://dx.doi.org/10.1111/1759-7714.13346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7113063PMC
April 2020

Intra-bone Bone Marrow Transplantation in Pig-to-Nonhuman Primates for the Induction of Tolerance Across Xenogeneic Barriers.

Methods Mol Biol 2020 ;2110:213-225

Yamada Laboratory, Department of Surgery, Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY, USA.

Mixed chimerism and thymic tissue transplantation strategies have achieved xenogeneic tolerance in pig-to-mouse models, and both have been extended to pig-to-baboon models. A mixed chimerism strategy has shown promise toward inducing tolerance in allogeneic models in mice, pigs, nonhuman primates (NHP), humans, and a rat-to-mouse small animal xeno-model. However, even though α-1,3-galactosyltransferase gene knockout (GalTKO) pigs have been used as bone marrow (BM) donors, direct intravenous injection of porcine BM cells was detected for only up to 4 days (peripheral macro-chimerism) in one case, and the rest lost chimerism within 2 days.Recent data in allogeneic models demonstrated that direct injection of donor BM cells into recipient BM spaces (intra-bone bone marrow transplantation: IBBMTx) produces rapid reconstitution and a higher survival rate compared to i.v. injection. In order to minimize the loss of injected porcine BM peripherally before reaching the BM space, Yamada developed a xeno-specific regimen including IBBMTx coated with a collagen gel matrix in a preclinical pig-to-baboon model (Yamada IBBMTx). This strategy aims to achieve improved, persistent macro-chimerism as well as engraftment of BM across a xenogeneic barrier. The initial study published in 2015 demonstrated that this IBBMTx strategy leads to markedly prolonged peripheral macro-chimerism detectable for up to 23 days. Furthermore, a more recent study using human CD47-transgenic (Tg) GalTKO pigs as xeno-donors achieved long-lasting macro-chimerism >60 days with evidence of reduction of anti-pig natural antibodies (nAb). This is the longest macro-chimerism that has ever been achieved in a preclinical large animal xenotransplant model to date. In this chapter, we introduce a brief summary of our achievements in regard to successful tolerance induction by utilizing our novel strategy of IBBMTx as well as describe the step-by-step methodology of surgical and in vitro procedures that are required for this project.
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http://dx.doi.org/10.1007/978-1-0716-0255-3_14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7412596PMC
January 2021

Co-transplantation of Vascularized Thymic Graft with Kidney in Pig-to-Nonhuman Primates for the Induction of Tolerance Across Xenogeneic Barriers.

Methods Mol Biol 2020 ;2110:151-171

Yamada Laboratory, Department of Surgery, Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY, USA.

Using advanced gene editing technologies, xenotransplantation from multi-transgenic alpha-1,3-galactosyltransferase knockout pigs has demonstrated marked prolongation of renal xenograft survival, ranging from days to greater than several months for life-supporting kidneys and >2 years in a heterotopic non-life-supporting cardiac xenograft model. However, continuous administration of multiple immunosuppressive drugs continues to be required, and attempts to taper immunosuppression have been unsuccessful. These data are consistent with previous reports indicating that the human-anti-porcine T cell response is similar or stronger than that across allogeneic barriers. Due to the strength of both the innate and adaptive immune responses in xenotransplantation, the level of continuous immunosuppression needed to control these responses and prolong xenograft survival has been associated with prohibitive morbidity and mortality. These facts provide compelling rationale to pursue a clinically applicable strategy for the induction of tolerance.Mixed chimerism and thymic tissue transplantation have both achieved xenogeneic tolerance in pig-to-mouse models, and both have recently been extended to pig-to-baboon models. Although these strategies are promising in small animal models, neither direct intravenous injection of porcine bone marrow cells nor direct fetal thymic tissue transplantation into recipients was able to achieve >2 days chimerism following BM Tx or the engraftment of thymic tissues across xenogeneic barriers in pig-to-nonhuman primate models. Several innovative procedures have been largely developed by Kazuhiko Yamada to overcome these failures. These include vascularized thymic transplantation, combined with either thymokidney (TK) or vascularized thymic lobe (VTL) transplantation. Utilizing the strategy of transplanting vascularized thymic grafts with kidney from the same GalT-KO donor without further gene modification, we have achieved longer than 6 months survival of life-supporting kidneys in a baboon. Notably, the recipient became donor specific unresponsive and developed new thymic emigrants. In this chapter, we introduce a brief summary of our achievements to date toward the successful induction of tolerance by utilizing our novel strategy of vascularized thymic transplantation (including thymokidney transplantation), as well as describe the step-by-step methodology of surgical and in vitro procedures which are required for this experiment.
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http://dx.doi.org/10.1007/978-1-0716-0255-3_11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7366292PMC
January 2021

Determination of Somatic Mutations and Tumor Mutation Burden in Plasma by CAPP-Seq during Afatinib Treatment in NSCLC Patients Resistance to Osimertinib.

Sci Rep 2020 01 20;10(1):691. Epub 2020 Jan 20.

Department of Genome Biology, Kinki University Faculty of Medicine, Osaka, Japan.

Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) were developed to target the EGFR T790M resistance mutation in non-small cell lung cancer (NSCLC) patients resistant to first- or second-generation EGFR-TKIs. To investigate the efficacy of afatinib treatment for EGFR T790M-positive NSCLC patients showing resistance to osimertinib and alterations in somatic mutations and tumor mutation burden (TMB) in plasma circulating tumor DNA (ctDNA) during afatinib treatment, we conducted a prospective study using Cancer Personalized Profiling by deep Sequencing (CAPP-Seq). Nine NSCLC patients with EGFR T790M mutation who showed resistance to third-generation EGFR-TKIs were enrolled in this study and treated with afatinib. Plasma samples were collected before treatment, 4 weeks after treatment, and at disease progression. The mutation profile and TMB in plasma ctDNA were analyzed by CAPP-Seq. The objective response rate and median progression-free survival associated with afatinib were 0% and 2.0 months, respectively. The C797S mutation-mediated resistance to osimertinib was observed in one patient and following afatinib treatment in two patients; the C797S mutations occurred in the same allele as the T790M mutation. After afatinib treatment, afatinib-sensitive mutant alleles, such as ERBB2, and TMB decreased. We have demonstrated that detection of mutant allele frequency and TMB of ctDNA by CAPP-Seq could help determine the effectiveness of and resistance to afatinib. Although afatinib monotherapy for T790M-positive NSCLC resistant to osimertinib was less effective, the action for multiclonal mutant alleles and TMB might contribute to further treatment strategy.
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http://dx.doi.org/10.1038/s41598-020-57624-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6971280PMC
January 2020

Glutathione S-transferase omega 2 regulates cell growth and the expression of E-cadherin via post-transcriptional down-regulation of β-catenin in human esophageal squamous cells.

Carcinogenesis 2020 07;41(7):875-886

Department of Gastroenterology, The Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, Chiba, Japan.

Glutathione S-transferase omega 2 (GSTO2), which belongs to the superfamily of GST omega class, lacks any appreciable GST activity. Although GSTO2 exhibits thioltransferase and glutathione dehydrogenase activities, its precise expression and physiological functions are still unclear. In the present study, we found that GSTO2 is exclusively expressed in the basal cell layer in Ki67-negative non-proliferative cells in the human esophageal mucosa. GSTO2 overexpression in esophageal squamous cell carcinoma (ESCC) cell lines inhibited cell growth and colony formation, and GSTO2-transfected cells formed smaller tumors in nude mice compared with mock-transfected cells. Interestingly, GSTO2 induction suppressed the expressions of E-cadherin and β-catenin at the cell-cell contact site. We quantified the phosphorylation levels of key proteins of MAPK signaling pathway and identified phosphorylation of p38. Additionally, HSP27, a downstream molecule of p38, was accelerated in GSTO2-transfected cells, unlike in mock-transfected cells. When GSTO2-transfected cells were treated with a p38 inhibitor, the expression of β-catenin and the membrane localization of E-cadherin was recovered. We next examined GSTO2 expression in 61 ESCC tissues using quantitative reverse transcription polymerase chain reaction and immunostaining. The results showed that GSTO2 mRNA and protein were significantly reduced in ESCC compared with normal tissues. When human ESCC cell lines were treated with 5-aza-2'-deoxycytidine, a DNA-methyltransferase inhibitor, GSTO2 transcription was induced, suggesting that aberrant hypermethylation is the cause of the down-regulated expression. Our results indicate that GSTO2 expression inhibits the membrane localization of E-cadherin, probably by modulation of the p38 signaling pathway. Down-regulation of GSTO2 by DNA hypermethylation contributes to the growth and progression of ESCC.
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http://dx.doi.org/10.1093/carcin/bgz189DOI Listing
July 2020

Intra-bone bone marrow transplantation from hCD47 transgenic pigs to baboons prolongs chimerism to >60 days and promotes increased porcine lung transplant survival.

Xenotransplantation 2020 01 23;27(1):e12552. Epub 2019 Sep 23.

Columbia Center for Translational Immunology, Columbia University Medical Center, New York, New York.

Background: We have recently demonstrated that human-CD47 (hCD47) expressed on endothelial cells of porcine lung xenografts extended median graft survival from 3.5 days to 8.7 days in baboons. Intra-bone bone marrow transplantation (IBBMTx) in a pig-to-baboon model was previously shown to markedly prolong the duration of macrochimerism up to 21 days from 1 to 4 days by intravenous BMTx. We now examined whether the use of hCD47 transgenic (Tg) BM further prolonged the duration of chimerism following IBBMTx. We then tested if lung xenograft survival was prolonged following IBBMTx.

Methods: Baboons received GalTKO-hCD47/hCD55Tg (n = 5) or -hCD55Tg (n = 1) or -hCD46/HLA-E Tg (n = 1) pig IBBMTx. Macrochimerism, anti-pig T cells and antibody responses were assessed. Animals received lung xenografts from either hCD47+ or hCD47- porcine lungs 1-3 months later.

Results: All baboons that received hCD47Tg porcine IBBM maintained durable macrochimerism >30 days, and two maintained chimerism for >8 weeks. Notably, anti-pig antibody levels decreased over time and anti-pig cellular unresponsiveness developed following IBBMTx. Lungs from hCD47Tg IBBMTx matched pigs were transplanted at day 33 or day 49 after IBBMTx. These animals showed extended survival up to 13 and 14 days, while animals that received lungs from hCD47 negative pigs displayed no prolonged survival (1-4 days).

Conclusion: This is the first report demonstrating durable macrochimerism beyond 8 weeks, as well as evidence for B cell tolerance in large animal xenotransplantation. Using hCD47Tg pigs as both IBBMTx and lung donors prolongs lung xenograft survival. However, additional strategies are required to control the acute loss of lung xenografts.
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http://dx.doi.org/10.1111/xen.12552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007336PMC
January 2020

Transgenic expression of human CD47 reduces phagocytosis of porcine endothelial cells and podocytes by baboon and human macrophages.

Xenotransplantation 2020 01 8;27(1):e12549. Epub 2019 Sep 8.

Columbia Center for Translational Immunology (CCTI)/Surgery, Columbia University Medical Center, New York, NY, USA.

Background: Our initial studies utilizing a galactosyl-α1-3-galactosyltransferase gene knockout (GalTKO) pig-to-baboon renal transplant model demonstrated that the early development of nephrotic syndrome has been a significant obstacle to the long-term survival of baboon recipients. We have recently documented that sphingomyelin phosphodiesterase-3 (SMPDL3b) and CD80 expressed on podocytes in porcine kidney grafts contribute to this complication. We have hypothesized that one regulator of immune function is CD47 and that incompatibilities in CD47 between pig and baboon could potentially affect macrophage function, increasing the susceptibility of the kidney grafts to immunologically induced injury.

Methods: In order to address this hypothesis in vitro, we isolated and cultured porcine podocytes and ECs from GalTKO alone, human CD47 (hCD47)/hCD55 expressing transgenic (Tg) GalTKO swine, and GalTKO hCD46/hCD55 Tg swine along with baboon or human macrophages.

Results: We found that baboon macrophages phagocytosed porcine ECs in a similar manner to human macrophages, and this response was significantly reduced when porcine ECs and podocytes expressed hCD47/hCD55 but not hCD46/hCD55 without hCD47. Furthermore, masking hCD47 by anti-hCD47 antibody on hCD47/hCD55Tg ECs restored phagocytosis. These results are consistent with the hypothesis that CD47 incompatibility plays an important role in promoting macrophage phagocytosis of endogenous cells from the transplanted kidney.

Conclusions: The similar levels of phagocytosis of porcine cells by baboon and human macrophages suggest that the expression of hCD47Tg on glomerular cells in donor porcine kidneys may prove to be a key strategy for preventing proteinuria following kidney xenotransplantation in a pig-to-human as well as a pig-to-baboon model.
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http://dx.doi.org/10.1111/xen.12549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007337PMC
January 2020

Catechin and caffeine contents in green tea at different harvest periods and their metabolism in miniature swine.

Food Sci Nutr 2019 Aug 28;7(8):2769-2778. Epub 2019 Jul 28.

Department of Food Science & Biotechnology, Faculty of Agriculture Kagoshima University Kagoshima Japan.

The catechin content in green tea leaves varies according to cultivation conditions such as intensity of solar radiation, temperature, and precipitation, and thus, there is ambiguity about the best harvest time for obtaining optimal functional effects. In this study, the Yabukita (ordinary) and Benifuki varieties, which contain methylated catechin, were used to determine the difference in green tea catechins according to harvest times and tea manufacturing processes. Caffeine determination was also carried out to provide information about green tea intake for all age-groups of children and pregnant women. Determining the quantity of each catechin was difficult because of degradation, polymerization, and isomerization that had occurred during heat-drying in the refining process. In addition, the absorption of catechin compounds was tested using miniature swine because of their functional and physiological similarity to humans. Benifuki tea leaves contained epigallocatechin-3-(3"-O-methyl) gallate (EGCg3"Me) instead of epigallocatechin-3-(4"-O-methyl) gallate (EGCg4"Me). However, EGCg4"Me was detected during the entire intake period, but EGCg3"Me was not detected in the blood of miniature swine fed Benifuki tea. It is possible that the position of the methyl group was modified by the pig metabolism. Furthermore, caffeine from both Yabukita and Benifuki tea varieties was found to be easily accumulated in miniature swine. These results suggest that nonrefined September-October picking tea (autumn and winter tea) of the Benifuki variety is preferable over the Yabukita variety for consumption by children and pregnant women owing to its lower caffeine content and higher content of methylated catechin.
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http://dx.doi.org/10.1002/fsn3.1143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694591PMC
August 2019

Preparation of hybrid porcine thymus containing non-human primate thymic epithelial cells in miniature swine.

Xenotransplantation 2019 11 10;26(6):e12543. Epub 2019 Jul 10.

Department of Surgery, Columbia University Center for Translational Immunology, Columbia University, New York, New York.

Background: We have achieved greater than a 6-month survival of a life-supporting kidney co-transplanted with a vascularized thymic graft into non-human primates (NHPs). Although we have achieved pig-specific unresponsiveness in vitro, immunosuppression was not able to be fully weaned. Studies in mice and humanized mice suggest that a hybrid pig thymus (Hyb-thy)-containing host thymic epithelial cells (TECs) can optimize intra-thymic selection, achieving xenograft tolerance with improved reconstitution of T-cell function.

Methods: We have tested the feasibility of the preparation of a Hyb-thy that contains NHP TECs in the donor thymic grafts. We first prepared the Hyb-thy in the donor pigs 2-3 weeks before xeno-Tx. We performed six cases of Hyb-thy preparation in six juvenile miniature swine. Two pigs received non-manipulated cynomolgus monkey thymic cells that were isolated from an excised atrophic thymus via injection into their thymic lobes (Group 1). The remaining four received thymic cells that were isolated from non-atrophic thymic glands (Groups 2 and 3). Pigs in Group 2 received unmanipulated thymic cells in one thymic lobe, as well as CD2-positive cell-depleted TEC-enriched cells in the contralateral lobe. Pigs in Group 3 received TEC-enriched cells alone.

Results: All thymus-injected pigs received tacrolimus and rapamycin until endpoint (POD16). We detected cynomolgus monkey TEC networks in pig thymus from Groups 1 and 3, while pigs in Group 2 rejected the thymic cells. We demonstrated the preparation of Hyb-thy in pigs using tacrolimus plus rapamycin therapy.

Conclusions: Our results suggest that the enrichment of TEC from the excised NHP thymus facilitated NHP TEC engraftment in pig thymus.
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http://dx.doi.org/10.1111/xen.12543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6908759PMC
November 2019

The Protective Effects of Carbon Monoxide Against Hepatic Warm Ischemia-Reperfusion Injury in MHC-Inbred Miniature Swine.

J Gastrointest Surg 2020 05 26;24(5):974-982. Epub 2019 Jun 26.

Center for Advanced Biomedical Science and Swine Research, Division of Organ Replacement and Xenotransplantation Surgery M, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima City, Kagoshima, 890-8520, Japan.

Background: The development of treatment strategies to protect against ischemia-reperfusion injury (IRI) to livers is important not only for liver surgeries but also in regard to increasing the utilization of livers from marginal donors. In this study, we examined whether inhalational carbon monoxide (CO) therapy reduced IRI after a 45-min (min) warm ischemia (WI) in a miniature swine model.

Materials And Methods: Six CLAWN miniature swine underwent a 45-min hepatic WI induced by clamping the portal vein and proper hepatic artery. Three animals were subjected to control conditions while the remaining three were treated with CO inhalation for a total of 345-min, including 120-min after reperfusion to maintain a concentration of CO-Hb under 15% (CO-treated group). IRI of the livers was evaluated by liver function tests, serum pro-inflammatory cytokines, and liver biopsies.

Results: All controls had statistically significant increased levels of liver enzymes compared to the CO-treated group (p < 0.05). In controls, liver biopsies at 2 h after reperfusion showed marked histological changes including diffuse hemorrhage, congestion, necrosis, vacuolization, and neutrophil infiltration with apoptosis. In contrast, the CO-treated group showed less obvious or only minimal histological changes. Furthermore, increases in high-mobility group box 1, TNF-α, and IL-6 in sera that were induced by IRI in controls were markedly inhibited by the CO treatment.

Conclusion: We demonstrated that low-dose CO inhalation reduces hepatic warm IRI, potentially through downregulation of pro-inflammatory mediators and activation of anti-apoptotic pathways. To our knowledge, this is the first report demonstrating CO inhalation attenuated hepatic IRI following WI in a large animal model.
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http://dx.doi.org/10.1007/s11605-019-04283-0DOI Listing
May 2020

S nuclear quadrupole resonance study of dibenzyl disulfide toward understanding of cross-linked structures in rubber.

Solid State Nucl Magn Reson 2019 Sep 30;101:110-115. Epub 2019 May 30.

School of Materials and Chemical Technology, Tokyo Institute of Technology, 4259 Nagatsuta, Midori-ku, Yokohama, 226-8503, Japan.

Experimental and theoretical investigations of a sulfur-33 electric-field-gradient (EFG) tensor of disulfide bonds in S-labled dibenzyl disulfide have been presented. Temperature dependence of quadrupolar frequencies, ν, is observed in the temperature range between 80 and 280 K, in which single peaks appear in all the S nuclear quadrupole resonance (NQR) spectra. Analysis of nutation echo S NQR spectra at 200 K yields the quadrupolar coupling constant, C value, of 46.8(6) MHz and the asymmetry parameter, η, of 0.48(7). The orientation of the S EFG tensor of the disulfide is obtained by quantum chemical calculations: the largest EFG tensor component, V, is approximately perpendicular to the molecular plane (C-S-S), and the smallest component, V, is approximately 41° off the C-S bond. Extensive quantum chemical calculations are systematically performed to investigate dependences of S EFG tensors on changes of torsion angles in disulfide and trisulfide bonds, indicating that analysis of ν and C values potentially makes it possible to assign the secondary structures of cross-linking in a rubber.
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http://dx.doi.org/10.1016/j.ssnmr.2019.05.011DOI Listing
September 2019

Prognostic Value of Serum Tumor Markers in Patients With Stage III NSCLC Treated With Chemoradiotherapy.

In Vivo 2019 May-Jun;33(3):889-895

Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan.

Background/aim: Serum tumor markers such as carcinoembryonic antigen and cytokeratin subunit 19 fragment are generally monitored in non-small cell lung cancer (NSCLC) patients in the clinical practice. However, their clinical relevance in stage III NSCLC treated with concurrent chemoradiotherapy (CCRT) remains unclear. Herein, we examined the clinical relevance of tumor markers in those patients.

Patients And Methods: We retrospectively reviewed 62 consecutive patients with stage III NSCLC who received CCRT. We examined the associations of tumor marker levels with their prognosis.

Results: There was no correlation between pretreatment tumor marker levels and prognosis. Normal tumor marker levels post-CCRT were significantly associated with favorable progression-free survival (54.8 versus 14.5 months, p=0.02) and overall survival (71.7 versus 40.4 months, p=0.06) compared with high tumor marker levels post-CCRT.

Conclusion: We revealed that normal tumor markers levels post-CCRT in stage III NSCLC might be a useful surrogate marker for curing those patients.
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http://dx.doi.org/10.21873/invivo.11555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6559885PMC
August 2019