Publications by authors named "Hisahiro Matsubara"

346 Publications

Diagnostic Immunostaining and Tumor Markers Predict the Prognosis of Esophageal Neuroendocrine Cell Carcinoma Patients.

Ann Surg Oncol 2021 Apr 11. Epub 2021 Apr 11.

Department of Frontier Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.

Background: Esophageal neuroendocrine carcinoma (ENEC) has a poor prognosis, and predicting the prognosis by examining various markers may contribute to the determination of treatment strategies. Therefore, a multiple-institution retrospective study was performed to identify biomarkers using diagnostic immunohistochemistry and serum tumor markers that predict the prognosis of patients with ENEC.

Methods: The results of immunohistochemical examination and serum tumor markers were extracted from the data of 141 ENEC patients at 39 institutions certified by the Japan Esophageal Society. The study then examined correlations between these data and prognosis or treatment effects.

Results: The ENEC patients with positively for all expression of synaptophysin (Syn), chromogranin A (CgA), and CD56 had a significantly worse prognosis than the patients with other expression patterns. Additionally, surgery and chemoradiotherapy were significantly more effective treatments than chemotherapy for the patients who were not positive for all expressions of Syn, CgA, and CD56. In terms of serum tumor markers, the patients with a high neuron-specific enolase (NSE) value had a significantly worse prognosis than the patients with a normal NSE value, and complete response (CR) cases treated with chemotherapy were significantly fewer in the high-NSE group. The results of multivariate analysis demonstrated that high NSE levels were an independent poor prognostic factor for esophageal endocrine cell carcinoma.

Conclusion: This study showed that positivity for all expressions of Syn, CgA, and CD56, and a high NSE value were significantly worse prognostic factors for ENEC patients than other expression patterns and may be important prognostic biomarkers of ENEC.
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http://dx.doi.org/10.1245/s10434-021-09872-5DOI Listing
April 2021

[Investigation for Arc of Riolan-Conserving High Ligation Using Simulation CT Colonography in Preoperative Colorectal Cancer].

Gan To Kagaku Ryoho 2021 Mar;48(3):428-430

Dept. of Surgery, International University of Health and Welfare Ichikawa Hospital.

Background And Purpose: Simulation computed tomography colonography(sCTC), which combines CTC and 3-dimensional vascular imaging, is popular for the surgery of colorectal cancer. We experience anomaly, called arc of Riolan(aR), rarely but its definition and details are unclear. Using sCTC, we identified aR and investigated the simulation of aR-conserving high ligation.

Patient And Method: The patients were 3 cases of sigmoid colorectal cancer with aR in 369 patients who underwent sCTC before colorectal cancer surgery. We identified the running morphology of aR. And we classified Griffiths' point as presence(P)and absence(A). Narrow or mesh-shaped artery which were ischemic risk factors of intestinal tract was P groups and normal artery was A groups in the marginal artery of splenic flexure. We simulated aR-conserving lymph node dissection using sCTC.

Result: Case 1. The patient was 60-year-old man with rectal cancer, cT4aN1M0, Stage Ⅲa. The running morphology of aR was between the left branch of middle colic artery(MCA lt)and LCA. Griffiths point: P. Surgical simulation was D3 lymph node dissection with preservation of aR and high ligation of IMA. Pathological findings was pT3N1M0, Stage Ⅲa. Case 2. The patient was 65-year-old woman with sigmoid colon cancer, cT3N2M0, Stage Ⅲb. The running morphology of aR was between MCA lt and IMA. Griffiths point: P. Surgical simulation was D3 lymph node dissection with preservation of aR and high ligation of IMA. Pathological findings was pT3N2M0, Stage Ⅲb. Case 3. The patient was 75-year-old woman with sigmoid colon cancer, cT1bN0M0, Stage Ⅰ. The running morphology of aR was between first jejunal artery and IMA. Griffiths point: A. Surgical simulation was D3 lymph node dissection with preservation of aR and high ligation of IMA. Pathological findings was pT1bN0M0, Stage Ⅲb.

Conclusion: Using sCTC, we could identify the various running morphology of aR and simulate aR-conserving lymph node dissection in high ligation.
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March 2021

[A Case of Unresectable Colorectal Cancer with Complete Remission after Palliative Surgery Due to Continued Pharmacotherapy].

Gan To Kagaku Ryoho 2021 Mar;48(3):413-415

Dept. of Surgery, Numazu City Hospital.

A 50s-year-old man was admitted to our hospital because of abdominal pain and vomitting. CT showed a thickened wall of the sigmoid colon, marked enlargement of the oral side, and a 30 mm tumor on the left lateral section of the liver. We diagnosed colonic obstruction due to sigmoid colon cancer with liver metastasis. We failed to place a colonic stent for decompression, so we performed a colostomy using the cecum. An exploratory laparoscopy was performed instead of curative surgery due to peritoneal disseminations, followed by chemotherapy and molecular targeted therapy. Although primary lesion, liver metastatic lesion and disseminated lesions were reduced by pharmacotherapy the patient developed a grade 2 skin disorder around the colostomy. Therefore, it was determined that molecular targeted therapy could not be continued. The resection of the primary lesion and closure of the colostomy were performed to continue pharmacotherapy. Pharmacotherapy was resumed after operation. The patient is currently getting complete remission, undergoing maintenance therapy with no skin disorders. In this case, surgery was performed as part of the multidisciplinary treatment. It suggested that palliative surgery might be an effective option in multidisciplinary treatment.
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March 2021

Randomized phase II study of tegafur-uracil/leucovorin versus tegafur-uracil/leucovorin plus oxaliplatin after curative resection of high-risk stage II/III colorectal cancer (SOAC-1101 trial).

Int J Colorectal Dis 2021 Mar 14. Epub 2021 Mar 14.

Department of Frontier Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.

Purpose: This randomized phase II trial compared tegafur-uracil/leucovorin (UFT/LV) plus oxaliplatin (TEGAFOX) to UFT/LV as adjuvant chemotherapy for patients with high-risk stage II/III colorectal cancer.

Methods: From 2010 to April 2015, 159 patients who underwent curative resection were randomly assigned to receive TEGAFOX (85 mg/m oxaliplatin on days 1 and 15, 300 mg/m/day UFT and 75 mg/day LV on days 1-28, every 35 days for five cycles) or UFT/LV. The primary study endpoint was disease-free survival.

Results: The 3-year disease-free survival rate was 84.2% in the TEGAFOX arm, versus 62.1% for UFT/LV. The stratified hazard ratio for disease-free survival for TEGAFOX compared to UFT/LV was 0.338 (P < 0.01). The incidence of any-grade adverse events was significantly higher in the TEGAFOX arm (96.1%) than in the UFT/LV arm (76.6%; P < 0.01). The rates of any-grade neutropenia, thrombocytopenia, aspartate aminotransferase/alanine aminotransferase elevation, and peripheral sensory neuropathy were higher in the TEGAFOX group, whereas the incidence of grade ≥ 3 adverse events did not differ between the groups.

Conclusions: TEGAFOX is an additional adjuvant chemotherapy option for high-risk stage II/III colorectal cancer.

Trial Registration: UMIN ID: 000007696, date of registration: April 10, 2012.
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http://dx.doi.org/10.1007/s00384-021-03906-wDOI Listing
March 2021

Subtotal versus total gastrectomy for remnant gastric cancer: a systematic review and meta-analysis of observational studies.

Langenbecks Arch Surg 2021 Mar 10. Epub 2021 Mar 10.

Department of Frontier Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.

Purpose: Subtotal gastrectomy (SG) has become a general option for distal gastric cancer. However, the availability of an organ-preserving approach for the treatment of remnant gastric cancer (RGC) is still controversial. Thus, the objective of the present study was to assess the safety and efficacy of SG for RGC by integrating data from published articles.

Methods: We searched the PubMed, Cochrane Library, and Web of Science databases for studies that compared SG versus total gastrectomy (TG) for RGC published from the inception of the databases until May 2020. A meta-analysis was performed using the Review Manager Version 5.0 software program from the Cochrane Collaboration.

Results: Three retrospective cohort studies with 144 patients were included. The meta-analysis revealed that the operative time of the SG group was significantly shorter than that in the TG group (MD: -34.84. 95% CI: -59.97- -9.71, P = 0.007). There was no significant difference in intraoperative blood loss (MD: -109.19. 95% CI: -240.37-21.99, P =0.10), length of postoperative hospital stay (MD: 0.40. 95% CI: -3.03-3.83, P = 0.82), postoperative complications (RR: 1.41. 95% CI: 0.76-2.63, P = 0.28), or recurrence (RR: 2.33, 95% CI: 0.48-11.44, P = 0.30). SG for RGC tended to be correlated with favorable 5-year overall survival; however, the association was not statistically significant (HR: 0.89, 95% CI: 0.63-1.26, P = 0.51).

Conclusion: Organ-preserving approaches such as SG may be a safe and feasible treatment option for early-stage RGC.
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http://dx.doi.org/10.1007/s00423-021-02144-6DOI Listing
March 2021

Cell-free microRNA-1246 in different body fluids as a diagnostic biomarker for esophageal squamous cell carcinoma.

PLoS One 2021 10;16(3):e0248016. Epub 2021 Mar 10.

Department of Frontier Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.

Esophageal squamous cell carcinoma is a malignant tumor with unfavorable prognosis. In this study, we investigated the usefulness of microRNA (miR)-1246 detection in various body fluids as a biomarker for this disease. A total of 72 patients with esophageal squamous cell carcinoma were enrolled, and their blood, urine, and saliva samples were collected prior to treatment. Reverse transcription-polymerase chain reaction of miR-1246 was performed, and pre- and postoperative and intraday fluctuations in its expression were examined. The expression of miR-1246 in the blood and urine was significantly higher in the patients with esophageal squamous cell carcinoma than in 50 healthy control subjects. Receiver operating characteristic curves showed that the area under the curve values were 0.91 (sensitivity 91.7%, specificity 76.0%), 0.82 (sensitivity 90.3%, specificity 62.0%), and 0.80 (sensitivity 83.3%, specificity 66.0%) in the serum, urine, and saliva, respectively. A relatively high diagnostic performance of miR-1246 was observed in all samples, which was better than that of the existing biomarkers squamous cell carcinoma antigen, carcinoembryonic antigen, and cytokeratin 19 fragment. No clear correlation was observed in the levels of miR-1246 expression among the three body fluids. Postoperatively, serum samples displayed significantly decreased miR-1246 levels. Although not significant, changes in the miR-1246 levels were observed at all collection times, with large fluctuations in the saliva. Meanwhile, serum miR-1246 expression was found to be associated with the disease prognosis. The results indicate that the levels of miR-1246 in the urine, saliva, and serum are a useful biomarker for esophageal squamous cell carcinoma and support the use of urine samples instead of blood samples for noninvasive diagnosis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0248016PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946279PMC
March 2021

Esophageal cancer patients' survival after complete response to definitive chemoradiotherapy: a retrospective analysis.

Esophagus 2021 Feb 24. Epub 2021 Feb 24.

Department of Gastrointestinal Surgery, The University of Tokyo Graduate School of Medicine, Hongo 7-3-1, Bunkyo-ku, Tokyo, 113-8655, Japan.

Background: Chemoradiotherapy is an alternative to surgery for esophageal cancer, with a putatively equivalent outcome. However, disease recurrence after a complete response is common and if follow-up surveillance detects recurrence, salvage treatments for potentially curable disease must follow.

Methods: We conducted a nation-wide questionnaire survey of institutions in Japan certified by the Japanese Esophageal Society to investigate outcomes of primary thoracic esophageal cancer patients initially treated by chemoradiotherapy with complete response diagnoses. The primary endpoint was overall survival, the secondary endpoint disease recurrence. Outcomes of patients who had undergone salvage treatments were also investigated. Cases were excluded from analysis if endoscopic study, endoscopic biopsy, or computed tomography data were lacking.

Results: At 41 institutes 544 case records were collected; valid data on 392 patients were obtained; 5-year survival was 74.8%, 5-year disease-free survival, 66.8%. Clinical staging before treatment significantly affected both overall and disease-free survival rates, but differences between adjoining stages were unexpectedly small. The primary relapse site was classified as primary site (n = 58), regional lymph nodes (n = 36), or distant disease (n = 34). Salvage treatments with curative intent (surgery, endoscopic treatments, and additional radiation) were performed on 38, 23, and 4 cases; 5-year survival after esophagectomy (n = 22), endoscopic treatment (n = 23), and lymphadenectomy (n = 9) was 47.4%, 70.9%, and 33.3%, respectively.

Conclusions: A quarter of patients developed recurrent disease, mostly locoregional, after complete response. Complete response patients with originally advanced stage disease had fair clinical outcomes; salvage treatments after locoregional recurrence achieved modest long-term survival.
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http://dx.doi.org/10.1007/s10388-021-00817-1DOI Listing
February 2021

Myosin Light Chain 9/12 Regulates the Pathogenesis of Inflammatory Bowel Disease.

Front Immunol 2020 29;11:594297. Epub 2021 Jan 29.

Department of Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan.

The numbers of patients with inflammatory bowel disease (IBD), such as ulcerative colitis (UC) and Crohn's disease (CD), have been increasing over time, worldwide; however, the pathogenesis of IBD is multifactorial and has not been fully understood. Myosin light chain 9 and 12a and 12b (Myl9/12) are known as ligands of the CD69 molecule. They create "Myl9 nets" that are often detected in inflamed site, which play a crucial role in regulating the recruitment and retention of CD69-expressing effector cells in inflamed tissues. We demonstrated the strong expression of Myl9/12 in the inflamed gut of IBD patients and mice with DSS-induced colitis. The administration of anti-Myl9/12 Ab to mice with DSS-induced colitis ameliorated the inflammation and prolonged their survival. The plasma Myl9 levels in the patients with active UC and CD were significantly higher than those in patients with disease remission, and may depict the disease severity of IBD patients, especially those with UC. Thus, our results indicate that Myl9/12 are involved in the pathogenesis of IBD, and are likely to be a new therapeutic target for patients suffering from IBD.
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http://dx.doi.org/10.3389/fimmu.2020.594297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878395PMC
January 2021

Nationwide survey of neuroendocrine carcinoma of the esophagus: a multicenter study conducted among institutions accredited by the Japan Esophageal Society.

J Gastroenterol 2021 Apr 13;56(4):350-359. Epub 2021 Feb 13.

Department of Frontier Surgery, Chiba University, Graduate School of Medicine, Chiba, Japan.

Background: Esophageal neuroendocrine carcinoma (ENEC) is an extremely rare type of tumor characterized by a high malignant potential, rapid growth, and poor prognosis. Because the standard therapy for ENEC has been poorly defined, we herein aimed to attain a clear view of the current state of treatment for ENEC by performing a large-scale, multicenter study.

Methods: We conducted a questionnaire-based, retrospective clinical review of 142 patients with ENEC treated at 37 hospitals accredited by the Japan Esophageal Society from January 2010 to December 2015.

Results: The most frequent main treatment performed was an operation, followed by chemoradiotherapy, chemotherapy, and endoscopic submucosal dissection. Among the 67 patients who underwent surgery, 28 (19.7%) were not accurately diagnosed with NEC or a combined NEC tumor by pretreatment biopsy. The 5-year overall survival rate of all patients was 33.2%. Among patients with Stages III and IV disease, the prognosis was significantly better in patients who underwent chemoradiotherapy than in patients who underwent other treatments. Among patients with Stages I and II disease, however, there was no difference in survival rates between those who underwent surgery and chemoradiotherapy.

Conclusions: This nationwide survey is a valuable report of the current status of treatment of ENEC in a limited number of cases experienced at each participating institution. The survival benefit obtained from surgery was considered to be limited, especially for Stages III and IV ENEC. Accurate pretreatment histological diagnosis is essential to determine the most appropriate treatment strategy for patients with ENEC.
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http://dx.doi.org/10.1007/s00535-020-01756-xDOI Listing
April 2021

Genetic alterations in squamous cell lung cancer associated with idiopathic pulmonary fibrosis.

Int J Cancer 2021 Feb 3. Epub 2021 Feb 3.

Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Patients with idiopathic pulmonary fibrosis (IPF) are at higher risk of developing lung cancers including squamous cell lung carcinoma (SCC), which typically carries a poor prognosis. Although the molecular basis of cancer development subsequent to IPF has not been fully investigated, we recently reported two epigenetic phenotypes characterized by frequent and infrequent DNA hypermethylation in SCC, and an association of the infrequent hypermethylation phenotype with IPF-associated SCCs. Here, we conducted targeted exon sequencing in SCCs with and without IPF using the Human Lung Cancer Panel to investigate the genetic basis of IPF-associated SCC. SCCs with and without IPF displayed comparable numbers of total mutations (137 ± 22 vs 131 ± 27, P = .5), nonsynonymous mutations (72 ± 14 vs 69 ± 16, P = .5), indels (3.0 ± 3.5 vs 3.0 ± 3.9, P = 1) and synonymous mutations (62 ± 9.1 vs 60 ± 12, P = .5). Signature 1 was the predominant signature in SCCs with and without IPF. SETD2 and NFE2L2 mutations were significantly associated with IPF (44% vs 13%, P = .03 for SETD2; 38% vs 10%, P = .04 for NFE2L2). MYC amplification, assessed by copy number variant analysis, was also significantly associated with IPF (18.8% vs 0%, P = .04). Mutations in TP53 and CDKN2A were observed relatively frequently in SCCs with frequent hypermethylation (P = .02 for TP53 and P = .06 for CDKN2A). Survival analysis revealed that the SETD2 mutation was significantly associated with worse prognosis (P = .04). Collectively, we found frequent involvement of SETD2 and NFE2L2 mutations and MYC amplification in SCCs with IPF, and an association of a SETD2 mutation with poorer prognosis.
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http://dx.doi.org/10.1002/ijc.33499DOI Listing
February 2021

[A Case of Rapidly Growing Breast Spindle Cell Carcinoma].

Gan To Kagaku Ryoho 2020 Dec;47(13):2341-2342

Dept. of Frontier Surgery, Graduate School of Medicine, Chiba University.

We report a case of rapidly growing breast spindle cell carcinoma. The case was a 69-year-old female. Her chief complaint was right breast pain. She was being followed after surgery for left breast cancer but was seen because of right breast pain. In the right mammary gland CD area, a 27×27 mm large unclear mass lesion was observed, which had not been seen half a year prior. Right mastectomy and axillary dissection were performed following a preoperative diagnosis of pT2N1M0, pStage ⅡB ductal carcinoma. Currently, 2 years and 2 months have passed since the operation, and recurrence has not been observed. Case reports of rapidly growing breast spindle cell carcinoma are occasionally found, but no literature specifically defines acute growth. Here, we defined rapid growth using the tumor doubling time(DT)proposed by Gerstenberg et al. Of all the reported cases of breast spindle cell carcinoma, the DT was fewer than 90 days in most cases. Breast spindle cell carcinoma demonstrates rapid grown compared to normal breast cancer.
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December 2020

[A Case of Rectal Cancer with Collet-Sicard Syndrome].

Gan To Kagaku Ryoho 2020 Dec;47(13):2225-2226

Dept. of Surgery, Numazu City Hospital.

The case was a woman in her 50s. Total pelvic resection was performed for advanced rectal cancer(cT4b[vagina]N3M0, cStage Ⅲc), after neoadjuvant chemoradiation therapy. Five months after the operation, she was unable to stand due to severe back pain. Spinal MRI revealed multiple bone metastases and lumbar fractures. In addition, dysphagia and dysarthria rapidly progressed almost simultaneously with back pain. Initially, brain metastasis was suspected, but head MRI revealed Collet-Sicard syndrome due to skull base metastasis. Irradiation to the skull base and high cervical spine, thoracolumbar spine was started. After irradiation, her back pain and cranial nerve symptoms improved. She was discharged and received palliative treatment. About a month after discharge, she was hospitalized for recurrent dysphagia and died on day 5 of hospitalization. Collet-Sicard syndrome is caused by damage to the cranial nerves Ⅸ to Ⅻ and is often caused by a tumor. Trauma, vasculitis, and internal carotid artery dissection have been reported as other causes. Symptoms such as hoarseness, dysarthria, tongue atrophy, dysphagia, and headache have been reported. Collet-Sicard syndrome due to bone metastasis of colorectal cancer were very rare, and we found only one other report. We report our case with some literature considerations.
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December 2020

[A Case of Effective Peritoneo-Venous Shunt for Refractory Malignant Ascites in a Gastric Cancer Patient with Peritoneal Dissemination].

Gan To Kagaku Ryoho 2020 Dec;47(13):2059-2061

Dept. of Surgery, Numazu City Hospital.

This paper reports a case of refractory ascites in a patient with gastric cancer. A peritoneo-venous shunt(PVS)was inserted in the patient, which contributed to extending the duration of home-based care as well as improving the patient's quality of life. The patient was a female in her 70s. She was diagnosed with gastric cancer and underwent total gastrectomy. Five years and 7 months after the surgery, she was diagnosed with peritoneal recurrence. Ascites temporarily decreased following chemotherapy, but gradually worsened thereafter. Since the patient required frequent puncture drainage for the ascites, cell-free concentrated ascites reinfusion therapy(CART)was performed. However, on the day prior to the scheduled second course of CART, marked abdominal distension was observed. Therefore, a PVS was inserted. No PVS-associated complications were observed. Following the insertion of the PVS, the patient's abdominal circumference and body weight markedly improved. Best supportive care(BSC)was provided to the patient as she became weak after undergoing several courses of chemotherapy on an outpatient basis. On the other hand, the PVS was working properly. The patient was able to continue her daily life activities at home. She died from the cancer after 164 days of the PVS insertion.
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December 2020

[A Case of Intussusception Due to Ileal Malignant Lymphoma of AYA Generation].

Gan To Kagaku Ryoho 2021 Jan;48(1):142-144

Dept. of Surgery, Numazu City Hospital.

The case is a 17-year-old man. He had complained of right lower abdominal pain for a week. He had no symptoms such as fever, weight loss, or night sweats. He was diagnosed with intussusception by abdominal contrast-enhanced CT and was hospitalized. The day after hospitalization, lower gastrointestinal endoscopy was performed, and a tumor 25 mm in size was found in the invagination of the ileum. Intussusception was recovered by intestinal scope insufflation, and the tumor was found to be a type 1 tumor located approximately 5 cm proximal to the Bauhin's valve. On day 17 of hospitalization, he had intussusception again at the time of surgery, and performed laparoscopic reduction before performing laparoscopy-assisted partial resection of the small intestine and appendectomy. The postoperative course was good and he was discharged on POD12(on day 29 of hospitalization). Histopathological diagnosis was diffuse large B-cell lymphoma(DLBCL), and chemotherapy was to be administered at the referral hospital. In intussusception of the adolescents and young adults(AYA)generation, such as this case outside of childhood, it is necessary to treat the patient with consideration for the presence of neoplastic lesions such as malignant lymphoma. We report our case with some literature considerations.
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January 2021

Preoperative prediction of difficult laparoscopic cholecystectomy based on diffusion-weighted magnetic resonance imaging.

Asian J Endosc Surg 2021 Jan 3. Epub 2021 Jan 3.

Department of Frontier Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.

Introduction: Laparoscopic cholecystectomy is a common surgery with a varying difficulty level. Difficult laparoscopic cholecystectomy may be experienced by many surgeons. If difficult procedures are predicted preoperatively, surgeons may be able to plan the surgical approach and treatment accordingly. Studies have reported using blood and clinical imaging data to predict difficult cholecystectomy. However, to our knowledge, no studies have reported using MRI. The purpose of this study was to evaluate the usefulness of MRI as a predictor of difficult laparoscopic cholecystectomy.

Methods: We retrospectively evaluated 25 patients with cholecystitis or biliary colic who had undergone diffusion-weighted whole-body imaging before laparoscopic cholecystectomy. The apparent diffusion coefficient value of the cystic duct was measured and its relationship with operative time and blood loss was examined to assess the capacity of diffuse-weighted whole-body imaging to predict difficult cholecystectomy. Further, we collected blood data and compared its usefulness as a predictor.

Results: The apparent diffusion coefficient value of the cystic duct was significantly lower in patients with difficult laparoscopic cholecystectomy than in those with non-difficult procedures (P = .00007). White blood cell count and serum C-reactive protein level were significantly higher in patients with difficult cholecystectomy than in those with non-difficult procedures (P = .035, .030). In the receiver operating characteristic analysis, the apparent diffusion coefficient value was the best predictor.

Conclusion: Our results suggest that the apparent diffusion coefficient value of the cystic duct is a predictor of difficult laparoscopic cholecystectomy. In the future, it may be useful to study changes in coefficient values over time to determine optimal surgical timing.
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http://dx.doi.org/10.1111/ases.12911DOI Listing
January 2021

Clinical features of idiopathic esophageal perforation compared with typical post-emetic type: a newly proposed subtype in Boerhaave's syndrome.

Esophagus 2021 Jan 1. Epub 2021 Jan 1.

Department of Frontier Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.

Background: n our previous nationwide survey report on esophageal perforation, we proposed the existence of cases with idiopathic esophageal perforation at a certain rate.

Aims: To elucidate the clinical characteristics of idiopathic esophageal perforation, we performed a comparative analysis between cases with idiopathic type and post-emetic type esophageal perforation.

Methods: This study enrolled 139 patients with esophageal perforation (post-emetic type: idiopathic type = 115:24) as the subjects of nationwide survey on esophageal perforation. We conducted detailed studies on chief complaints, inflammatory responses, initial diagnosis, location and situation of the perforation site, time to therapeutic intervention, and prognosis between the two groups.

Results: Compared with post-emetic type, cases of idiopathic type tended to exhibit rear-side perforation (p = 0.052) and significantly less presented chest pain (p = 0.002). Consequently, cases of idiopathic type significantly missed to diagnose as esophageal perforation compared with post-emetic type (p = 0.042). With regard to inflammatory response, cases of post-emetic type experienced hyperthermia compared with idiopathic type (p = 0.033). On the other hand, cases of idiopathic type exhibited significantly higher level of C-reactive protein than post-emetic type (p = 0.004). In addition, it took longer time until starting treatment in the cases of idiopathic type (p < 0.0001) and the cases of idiopathic type showed significantly worse prognosis than the cases of post-emetic type (p = 0.009).

Conclusion: This study first focused on the characteristics of idiopathic esophageal perforation that have been included in so-called Boerhaave's syndrome. The pathophysiology of the idiopathic type should be separately understood from post-emetic type, because the diagnostic and prognostic features largely differ.
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http://dx.doi.org/10.1007/s10388-020-00802-0DOI Listing
January 2021

Anti-FIRΔexon2 autoantibody as a novel indicator for better overall survival in gastric cancer.

Cancer Sci 2021 Feb 2;112(2):847-858. Epub 2021 Jan 2.

Department of Laboratory Medicine & Division of Clinical Genetics, Chiba University Hospital, Chiba, Japan.

There is no clinically available biomarker for efficiently indicating the overall survival or therapy response of gastric cancer (GC). The autoantibodies (Abs) in the sera of anti-far-upstream element-binding protein-interacting repressor-lacking exon2 (FIRΔexon2), anti-sorting nexin 15, and anti-spermatogenesis and oogenesis-specific basic helix-loop-helix 1 were markedly higher in GC patients than in healthy donors (HDs). These Abs were identified by large-scale serological identification of antigens by recombinant cDNA expression cloning screenings and their expression levels were evaluated by amplified luminescence proximity homogeneous assay. In particular, compared with age-matched HDs, the level of anti-FIRΔexon2 Abs in GC patients was significantly higher (P < .001). The Spearman's rank correlation analysis between anti-FIRΔexon2 Abs and clinically available tumor markers such as carcinoembryonic antigen (CEA) was statistically insignificant, indicating that FIRΔexon2 Abs is an independent biomarker. We performed receiver-operating curve analysis to evaluate the anti-FIRΔexon2 Ab as a candidate biomarker with CEA and carbohydrate antigen 19-9 (CA19-9). The overall survival of GC patients with high anti-FIRΔexon2 Abs titer was significantly favorable (P = .04) than that of GC patients who were below detection level of anti-FIRΔexon2 Abs. However, clinical stages were not apparently correlated with the levels of anti-FIRΔexon2 Ab, CEA, and CA19-9. In conclusion, anti-FIRΔexon2 Abs detected in GC patients is a potential biomarker for monitoring a better prognosis. Hence, anti-FIRΔexon2 Abs is a promising biomarker for indicating better overall survival of gastric cancer patients.
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http://dx.doi.org/10.1111/cas.14767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894018PMC
February 2021

New Assay System Elecsys Anti-p53 to Detect Serum Anti-p53 Antibodies in Esophageal Cancer Patients and Colorectal Cancer Patients: Multi-institutional Study.

Ann Surg Oncol 2020 Nov 18. Epub 2020 Nov 18.

Department of Surgery, School of Medicine, Toho University, Tokyo, Japan.

Background: Several recent studies suggest that serum anti-p53 antibodies (s-p53-Abs) may be combined with other markers to detect esophageal and colorectal cancer. In this study, we assessed the sensitivity and specificity of s-p53-Abs detection of a new electrochemiluminescence immunoassay (ECLIA; Elecsys anti-p53).

Methods: Elecsys anti-p53 assay was used to analyze the level of s-p53-Abs in blood sera from patients with esophageal or colorectal cancer taken before treatment. Control blood sera from healthy volunteers, patients with benign diseases, and patients with autoimmune diseases served as a reference. In addition, squamous cell carcinoma antigen (SCC-Ag) and cytokeratin 19 fragments (CYFRA21-1) were assessed in patients with esophageal cancer, and carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 were assessed in patients with colorectal cancer.

Results: Samples from 281 patients with esophageal cancer, 232 patients with colorectal cancer, and 532 controls were included in the study. The median value of s-p53-Abs in control samples was < 0.02 μg/mL (range < 0.02-29.2 μg/mL). Assuming 98% specificity, the cut-off value was determined as 0.05 μg/mL. s-p53-Abs were detected in 20% (57/281) of patients with esophageal cancer and 18% (42/232) of patients with colorectal cancer. In combination with SCC-Ag and CEA, respectively, s-p53-Abs detected 51% (144/281) of patients with esophageal and 53% (124/232) of patients with colorectal cancer.

Conclusions: The new s-p53-Abs assay Elecsys anti-p53 was useful in detecting esophageal and colorectal cancers with high specificity. Adding s-p53-Abs to conventional markers significantly improved the overall detection rates.
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http://dx.doi.org/10.1245/s10434-020-09342-4DOI Listing
November 2020

Predictor of respiratory disturbances during gastric endoscopic submucosal dissection under deep sedation.

World J Gastrointest Endosc 2020 Oct;12(10):378-387

Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan.

Background: Sedation is commonly performed for the endoscopic submucosal dissection (ESD) of early gastric cancer. Severe hypoxemia occasionally occurs due to the respiratory depression during sedation.

Aim: To establish predictive models for respiratory depression during sedation for ESD.

Methods: Thirty-five adult patients undergoing sedation using propofol and pentazocine for gastric ESDs participated in this prospective observational study. Preoperatively, a portable sleep monitor and STOP questionnaires, which are the established screening tools for sleep apnea syndrome, were utilized. Respiration during sedation was assessed by a standard polysomnography technique including the pulse oximeter, nasal pressure sensor, nasal thermistor sensor, and chest and abdominal respiratory motion sensors. The apnea-hypopnea index (AHI) was obtained using a preoperative portable sleep monitor and polysomnography during ESD. A predictive model for the AHI during sedation was developed using either the preoperative AHI or STOP questionnaire score.

Results: All ESDs were completed successfully and without complications. Seventeen patients (49%) had a preoperative AHI greater than 5/h. The intraoperative AHI was significantly greater than the preoperative AHI (12.8 ± 7.6 events/h 9.35 ± 11.0 events/h, = 0.049). Among the potential predictive variables, age, body mass index, STOP questionnaire score, and preoperative AHI were significantly correlated with AHI during sedation. Multiple linear regression analysis determined either STOP questionnaire score or preoperative AHI as independent predictors for intraoperative AHI ≥ 30/h (area under the curve [AUC]: 0.707 and 0.833, respectively) and AHI between 15 and 30/h (AUC: 0.761 and 0.778, respectively).

Conclusion: The cost-effective STOP questionnaire shows performance for predicting abnormal breathing during sedation for ESD that was equivalent to that of preoperative portable sleep monitoring.
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http://dx.doi.org/10.4253/wjge.v12.i10.378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7579530PMC
October 2020

[A Case of Malignant Pleural Effusion Implanted Subcutaneous Pleural Port].

Gan To Kagaku Ryoho 2020 Oct;47(10):1489-1491

Dept. of Gastrointestinal Surgery, International University of Health and Welfare Shioya Hospital.

A 74-year-old man with malignant pleural effusion due to recurrent gastric cancer underwent a failed pleurodesis. He subsequently underwent subcutaneous implantable pleural port implantation surgery followed by outpatient chemotherapy for 1 month. His disease progressed and he was unable to go to the hospital. He requested home care, so a nurse practitioner visited his home and drained the pleural effusion from the subcutaneous implantable pleural port. About 3 weeks after starting home care, he died at home. Pleurodesis is a common treatment for malignant pleural effusion; however, if a patient does not respond, long-term hospitalization is required due to manage port drainage. The subcutaneous implantable pleural port may aid provision of effective home care.
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October 2020

Usefulness of serum miR-1246/miR-106b ratio in patients with esophageal squamous cell carcinoma.

Oncol Lett 2020 Dec 10;20(6):350. Epub 2020 Oct 10.

Department of Frontier Surgery, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260-8670, Japan.

The function of microRNAs (miRs) is associated with the development and progression of various malignancies, with miRs presenting stably in the serum. The current study assessed the role of miR-1246 and miR-106b in the serum of patients with esophageal squamous cell carcinoma (ESCC). A comprehensive microarray analysis of miR expression was performed using the serum of patients with ESCC, which were subsequently validated via reverse transcription-quantitative PCR. A total of 55 test samples were obtained from Chiba University and 101 validation samples were gained from Chiba Cancer Center. The results revealed that miR-1246 expression significantly increased and miR-106b expression significantly decreased in each cohort. Receiver operating characteristic analysis revealed that the area under the curve (AUC) value of miR-1246 was 0.816 (sensitivity, 72.7%; specificity, 69.2%) and 0.779 (sensitivity, 71.3%; specificity, 70.6%) for the test and validation cohorts, respectively. The AUC of miR-106b was 0.716 (sensitivity, 65.5%; specificity, 61.6%) and 0.815 (sensitivity, 74.3%; specificity, 73.5%), respectively. In addition, the AUC of the miR-1246/miR-106b ratio was 0.901 (sensitivity, 80.0%; specificity, 80.0%) and 0.903 (sensitivity, 82.1%; specificity, 82.3%), respectively, which indicated a higher diagnostic ability compared with that of miR-1246 or miR-106b alone. The high miR-1246/miR-106b ratio group was associated with clinicopathological factors such as depth of invasion, progression, lymph node metastasis, and poor prognosis. Therefore, effective biomarkers may be generated by combining individual miRs obtained by comprehensive analysis of ESCC patient sera.
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http://dx.doi.org/10.3892/ol.2020.12213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586286PMC
December 2020

Comprehensive registry of esophageal cancer in Japan, 2013.

Esophagus 2021 Jan 13;18(1):1-24. Epub 2020 Oct 13.

Department of Healthcare Quality Assessment, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Background: Esophageal cancer is the eighth most common cause of cancer mortality in Japan. More than 11,000 people had died from esophageal cancer in 2018. The Japan Esophageal Society has collected the data on patients' characteristics, performed treatment, and outcomes annually.

Methods: We analyzed the data of patients who had first visited the participating hospitals in 2013. In 2019, the data collection method was changed from an electronic submission to a web-based data collection using the National Clinical Database (NCD). Japanese Classification of Esophageal Cancer 10th by the Japan Esophageal Society (JES) and UICC TNM Classification 7th were used for cancer staging RESULTS: A total of 8019 cases were registered from 334 institutions in Japan. Squamous cell carcinoma and adenocarcinoma accounted for 87.8% and 6.3%, respectively. The 5-year survival rates of patients treated using endoscopic resection, concurrent chemoradiotherapy, radiotherapy alone, or esophagectomy were 88.3%, 32.4%, 24.4%, and 59.3%, respectively. Esophagectomy was performed in 4910 cases. The operative and the hospital mortality rates were 0.77% and 1.98%, respectively. The survival curves showed a good discriminatory ability both in the clinical and pathologic stages by the JES system. The 5-year survival rate of patients with pStage IV in the UICC classification that included patients with supraclavicular node metastasis was better than that of patients with pStage IVb in JES classification.

Conclusion: We hope this report contributes to improving all aspects of the diagnosis and treatment of esophageal cancer in Japan.
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http://dx.doi.org/10.1007/s10388-020-00785-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794110PMC
January 2021

Prognostic benefit of conversion surgery for HER2 positive stage IV gastric cancer; a case series study of eleven patients treated with trastuzumab-based chemotherapy.

Surg Case Rep 2020 Sep 24;6(1):219. Epub 2020 Sep 24.

Department of Frontier Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8677, Japan.

Background: Since the ToGA trial, trastuzumab-based chemotherapy is the standard treatment for HER2 positive stage IV gastric cancer. However, it is not yet clear whether surgical resection after trastuzumab-based chemotherapy (conversion surgery) can improve survival of HER2 positive stage IV gastric cancer. The purpose of this study is to evaluate the prognostic benefit of conversion surgery in HER2 positive stage IV gastric cancer patients.

Case Presentation: We retrospectively investigated the medical records of the patients with HER2 positive (IHC3(+) or IHC2(+)/FISH(+)) stage IV gastric cancer treated with trastuzumab-based chemotherapy as the first line treatment. Overall survival (OS) was compared between patients with conversion surgery and without. Eleven HER2 positive stage IV gastric cancer patients treated with trastuzumab-based chemotherapy as the first line treatment were evaluated. Response rate was 63.6%, and 6 of 11 patients could receive conversion surgery. R0 resection was achieved in four patients. In Kaplan-Meier analysis, patients who received conversion surgery showed significantly better OS than those without surgery (3-year survival rate, 66.7% vs. 20%, P = 0.03). The median OS of patients who achieved R0 resection is 51.8 months.

Conclusions: Conversion surgery might have a survival benefit for HER2 positive stage IV gastric cancer patients. If curative surgery is technically possible, conversion surgery could be a treatment option for HER2 positive stage IV gastric cancer.
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http://dx.doi.org/10.1186/s40792-020-00984-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7516002PMC
September 2020

Tumor-derived exosomes influence the cell cycle and cell migration of human esophageal cancer cell lines.

Cancer Sci 2020 Dec 8;111(12):4348-4358. Epub 2020 Oct 8.

Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.

Our laboratory previously reported the usefulness as biomarkers of exosomes in the plasma of esophageal squamous cell carcinoma (ESCC) patients. However, the influence of tumor-derived exosomes on the tumor itself and underlying mechanisms remain unclear. We here report changes in the phenotype and gene expression when cancer cells exist in an environment with tumor-derived exosomes. The exosomes were isolated from the culture medium of human ESCC cells (TE2, T.Tn) by ultracentrifugation; cell proliferation assay, wound-healing assay, and fluorescence imaging of the cell cycle were performed to clarify the phenotypic changes in the high concentration of tumor-derived exosomes. Gene expression changes were also assessed by mRNA microarray, and the data were analyzed by gene set enrichment analysis (GSEA). The data revealed that the proliferation of both TE2 and T.Tn was inhibited, and cell migration ability was upregulated in the exosome exposure group (P < .05). Fluorescence imaging using a fluorescent ubiquitination-based cell cycle indicator expressing ESCC cells revealed that the ratio of G1-phase cells was significantly increased in the exosome exposure group (P < .05). Findings of the GSEA clarified that high-density exposure of cancer-derived exosomes to their parent cancer cells downregulated the expression of genes related to cell proliferation and cell cycle, and upregulated the expression of genes related to actin filament length and extracellular structure organization. In conclusion, an environment of high-density tumor-derived exosomes induces changes in the gene expression and phenotype of tumor cells and may lead to tumor progression or malignant transformation.
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http://dx.doi.org/10.1111/cas.14660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734159PMC
December 2020

Planned Versus On-Demand Relaparotomy Strategy in Initial Surgery for Non-occlusive Mesenteric Ischemia.

J Gastrointest Surg 2020 Sep 15. Epub 2020 Sep 15.

Department of Surgery, Tsuchiura Kyodo General Hospital, 4-1-1 Otsuno, Tsuchiura, Ibaraki, Japan.

Background: There has been insufficient evidence regarding a treatment strategy for patients with non-occlusive mesenteric ischemia (NOMI) due to the lack of large-scale studies. We aimed to evaluate the clinical benefit of strategic planned relaparotomy in patients with NOMI using detailed perioperative information.

Methods: We conducted a multicenter retrospective cohort study that included NOMI patients who underwent laparotomy. In-hospital mortality, 28-day mortality, incidence of total adverse events, ventilator-free days, and intensive care unit (ICU)-free days were compared between groups experiencing the planned and on-demand relaparotomy strategies. Analyses were performed using a multivariate mixed effects model and a propensity score matching model after adjusting for pre-operative, intra-operative, and hospital-related confounders.

Results: A total of 181 patients from 17 hospitals were included, of whom 107 (59.1%) were treated using the planned relaparotomy strategy. The multivariate mixed effects regression model indicated no significant differences for in-hospital mortality (61 patients [57.0%] in the planned relaparotomy group vs. 28 patients [37.8%] in the on-demand relaparotomy group; adjusted odds ratio [95% confidence interval] = 1.94 [0.78-4.80]), as well as in 28-day mortality, adverse events, and ICU-free days. Significant reduction in ventilator-free days was observed in the planned relaparotomy group. Propensity score matching analysis of 61 matched pairs with comparable patient severity did not show superiority of the planned relaparotomy strategy.

Conclusions: The planned relaparotomy strategy, compared with on-demand relaparotomy strategy, did not show clinical benefits after the initial surgery of patients with NOMI. Further studies estimating potential subpopulations who may benefit from this strategy are required.
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http://dx.doi.org/10.1007/s11605-020-04792-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491869PMC
September 2020

[A Case of Primary Amelanotic Malignant Melanoma of the Esophagus, Wherein Pseudoprogression Was Suspected during Immune Checkpoint Inhibitor Treatment].

Gan To Kagaku Ryoho 2020 Aug;47(8):1251-1253

Dept. of Surgery, Funabashi Municipal Medical Center.

A 78-year-old man was admitted to our hospital with a diagnosis of esophageal cancer and gastric cancer. Gastroscopy showed a type 2 tumor located in the cardia from the lower esophagus, and a pathological examination showed malignant melanoma. Based on the physical examination and other imaging tests, the patient was diagnosed with primary amelanotic malignant melanoma of the esophagus, but the tumor was unresectable due to extensive lymph node metastasis. According to the guideline, immune checkpoint inhibitor(nivolumab)was used for treatment, but because the tumor progressed after 2 courses and the performance status of the patient worsened, aggressive treatment was ended. Six weeks after finishing treatment, computed tomography showed that the tumor had shrunk to some extent. The patient ultimately died from aspiration pneumonia 4 months after the first consultation. The patient was thought to have had an immune-related adverse event, with the tumor showing pseudoprogression.
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August 2020

Magnetic compression anastomosis is effective in treating stenosis after esophageal cancer surgery: a case report.

Surg Case Rep 2020 Aug 17;6(1):213. Epub 2020 Aug 17.

Department of Frontier Surgery Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba, 260-8670, Japan.

Background: Esophagostomy is important in the treatment of esophageal cancer. However, esophagectomy has a higher risk of postoperative complications. Treatment for complications is often difficult, and in some cases, oral intake is no longer possible. Recently, magnetic compression anastomosis (MCA) was developed; it is a relatively safe method of anastomosis that does not require surgery in patients with stricture, obstruction, or dehiscence of the anastomosis after surgery.

Case Presentation: The patient was a 76-year-old Japanese man. He underwent esophagectomy with a three-field dissection for esophageal cancer. A cervical esophagostomy and chest drainage were performed for necrosis of the gastric tube. Following infection control, colon interposition was performed. However, after the operation, the colon necrotized and formed an abscess. Drainage controlled the infection, but the colon was completely obstructed. The patient was referred to our hospital to restore oral ingestion. Contrast studies showed that the length of the occlusion was 10 mm. The reconstruction was examined; reanastomosis by surgery was judged to be a high risk, so the strategy of anastomosis by MCA was adopted. In the operation, the anterior chest was opened to expose the colon, and a magnet was inserted directly into the blind end of the colon. The magnet was guided to the blind end of the esophagus using an oral endoscope. Two weeks after MCA, a contrast study confirmed the passage of the contrast agent from the esophagus to the colon. The patient eventually took 18 bougies after the MCA. However, since then, he has not needed a bougie. As of 1 year and 8 months after the MCA, the patient is living at home with oral intake restored.

Conclusions: MCA is an effective and safe treatment for complete stenosis after esophageal cancer surgery.
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http://dx.doi.org/10.1186/s40792-020-00974-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431484PMC
August 2020

Interferon-γ induced PD-L1 expression and soluble PD-L1 production in gastric cancer.

Oncol Lett 2020 Sep 19;20(3):2161-2168. Epub 2020 Jun 19.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260-8670, Japan.

Programmed death-ligand 1 (PD-L1) plays an essential role in tumor cell escape from anti-tumor immunity in various types of cancer, including gastric cancer (GC). The present study investigated the intracellular and membrane-bound expression of PD-L1 in the GC cell lines MKN1, MKN74, KATO III and OCUM-1. Furthermore, soluble PD-L1 (sPD-L1) level in the supernatant of GC cells and the serum of patients with GC and healthy controls was determined by ELISA. Interferon (IFN)-γ treatment of cells resulted in increased cytoplasmic expression of PD-L1 in GC cells in a dose-dependent manner, except for MKN74 cells; however, there was no association between tumor necrosis factor-α treatment and enhanced PD-L1 expression. Concordant with these findings, results from flow cytometry analysis demonstrated that membrane-bound PD-L1 expression was also increased following GC cell treatment with IFN-γ in a dose-dependent manner. In addition, significant sPD-L1 overproduction was observed only in the culture supernatant of OCUM-1 cells. Serum level of sPD-L1 was significantly increased in patients with GC, in particular in stage IV patients, compared with healthy controls. In conclusion, the present study demonstrated that IFN-γ treatment increased the intracellular and membrane-bound PD-L1 expression in GC cells. In addition, sPD-L1 was detected not only in the supernatant of GC cells but also in the serum of patients with GC. Further investigation on the underlying mechanism of regulation of PD-L1 expression and sPD-L1 production is required.
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http://dx.doi.org/10.3892/ol.2020.11757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400993PMC
September 2020

A phase 2 basket trial of combination therapy with trastuzumab and pertuzumab in patients with solid cancers harboring human epidermal growth factor receptor 2 amplification (JUPITER trial).

Medicine (Baltimore) 2020 Aug;99(32):e21457

Center for Innovative Cancer Treatment.

Introduction: Human epidermal growth factor receptor 2 (HER2) gene amplification and mutations have emerged as oncogenic drivers and therapeutic targets not limited to breast and gastric cancers, but also in a variety of cancers. However, even if an actionable gene alteration is found, the incidence of HER2 amplification in these cancers is less than 5%. It is too difficult to conduct a conventional randomized, controlled trial in a rare fraction. Therefore, we have designed a organ-agnostic basket study, which covers a variety of solid cancers harboring HER2 amplification, in 1 study protocol.

Methods/design: This trial is a multicenter, single-arm, basket phase 2 study in Japan. Patients with solid cancers harboring HER2 amplification that have progressed with standard treatment, or rare cancers for which there is no standard treatment, will be eligible. Target cancers include bile duct, urothelial, uterine, ovarian, and other solid cancers where HER2 amplification is detected by comprehensive genomic profiling using next-generation sequencing technology. A total of 38 patients will be treated with combination therapy with trastuzumab and pertuzumab every 3 weeks until disease progression, unmanageable toxicity, death, or patient refusal. The primary endpoint is the objective response rate, and secondary endpoints are progression-free survival, overall survival, and duration of response.

Discussion: The aim of this trial is to evaluate the safety and efficacy of combination therapy with trastuzumab and pertuzumab in patients with locally advanced or metastatic, solid cancers harboring HER2 amplification. Instead of focusing on 1 organ type, our trial design uses a basket study focusing on HER2 amplification, regardless of the site or origin of the cancer. The results of our study will advance clinical and scientific knowledge concerning the treatment of locally advanced, rare solid cancers harboring HER2 amplification, using the combination of trastuzumab and pertuzumab.

Trial Registration: This trial was registered in Japan Registry of Clinical Trials (jCRT) on February 25, 2019, as jRCT2031180150.
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http://dx.doi.org/10.1097/MD.0000000000021457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592999PMC
August 2020

Quantification of Structural Heterogeneity Using Fractal Analysis of Contrast-Enhanced CT Image to Predict Survival in Gastric Cancer Patients.

Dig Dis Sci 2020 Jul 20. Epub 2020 Jul 20.

Department of Frontier Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8677, Japan.

Background: Malignant tumor essentially implies structural heterogeneity. Fractal analysis of medical imaging has a potential to quantify this structural heterogeneity in the tumor AIMS: The purpose of this study is to quantify this structural abnormality in the tumor applying fractal analysis to contrast-enhanced computed tomography (CE-CT) image and to evaluate its biomarker value for predicting survival of surgically treated gastric cancer patients.

Methods: A total of 108 gastric cancer patients (77 men and 31 women; mean age: 69.1 years), who received curative surgery without any neoadjuvant therapy, were retrospectively investigated. Portal-phase CE-CT images were analyzed with use of a plug-in tool for ImageJ (NIH, Bethesda, USA), and the fractal dimension (FD) in the tumor was calculated using a differential box-counting method to quantify structural heterogeneity in the tumor. Tumor FD was compared with clinicopathologic features and disease-specific survival (DSS).

Results: High FD value of the tumor significantly associated with high T stage and high pathological stage (P = 0.009, 0.007, respectively). In Kaplan-Meier analysis, patients with higher FD tumors (FD > 0.9746) showed a significantly worse DSS (P = 0.009, log rank). Multivariate analysis demonstrated that tumor FD, T stage, and N stage were independent prognostic factors for DSS. In subset analysis of lymph-node positive gastric cancers, only tumor FD was an independent prognostic factor for DSS.

Conclusion: CT fractal analysis can be a useful biomarker for gastric cancer patients, reflecting survival and clinicopathologic features.
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http://dx.doi.org/10.1007/s10620-020-06479-wDOI Listing
July 2020