Publications by authors named "Michiaki Unno"

520 Publications

The association between ERK inhibitor sensitivity and molecular characteristics in colorectal cancer.

Biochem Biophys Res Commun 2021 May 11;560:59-65. Epub 2021 May 11.

Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan.

The mitogen-activated protein kinase (MAPK) pathway plays an important role in the colorectal cancer (CRC) progression, being supposed to be activated by the gene mutations, such as BRAF or KRAS. Although the inhibitors of extracellular signal-regulated kinase (ERK) have demonstrated efficacy in the cells with the BRAF or KRAS mutations, a clinical response is not always associated with the molecular signature. The patient-derived organoids (PDO) have emerged as a powerful in vitro model system to study cancer, and it has been widely applied for the drug screening. The present study aims to analyze the association between the molecular characteristics which analyzed by next-generation sequencing (NGS) and sensitivity to the ERK inhibitor (i.e., SCH772984) in PDO derived from CRC specimens. A drug sensitivity test for the SCH772984 was conducted using 14 CRC cell lines, and the results demonstrated that the sensitivity was in agreement with the BRAF mutation, but was not completely consistent with the KRAS status. In the drug sensitivity test for PDO, 6 out of 7 cases with either BRAF or KRAS mutations showed sensitivity to the SCH772984, while 5 out of 6 cases of both BRAF and KRAS wild-types were resistant. The results of this study suggested that the molecular status of the clinical specimens are likely to represent the sensitivity in the PDOs but is not necessarily absolutely overlapping. PDO might be able to complement the limitations of the gene panel and have the potential to provide a novel precision medicine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2021.04.130DOI Listing
May 2021

Serine/Threonine Kinase 11 Plays a Canonical Role in Malignant Progression of KRAS-mutant and GNAS-wild-type Intraductal Papillary Mucinous Neoplasms of the Pancreas.

Ann Surg 2021 Mar 3. Epub 2021 Mar 3.

*Department of Investigative Pathology, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan †Institute of Biomedical Research, Sapporo Higashi Tokushukai Hospital, Sapporo, 065-0033, Japan ‡Cancer Genomics and Precision Medicine, Department of Medicine, Asahikawa Medical University, Asahikawa, 078-8510, Japan §Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan ¶Department of Surgery I, Yamagata University Graduate School of Medical Science, Yamagata, 990-9585, Japan. ||Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo 162-8666, Japan.

Objective: We aimed to elucidate the clinicopathobiological significance of Serine/Threonine Kinase 11 (STK11) in pancreatic intraductal papillary mucinous neoplasms (IPMNs).

Background: STK11 is a tumor suppressor involved in certain IPMNs, however, its significance is not well known.

Methods: In 184 IPMNs without Peutz-Jeghers syndrome, we analyzed expression of STK11 and phosphorylated-AMPKα in all cases, and p16, p53, SMAD4, and β-catenin in 140 cases by immunohistochemistry; and we analyzed mutations in 37 genes, including whole coding exons of STK11, CDKN2A, TP53, and SMAD4, and hotspots of KRAS, BRAF, and GNAS in 64 cases by targeted sequencing. KRAS and GNAS were additionally analyzed in 86 STK11-normal IPMNs using digital-PCR.

Results: Consistent loss or reduction of STK11 expression was observed in 26/184 (14%) IPMNs. These STK11-aberrant IPMNs were 17/45 (38%) pancreatobiliary, 8/27 (30%) oncocytic, 1/54 (2%) gastric, and 0/58 (0%) intestinal subtypes (P = 8.5E-11), and 20/66 (30%) invasive, 6/74 (8%) high-grade, and 0/44 (0%) low-grade (P = 3.9E-06). Sixteen somatic STK11 mutations (5 frameshift, 6 nonsense, 1 splicing, and 4 missense) were detected in 15/26 STK11-aberrant IPMNs (P = 4.1E-06). All STK11-aberrant IPMNs were GNAS-wild-type and 96% of them were KRAS or BRAF-mutant. Morphologically, STK11-aberrant IPMNs presented "fern-like" arborizing papillae with thin fibrovascular core. Phosphorylated-AMPKα was downregulated in STK11-aberrant IPMNs (92%, P = 6.8E-11). Patients with STK11-aberrant IPMNs showed poorer survival than patients with STK11-normal IPMNs (P = 3.6E-04 overall; P = 6.1E-04 disease-free).

Conclusion: STK11 may play a canonical role in malignant progression and poor survival of patients with IPMNs. Aberrant STK11-driven phosphorylated AMPK downregulation may provide therapeutic opportunities with mTOR inhibitors/AMPK activators.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/SLA.0000000000004842DOI Listing
March 2021

The anti-angiogenic agent lenvatinib induces tumor vessel normalization and enhances radiosensitivity in hepatocellular tumors.

Med Oncol 2021 Apr 21;38(6):60. Epub 2021 Apr 21.

Department of Medical Physics, Graduate School of Medicine, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan.

The evaluation of angiogenesis inhibitors requires the analysis of the precise structure and function of tumor vessels. The anti-angiogenic agents lenvatinib and sorafenib are multi-target tyrosine kinase inhibitors that have been approved for the treatment of hepatocellular carcinoma (HCC). However, the different effects on tumor vasculature between lenvatinib and sorafenib are not well understood. In this study, we analyzed the effects of both drugs on vascular structure and function, including vascular normalization, and investigated whether the normalization had a positive effect on a combination therapy with the drugs and radiation using micro X-ray computed tomography with gold nanoparticles as a contrast agent, as well as immunohistochemical analysis and interstitial fluid pressure (IFP) measurement. In mice subcutaneously transplanted with mouse HCC cells, treatment with lenvatinib or sorafenib for 14 days inhibited tumor growth and reduced the tumor vessel volume density. However, analysis of integrated data on vessel density, rates of pericyte-covering and perfused vessels, tumor hypoxia, and IFP measured 4 days after drug treatment showed that treatment with 3 mg/kg of lenvatinib significantly reduced the microvessel density and normalized tumor vessels compared to treatment with 50 mg/kg of sorafenib. These results showed that lenvatinib induced vascular normalization and improved the intratumoral microenvironment in HCC tumors earlier and more effectively than sorafenib. Moreover, such changes increased the radiosensitivity of tumors and enhanced the effect of lenvatinib and radiation combination therapy, suggesting that this combination therapy is a powerful potential application against HCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12032-021-01503-zDOI Listing
April 2021

Stomatin‑like protein 2 induces metastasis by regulating the expression of a rate‑limiting enzyme of the hexosamine biosynthetic pathway in pancreatic cancer.

Oncol Rep 2021 Jun 13;45(6). Epub 2021 Apr 13.

Department of Surgery, Tohoku University Graduate School of Medicine, Seiryo‑machi, Aoba‑ku, Sendai 980‑8574, Japan.

Stomatin‑like protein 2 (SLP‑2) is associated with poor prognosis in several types of cancer, including pancreatic cancer (PC); however, the molecular mechanism of its involvement remains elusive. The present study aimed to elucidate the role of this protein in the development of PC. Human PC cell lines AsPC‑1 and PANC‑1 were transfected by a vector expressing SLP‑2 shRNA. Analyses of cell proliferation, migration, invasion, chemosensitivity, and glucose uptake were conducted, while a mouse xenograft model was used to evaluate the functional role of SLP‑2 in PC. Immunohistochemical analysis was retrospectively performed on human tissue samples to compare expression between the primary site (n=279) and the liver metastatic site (n=22). Furthermore, microarray analysis was conducted to identify the genes correlated with SLP‑2. analysis demonstrated that cells in which SLP‑2 was suppressed exhibited reduced cell motility and glucose uptake, while analysis revealed a marked decrease in the number of liver metastases. Immunohistochemistry revealed that SLP‑2 was increased in liver metastatic sites. Microarray analysis indicated that this protein regulated the expression of glutamine‑fructose‑6‑phosphate transaminase 2 (GFPT2), a rate‑limiting enzyme of the hexosamine biosynthesis pathway. SLP‑2 contributed to the malignant character of PC by inducing liver metastasis. Cell motility and glucose uptake may be induced via the hexosamine biosynthesis pathway through the expression of GFPT2. The present study revealed a new mechanism of liver metastasis and indicated that SLP‑2 and its downstream pathway could provide novel therapeutic targets for PC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3892/or.2021.8041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042670PMC
June 2021

Prognostic value of an inflammation-based nutritional score for patients with initially unresectable pancreatic adenocarcinoma undergoing conversion surgery following chemo-/radiotherapy.

Surg Today 2021 Apr 7. Epub 2021 Apr 7.

Department of Surgery, Tohoku University Graduate School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.

Purpose: To clarify the prognostic value of the preoperative nutrition status of patients undergoing conversion surgery (CS) for initially unresectable pancreatic adenocarcinoma (UR-PA).

Methods: The subjects of this retrospective study were 41 consecutive patients with initially UR-PA treated with chemo-/radiotherapy and subsequent CS between 2007 and 2014, at Tohoku University Hospital. The preoperative Glasgow Prognostic Score (GPS) was 0, conveying normal nutrition, in 25 patients (N group) and 1-2, conveying malnutrition, in 16 patients (M group). The clinicopathological factors influencing overall survival were defined by uni- and multivariate analyses.

Results: The M group had a significantly worse prognosis than the N group (median overall survival (mOS) 9.6 vs 40.7 months, p = 0.001). Multivariate analysis identified a GPS of 1-2 as an independent predictor of worse prognosis [hazard ratio (HR)3.437, p = 0.032], followed by CA19-9 elevation before CS (HR4.089, p = 0.012) and pathological lymph node metastases (HR2.314, p = 0.046). Patients who maintained a favorable nutritional status (GPS 0) during preoperative treatment had a significantly better prognosis, whereas those whose nutritional status deteriorated (elevated to GPS 1-2) had poorer survival (mOS 40.7 vs. 9.7 months, p = 0.003) CONCLUSION: Preoperative malnutrition status (GPS 1-2) is considered an independent predictor of a worse prognosis for patients undergoing CS for initially UR-PA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00595-021-02279-5DOI Listing
April 2021

Pathways for the development of multiple epithelial types of intraductal papillary mucinous neoplasm of the pancreas.

J Gastroenterol 2021 Apr 1. Epub 2021 Apr 1.

Department of Investigative Pathology, Tohoku University Graduate School of Medicine, 2-1 Seiryomachi, Aobaku, Sendai, 980-8575, Japan.

Background: Intraductal papillary mucinous neoplasm (IPMN) of the pancreas is categorized into four distinct types: the gastric, intestinal, pancreatobiliary, and oncocytic. Each type is associated with specific clinicopathological features. We aimed to uncover the molecular mechanisms underlying the development of these types of IPMN.

Methods: We obtained 103 lesions of various types, including 49 gastric, 26 intestinal, 22 pancreatobiliary, and 6 oncocytic lesions, from 43 IPMNs, including 36 with multiple types. Comparative analysis was performed by targeted sequencing of 37 genes in different lesion types within each pancreas.

Results: Gastric-type low-grade lesions were observed in all 36 tumors with multiple types, with 245 mutations identified across all samples. The average number of mutations was significantly different between different lesion grades and types: 1.88 for low-grade lesions, 2.77 for high-grade lesions, and 2.38 for invasive lesions (p = 0.0067); and 1.96 for gastric-type lesion, 2.92 for intestinal-type lesion, 2.73 for pancreatobiliary-type lesion, and 2.17 for oncocytic-type lesion (p = 0.0163). Tracing of mutations between lesions containing multiple types in the same pancreas suggested three developmental pathways, denoted as "progressive", "divergent", and "independent". The progressive and divergent pathways indicate an ancestral lesion that was mostly gastric-type and low-grade may progress or diversify into lesions of other types and/or higher grades. The independent pathway suggests that some high-grade lesions of any type may develop independently.

Conclusion: These findings suggest that gastric-type low-grade lesions have a risk of progression into high-grade lesions of other types. Therefore, low-grade gastric-type IPMNs should be under constant surveillance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00535-021-01783-2DOI Listing
April 2021

Survey of surgical resections for neuroendocrine liver metastases: A project study of the Japan Neuroendocrine Tumor Society (JNETS).

J Hepatobiliary Pancreat Sci 2021 Mar 31. Epub 2021 Mar 31.

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

Background/purpose: Hepatic resection is considered the treatment of choice for neuroendocrine liver metastases (NELM). However, the safety and efficacy of resection have not been fully evaluated using a large cohort. The aim of the present study was to collect real-world data regarding hepatic resections for NELM.

Methods: A retrospective, multicenter survey was conducted. The background characteristics of patients undergoing an initial hepatic resection for NELM, the operative details, pathological findings, and patient outcomes were investigated.

Results: A total of 222 patients were enrolled from 30 institutions. The primary tumor site was the pancreas in 58.6%, and the presentation of NELM was synchronous in 63.1% of the cases. Concomitant resection of the primary tumor and liver metastases was performed for 66.4% of the synchronous metastases, and the 90-day morbidity and mortality rates were 12.6% and 0.9%, respectively. The operations resulted in R2 resections in 26.1% of the cases, and 83.4% of the patients experienced recurrence after R0/1 resections. However, the patients were treated using multiple modalities after R2 resection or recurrence, and the overall survival rate was relatively favorable, with 5-year and 10-year survival rates of 70.2%, and 43.4%, respectively. Univariable and multivariable analyses identified the tumor grading (G3) of the primary tumor as a significant prognostic factor for both the recurrence-free and overall survivals.

Conclusions: The present data confirmed the safety of the surgical resection of NELM. Although recurrences were frequent, the survival outcomes after resection were favorable when a multi-disciplinary treatment approach was used.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jhbp.956DOI Listing
March 2021

Increased neutrophil-lymphocyte ratio predicts recurrence in patients with well-differentiated pancreatic neuroendocrine neoplasm based on the 2017 World Health Organization classification.

BMC Surg 2021 Mar 31;21(1):176. Epub 2021 Mar 31.

Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan.

Background: The prognostic values of inflammation-based markers in well-differentiated pancreatic neuroendocrine neoplasms, diagnosed according to the new 2017 World Health Organization classification, have remained unclear. Therefore, we assessed the ability to predict the recurrence of such markers after curative resection in patients with these neoplasms.

Methods: Circulating/systemic neutrophil-lymphocyte, monocyte-lymphocyte, platelet-lymphocyte, and platelet-white cell ratios were evaluated in 120 patients who underwent curative resection for well-differentiated pancreatic neuroendocrine neoplasms without synchronous distant metastasis between 2001 and 2018. Recurrence-free-survival and overall survival were compared using Kaplan-Meier analysis and log-rank tests. Univariate or multivariate analyses, using a Cox proportional hazards model, were used to calculate hazard ratios with 95% confidence intervals.

Results: Univariate analysis demonstrated that preoperative neutrophil-lymphocyte ratio, tumor size, European Neuroendocrine Tumor Society TMN classification, 2017 World Health Organization classification, and venous invasion were associated with recurrence. The optimal preoperative neutrophil-lymphocyte ratio cut-off value was 2.62, based on receiver operating characteristic curve analysis. In multivariate analysis, a higher preoperative neutrophil-lymphocyte ratio (HR = 3.49 95% CI 1.05-11.7; P = 0.042) and 2017 World Health Organization classification (HR = 8.81, 95% CI 1.46-168.2; P = 0.015) were independent recurrence predictors.

Conclusions: The circulating/systemic neutrophil-lymphocyte ratio is a useful and convenient preoperative prognostic marker of recurrence in patients with well-differentiated pancreatic neuroendocrine neoplasm based on the 2017 World Health Organization classification.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12893-021-01178-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011407PMC
March 2021

Defining the Optimal Method for Measuring Metabolic Tumor Volume on Preoperative F-Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography as a Prognostic Predictor in Patients With Pancreatic Ductal Adenocarcinoma.

Front Oncol 2021 12;11:646141. Epub 2021 Mar 12.

Department of Nuclear Medicine and Radiology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.

Objectives: Metabolic tumor volume (MTV) on F-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) is a promising prognostic predictor in pancreatic ductal adenocarcinoma (PDAC). However, the optimal segmentation method and threshold value to determine MTV for PDAC are still unclear. We explored the optimal method and threshold value for the prognostic value of MTV measured on pre-treatment F-FDG-PET/CT.

Methods: Seventy-three patients with resected PDAC who underwent F FDG-PET/CT before surgical resection were enrolled. MTV values of the tumor were measured on FDG-PET/CT by the two fixed-threshold methods using threshold values as 2.0, 2.5, 3.0, and 3.5 for the absolute method and 35%, 40%, 42%, 45%, and 50% for the relative method. Receiver operating characteristic curve analysis for prediction of 1-year survival rates was conducted for determining the optimal threshold values, and we selected the optimal method and threshold value considering area under the curve. The prognostic values of each FDG-PET/CT parameter for disease-specific survival and recurrence-free survival were assessed with Kaplan-Meier method and Cox proportional hazard models.

Results: In receiver operating characteristic curve analysis, MTV by the fixed-absolute threshold method based on a threshold value of 3.5 (MTV3.5) performed best in our study with area under the curve 0.724, sensitivity of 65%, and specificity of 75%. In univariate and multivariate analyses, MTV3.5 was significantly associated with disease-specific and recurrence-free survival.

Conclusions: MTV3.5 by absolute threshold on pre-treatment FDG-PET/CT was the best independent prognostic predictor in resectable PDAC compared with other absolute threshold values and relative threshold values.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2021.646141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994512PMC
March 2021

Oral recombinant methioninase combined with paclitaxel arrests recalcitrant ovarian clear cell carcinoma growth in a patient-derived orthotopic xenograft (PDOX) nude-mouse model.

Cancer Chemother Pharmacol 2021 Mar 25. Epub 2021 Mar 25.

AntiCancer, Inc, 7917 Ostrow Street, San Diego, 92111, CA, USA.

Purpose: Advanced ovarian clear cell carcinoma (OCCC) is a recalcitrant disease, often resistant to the first-line platinum-based therapy. Using a novel patient-derived orthotopic xenograft (PDOX) nude-mouse model of OCCC, we tested whether oral-recombinant methioninase (o-rMETase) could enhance the efficacy of paclitaxel (PTX).

Methods: The OCCC PDOX model was established and passaged in nude mice. The OCCC PDOX models were randomized into 5 groups. G1: untreated control; G2: paclitaxel (PTX) (20 mg/kg, intraperitoneal (i.p.) injection, weekly); G3: o-rMETase (100 units, oral, daily); G4: PTX (20 mg/kg, i.p. injection, weekly) + carboplatinum (CBDCA) (40 mg/kg, i.p. injection weekly); G5: PTX (20 mg/kg, i.p. injection, weekly) + o-rMETase (100 units, oral, daily). The treatment period was 2 weeks.

Results: The combination of PTX and o-rMETase arrested OCCC tumor growth (relative tumor volume: 1.09 ± 0.63 (mean ± SD)) compared with the untreated control (relative tumor volume: 3.92 ± 1.04 (mean ± SD)) (p < 0.0001). There was no significant difference in relative tumor volume between PTX plus o-rMETase and PTX plus CBDCA (relative tumor volume: 1.39 ± 0.37 (mean ± SD)) (p = 0.93).

Conclusion: PTX plus o-rMETase arrested the OCCC tumor growth. o-rMETase is readily administered and can greatly enhance first-line therapy of a recalcitrant cancer. The novel and effective treatment strategy in the present report has future clinical potential for patients with OCCC, especially for patients who cannot well tolerate platinum-based therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00280-021-04261-xDOI Listing
March 2021

A rare case of penetration related to ischemic duodenitis after ventricular assist device implantation for dilated cardiomyopathy.

Clin J Gastroenterol 2021 Mar 24. Epub 2021 Mar 24.

Division of Gastroenterology, Tohoku University Graduate School of Medicine, Tohoku University Hospital, 1-1, Seiryo-Cho, Aoba-Ku, Sendai, Miyagi, 980-8574, Japan.

A 66-year-old man with a history of diabetes and dilated cardiomyopathy underwent the implantation of a ventricular assist device (VAD) at the age of 62. He suffered from epigastralgia for a month and then visited our hospital with complaints of severe epigastralgia and hematemesis. A physical examination revealed abdominal distension without rigidity. Laboratory data showed severe systemic inflammation, multiple organ failure, and disseminated intravascular coagulation. Computed tomography showed multifocal thickness of the gastroduodenal wall with surrounding panniculitis, gas in a portal vein and a perigastric vein. Emergency esophago-gastro duodenoscopy (EGD) demonstrated a large erosion in the antrum of the stomach, and penetration surrounded by circumferentially ischemic mucosa in the second and third portions of the duodenum. Based on informed consent, conservative therapy was performed, and his condition improved enabling the start of oral intake on the 37th hospital day. However, 7 days later, there was a relapse of epigastralgia after a meal. Gastrointestinal series and EGD revealed a 10-mm-long pinhole-like stricture at the site. After laparoscopic gastro-jejunal bypass surgery, he has remained in a good condition for 2 years. We demonstrated a rare case of penetration due to severe ischemic duodenitis 4 years after VAD implantation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12328-021-01346-1DOI Listing
March 2021

Novel candidate factors predicting the effect of S-1 adjuvant chemotherapy of pancreatic cancer.

Sci Rep 2021 Mar 22;11(1):6541. Epub 2021 Mar 22.

Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan.

The collagen gel droplet-embedded drug sensitivity test (CD-DST) was revealed to be useful for predicting the effect of S-1 adjuvant chemotherapy for pancreatic ductal adenocarcinoma (PDAC). However, collection of an adequate number of PDAC cells is difficult due to the surrounding fibroblasts. Thus, the aim of this study was to discover novel biomarkers to predict chemosensitivity based on the CD-DST results. Proteomics analysis was performed using liquid chromatography tandem mass spectrometry (LC-MS/MS). Candidate proteins were validated in patients with 5-FU CD-DST results via immunohistochemistry (IHC). The relationships between the candidate proteins and the effect of the adjuvant S-1 were investigated via IHC. Among the 2696 proteins extracted by LC-MS/MS, C1TC and SAHH could accurately predict the CD-DST results. Recurrence-free survival (RFS) was significantly improved in the IHC-positive group compared with the IHC-negative group in both factors. The negative group did not show a significant difference from the group that did not receive S-1. The double-positive group was associated with significantly prolonged RFS compared to the no adjuvant chemotherapy group. C1TC and SAHH have been shown to be useful biomarkers for predicting 5-FU sensitivity as a substitute for the CD-DST in adjuvant chemotherapy for PDAC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-86099-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985196PMC
March 2021

Development of a system combining comprehensive genotyping and organoid cultures for identifying and testing genotype-oriented personalised medicine for pancreatobiliary cancers.

Eur J Cancer 2021 May 19;148:239-250. Epub 2021 Mar 19.

Department of Investigative Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan. Electronic address:

Background: Pancreatobiliary cancer is a highly aggressive tumour with a dismal prognosis. Personalised medicine represents a promising and effective therapeutic approach for this intractable disease. In this study, we aimed to establish a system for identifying and testing genotype-oriented targeted drugs for pancreatobiliary cancers by combining exome sequencing and organoid culture of primary tumours.

Methods: Tumour cells isolated from resected tumours were subjected to organoid cultures based on published protocols with modifications. Exome sequencing was performed on the primary tumours. Histopathological and molecular features of the primary tumours were validated in the corresponding organoids. Genotype-oriented candidate targeted drugs were identified from exome sequencing, and their efficacies were tested in the organoids.

Results: Organoid cultures succeeded in 30 of 54 (55.6%) cases. Six primary cancers of the biliary tract and gall bladder were subjected to exome sequencing, which revealed a variety of somatic mutations of genes involved in signalling pathways, epigenetic modifiers, genome maintenance and metabolic enzymes. Most of the organoids of these 6 cases showed identical histopathological features and genomic aberrations as those of the primary tumours. Some of the aberrations were candidates for targeted therapies. Integrin-linked kinase (ILK) was one such candidate target, and an ILK inhibitor was confirmed to suppress proliferation of patient-derived organoids.

Conclusions: By combining exome sequencing and organoid culture, our model enabled to identify genotype-oriented targets for personalised medicine and to test efficacies of candidate targeted drugs in the organoids. The current proof-of-concept approach could increase therapeutic opportunities for patients with pancreatobiliary cancers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejca.2021.01.047DOI Listing
May 2021

Acinar Cell Carcinoma with Morphological Change in One Month.

Intern Med 2021 Mar 22. Epub 2021 Mar 22.

Division of Gastroenterology, Tohoku University Graduate School of Medicine, Japan.

A 64-year-old man was admitted to our hospital to undergo examination of a pancreatic tumor accompanied by sudden epigastric pain. The tumor had a well-defined oval shape that was mostly less enhanced, with the exception of part of the tumor on the pancreatic head side, on contrast enhanced (CE)-CT. However, CE-CT performed one-month later revealed that the viable part of the tumor grew toward the pancreatic tail with the reduction of necrotic tissue. We performed distal pancreatectomy and the tumor was diagnosed as acinar cell carcinoma (ACC). One important characteristic of ACC is that it may develop morphological changes within a short period of time.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2169/internalmedicine.7121-21DOI Listing
March 2021

Silencing of LRRFIP1 enhances the sensitivity of gemcitabine in pancreatic cancer cells by activating JNK/c-Jun signaling.

Pancreatology 2021 Mar 3. Epub 2021 Mar 3.

Department of Surgery, Tohoku University Graduate School of Medicine, Japan.

Background: The epithelial-mesenchymal transition (EMT) in cancer cells has been shown to closely associate with the survival and drug resistance of cancer cells. We recently provided evidence that Wnt signal activator leucine-rich repeat in flightless-1-interacting protein 1 (LRRFIP1) regulates EMT in pancreatic cancer. LRRFIP1 silencing inhibits the translocation of β-catenin to the nucleus, which led to reverse EMT in cancer cells. It was suggested that LRRFIP1 was implicated in gemcitabine sensitivity by regulating EMT signaling.

Methods: Gemcitabine chemosensitivity was investigated in LRRFIP1-knockdown pancreatic cancer cells (PANC-1 and MIA Paca-2). In addition, the effects of LRRFIP1 knockdown on JNK/SAPK (stress activated-protein kinase) signaling and apoptosis were evaluated.

Results: LRRFIP1 silencing accelerates gemcitabine-induced caspase activity and cell death in pancreatic cancer cells. It was also revealed that gemcitabine-induced phosphorylation of c-Jun N-terminal kinase (JNK) and c-Jun were increased in LRRFIP1 knockdown cells. The activation of JNK/c-Jun in LRRFIP1-knockdown cells was significantly diminished by the inhibition of Rac activity. It was confirmed that the acquisition of gemcitabine sensitivity by LRRFIP1 silencing largely depends on the stimulation of JNK/SAPK (stress activated-protein kinase) signaling.

Conclusions: Our findings suggest that reversing EMT and transient activation of JNK might be essential for the gemcitabine sensitivity in LRRFIP1 knockdown pancreatic cancer cells. Our discoveries highlight the potential role of LRRFIP1 in the chemosensitivity related to the regulation of EMT signaling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pan.2021.02.018DOI Listing
March 2021

Surgical resection for liver metastasis and local recurrence of pheochromocytoma 16 years after primary surgery: A case report.

Int J Surg Case Rep 2021 Apr 27;81:105712. Epub 2021 Feb 27.

Department of Surgery, Graduate School of Medicine, Tohoku University, Japan.

Introduction And Importance: Pheochromocytomas arise from the adrenal medulla and are rare. Pheochromocytomas metastasize to bone, lung and liver, and surgery might be the curative treatment. However, few cases are detected when they are resectable lesions because of difficulty in diagnosis and rapid growth. We herein report a patient who underwent resection of liver metastasis and local recurrence of pheochromocytoma.

Case Presentation: A 74-year-old woman visited our hospital for treatment for liver and retroperitoneal tumors. She had undergone left adrenal gland resection for pheochromocytoma 16 years earlier. Eleven years after primary surgery, breast cancer was diagnosed and resected. During the breast cancer follow-up, a liver tumor was identified with computed tomography. Breast cancer recurrence and metastasis were considered, so chemotherapy was administered first. However, the liver tumor gradually enlarged, and another lesion appeared in the retroperitoneum. The tumors were diagnosed as pheochromocytoma recurrence using I-metaiodobenzylguanidine scintigraphy, and she underwent resection of the local recurrence and liver metastasis. She was discharged on postoperative day 25 without complications, and no evidence of recurrence occurred more than 3.5 years postoperatively.

Clinical Discussion: All pheochromocytomas have metastatic potential; however, there are no reliable markers to predict malignancy. Early detection of recurrence by regular imaging and complete resection are important in the treatment. If the recurrence was oligometastasis and tumor growth is slow, surgical resection may be eligible.

Conclusion: A favorable outcome resulted from complete resection for liver metastasis and local recurrence of pheochromocytoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijscr.2021.105712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941035PMC
April 2021

Clinical characteristics of immunoglobulin IgG4-related sclerosing cholangitis: Comparison of cases with and without autoimmune pancreatitis in a large cohort.

Dig Liver Dis 2021 Mar 1. Epub 2021 Mar 1.

Kansai Medical University Kori Hospital, Kori, Japan.

Background: The clinical characteristics of IgG4-related sclerosing cholangitis (IgG4-SC) especially without autoimmune pancreatitis (AIP) have not been investigated in a large cohort.

Aims: To clarify the clinical characteristics of IgG4-SC and IgG4-SC without AIP.

Methods: We retrospectively reviewed imaging, serology, other organ involvement (OOI) and histology of 872 patients with IgG4-SC who participated in a Japanese nationwide survey in 2019, and compared these items between IgG4-SC with and without AIP.

Results: AIP was present in 83.7% (730/872) of IgG4-SC. In IgG4-SC, bile duct wall thickening was observed on ultrasound (528/650; 81.2%), computed tomography (375/525; 71.4%) and magnetic resonance imaging or cholangiopancreatography (290/440; 65.9%). An elevated serum IgG4 level (≥ 135 mg/dL) was found in 88.0% (322/366). IgG4-related OOI other than AIP was observed in 25.2% (211/836). The proportion of females was significantly higher in IgG4-SC without AIP (28.9% vs. 20.1%; p = 0.025). Hilar stricture was the most common cholangiographic type in IgG4-SC without AIP (39/107; 36.4%).There were no significant differences between IgG4-SC with and without AIP in the rates of bile duct wall thickening, elevated serum IgG4 level, or IgG4-related OOI.

Conclusions: The clinical characteristics of IgG4-SC was similar between IgG4-SC with and without AIP in a large cohort.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.dld.2021.02.009DOI Listing
March 2021

Safety of Combined Division vs Separate Division of the Splenic Vein in Patients Undergoing Distal Pancreatectomy: A Noninferiority Randomized Clinical Trial.

JAMA Surg 2021 May;156(5):418-428

Second Department of Surgery, Wakayama Medical University, Kimiidera, Wakayama, Japan.

Importance: In distal pancreatectomy (DP), the splenic vein is isolated from the pancreatic parenchyma prior to being ligated and divided to prevent intra-abdominal hemorrhage from the splenic vein stump with pancreatic fistula (PF). Conversely, dissecting the splenic vein with the pancreatic parenchyma is easy and time-saving.

Objective: To establish the safety of combined division of the splenic vein compared with separate division of the splenic vein.

Design, Setting, And Participants: This study was designed as a multicenter prospective randomized phase 3 trial. All results were analyzed using the modified intent-to-treat set. Patients undergoing DP for pancreatic body and tail tumors were eligible for inclusion. Patients were randomly assigned between August 10, 2016, and July 30, 2019.

Interventions: Patients were centrally randomized (1:1) to either separate division of the splenic vein or combined division of the splenic vein.

Main Outcomes And Measures: The primary end point was the incidence of grade B/C PF, and the incidence of intra-abdominal hemorrhage was included as one of the secondary end points.

Results: A total of 318 patients were randomly assigned, and 2 patients were excluded as ineligible. Of the 316 remaining patients, 150 (50.3%) were male. The modified intent-to-treat population constituted 159 patients (50.3%) in the separate division group and 157 patients (49.7%) in the combined division group. In the modified intent-to-treat set, the proportion of grade B/C PF in the separate division group was 27.1% (42 of 155) vs 28.6% (44 of 154) in the combined division group (adjusted odds ratio, 1.108; 95% CI, 0.847-1.225; P = .047), demonstrating noninferiority of the combined division of the splenic vein against separate division. The incidence of postoperative intra-abdominal hemorrhage in the 2 groups was identical at 1.3%.

Conclusions And Relevance: This study demonstrated noninferiority of the combined division of the splenic vein compared with separate division of the splenic vein regarding safety. Thus, isolating the splenic vein from the pancreatic parenchyma is deemed unnecessary.

Trial Registration: ClinicalTrials.gov Identifier: NCT02871804.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamasurg.2021.0108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931136PMC
May 2021

ASO Author Reflections: Preceding Systemic Chemotherapy Might Provide Better Prognosis for Pancreatic Ductal Adenocarcinoma with Positive Peritoneal Cytology.

Ann Surg Oncol 2021 Feb 25. Epub 2021 Feb 25.

Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1245/s10434-021-09755-9DOI Listing
February 2021

Preceding Systemic Chemotherapy for Patients with Pancreatic Ductal Adenocarcinoma with Positive Peritoneal Cytology Provides Survival Benefit Compared with Up-Front Surgery.

Ann Surg Oncol 2021 Feb 20. Epub 2021 Feb 20.

Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan.

Background: The significance of surgical resection in pancreatic ductal adenocarcinoma (PDAC) with positive peritoneal cytology (PPC) is controversial. This study aimed to evaluate whether preceding chemotherapy could be beneficial for patients with PDAC with PPC.

Methods: Between 2017 and 2019, 34 consecutive PDAC patients diagnosed with PPC without distant metastasis were retrospectively reviewed. Twenty-three patients did not receive neoadjuvant treatment (NAT) and 11 received NAT. All patients received systemic chemotherapy after PPC was confirmed, and they underwent surgical resection if PPC turned negative. The treatment course, ratio of conversion surgery (CS), and prognosis were evaluated. Moreover, the prognosis of PPC patients who underwent up-front surgery without NAT between 2003 and 2016 was analyzed as a comparative cohort.

Results: The median survival time (MST) of the patients without NAT was 31.4 months. CS was performed in 52.2% of the patients. Patients who underwent CS had better prognoses than those who did not undergo CS (p = 0.005). The CS rate was significantly higher in resectable PDAC (78.5%) than in borderline/unresectable PDAC (11.1%) (p = 0.002). The prognosis of patients with resectable PDAC was improved with preceding chemotherapy compared with up-front surgery (MST 13.0 months; p = 0.016). After NAT, the CS rate was low (27.3%), and the MST was only 14.1 months.

Conclusions: As an initial treatment for PDAC patients with PPC, chemotherapy may lead to a favorable prognosis. Especially, resectable PDAC is associated with a greater chance of improved prognosis. Future studies are required to ascertain whether up-front surgery or preceding chemotherapy should be performed for these patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1245/s10434-021-09718-0DOI Listing
February 2021

Salvage esophagectomy for local recurrent esophageal cancer after definitive chemoradiotherapy followed by photodynamic therapy: A case report.

Int J Surg Case Rep 2021 Mar 3;80:105617. Epub 2021 Feb 3.

Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan.

Introduction: Photodynamic therapy (PDT) is performed as a salvage treatment for patients with residual or recurrent esophageal cancer after chemoradiotherapy (CRT). Although PDT is considered less invasive than salvage surgery, it is unclear how deep its effects are and whether it causes damage to adjacent tissues. Herein, we report a case of esophageal cancer treated with PDT followed by esophagectomy. In this case, we evaluated the effect of PDT on adjacent tissues based on surgical and pathological examination.

Presentation Of Case: A 58-year-old man with dysphagia was diagnosed with esophageal squamous cell carcinoma (SqCC; T1N0M0, Stage I) in the upper thoracic esophagus. He underwent definitive CRT with two courses of 5-fluorouracil and cisplatin every 4 weeks with 60 Gy of radiation. Twelve months after CRT, endoscopic examination revealed local recurrence, and PDT using talaporfin sodium was performed. The tumor recurred again 6 months after PDT, and robot-assisted thoracoscopic esophagectomy was performed as a definitive treatment. Tissues around the left side of the esophagus and thoracic duct were tightly adherent with severe fibrosis and were successfully removed by extended resection. Histopathological examinations showed that the esophageal wall and peri-esophageal tissue were replaced by fibrous tissue and this extended even beyond the tumor.

Discussion: The primary tumor was limited to the submucosal layer, and the target for irradiation had some longitudinal margins. Therefore, PDT can cause intense inflammation in tissues adjacent to the tumor.

Conclusions: It is necessary to consider the location when performing salvage esophagectomy after PDT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijscr.2021.02.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893415PMC
March 2021

Clinical diagnostic criteria for IgG4-related sclerosing cholangitis 2020: (Revision of the clinical diagnostic criteria for IgG4-related sclerosing cholangitis 2012).

J Hepatobiliary Pancreat Sci 2021 Mar 26;28(3):235-242. Epub 2021 Feb 26.

Division of Hepato-Biliary Pancreatic Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan.

Several years have passed since the clinical diagnostic criteria for IgG4-related sclerosing cholangitis 2012 were published. New findings and knowledge have accumulated since then. The Research Committees for IgG4-related Diseases and for Intractable Diseases of the Liver and Biliary Tract, in association with the Ministry of Health, Labor, and Welfare of Japan and the Japan Biliary Association, have established a working group consisting of researchers specializing in IgG4-SC and have drawn up new clinical diagnostic criteria for IgG4-SC 2020. The diagnosis of IgG4-SC is based on a combination of the following six criteria: (a) narrowing of the intra- or extrahepatic bile duct; (b) thickening of the bile duct wall; (c) serological findings; (d) pathological findings; (e) other organ involvement; and (f) effectiveness of steroid therapy. These new diagnostic criteria for IgG4-SC are useful in practice for general physicians and other non-specialists.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jhbp.913DOI Listing
March 2021

Bleeding from jejunal varices formed at the Roux-en-Y jejunum site caused by the compression of the left renal vein after living donor liver transplantation with renoportal anastomosis.

Surg Case Rep 2021 Feb 6;7(1):43. Epub 2021 Feb 6.

Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, Japan.

Background: Renoportal anastomosis is an option for the portal vein reconstruction of a liver transplantation with grade 4 portal vein thrombosis and a splenorenal shunt. Here, we report the case of gastrointestinal bleeding who underwent living donor liver transplantation (LDLT) with renoportal anastomosis.

Case Presentation: Six-year-old female patient who underwent LDLT with renoportal anastomosis at 1 year of age had severe anemia with normal liver function during the follow-up period. The varices at the Roux-en-Y jejunum were considered the source of bleeding, and the compression of the left renal vein, which is known as a cause of Nutcracker syndrome, seemed to induce venous hypertension through the splenorenal shunt, which might induce the formation of the varices. She underwent percutaneous transhepatic sclerotherapy of the varices, and the anemia improved at her last follow-up, 6 months after sclerotherapy. This is the first reported case of Roux-en-Y jejunal varices bleeding related to the compression of the left renal vein after LDLT was performed with renoportal anastomosis.

Conclusions: Although renoportal anastomosis should be cautiously performed when there are no options for severe portal vein thrombosis, the status of the left renal vein and new collateral formation should be observed carefully during the follow-up period in pediatric cases of renoportal anastomosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40792-021-01129-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867670PMC
February 2021

A case of esophageal achalasia presenting with empyema and septic shock differentiated from esophageal rupture.

Clin J Gastroenterol 2021 Apr 1;14(2):422-426. Epub 2021 Feb 1.

Department of Surgery, Tohoku University Graduate School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan.

The patient was a 44-year-old man with a history of schizophrenia. He had a history of esophageal dysphagia and vomiting and presented with sudden strong epigastric pain. He was taken to a medical emergency center in a state of septic shock. Computed tomography revealed a left thoracic abscess, and esophageal rupture was suspected. He was referred to our department for treatment. Gastrointestinal series and gastrointestinal endoscopy revealed marked esophageal dilation and strong contraction of the lower esophageal sphincter. We, therefore, diagnosed the patient with empyema thoracis secondary to aspiration pneumonia due to esophageal achalasia. Conservative treatment with antibiotics and computed tomography-guided chest drainage was initiated, but the inflammation persisted. Thus, we successfully performed a per-oral endoscopic myotomy to manage achalasia symptoms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12328-021-01349-yDOI Listing
April 2021

A Case of IgG4-related Diaphragmatic Inflammatory Pseudotumor.

Intern Med 2021 Feb 1. Epub 2021 Feb 1.

Division of Gastroenterology, Tohoku University Graduate School of Medicine, Japan.

A 71-year-old man underwent surgery for a pancreatic neuroendocrine tumor. Follow-up imaging showed swelling of the remnant pancreas, and he was histologically diagnosed with autoimmune pancreatitis based on endoscopic ultrasonography-guided fine-needle aspiration specimens. After two years, a tumor appeared on the liver surface. Although we planned to perform laparoscopic partial hepatectomy, the intraoperative findings showed that the tumor was located in the diaphragm. Partial resection of the diaphragm was performed, and the final diagnosis was an immunoglobulin G4-related inflammatory pseudotumor in the diaphragm. To our knowledge, this is the first reported case of an immunoglobulin G4-related diaphragmatic inflammatory pseudotumor.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2169/internalmedicine.6589-20DOI Listing
February 2021

Malignant rhabdoid tumours of the small intestine with multiple organ involvement: Case report.

Int J Surg Case Rep 2021 Feb 22;79:386-389. Epub 2021 Jan 22.

Department of Surgery, Iwaki City Medical Center, 16 Kuzehara, Uchigou Mimaya-machi, Iwaki City, Fukushima, 973-8555, Japan.

Introduction And Importance: Malignant rhabdoid tumours (MRTs) were first described as an infrequent variant of Wilms' tumour and have been reported in several organs. The small intestine is a rare site for MRTs.

Case Presentation: A 70-year-old man presented with appetite loss and melena. Haemorrhagic small intestinal tumours, swollen mesenteric and paraaortic lymph nodes, a tumour in the left kidney, and multiple tumours in the lung were found. He underwent partial resection of two haemorrhagic small intestinal tumours classified as MRTs based on the results of a pathological examination. However, melena appeared again on postoperative day 6. We performed another operation and resected approximately 180 cm of the small intestine that contained multiple tumours. All lesions were classified as MRTs. Unfortunately, melena appeared again 4 days after the second operation. He did not want invasive therapy and died from massive melena 2 months after the initial surgery.

Clinical Discussion: MRTs of the small intestine are uncommon and have an extremely poor prognosis. Although curative resection is an important treatment, cases of metastasis at diagnosis and postoperative early recurrence have been observed, as was the case for the patient described herein. In these cases, effective systemic therapy is necessary. Recently, tumour suppressor genes were shown to be involved in the occurrence of MRT, and new therapies for MRT have been studied.

Conclusion: We herein conclude effective systemic therapy is necessary for MRTs with multiple organ involvement. The development of new drugs for this disease is ongoing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijscr.2021.01.081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847821PMC
February 2021

Improvement of hepatocyte engraftment by co-transplantation with pancreatic islets in hepatocyte transplantation.

J Tissue Eng Regen Med 2021 Apr 19;15(4):361-374. Epub 2021 Feb 19.

Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan.

Because of the fragility of isolated hepatocytes, extremely poor engraftment of transplanted hepatocytes remains a severe issue in hepatocyte transplantation. Therefore, improving hepatocyte engraftment is necessary to establish hepatocyte transplantation as a standard therapy. Since the pancreatic islets are known to have favorable autocrine effects, we hypothesized that the transplanted islets might influence not only the islets but also the nearby hepatocytes, subsequently promoting engraftment. We evaluated the effects of islet co-transplantation using an analbuminemic rat model (in vivo model). Furthermore, we established a mimicking in vitro model to investigate the underlying mechanisms. In an in vivo model, the hepatocyte engraftment was significantly improved only when the islets were co-transplanted to the nearby hepatocytes (p < 0.001). Moreover, the transplanted hepatocytes appeared to penetrate the renal parenchyma together with the co-transplanted islets. In an in vitro model, the viability of cultured hepatocytes was also improved by coculture with pancreatic islets. Of particular interest, the coculture supernatant alone could also exert beneficial effects comparable to islet coculture. Although insulin, VEGF, and GLP-1 were selected as candidate crucial factors using the Bio-Plex system, beneficial effects were partially counteracted by anti-insulin receptor antibodies. In conclusion, this study demonstrated that islet co-transplantation improves hepatocyte engraftment, most likely due to continuously secreted crucial factors, such as insulin, in combination with providing favorable circumstances for hepatocyte engraftment. Further refinements of this approach, especially regarding substitutes for islets, could be a promising strategy for improving the outcomes of hepatocyte transplantation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/term.3170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048420PMC
April 2021

[A Case of Sigmoid Colon Cancer with Thrombotic Microangiopathy].

Gan To Kagaku Ryoho 2020 Dec;47(13):2358-2360

Dept. of Surgery, Tohoku University Graduate School of Medicine.

A 50's man was referred to our hospital because of sigmoid colon cancer with multiple liver metastases and para-aortic lymph node metastases. Although blood test showed elevated D-dimer(50 μg/mL), there was no significant thrombus in contrast-enhanced CT scan. Since cancer pain and symptoms of bowel obstruction had continued after endoscopic stent placement, we resected primary lesion. Despite anemia and elevated D-dimer level had persisted after the operation, there were no obvious bleeding source nor thrombus. Continuous intravenous heparin infusion was started for hypercoagulability. Then, D-dimer and CRP levels were promptly decreased. Since schizocyte and giant platelets were observed in peripheral blood smear, he was eventually diagnosed with thrombotic microangiopathy as a paraneoplastic syndrome. However D- dimer and CRP levels were re-elevated, and it seemed to be necessary to control cancer progression. Thus, cetuximab monotherapy was started considering his performance status. After starting cetuximab, fever and CRP level were immediately improved. Cetuximab appeared to be very effective, but he died of acute subdural hematoma. Continuous intravenous heparin infusion was supposed to be effective in the treatment of thrombotic microangiopathy along with the management of cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
December 2020

[A Case of Radically Resected Sigmoid Colon Cancer with Bladder Invasion after Chemotherapy and Weight Loss in an Extremely Obese Patient].

Gan To Kagaku Ryoho 2020 Dec;47(13):2320-2322

Dept. of Surgery, Tohoku University Graduate School of Medicine.

A 30's extremely obese patient(body mass index: BMI 45 kg/m2)was referred to our hospital with a chief complaint of bloody urine and stool. Colonoscopy revealed a sigmoid colon tumor. Barium enema examination revealed stenosis of the sigmoid colon. CT scan showed a tumor in the sigmoid colon, with bladder invasion. The para-aortic lymph node was partially swollen. We considered surgery to be high risk because of the patient's severe obesity. Therefore, we decided to examine the possibility of radical surgery followed by chemotherapy(mFOLFOX6/cetuximab)with weight reduction. Following this, the tumor had shrunk remarkably, and the patient's BMI decreased from 45 kg/m2 to 39 kg/m2. The visceral fat area was reduced from 298 cm2 to 199 cm2 at the umbilical level. We then performed a sigmoid colectomy with partial resection of the bladder. Thus, chemotherapy combined with weight loss enabled us to perform radical surgery safely for a locally advanced sigmoid colon cancer in a patient with severe obesity.
View Article and Find Full Text PDF

Download full-text PDF

Source
December 2020

[A Case of Initially Locally Advanced Pancreatic Cancer Curatively Resected after Carbon-Ion Radiotherapy with Gemcitabine].

Gan To Kagaku Ryoho 2020 Dec;47(13):2266-2268

Dept. of Surgery, Tohoku University Graduate School of Medicine.

Background: The neoadjuvant therapy against locally advanced pancreatic cancer(LAPC)have been developed by combining radiation with chemotherapy. We experienced a case of LAPC performed R0 resection and obtained high histopathological effect by carbon-ion radiotherapy with gemcitabine(GEM).

Case Presentation: A 65-year-old male with epigastric and back pain was suspected as pancreas cancer by FDG-PET/CT scan, and was referred to our hospital. CT scan revealed a tumor in pancreatic body with poor contrast effect and with invasion to celiac artery, common hepatic artery and portal vein, and diagnosed as pancreatic adenocarcinoma by endoscopic ultrasound-fine needle aspiration(EUS-FNA). Therefore we diagnosed the tumor as pancreatic body cancer, cT4, cN1a, cM0, cStage Ⅲ, UR-LA. GEM plus nab-paclitaxel(GnP)were administered for 4 months followed by carbon-ion radiotherapy with GEM at other hospital. Distal pancreatectomy with en bloc celiac axis resection(DP-CAR)was performed 3 months after irradiation. High therapeutic effect was obtained histopathologically( Evans grade Ⅲ), and lesions outside the pancreas disappeared except for metastasis to one lymph node (ypT1c, ypN1a, ycM0, ypStage ⅡB), and R0 resection was performed.

Conclusion: Carbon-ion radiotherapy with chemotherapy for LAPC may improve curative resection rate.
View Article and Find Full Text PDF

Download full-text PDF

Source
December 2020