Publications by authors named "Hirofumi Kawakubo"

159 Publications

Exploratory prospective study of the influence of radical esophagectomy on perioperative physical activity in patients with thoracic esophageal cancer.

Dis Esophagus 2021 Jul 12. Epub 2021 Jul 12.

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

Sarcopenia, which involves two important aspects, namely skeletal muscle loss and decreased physical function, was suggested as a poor prognostic factor in esophageal cancer surgery. The purpose of this study was to clarify the perioperative change in daily physical activity and propose effective preventive strategies. We prospectively enrolled patients with esophageal cancer who were scheduled to undergo radical esophagectomy. Their daily physical activities were recorded using an accelerometer before surgery, immediately after discharge, and 6 months after surgery. The relationships of physical activity level and the perioperative factors, especially skeletal muscle change, with the risk factors of low daily activity level were investigated. The data of 20/28 enrolled patients were analyzed. The mean activity level of the 20 patients decreased after discharge and subsequently recovered on postoperative month 6. The percentage of activity levels >1.5 metabolic equivalents/day after discharge significantly correlated to the change rate in total muscle cross-sectional area from baseline to POM 6 (r = 0.452, P = 0.045). In a stepwise multiple regression analysis, age, neoadjuvant chemotherapy, and anastomotic leakage were identified as negative associated factors of activity time at >1.5 metabolic equivalents at postoperative month 6. Activity level immediately after discharge was significantly associated with skeletal muscle loss at postoperative month 6 in patients with esophageal cancer who underwent esophagectomy. Elderly patients and patients who received neoadjuvant chemotherapy and had an anastomotic leakage might require intensive prevention. Prospective interventions aimed at increasing daily activity can prevent sarcopenia.
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http://dx.doi.org/10.1093/dote/doab043DOI Listing
July 2021

Current status and challenges in sentinel node navigation surgery for early gastric cancer.

Chin J Cancer Res 2021 Apr;33(2):150-158

Department of Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan.

As an optimal surgical procedure to accurately evaluate lymph node (LN) metastasis during surgery with minimal surgical resection, we have been developing sentinel node (SN) biopsy for early gastric cancer since the 1990s. Twelve institutions from the Japanese Society of Sentinel Node Navigation Surgery (SNNS), including Keio University Hospital, conducted a multicenter prospective trial to validate the SN concept using the dual-tracer method with blue dye and a radioisotope. According to the results, 397 patients were included in the final analysis, and the overall accuracy in detecting LN metastasis using SN biopsy was 99% (383 of 387). Based on the validation study, we are targeting cT1N0 with a primary tumor of ≤4 cm in diameter as an indication for SN biopsy for gastric cancer. We are currently running a multicenter nonrandomized phase III trial to assess the safety and efficacy of SN navigation surgery. The Korean group has reported the result of a multicenter randomized phase III trial. Since meticulous gastric cancer in the remnant stomach was rescued by subsequent gastrectomy, the disease-specific survival was comparable between the two techniques, implying that SN navigation surgery can be an alternative to standard gastrectomy. With the development of SN biopsy procedure and treatment modalities, the application of SN biopsy will be expanded to achieve an individualized minimally invasive surgery.
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http://dx.doi.org/10.21147/j.issn.1000-9604.2021.02.03DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8181877PMC
April 2021

Prognostic Significance of Stratification Using Pathological Stage and Response to Neoadjuvant Chemotherapy for Esophageal Squamous Cell Carcinoma.

Ann Surg Oncol 2021 Jun 17. Epub 2021 Jun 17.

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

Purpose: Risk stratification to select appropriate candidates for adjuvant therapy is required for esophageal cancer patients based on adjuvant therapy advancement including immunotherapy. The current study aims to develop a novel staging system using pathological stage (pStage) and response to neoadjuvant chemotherapy (NAC) for esophageal squamous cell carcinoma (ESCC).

Methods: ESCC patients who received NAC and underwent transthoracic esophagectomy at two Japanese high-volume esophageal centers were retrospectively reviewed. The prognostic value of NAC response was evaluated within the same pStage, and a novel risk stratification to predict cancer-specific survival (CSS) was developed.

Results: The HR (95% CI) of pathological responders in pStage 0-I, II, III, and IV was 0.29 (0.07-1.17), 0.37 (0.12-1.10), 0.37 (0.15-0.92), and 0.24 (0.06-0.98), respectively. Responders in pStage 0-II were classified to be in the same class and those in pStage III/IV in another group, because the 5-year CSS (5y-CSS) rate of responders in pStage 0-I, II, III, and IV was 94%, 92%, 76%, and 71%, respectively. Combining nonresponders in pStage 0-II as the same group, all patients were subdivided into five groups. Intriguingly, the 5y-CSS in pStage III-IV responders was 75%, almost identical to that of nonresponders in pStage 0-II (78%).

Conclusions: The histological response influenced the long-term outcomes of patients who underwent esophagectomy after NAC, even within groups stratified by pathologic stage. The current risk stratification system will contribute to selecting appropriate candidates for adjuvant therapy.
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http://dx.doi.org/10.1245/s10434-021-10221-9DOI Listing
June 2021

Prognostic impact of thoracic duct lymph node metastasis in esophageal squamous cell carcinoma.

Ann Gastroenterol Surg 2021 May 19;5(3):321-330. Epub 2021 Jan 19.

Department of Surgery Keio University School of Medicine Tokyo Japan.

Aim: We have previously reported the existence of lymph nodes surrounding the thoracic duct ( TDLN) and transthoracic esophagectomy (TTE) with thoracic duct (TD) resection increased the number of lymph nodes (LNs) retrieved. The current study aims to evaluate the prognostic impact of TDLN metastasis in esophageal cancer patients subdivided by its location and comparing the patients' survival with those with extra-regional LN metastasis.

Methods: Patients who underwent TTE with TD resection for esophageal squamous cell carcinoma (ESCC) were reviewed. Patients were classified into those with or without TDLN metastasis, and clinicopathological factors were compared between groups. TDLN was further divided into TDLN-Ut/Mt/Lt based on the location in the mediastinum. The relapse-free survival (RFS) and overall survival (OS) were compared between groups.

Results: Of 232 patients, TDLN metastasis was observed in 17 (7%). RFS and OS were significantly worse in the TDLN metastasis group. TDLN metastasis was shown to be an independent prognostic factor for RFS and OS in the multivariate analysis. The negative prognostic impact of TDLN metastasis was evident in TDLN-Mt/Lt. The RFS and OS of patients with TDLN metastasis were almost identical to those with positive LN metastasis in extra-regional LNs.

Conclusion: TDLN metastasis was proven to be a strong prognostic indicator. Although the TDLN has been included in the classification of regional LN in the current staging systems, it could be independently classified from the current regional LNs. Given that neoadjuvant therapy has been a standard, we might need to introduce adjuvant therapy when TDLN metastasis is observed.
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http://dx.doi.org/10.1002/ags3.12432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164460PMC
May 2021

Factors predicting major complications, mortality, and recovery in percutaneous endoscopic gastrostomy.

JGH Open 2021 May 31;5(5):590-598. Epub 2021 Mar 31.

Division of Gastroenterology and Hepatology, Department of Internal Medicine Keio University School of Medicine Tokyo Japan.

Background And Aim: Percutaneous endoscopic gastrostomy (PEG) has been used in patients with dysphagia and inadequate food intake via an oral route. Despite being a procedure with a high success rate, complications and death have been reported. The aim was to identify the factors related to major complications and mortality, as well as PEG removal prognostic factors due to improvement of their general condition.

Methods: Patient characteristics, comorbidities, laboratory data, concomitant medication, sedation, and indication for PEG placement were collected. Major complications, mortality, and PEG removal factors were assessed.

Results: A total of 388 patients were enrolled. There were 15 (3.9%) cases of major complications, with major bleeding being the most frequent in 6 (1.5%) patients. Corticosteroids were the independent variable associated with major complications (odds ratio [OR] 5.85; 95% confidence interval [CI] 1.71-20;  = <0.01). Advanced cancer (hazard ratio [HR] 0.5; 95% CI 0.3-1;  = 0.05), albumin (HR 0.6; 95% CI 0.4-0.9;  = <0.01), and C-reactive protein (CRP) (HR 1.1; CI 1-1.2;  = 0.01) were considered risk factors for mortality. Previous pneumonia (HR 0.4; CI 0.2-0.9;  = 0.02) was a factor for permanent use of a PEG; however, oncological indication (HR 8.2; CI 3.2-21;  = <0.01) was factors for PEG withdrawal.

Conclusions: Chronic corticosteroid users potentially present with major complications. Low albumin levels and elevated CRP were associated with death. Previous aspiration pneumonia was a factor associated with permanent use of PEG; however, patients with oncological indication were the most benefited.
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http://dx.doi.org/10.1002/jgh3.12538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8114989PMC
May 2021

Clinical usefulness of sputum culture on the first postoperative day to predict early postoperative pneumonia after esophagectomy for esophageal cancer.

Esophagus 2021 May 16. Epub 2021 May 16.

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

Background: Postoperative pneumonia is a serious prognostic problem that can appear after esophagectomy in patients with esophageal cancer. The past reports have considered the usefulness of perioperative culture examinations for predicting postoperative pneumonia; however, the direct relationship between these examinations and postoperative complications remains unclear.

Methods: This study retrospectively analyzed esophageal cancer patients who underwent esophagectomy followed by sputum culture on the first postoperative day. The bacterial species that frequently cause hospital-acquired pneumonia were chosen as the target species in this study. The relationship between culture examination and postoperative pneumonia within one week (7 days) after esophagectomy was investigated.

Results: Sputum cultures on the first postoperative day were investigated in 238 patients who underwent esophagectomy for esophageal cancer. Forty-one patients developed pneumonia within one week after surgery. The target bacterial species were detected in 26 of 238 sputum cultures (10.9%). In the univariate analysis, a Brinkman index, detection of target bacterial species, detection of Gram-positive cocci, and Gram-negative rods were significantly associated with postoperative pneumonia. In the three independent multivariate analyses, the target bacterial species, Gram-positive cocci, and Gram-negative rods (p = 0.001, 0.042, and < 0.001) were individually identified as independent risk factors of postoperative pneumonia in addition to a Brinkman index.

Conclusions: Detection of target bacterial species by sputum culture on the first postoperative day after esophagectomy was an independent risk factor of postoperative pneumonia within 7 days after surgery. Prospective studies for the prevention of early postoperative pneumonia using sputum culture on the first postoperative day can be considered.
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http://dx.doi.org/10.1007/s10388-021-00834-0DOI Listing
May 2021

Essential updates 2019/2020: Perioperative and surgical management of gastric cancer.

Ann Gastroenterol Surg 2021 Mar 5;5(2):162-172. Epub 2021 Feb 5.

Department of Surgery Keio University School of Medicine Tokyo Japan.

Perioperative and surgical management of gastric cancer have been changing as pivotal phase II trials and landmark phase III trials offer new insights to the existing knowledge. The results of many landmark trials have been published or presented in the past year, many of which have changed or will change current clinical practice. For example, FLOT4 has completely changed the regimen of perioperative chemotherapy in Europe. Furthermore, evidence for minimally invasive surgery for clinical Stage I was firmly established by KLASS-01 and JCOG0912 for distal gastrectomy and CLASS-02, KLASS-03, and JCOG1401 for total gastrectomy. Moreover, promising results were provided by CLASS-01 and KLASS-02 for locally advanced gastric cancer. For adjuvant chemotherapy, JACCRO GC-07 (START-2) has provided a new doublet regimen for pathological Stage III, which is often refractory to chemotherapy. Conversely, JCOG0501 poses a significant challenge for advanced tumors, such as large type 3 and scirrhous (type 4) tumors. In this review, we briefly review recent updates and discuss future perspectives of gastric cancer treatment.
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http://dx.doi.org/10.1002/ags3.12438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034698PMC
March 2021

A case of synchronous intramucosal gastric carcinoma with multiple lymph node metastases.

Surg Case Rep 2021 Apr 2;7(1):80. Epub 2021 Apr 2.

Department of Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, Japan.

Background: In Japan, the prevalence of synchronous multiple intramucosal gastric carcinoma is reported to be 5-15%. Here is a case of a synchronous small gastric carcinoma fulfilling the definite indication and curative criteria for endoscopic submucosal dissection with multiple lymph node metastases.

Case Presentation: A Japanese woman in her fifties with a history of endoscopic resection for mucosal poorly differentiated adenocarcinoma was evaluated, with the UICC TNM classification stage being cT1aN0M0 cStageIA. She had undergone total gastrectomy with D1 + lymph node dissection. Histopathological examination revealed 16 individual sporadic lesions in the gastric body, with maximum diameter 3 mm and localization in the lamina propria. Twenty-seven nodes were resected, and metastasis of the carcinoma was revealed in 24 nodes.

Conclusions: Undifferentiated intramucosal gastric cancer has a relatively high probability of lymph node metastasis; however, synchronous early lesions are often overlooked. Frequent follow-up examinations may increase the detection of multiple gastric cancers.
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http://dx.doi.org/10.1186/s40792-021-01149-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018999PMC
April 2021

Relationship Between Early Postoperative Change in Total Psoas Muscle Area and Long-term Prognosis in Esophagectomy for Patients with Esophageal Cancer.

Ann Surg Oncol 2021 Mar 30. Epub 2021 Mar 30.

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

Purpose: Postoperative sarcopenia following esophagectomy for esophageal cancer has become a severe problem due to the increasing number of elderly patients undergoing surgery. This study aimed to clarify the relationship between early postoperative skeletal muscle change and cancer prognosis, and propose effective interventions to prevent sarcopenia.

Methods: This study retrospectively analyzed 152 patients who underwent esophagectomy for esophageal cancer. Total psoas muscle area (TPA) was measured before surgery as baseline and on postoperative day 7 (± 2). The effect of early postoperative skeletal muscle loss on 5-year survival was investigated. Moreover, 5-year survival in patients with postoperative complications and a high inflammatory status, which were previously reported as poor prognostic factors of esophageal cancer, was also investigated.

Results: Among the 152 patients, 52 (34.2%) showed a decrease in TPA, while 100 (65.8%) maintained their TPA. The TPA decreasing group exhibited poor 5-year overall survival (OS) (p = 0.003) and 5-year recurrence-free survival (RFS) (p < 0.001). The TPA decreasing group also showed a poor 5-year OS in patients who developed severe postoperative complications (p = 0.015). Multivariate analyses showed that decreased TPA was found to be independently associated with OS (p = 0.017) as well as RFS (p = 0.002).

Conclusions: Our findings suggested a relationship between decreased TPA within 1 week after esophagectomy and long-term prognosis among patients with esophageal cancer. If TPA can be maintained, the prognosis was better even in cases with serious complications.
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http://dx.doi.org/10.1245/s10434-021-09623-6DOI Listing
March 2021

Prognostic Significance of the Number and Extent of Metastatic Lymph Nodes in Patients with Esophageal Cancer: Comparison of the Union for International Cancer Control 8th Edition and Japan Esophageal Society Japanese Classification of Esophageal Cancer 11th Edition Classifications for Esophageal Cancer.

Ann Surg Oncol 2021 Mar 21. Epub 2021 Mar 21.

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

Background: The tumor, node, metastasis staging system of the Union for International Cancer Control (UICC) has been used worldwide for esophageal cancer, and, in Japan, the Japan Esophageal Society Japanese Classification of Esophageal Cancer (JES) has also been used; however, there is a big difference between the two classifications with regard to node staging. We hypothesized that these two node staging systems may lead to different outcome predictions in terms of tumor location.

Methods: This study enrolled 409 patients who underwent esophagectomy at Keio University Hospital, Tokyo, Japan, between January 2005 and December 2017. We included those who underwent R0 or R1 resection or esophagectomy with additional organ excision, and excluded those who underwent salvage surgery. Thereafter, we investigated how the number or spread of metastatic lymph nodes affected the prognosis.

Results: For all 409 patients, the 5-year overall survival rate was 64.1% and the 5-year recurrence-free survival rate was 58.4%. The concordance indices were 0.756 for UICC 8th edition pathological node staging and 0.732 for JES 11th edition pathological node staging (p = 0.06). Based on tumor location, the difference in the concordance indices between these two classifications was greatest for lower thoracic esophageal tumors (p = 0.02).

Conclusions: For all patients, the UICC 8th edition node staging system tended to reflect survival more precisely than that of the JES 11th edition. For lower thoracic esophageal tumors in particular, the former node staging system could be more useful.
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http://dx.doi.org/10.1245/s10434-020-09545-9DOI Listing
March 2021

ASO Author Reflections: How to Control Hypothyroidism and Hypoparathyroidism Following Pharyngo-Laryngo-Esophagectomy for Cervical Esophageal Cancer.

Ann Surg Oncol 2021 Mar 11. Epub 2021 Mar 11.

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

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http://dx.doi.org/10.1245/s10434-021-09706-4DOI Listing
March 2021

Usefulness of Neutrophil to Lymphocyte Ratio at Recurrence for Predicting Long-Term Outcomes in Patients with Recurrent Esophageal Squamous Cell Carcinoma.

Ann Surg Oncol 2021 Jun 10;28(6):3001-3008. Epub 2021 Mar 10.

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

Background: Although radical esophagectomy with multifield lymph node dissection is a promising treatment to achieve long-term survival for resectable esophageal cancer, survival after postoperative recurrence remains poor. To select the optimal treatment for patients with recurrent esophageal cancer, simple, objective indicators for predicting of long-term outcomes are needed.

Patients And Methods: We conducted a single-institution, retrospective cohort study between 2004 and 2019, wherein 586 patients underwent transthoracic esophagectomy for primary esophageal squamous cell carcinoma. Of these, 133 patients with postoperative recurrence were included in this analysis. Several predictors of survival after recurrence were investigated.

Results: Among all patients, the 1- and 3-year survival rates after recurrence were 48.0% and 23.1%, respectively. On multivariate analysis, the neutrophil to lymphocyte ratio (NLR) at recurrence was identified as a significant predictor of death after recurrence (hazard ratio 1.061; 95% confidence interval 1.002-1.125; p = 0.043). Time-dependent receiver operating characteristics curves showed that the area under the curve value of the NLR at recurrence was superior to the modified Glasgow Prognostic Score at recurrence in all terms. To simulate the clinical decision process, we set the cut-off NLR at recurrence for survival using survival classification and regression tree (CART) and defined the optimal cut-off value as 3.374.

Conclusions: NLR at recurrence was a significant indicator of survival after recurrence in patients with recurrent esophageal cancer. CART analysis was used to determine the optimal cut-off value for the prediction of survival, allowing the NLR to be used clinically to facilitate decision making.
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http://dx.doi.org/10.1245/s10434-021-09637-0DOI Listing
June 2021

ASO Author Reflections: The Definition for Metastatic Lymph Nodes of Esophageal Cancer and Future Perspective.

Ann Surg Oncol 2021 Mar 5. Epub 2021 Mar 5.

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

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http://dx.doi.org/10.1245/s10434-020-09578-0DOI Listing
March 2021

Performance of a deep learning-based identification system for esophageal cancer from CT images.

Esophagus 2021 Jul 26;18(3):612-620. Epub 2021 Feb 26.

Department of Biosciences and Informatics, Keio University, 3-13-1 Hiyoshi, Kohoku-ku, Yokohama, 223-8522, Japan.

Background: Because cancers of hollow organs such as the esophagus are hard to detect even by the expert physician, it is important to establish diagnostic systems to support physicians and increase the accuracy of diagnosis. In recent years, deep learning-based artificial intelligence (AI) technology has been employed for medical image recognition. However, no optimal CT diagnostic system employing deep learning technology has been attempted and established for esophageal cancer so far.

Purpose: To establish an AI-based diagnostic system for esophageal cancer from CT images.

Materials And Methods: In this single-center, retrospective cohort study, 457 patients with primary esophageal cancer referred to our division between 2005 and 2018 were enrolled. We fine-tuned VGG16, an image recognition model of deep learning convolutional neural network (CNN), for the detection of esophageal cancer. We evaluated the diagnostic accuracy of the CNN using a test data set including 46 cancerous CT images and 100 non-cancerous images and compared it to that of two radiologists.

Results: Pre-treatment esophageal cancer stages of the patients included in the test data set were clinical T1 (12 patients), clinical T2 (9 patients), clinical T3 (20 patients), and clinical T4 (5 patients). The CNN-based system showed a diagnostic accuracy of 84.2%, F value of 0.742, sensitivity of 71.7%, and specificity of 90.0%.

Conclusions: Our AI-based diagnostic system succeeded in detecting esophageal cancer with high accuracy. More training with vast datasets collected from multiples centers would lead to even higher diagnostic accuracy and aid better decision making.
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http://dx.doi.org/10.1007/s10388-021-00826-0DOI Listing
July 2021

SQAP, an acyl sulfoquinovosyl derivative, suppresses expression of histone deacetylase and induces cell death of cancer cells under hypoxic conditions.

Biosci Biotechnol Biochem 2021 Jan;85(1):85-91

Department of Applied Biological Science, Tokyo University of Science, Chiba, Japan.

Sulfoglycolipid, SQAP, is a radiosensitizing agent that makes tumor cells more sensitive to radiation therapy. A previous study revealed that SQAP induced the degradation of hypoxia-inducible factor-1α (HIF-1α) and inhibited angiogenesis in a hepatoma model mouse. Herein, we examined the biological activities of SQAP against hepatocarcinoma cells under low oxygen conditions. Cell growth inhibition of SQAP under hypoxic conditions was significantly higher than that under normoxic conditions. In addition, SQAP was found to impair the expression of histone deacetylase (HDAC) under low oxygen conditions. Our present data suggested that SQAP induced the degradation of HIF-1α and then decreased the expression of HDAC1. Unlike known HDAC inhibitors, SQAP increased the acetylation level of histone in cells without inhibition of enzymatic activity of HDACs. Our data demonstrated hypoxia-specific unique properties of SQAP.
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http://dx.doi.org/10.1093/bbb/zbaa015DOI Listing
January 2021

IL-8/CXCR2 Signalling Promotes Cell Proliferation in Oesophageal Squamous Cell Carcinoma and Correlates With Poor Prognosis.

Anticancer Res 2021 Feb;41(2):783-794

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

Background/aim: The inflammatory cytokine IL-8 and its receptor CXCR2 are key signalling pathway molecules in cancer development. We hypothesized that IL-8/CXCR2 signalling promotes tumour progression in oesophageal squamous cell carcinoma (ESCC) patients.

Materials And Methods: We examined the relationship between IL-8/CXCR2 expression and clinicopathological factors by immunohistochemistry in samples from 63 patients with resectable ESCC. The effects of IL-8/CXCR2 signalling on cell proliferation and gene expression were examined in vitro and in vivo using ESCC cell lines.

Results: Increased IL-8/CXCR2 signalling was associated with shorter overall survival (p<0.05) and recurrence-free survival (p<0.05) in ESCC patients. Multivariate analysis identified IL-8/CXCR2 expression as a prognostic factor for surgically treated ESCC (p<0.05). In vitro, IL-8 exposure or over-expression significantly enhanced ESCC cell proliferation. SB225002, a CXCR2-specific antagonist, and IL-8 siRNA significantly suppressed cell proliferation.

Conclusion: IL-8/CXCR2 expression is an independent prognostic factor for surgically treated ESCC, and IL-8/CXCR2 signalling contributes to ESCC cell proliferation.
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http://dx.doi.org/10.21873/anticanres.14830DOI Listing
February 2021

Association of preoperative sarcopenia with postoperative dysphagia in patients with thoracic esophageal cancer.

Dis Esophagus 2020 Dec 12. Epub 2020 Dec 12.

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

Background: The purpose of the current study was to clarify the relationship between clinical features of dysphagia after esophagectomy and preoperative sarcopenia.

Methods: A total of 187 cases were included in the current study. The psoas cross-sectional area on pre-treatment computed tomography was measured in thoracic esophageal cancer patients who underwent curative resection. The psoas muscle index (PMI) cut-off levels for sarcopenia were 6.36 cm2/m2 for men and 3.92 cm2/m2 for women. Swallowing function was evaluated using videofluoroscopic swallowing study (VFSS) and fiberoptic endoscopic evaluation of swallowing (FEES) at postoperative days 7-15, and classified according to the food intake level scale (FILS). Perioperative swallowing rehabilitation was performed in all cases.

Results: In the 187 included patients, the median PMI was 5.42 cm2/m2 for men and 3.43 cm2/m2 for women, and 133 cases (71%) met the sarcopenia criteria. The FILS <4 (no oral intake) was 15% in the non-sarcopenia group, and 38% in the sarcopenia group (P = 0.003). There was no significant difference in the incidence of postoperative complications, including pneumonia and re-admission due to pneumonia, between the two groups. Preoperative sarcopenia and recurrent laryngeal nerve palsy were be independent risk factors for postoperative dysphagia.

Conclusions: Sarcopenic patients with esophageal cancer develop postoperative dysphagia more often than non-sarcopenic patients. Prehabilitation and nutritional support for patients with preoperative sarcopenia could play an important role to mitigate postoperative dysphagia.
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http://dx.doi.org/10.1093/dote/doaa121DOI Listing
December 2020

Prospective evaluation and refinement of an S-1 dosage formula based on renal function for clinical application.

Cancer Sci 2021 Feb 6;112(2):751-759. Epub 2021 Jan 6.

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

In patients with impaired renal function, S-1-related toxicities increase due to higher exposure of 5-fluorouracil (5-FU). Our previous pharmacokinetic study in 16 cancer patients with various renal functions developed an S-1 dosage formula based on individual creatinine clearance (CLcr) and body surface area (BSA). To evaluate and refine the formula, this prospective study was conducted. Thirty-three patients with various renal functions received S-1 for 4 weeks at doses determined by the nomogram derived from the previously developed formula. A series of blood samples were collected after the first dose to calculate the area under the concentration-time curve (AUC) of 5-FU. Thirty patients with BSA of 1.14-1.84 m and CLcr of 23.8-96.4 mL/min were assessable for pharmacokinetics. The observed daily AUC ranged from 712.6 to 2868.7 ng·h/mL, and 18 patients achieved the target AUC (1447.8 ± 545.4 ng·h/mL). Three patients experienced S-1-related grade 3 adverse events during the first course. In the population pharmacokinetic analysis from the combined data of 46 patients in this study and the previous study, sex was identified as a statistically significant covariate for 5-FU clearance. Hence, the refined formula includes sex as an additional factor: Recommended daily dose = target AUC × (14.5 + 8.23 × SEX [0 for female and 1 for male] + 0.301 × CLcr) × BSA. Revised nomograms for recommended daily doses derived from the refined formula can be used in clinical practice to achieve the target AUC ensuring efficacy and safety of S-1.
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http://dx.doi.org/10.1111/cas.14758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894007PMC
February 2021

Safety and feasibility of laparoscopic and endoscopic cooperative surgery for duodenal neoplasm: a retrospective multicenter study.

Endoscopy 2020 Dec 2. Epub 2020 Dec 2.

Department of Upper Gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Japan.

Background:  A delayed perforation can often occur after endoscopic treatment for duodenal neoplasms and may be fatal due to leakage of pancreatic and bile juices. We aimed to evaluate the feasibility and safety of laparoscopic and endoscopic cooperative surgery for duodenal neoplasms (D-LECS) in a multicenter, retrospective study.

Methods:  The clinical characteristics and surgical outcomes of 206 patients with duodenal neoplasms in whom D-LECS had initially been attempted at one of 14 institutions were reviewed retrospectively.

Results:  Of the 206 patients, 63 (30.6 %), 128 (62.1 %), and 15 patients (7.3 %) had lesions at the bulb, second portion, and third portion of the duodenum, respectively. The rates of en bloc and R0 resections during D-LECS were 96.1 % and 95.1 %, respectively. Intraoperative and delayed perforations occurred in 10 (4.9 %) and 5 patients (2.4 %), respectively. No cases of recurrence were observed. Surgical duration of ≥ 180 minutes was an independent risk factor for postoperative complications.

Conclusions:  The results revealed that D-LECS was performed with oncological safety and technical feasibility.
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http://dx.doi.org/10.1055/a-1327-5939DOI Listing
December 2020

Distribution of Residual Disease and Recurrence Patterns in Pathological Responders After Neoadjuvant Chemotherapy for Esophageal Squamous Cell Carcinoma.

Ann Surg 2020 Oct 16. Epub 2020 Oct 16.

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

Objective: This study aimed to elucidate the residual disease distribution and recurrence patterns in patients with ESCC responding to NAC.

Summary Background Data: To appropriately plan a prospective trial for the organ preservation approach which includes additional chemoradiotherapy in patients who responded to NAC, the distribution of residual disease needs to be elucidated. Given that the residual tumor is located in the regional field, chemoradiotherapy can be safely added to eliminate the residual disease.

Methods: Overall, 483 patients with resectable ESCC who received NAC followed by transthoracic esophagectomy at 2 high-volume centers were reviewed. The recurrence-free survival, overall survival (OS), and residual and recurrent tumor patterns were compared among the pathological responses.

Results: Compared with nonpathological responders, pathological responders exhibited significantly longer recurrence-free survival [hazard ratio of Grade 1b/2/3 compared with Grade 0; 0.25 (P < 0.001) /0.17 (P < 0.001) /0.16 (P = 0.003)] and OS [hazard ratio of Grade 1b/2/3 compared with Grade 0; 0.26 (P < 0.001) /0.12 (P < 0.001) /0.11 (P = 0.003)]. In terms of the distribution of recurrence, the percentages of solitary recurrence in the regional field out of all recurrence was significantly higher in patients with Grade 1b (60%) / 2 (67%) / 3 (67%) whereas less than 25% in Grade 0 or 1a.

Conclusions: It was found that postoperative recurrence in responders occurred in the regional field mostly as a solitary lesion without the distant failure, indicating that the residual tumor cells can be eliminated by additional chemoradiotherapy.
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http://dx.doi.org/10.1097/SLA.0000000000004436DOI Listing
October 2020

A multicenter non-randomized phase III study of sentinel node navigation surgery for early gastric cancer.

Jpn J Clin Oncol 2021 Feb;51(2):305-309

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

This prospective multicenter non-randomized phase III study aims to evaluate the long-term outcome of sentinel node navigation surgery for early gastric cancer compared with conventional distal or total gastrectomy. Clinically diagnosed primary T1N0M0 gastric cancer patients with a single lesion (≤40 mm) and without previous endoscopic treatment will be enrolled in this study. Sentinel nodes are identified by dye and radioisotope tracers and are subjected to intraoperative rapid pathology. For patients with negative sentinel node metastasis, individualized surgery consisting of limited stomach resection and sentinel node basin dissection is performed, while standard gastrectomy with D2 lymph node dissection is employed for the positive sentinel node patients. A total of 225 patients will be accrued from 13 hospitals that have experience in sentinel node mapping. The primary endpoint is 5-year relapse-free survival. The secondary endpoints are overall survival, sentinel node detection rate, diagnostic accuracy for sentinel node, distribution of sentinel nodes and metastatic sentinel node/non-sentinel node, and postoperative quality of life.
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http://dx.doi.org/10.1093/jjco/hyaa179DOI Listing
February 2021

Soluble recombinant human thrombomodulin suppresses inflammation-induced gastrointestinal tumor growth in a murine peritonitis model.

Mol Cell Biochem 2020 Dec 7;475(1-2):195-203. Epub 2020 Aug 7.

Department of Surgery, School of Medicine, Keio University, 35, Shinanomachi, Shinjuku, Tokyo, Japan.

Regulatory T cells (Tregs) and transforming growth factor β (TGF-β) are believed to play key roles in both postoperative pro-inflammatory and anti-inflammatory responses of malignancies. Recombinant human thrombomodulin (rTM) is implied to inhibit the interaction between TGF-β and Tregs. The aim of this study is to evaluate the antitumor effects of rTM against gastrointestinal tumors under systemic inflammation. Mice were subjected to cecal ligation and puncture and percutaneous allogeneic tumor implantation. rTM were introduced by percutaneous injection into the abdominal cavity. The effects of rTM were evaluated by weight of implanted tumor, proportion of Tregs in peripheral blood lymphocytes (PBL) and tumor infiltrating lymphocytes (TIL) and temporal evaluation of serum cytokines. The effect of rTM was also evaluated on the in vitro differentiation of naïve T cells into induced Tregs induced by TGF-β and interleukin (IL) -2. rTM significantly inhibited the proliferation of the implanted tumor cells in an inflammation-dependent manner. rTM also reduced the fractions of regulatory T cells and induced regulatory T cells among both PBL and TIL. Temporal evaluation of serum cytokine levels in the model mice showed that rTM significantly suppressed the increases in the serum levels of IL-2 and TGF-β. An in vitro differentiation assay revealed that rTM inhibited the differentiation of naïve T cells into Tregs triggered by IL-2- and TGF-β. rTM has suppressive effects on inflammation-induced gastrointestinal tumor growth by suggestively affecting differentiation of Tregs.
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http://dx.doi.org/10.1007/s11010-020-03872-xDOI Listing
December 2020

Validation Study of Fibrinogen and Albumin Score in Esophageal Cancer Patients Who Underwent Esophagectomy: Multicenter Prospective Cohort Study.

Ann Surg Oncol 2021 Feb 31;28(2):774-784. Epub 2020 Jul 31.

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

Purpose: To arrange multidisciplinary treatment for esophageal cancer, a simple and accurate predictive marker for prognosis is required. The current multicenter prospective study aims to validate the prognostic significance of fibrinogen and albumin score (FA score) for esophageal cancer patients.

Patients And Methods: Patients who were planned to undergo surgical resection for esophageal cancer at four participating institutions were enrolled in this study. Patient background, clinicopathological factors, and blood concentration of plasma fibrinogen and albumin were collected. Patients with elevated fibrinogen and decreased albumin levels were allocated a score of 2; those with only one of these abnormalities were allocated a score of 1; and those with neither of these abnormalities were allocated a score of 0. Recurrence-free survival (RFS) and overall survival (OS) were evaluated as a primary endpoint.

Results: From four participating institutions, 133 patients were registered for the current analysis. The distribution of FA score of 0/1/2 was 84 (63%)/34 (26%)/15 (11%), respectively. In the analysis of primary endpoint, the preoperative FA score significantly classified RFS (FA score 1/2: HR 2.546, p = 0.013/6.989, p < 0.001) and OS (FA score 1/2: HR 2.756, p = 0.010/6.970, p < 0.001). We further evaluated the prognostic significance of FA score under stratification by pStage. As a result, with increasing FA score, RFS and OS were significantly worse in both pStage 0-I and II-IV groups.

Conclusions: The prognostic impact of preoperative FA score was confirmed for esophageal cancer patients in the current multicenter prospective trial. FA score can be considered to predict postoperative survival and rearrange the treatment strategy before esophagectomy.
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http://dx.doi.org/10.1245/s10434-020-08958-wDOI Listing
February 2021

ASO Author Reflections: Prediction of the Therapeutic Efficacy in Patients with Neoadjuvant Chemotherapy for Esophageal Squamous Cell Carcinoma.

Ann Surg Oncol 2020 Dec 26;27(Suppl 3):795-796. Epub 2020 Jun 26.

Department of Gastroenterological Surgery, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.

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http://dx.doi.org/10.1245/s10434-020-08772-4DOI Listing
December 2020

Long-term outcome of endoscopic resection for intramucosal esophageal squamous cell cancer: a secondary analysis of the Japan Esophageal Cohort study.

Endoscopy 2020 11 24;52(11):967-975. Epub 2020 Jun 24.

Department of Clinical Oncology, Kyoto University Hospital, Kyoto, Japan.

Background: Prospectively collected long-term data of patients undergoing endoscopic resection for superficial esophageal squamous cell carcinoma (ESCC) are limited. The aim of this study was to determine the prospectively collected long-term outcomes of endoscopic resection for ESCC as a secondary analysis of the Japan Esophageal Cohort (JEC) study.

Methods: Patients who underwent endoscopic resection of intramucosal ESCC at 16 institutions between September 2005 and May 2010 were enrolled in the JEC study. All patients underwent endoscopic examination with iodine staining at 3 and 6 months after resection, and every 6 months thereafter. We investigated clinical courses after endoscopic resection, survival rates, and cumulative incidence of metachronous ESCC.

Results: 330 patients (mean age 67.0 years) with 396 lesions (mean size 20.4 mm) were included in the analysis. Lesions were diagnosed as high-grade intraepithelial neoplasia in 17.4 % and as squamous cell carcinoma in 82.6 % (limited to epithelium in 28.4 %, to lamina propria in 55.4 %, and to muscularis mucosa in 16.2 %). En bloc resection was achieved in 291 (73.5 %). The median follow-up period was 49.4 months. Local recurrences occurred in 13 patients (3.9 %) and were treated by endoscopic procedures. Lymph node metastasis occurred in two patients (0.6 %) after endoscopic resection. The 5-year overall, disease-specific, and metastasis-free survival rates were 95.1 %, 99.1 %, and 94.6 %, respectively. The 5-year cumulative incidence rate of metachronous ESCC was 25.7 %.

Conclusions: Our study demonstrated that endoscopic resection is an effective treatment for intramucosal ESCC, with favorable long-term outcomes.
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http://dx.doi.org/10.1055/a-1185-9329DOI Listing
November 2020

Aqueous olanexidine versus aqueous povidone-iodine for surgical skin antisepsis on the incidence of surgical site infections after clean-contaminated surgery: a multicentre, prospective, blinded-endpoint, randomised controlled trial.

Lancet Infect Dis 2020 11 15;20(11):1281-1289. Epub 2020 Jun 15.

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

Background: Surgical site infection (SSI) is the most common problem after surgery. Although several guidelines have indicated the efficacy of antiseptics, such as chlorhexidine-alcohol and povidone-iodine, in reducing SSI rate, the optimal recommendation is still not established. Olanexidine might have higher bactericidal activity than other antiseptic agents. However, no randomised study has evaluated the efficacy and safety of olanexidine over conventional antiseptics. We compared the effect of aqueous olanexidine and aqueous povidone-iodine on the incidence of SSI following clean-contaminated surgery.

Methods: This was a multicentre, prospective, randomised, blinded-endpoint superiority trial for surgical skin antisepsis in clean-contaminated gastrointestinal and hepatobiliary pancreatic surgeries in four Japanese hospitals. Patients aged 20 years or older who underwent elective clean-contaminated wound surgery were randomly assigned in a 1:1 replacement ratio using a computer-generated block randomisation. Patients were randomly assigned to surgical skin antisepsis with an aqueous formulation of 1·5% olanexidine or surgical skin antisepsis with an aqueous formulation of 10% povidone-iodine before surgery. We used olanexidine in a ready-to-use applicator, and povidone-iodine was administered by a brush or by compression using pliers. Both antiseptics were applied from the papilla with a cranial limit and to the upper thigh with a caudal limit. The antiseptics were allowed to dry for 3 min, and then surgery started. Participants, some investigators, and data analysts were masked to treatment allocation. Participant enrolment was done by non-masked investigators. The primary outcome was 30-day SSI assessed in the intention-to-treat population. The surgical wound site of each participant was observed daily. After discharge, participants underwent at least one outpatient visit within 30 days after surgery. This trial is registered with University hospital Medical Information Network, 000031560.

Findings: Between June 10, 2018, and April 18, 2019, 883 patients were assessed for eligibility. 587 patients were eligible and 294 received olanexidine and 293 received aqueous povidone-iodine before surgery. 30-day SSI occurred in 19 (7%) patients in the olanexidine group and 39 patients (13%) patients in the povidone-iodine group (adjusted risk difference -0·069; 90% CI -0·109 to -0·029; adjusted risk ratio [RR] 0·48, 90% CI 0·30 to 0·74; p=0·002). Five patients (2%) in the olanexidine group and five (2%) in the povidone-iodine group developed adverse skin reactions (adjusted RR 0·99, 95% CI 0·29 to 3·40; p=1·00).

Interpretation: Olanexidine significantly reduced the occurrence of overall SSI and superficial incisional SSI compared with aqueous povidone-iodine in clean-contaminated surgery. Our results indicate that olanexidine might have a role to prevent SSI in patients who undergo clean-contaminated surgeries.

Funding: Keio University and Ohyama Health Foundation.
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http://dx.doi.org/10.1016/S1473-3099(20)30225-5DOI Listing
November 2020
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