Publications by authors named "Yasuhiro Shirakawa"

118 Publications

Phase I dose-escalation study of endoscopic intratumoral injection of OBP-301 (Telomelysin) with radiotherapy in oesophageal cancer patients unfit for standard treatments.

Eur J Cancer 2021 Aug 18;153:98-108. Epub 2021 Jun 18.

Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan. Electronic address:

Purpose: OBP-301 (Telomelysin) is an attenuated type-5 adenovirus that contains the human telomerase reverse transcriptase promoter to regulate viral replication. OBP-301 sensitises human cancer cells to ionising radiation by inhibiting DNA repair, and radiation enhances coxsackievirus and adenovirus receptor-mediated OBP-301 infection on the contrary. We assessed OBP-301 with radiotherapy in oesophageal cancer patients unfit for standard chemoradiation treatments.

Methods: A phase I dose-escalation study of OBP-301 with radiotherapy was conducted in 13 histologically confirmed oesophageal cancer patients deemed unfit to undergo surgery or chemotherapy. Study treatment consisted of OBP-301 administration by intratumoural needle injection using a flexible endoscope on days 1, 18 and 32. Radiotherapy was administered concurrently over 6 weeks, beginning on day 4, to a total of 60 Gy.

Results: Of the 13 patients, 7, 3 and 3 patients were treated with 10, 10 and 10 virus particles, respectively. Study group comprised 10 males and 3 females, with a median age of 82 years (range, 53-91 years). All patients developed a transient, self-limited lymphopenia. Distribution studies revealed transient virus shedding in the plasma. Eight patients had local complete response (CR); all of them exhibited no pathologically viable malignant cells in biopsy specimens, and 3 patients had a partial response. The objective response rate was 91.7%. The clinical CR rate was 83.3% in stage I and 60.0% in stage II/III. Histopathological examination revealed massive infiltration of CD8 cells and increased PD-L1 expression.

Conclusion: Multiple courses of endoscopic intratumoural OBP-301 injection with radiotherapy are feasible and provide clinical benefits in patients with oesophageal cancer unfit for standard treatments.
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http://dx.doi.org/10.1016/j.ejca.2021.04.043DOI Listing
August 2021

Early intervention of the perioperative multidisciplinary team approach decreases the adverse events during neoadjuvant chemotherapy for esophageal cancer patients.

Esophagus 2021 May 17. Epub 2021 May 17.

Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.

Background: Multidisciplinary team (MDT) approach has become a standard for perioperative patient care, including in esophageal cancer. In our institution, the Perioperative Management Center (PERiO) has been doing an MDT approach for patients undergoing esophageal cancer surgery since 2009. On the other hand, neoadjuvant therapy has also been becoming standard for many malignancies, including esophageal cancer. In Japan, neoadjuvant chemotherapy (NAC) for esophageal cancer is standard now. However, there have been no reports about when is the best time to start the MDT approach for patients with neoadjuvant therapy. In this study, the best start time for the MDT approach for esophageal cancer patients with NAC was examined from the perspective of adverse events during chemotherapy and perioperative period.

Methods: All cases underwent thoracoscopic esophagectomy in the prone position (TEPP) after NAC. The PERiO Intervention group that started before NAC (n = 100) was compared with the PERiO Intervention group that started after NAC (n = 77). Eventually, 54 paired cases were matched by propensity score matching.

Results: The adverse event rate during chemotherapy, especially oral complications, was significantly decreased in the PERiO Intervention started before the NAC group (P = 0.007). Furthermore, weight loss during the period from chemotherapy to surgery was significantly reduced in the group that started before NAC (P = 0.033).

Conclusion: The MDT approach should be started before NAC in patients undergoing esophageal cancer surgery to prevent adverse events during chemotherapy and provide safe perioperative conditions.
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http://dx.doi.org/10.1007/s10388-021-00844-yDOI Listing
May 2021

Nanog is a promising chemoresistant stemness marker and therapeutic target by iron chelators for esophageal cancer.

Int J Cancer 2021 Jul 5;149(2):347-357. Epub 2021 Apr 5.

Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.

Esophageal cancer is a disease showing poor prognosis. Although combination chemotherapy using cisplatin (CDDP) and 5-fluorouracil is standard for unresectable esophageal cancer, the response rate is 35%. Cancer stem cells (CSCs) and inflammation are reportedly responsible for the poor prognosis of esophageal cancer. However, comprehensive analyses have not been conducted and proposals for progress remain lacking. Iron is known to be a key factor in the stemness of CSCs. Our study focused on the therapeutic potential of iron control using iron chelators for CSCs in esophageal cancer. Among 134 immunohistochemically analyzed cases, Nanog expression was high in 98 cases and low in 36 cases. High Nanog expression correlated with low overall and disease-free survivals. The iron chelators deferasirox (DFX) and SP10 suppressed the proliferation and expression of stemness markers in TE8 and OE33 cells. DFX and SP10 did not induce compensatory interleukin (IL)-6 secretion, although CDDP did result in high induction. Moreover, BBI608 and SSZ, as other CSC-targeting drugs, could not suppress the expression of stemness markers. Overall, Nanog expression appears related to poor prognosis in esophageal cancer patients, and inhibition of stemness and compensatory IL-6 secretion by iron chelators may offer a novel therapeutic strategy for esophageal cancer.
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http://dx.doi.org/10.1002/ijc.33544DOI Listing
July 2021

Simultaneous laparoscopic hiatal hernia repair and pyloroplasty for a type 3 hiatal hernia with post-ESD pyloric stenosis for early gastric cancer.

Asian J Endosc Surg 2021 Feb 5. Epub 2021 Feb 5.

Department of Surgery, Hiroshima City Hiroshima Citizens Hospital, Hiroshima, Japan.

We present a case of early gastric cancer in the pylorus with a type 3 hiatal hernia, which was treated by endoscopic submucosal dissection (ESD). A 70-year-old man was referred to our hospital with a hiatal hernia. Endoscopy revealed early gastric cancer, and we performed an ESD adaptation at the pylorus. The ESD was successful, but post-ESD pyloric stenosis occurred. Symptoms of hiatal hernia worsened because of the pyloric stenosis. Laparoscopic hiatal hernia repair with Toupet fundoplication and Heineke-Mikulicz pyloroplasty was simultaneously performed. The postoperative course was good, and follow-up after discharge was uneventful. To our knowledge, there have been no reports in which laparoscopic hiatal hernia repair, fundoplication, and pyloroplasty were simultaneously performed for a substantial hiatal hernia with post-ESD pyloric stenosis.
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http://dx.doi.org/10.1111/ases.12919DOI Listing
February 2021

Fibroblast activation protein targeted near infrared photoimmunotherapy (NIR PIT) overcomes therapeutic resistance in human esophageal cancer.

Sci Rep 2021 Jan 18;11(1):1693. Epub 2021 Jan 18.

Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan.

Cancer-associated fibroblasts (CAFs) have an important role in the tumor microenvironment. CAFs have the multifunctionality which strongly support cancer progression and the acquisition of therapeutic resistance by cancer cells. Near-infrared photoimmunotherapy (NIR-PIT) is a novel cancer treatment that uses a highly selective monoclonal antibody (mAb)-photosensitizer conjugate. We developed fibroblast activation protein (FAP)-targeted NIR-PIT, in which IR700 was conjugated to a FAP-specific antibody to target CAFs (CAFs-targeted NIR-PIT: CAFs-PIT). Thus, we hypothesized that the control of CAFs could overcome the resistance to conventional chemotherapy in esophageal cancer (EC). In this study, we evaluated whether EC cell acquisition of stronger malignant characteristics and refractoriness to chemoradiotherapy are mediated by CAFs. Next, we assessed whether the resistance could be rescued by eliminating CAF stimulation by CAFs-PIT in vitro and in vivo. Cancer cells acquired chemoradiotherapy resistance via CAF stimulation in vitro and 5-fluorouracil (FU) resistance in CAF-coinoculated tumor models in vivo. CAF stimulation promoted the migration/invasion of cancer cells and a stem-like phenotype in vitro, which were rescued by elimination of CAF stimulation. CAFs-PIT had a highly selective effect on CAFs in vitro. Finally, CAF elimination by CAFs-PIT in vivo demonstrated that the combination of 5-FU and NIR-PIT succeeded in producing 70.9% tumor reduction, while 5-FU alone achieved only 13.3% reduction, suggesting the recovery of 5-FU sensitivity in CAF-rich tumors. In conclusion, CAFs-PIT could overcome therapeutic resistance via CAF elimination. The combined use of novel targeted CAFs-PIT with conventional anticancer treatments can be expected to provide a more effective and sensible treatment strategy.
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http://dx.doi.org/10.1038/s41598-021-81465-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814141PMC
January 2021

Paraesophageal hernia repair can decrease BNP levels.

Surg Endosc 2021 Jan 4. Epub 2021 Jan 4.

Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.

Background: Although the main manifestation of giant paraesophageal hernia (PEH) is disordered meal passage due to gastric torsion, the contents of the hernia sometimes squeeze the heart and lungs and induce the symptoms of respiratory or heart failure. Furthermore, the quality of life (QOL) of patients with a heavy cardiac load deteriorates. In this study, changes in a heart failure marker and symptoms of cases with a giant PEH from before to after laparoscopic surgery were examined.

Methods: Levels of brain natriuretic peptide (BNP) as a heart failure marker were measured before and after radical laparoscopic surgery in cases of type III, IV type of giant PEH. Changes of the symptoms due to heart failure were also investigated.

Results: A total of 75 hiatal hernia surgeries were performed in 2012-2019. Of them, 50 had a giant PEH, and 20 (40.0%) had heart failure symptoms such as fatigue and exertional dyspnea. In the giant PEH cases, BNP could be measured before and after surgery to evaluate the presence of heart failure in 23 cases; postoperative BNP levels decreased from the preoperative values in 18 of them. Furthermore, in many cases, chest symptoms also improved.

Conclusions: Radical laparoscopic surgery can reduce heart failure due to giant PEH. Therefore, in addition to conventional surgical indication criteria such as vomiting and food loss, increased cardiac load may be added to the new surgical indication criteria.
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http://dx.doi.org/10.1007/s00464-020-08202-2DOI Listing
January 2021

Changing color and intensity of LED lighting across the day impacts on circadian melatonin rhythms and sleep in healthy men.

J Pineal Res 2021 Apr 18;70(3):e12714. Epub 2021 Jan 18.

Centre for Chronobiology, Psychiatric Hospital of the University of Basel, Basel, Switzerland.

We examined whether dynamically changing light across a scheduled 16-h waking day influences sleepiness, cognitive performance, visual comfort, melatonin secretion, and sleep under controlled laboratory conditions in healthy men. Fourteen participants underwent a 49-h laboratory protocol in a repeated-measures study design. They spent the first 5 hours in the evening under standard lighting, followed by an 8-h nocturnal sleep episode at habitual bedtimes. Thereafter, volunteers either woke up to static light or to a dynamic light that changed spectrum and intensity across the scheduled 16-h waking day. Following an 8-h nocturnal sleep episode, the volunteers spent another 11 hours either under static or dynamic light. Static light attenuated the evening rise in melatonin levels more compared to dynamic light as indexed by a significant reduction in the melatonin AUC prior to bedtime during static light only. Participants felt less vigilant in the evening during dynamic light. After dynamic light, sleep latency was significantly shorter in both the baseline and treatment night while sleep structure, sleep quality, cognitive performance, and visual comfort did not significantly differ. The study shows that dynamic changes in spectrum and intensity of light promote melatonin secretion and sleep initiation in healthy men.
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http://dx.doi.org/10.1111/jpi.12714DOI Listing
April 2021

Initial introduction of robot-assisted, minimally invasive esophagectomy using the microanatomy-based concept in the upper mediastinum.

Surg Endosc 2020 Nov 10. Epub 2020 Nov 10.

Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.

Background: We have recently standardized upper mediastinal lymph node dissection (UMLND) using a microanatomy-based concept in thoracoscopic esophagectomy in the prone position (TEPP), and introduced robot-assisted minimally invasive esophagectomy (RAMIE) using the same concept as in TEPP while aiming at solo surgery. The purpose of this study was to investigate the outcomes of RAMIE using the microanatomy-based concept in the initial introduction phase.

Methods: We have performed more than 500 TEPP procedures as minimally invasive esophagectomy (MIE). After performing about 400 cases of MIE, we established a microanatomy-based standardization of UMLND. In October 2018, we introduced RAMIE, and have performed 75 procedures in 20 months. Two groups were analyzed: a group after microanatomy-based standardization in TEPP (100 cases after completing 400 cases of TEPP) and a RAMIE group (75 cases). Finally, 51 paired cases were matched using a propensity score. Furthermore, the change in postoperative short-term outcome for RAMIE in the initial introduction phase was analyzed.

Results: Although there were no significant differences between the two groups in the number of upper mediastinal lymph nodes dissected, there was a significant decrease (P = 0.036) in intraoperative blood loss volume with RAMIE, representing a definite benefit for patients. The thoracoscopic operative time for RAMIE decreased by almost 100 min following less than 50 cases of experience, reaching the same level as that for recent TEPP, but with only one-tenth the operator experience. There were no significant differences in the total postoperative morbidity rate including the recurrent laryngeal nerve palsy rate.

Conclusion: RAMIE has been introduced safely and smoothly using the microanatomy-based concept established in TEPP.
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http://dx.doi.org/10.1007/s00464-020-08154-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654354PMC
November 2020

Risk factor of mediastinal lymph node metastasis of Siewert type I and II esophagogastric junction carcinomas.

Langenbecks Arch Surg 2020 Dec 5;405(8):1101-1109. Epub 2020 Nov 5.

Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan.

Background: Incidence of esophagogastric junction (EGJ) carcinoma has been increasing worldwide. Several studies revealed that the distance from the EGJ to the proximal edge of the primary tumor (esophageal invasion: EI) may be a significant indicator of metastasis in the mediastinal lymph nodes in patients with Siewert type II carcinomas. However, few studies have been conducted in patients with carcinomas located at Siewert type II sequentially to upper carcinomas (Siewert type I) for mediastinal metastasis regardless of histological types.

Methods: This was a single-center retrospective cohort study. EGJ carcinomas located at Siewert type I and II regions including both squamous cell carcinoma (SCC) and adenocarcinoma were analyzed in terms of lymph node metastasis patterns.

Results: We included 121 patients in this study. Thirty-three (27.3%) patients had SCC. In multivariate analysis, the distance of EI (> 20 mm) was an independent risk factor (OR 11.80, p = 0.005) for lower mediastinal lymph node metastasis. In terms of above the middle mediastinal metastasis, the distance of EI (> 30 m), histological type (SCC), and tumor size (> 40 mm) were risk factors in univariate analysis. Furthermore, EI was significant (OR 13.50, p = 0.026) in multivariate analysis.

Conclusions: The distance of EI was the independent risk factor for mediastinal lymph node metastasis, especially > 20 mm related with a higher risk for mediastinal lymph node metastasis. Furthermore, EGJ carcinoma patients who have EI > 30 mm, large SCC carcinoma, and multiple lymph node metastasis might be considered the middle-upper mediastinal lymph node dissection by transthoracic approach.
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http://dx.doi.org/10.1007/s00423-020-02017-4DOI Listing
December 2020

[Esophageal Reconstruction with Vascular Anastomosis and Perioperative Management].

Kyobu Geka 2020 Sep;73(10):887-891

Department of Gastroenterological Surgery, Okayama University, Okayama, Japan.

Esophageal reconstruction using intestine is often performed for esophageal cancer patients in cases where the stomach cannot be used. We have previously performed reconstruction using ileocolon with supercharge and drainage as our 1st choice in those cases. However, a less invasive, simpler, and safer reconstructive technique using pedicled jejunal flap has recently become popular at our facility. When making the pedicled jejunal flap, the 1st jejunal vascular arcade was preserved, which in many cases allowed it to be pulled up to the cervical region by processing and transection up to the 2nd jejunal vascular branch. But supercharge and superdrainage may be required for pedicled jejunal flap reconstruction when blood flow of jejunal flap is not good condition. And free jejunal reconstruction is performed to reconstruction after cervical esophagectomy. Vascular anastomosis is essential for free jejunal reconstruction. This article describes the surgical technique and perioperative management of esophageal reconstruction with vascular anastomosis.
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September 2020

Long-term outcomes of endoscopic versus surgical resection for MM-SM1 esophageal squamous cell carcinoma using propensity score analysis.

Esophagus 2021 Jan 2;18(1):72-80. Epub 2020 Sep 2.

Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan.

Background: Esophageal squamous cell carcinoma (ESCC) confined to the muscularis mucosae (MM) or up to 200 µm of the submucosa (SM1) confers the risk for lymph node metastasis, and is defined as relative indication for endoscopic submucosal dissection (ESD) by the Japan Esophageal Society guidelines. Although additional surgical treatment after ESD is recommended, long-term outcomes of ESD compared with those of surgery have not been clarified. This study aimed to evaluate the long-term outcomes of ESD and surgery for cN0M0 relative indication lesions of ESCC.

Methods: Between 2006 and 2016, patients with relative indication lesions of ESCC who underwent ESD or surgery at nine participating hospitals were examined retrospectively. Using propensity score matching, we evaluated survival curves for and hazard ratios associated with endoscopic submucosal dissection and surgery.

Results: In total, 155 lesions in the ESD group and 106 lesions in the surgery group met the pathological criteria of relative indication for endoscopic resection. After matching, 50 matched pairs of patients who underwent ESD or surgery were selected. The 5-year overall survival rates were 84.5% [95% confidence interval (CI) 68-93] in the ESD group and 79% [95% CI 60-90] in the surgery group. The hazard ratio of mortality for ESD compared with that for surgery estimated by Cox regression analysis was 0.79 (95% CI 0.3-2.06, p = 0.63).

Conclusions: Compared with surgery, ESD does not compromise long-term outcomes. ESD alone or ESD with chemotherapy and/or radiotherapy may be an option for the treatment of MM and SM1 ESCC.
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http://dx.doi.org/10.1007/s10388-020-00775-0DOI Listing
January 2021

A case of esophageal cancer with an aberrant right subclavian artery treated with mediastinoscopic esophagectomy.

Asian J Endosc Surg 2021 Apr 26;14(2):293-296. Epub 2020 Aug 26.

Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.

An aberrant right subclavian artery (ARSA) is one of the famous anatomical abnormalities with a prevalence of 0.16-4.4%. In esophagectomy, anatomical abnormalities of the ARSA could cause complications with some surgical procedures. An 85-year old man was referred to our department for esophageal adenocarcinoma that was at a slightly high position for esophagectomy with the abdominal approach. However, he had a significant past medical history. This risk factor made it difficult to perform thoracoscopic esophagectomy. He underwent mediastinoscopic esophagectomy (ME) with the left cervical and laparoscopic approach. The ARSA presented no difficulties with the ME surgical technique including the dissection of the left recurrent laryngeal nerve lymph node. Although this patient had a respiratory dysfunction and some difficulties in a prone position, ME enabled a safe esophagectomy with lymph node dissection.
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http://dx.doi.org/10.1111/ases.12859DOI Listing
April 2021

Recent advances in minimally invasive esophagectomy for squamous esophageal cancer.

Ann N Y Acad Sci 2020 12 11;1482(1):113-120. Epub 2020 Aug 11.

Division of Upper GI and Metabolic Surgery, Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong.

Over the past decade there has been tremendous development in the clinical application of minimally invasive esophagectomy (MIE) for the treatment of squamous esophageal carcinoma. The major challenges in the performance of MIE include limitations in visualization and manipulation within the confined, rigid thoracic cavity; the need for adequate patient positioning and anesthetic techniques to accommodate the surgical exposure; and changes in the surgical steps for achieving radical nodal dissection, especially for the superior mediastinum. The surgical procedure for MIE is more and more standardized, and there is an increasing practice of MIE worldwide. Randomized trials and meta-analyses have confirmed the advantages of MIE over open esophagectomy, including a significantly lower rate of complications and shorter hospital stays. The recent application of robotics technologies for MIE has further enhanced the quality and safety of the surgical dissection, while intraoperative nerve monitoring has contributed to a lower rate of recurrent laryngeal nerve palsy. With the application of new technologies, we expect further improvement in surgical outcomes for MIE in the treatment of squamous esophageal cancer.
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http://dx.doi.org/10.1111/nyas.14461DOI Listing
December 2020

High incidence of tracheobronchial diverticulum in esophageal cancer patients: a retrospective survey alerting pitfall during thoracoscopic esophagectomy.

Gen Thorac Cardiovasc Surg 2020 Sep 3;68(9):1018-1023. Epub 2020 Aug 3.

Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan.

Objectives: Although tracheobronchial diverticulum (DV) rarely cause problems, attention should be paid during esophagectomy, which requires careful dissection around the trachea and bronchi. Here, we retrospectively review cases of tracheobronchial DVs among esophageal cancer patients and report two cases of bronchial DV injury during thoracoscopic esophagectomy that were successfully repaired.

Methods: The thin-section CT images of esophageal cancer patients who underwent thoracoscopic esophagectomy from January 2013 to December 2015 were retrospectively reviewed. The localization, number, and size (largest axial diameter) of all detected DVs were recorded.

Results: A total of 180 patients were enrolled in this study. The incidence of tracheal DV was 5.0%, and that of bronchial DV was 40.0%. The median diameter of the tracheal diverticula was 2.45 [interquartile range (IQR) 2.00-8.17] mm and that of the bronchial diverticula was 1.90 (IQR 1.51-2.46) mm. All tracheal diverticula presented at the right tracheal wall 4.5-6.0 cm below the vocal cords; bronchial diverticula presented at the subcarinal lesions. We experienced two cases with bronchial diverticulum injuries during thoracoscopic esophagectomy, which were repaired by primary closure and confirmed that there was no air leak. No postoperative complications associated with bronchial injury occurred in either patient.

Conclusion: Since tracheobronchial DVs are not as rare as previously thought, careful evaluation of thin-slice CT scans is necessary before thoracoscopic esophagectomy. If a tracheobronchial DV is injured during surgery, it is important to carefully repair it and confirm that there is no air leak to avoid complications.
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http://dx.doi.org/10.1007/s11748-020-01421-3DOI Listing
September 2020

Skeletal muscle loss in the postoperative acute phase after esophageal cancer surgery as a new prognostic factor.

World J Surg Oncol 2020 Jun 26;18(1):143. Epub 2020 Jun 26.

Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikatacho, Kita-ku, Okayama, 700-8558, Japan.

Background: The postoperative survival rate of patients with esophageal squamous cell carcinoma (ESCC) remains poor compared with other gastrointestinal cancers. We hypothesized that skeletal muscle loss in the postoperative acute phase might be a new predictor for long-term prognosis after highly invasive surgery such as ESCC surgery.

Methods: The following items were retrospectively investigated. First, whether skeletal muscle loss occurred in the postoperative acute phase of ESCC was verified. Second, the preoperative and intraoperative factors involved in skeletal muscle loss in the postoperative acute phase of ESCC were investigated. Then, whether skeletal muscle loss in the postoperative acute phase affected long-term prognosis was examined. The medical records of consecutive patients who underwent radical esophagectomy for ESCC between January 2010 and February 2015 were retrospectively reviewed; 72 cases were eligible for this study. The total psoas major muscle mass index (TPI) at the level of the third lumbar vertebra (L3) was measured using computed tomography (CT) before surgery and 3 days after surgery. The long-term prognosis was estimated by the Kaplan-Meier method and the multivariate logistic regression model.

Results: There was already a significant reduction of TPI in the acute phase up to POD 3 after ESCC surgery in comparison with the preoperative baseline TPI (P < 0.001). The TPI reduction rate was significantly milder in cases with less blood loss during surgery and in cases that underwent thoracoscopic esophagectomy than in cases that underwent open esophagectomy. The 3-year overall survival rate was significantly different between the TPI reduction rate severe group and the TPI reduction rate mild group.

Conclusion: Skeletal muscle loss occurred even in the postoperative acute phase. Furthermore, it is very significant that skeletal muscle loss in the postoperative acute phase of ESCC surgery is involved in the long-term prognosis.
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http://dx.doi.org/10.1186/s12957-020-01908-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7320551PMC
June 2020

Association of dental occlusal support with the Prognostic Nutritional Index in patients with esophageal cancer who underwent esophagectomy.

Esophagus 2021 Jan 7;18(1):49-55. Epub 2020 Jun 7.

Department of Preventive Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata-cho, Kitaku, Okayama, 700-8558, Japan.

Background: The Prognostic Nutritional Index is useful for predicting surgical risk and overall survival based on preoperative immunological and nutritional status in patients undergoing digestive organ cancer surgery. The purpose of this study was to examine the association between the Prognostic Nutritional Index and dental status in patients with esophageal cancer who underwent esophagectomy.

Methods: This retrospective case-control study included 73 patients who underwent resection of esophageal cancer (69 males, 4 females; age 36-83). General and dental status were evaluated. The Prognostic Nutritional Index was calculated based on the serum albumin concentration and the total lymphocyte count, and subjects were divided into two groups based on index scores: a higher group, characterized by scores ≥ 45 (n = 54); and a lower group, characterized by scores < 45 (n = 19). Univariate analysis and multiple logistic regression analyses were used to compare between groups.

Results: Total protein, C-reactive protein, the number of sound and total decayed, missing and filled teeth, and the rate of patients with poor dental occlusal support showed significant differences between the lower and higher Prognostic Nutritional Index groups (p < 0.05). Stepwise logistic regression analysis by backward selection approach showed that low total protein, few sound teeth, and poor status of dental occlusal support were significantly associated with the lower Prognostic Nutritional Index (p = 0.007, 0.042, and 0.009, respectively).

Conclusion: Dental status, especially dental occlusal support and the number of sound teeth, showed a positive relationship with the Prognostic Nutritional Index in esophageal cancer patients who underwent esophagectomy.
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http://dx.doi.org/10.1007/s10388-020-00751-8DOI Listing
January 2021

Intraoperative fluid therapy and postoperative complications during minimally invasive esophagectomy for esophageal cancer: a single-center retrospective study.

J Anesth 2020 06 30;34(3):404-412. Epub 2020 Mar 30.

Department of Anesthesiology and Resuscitology, Okayama University Hospital, 2-5-1, Shikata-cho, Kita-ku, Okayama, 700-8558, Japan.

Purpose: Compared with open thoracotomy, minimally invasive esophagectomy (MIE) methods, such as transhiatal or thoracoscopic esophagectomy, likely have lower morbidity. However, the relationship between intraoperative fluid management and postoperative complications after MIE remains unclear. Thus, we investigated the association of cumulative intraoperative fluid balance and postoperative complications in patients undergoing MIE.

Methods: This single-center retrospective cohort study examined patients undergoing thoracoscopic esophagectomy for esophageal cancer in the prone position. Postoperative complications included pneumonia, arrhythmia, thrombotic events and acute kidney injury (AKI). We compared patients with higher and lower intraoperative fluid balance (higher and lower than the median). Multivariable logistic regression analyses were performed to estimate the odds ratio of intraoperative fluid balance status on the incidence of postoperative complications.

Results: In total, 135 patients were included in the study. Postoperative complications occurred in 43 (32%), including cardiac arrhythmia (n = 12, 9%), thrombosis (n = 20, 15%), pneumonia (n = 13, 10%), and AKI required hemodialysis (n = 1, 1%). Patients with a higher fluid balance had higher incidence of complications than those with a lower fluid balance (46% vs. 18%, p < 0.001). After adjusting for age, ASA-PS ≥ III, blood loss, and the use of radical surgery, the higher intraoperative fluid balance group was significantly and independently associated with postoperative complications (adjusted OR 5.31, 95% CI 2.26-13.6, p < 0.0001).

Conclusions: In patients undergoing thoracoscopic esophagectomy in the prone position, a greater intraoperative positive fluid balance was independently associated with a higher incidence of complications.
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http://dx.doi.org/10.1007/s00540-020-02766-yDOI Listing
June 2020

Surgical site infection caused by Aeromonas hydrophila presenting as necrotizing soft tissue infection after esophagectomy.

J Dermatol 2020 Jun 24;47(6):673-676. Epub 2020 Mar 24.

Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.

Several virulence factors of Aeromonas such as hemolysin, proteases and lipases have been characterized. The relationship between these virulence factors and disease remains unclear. A 71-year-old man underwent thoracoscopic esophagectomy, lymph node dissection and Roux-en-Y reconstruction for esophageal cancer. On postoperative day 1, redness around the wound on the thoracic abdominal wall gradually enlarged and necrosis became apparent with septic shock. Necrotizing soft tissue infection was suspected and emergency surgical debridement was performed. Blood and wound cultures were positive for Aeromonas hydrophila. The strain was found to have hemolytic activity, proteolytic activity and extremely high elastolytic activity. In addition, the strain actively produced elastolytic metalloprotease, which may contribute to extensive tissue necrosis.
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http://dx.doi.org/10.1111/1346-8138.15323DOI Listing
June 2020

Microanatomy-based standardization of left upper mediastinal lymph node dissection in thoracoscopic esophagectomy in the prone position.

Surg Endosc 2021 01 10;35(1):349-357. Epub 2020 Feb 10.

Department of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, 2-5-1 Shikatacho, Kita-ku, Okayama, 700-8558, Japan.

Background: Although thoracoscopic esophagectomy in the prone position (TEPP) has become a standard procedure for esophageal cancer surgery, upper mediastinal lymph node dissection (UMLND) on the left side remains an issue. We have recently developed a new standardized approach to left UMLND in TEPP based on the microanatomy of the membranes and layers with the aim of achieving quick and safe surgery. The purpose of this study was to establish and evaluate our new standardized procedure in left UMLND.

Patients And Methods: Patients were divided into 2 groups: a pre-standardization group (n = 100) and a post-standardization group (n = 100). Eventually, 83 paired cases were matched using propensity score matching. In our new standardized procedure, left UMLND was performed while focusing on the visceral sheath, vascular sheath, and the fusion layer between them using a magnified view.

Results: The thoracoscopic operative time was significantly shorter (P < 0.001) in the post-standardization group [n = 83; 209.0 (176.0-235.0) min] than in the pre-standardization group [n = 83; 235.5 (202.8-264.5) min]. No significant differences were found in the number of mediastinal lymph nodes dissected or intraoperative blood loss between the two groups. There was a tendency for the total postoperative morbidity to decrease in the post-standardization group. Furthermore, the left recurrent laryngeal nerve palsy rate was significantly lower in the post-standardization group (18.1% to 8.7%, P = 0.015).

Conclusion: Microanatomy-based standardization contributes to safe and efficient left UMLND.
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http://dx.doi.org/10.1007/s00464-020-07407-9DOI Listing
January 2021

Induction chemoradiotherapy including docetaxel, cisplatin, and 5-fluorouracil for locally advanced esophageal cancer.

Esophagus 2020 04 2;17(2):127-134. Epub 2020 Jan 2.

Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikatacho, Kita-ku, Okayama, 700-8558, Japan.

Background: Locally advanced esophageal cancer (EC) invading surrounding organs (T4b) is difficult to treat. In general, definitive chemoradiotherapy (d-CRT) has been chosen as treatment for such cases. However, the outcome has not been good. Recently, the effectiveness of d-CRT with docetaxel, cisplatin, and 5-fluorouracil (DCF-RT) has been reported. Furthermore, surgery after d-CRT has a better prognosis than d-CRT alone in some reports, although it has a high risk of surgical complications. This study investigated the effectiveness and safety of induction DCF-RT.

Methods: The subjects were EC patients who underwent induction DCF-RT in Okayama University Hospital between January 2011 and December 2017. Their background characteristics, treatment details, histopathological factors, adverse events during CRT, postoperative complications, and overall survival (OS) were assessed.

Results: A total of 16 cases were performed induction DCF-RT. In 10 cases, death occurred, with 9 cancer-related deaths, and 1 death due to other disease. For all cases, OS was 37.5% at 3 years. 12 cases underwent esophagectomy after DCF-RT. Their OS was 50% at 3 years. 13 patients (81.3%) had Grade 3 febrile neutropenia. In 7 cases (62.5%), fasting for the treatment of diarrhea was needed. Three patients (25%) developed anastomotic leakage. Some recurrent laryngeal nerve paralysis was observed in 6 cases (50%).

Conclusion: Although the rates of adverse events and surgical complications were slightly higher than in past reports, they were acceptable. It is useful to perform induction DCF-RT for T4b EC.
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http://dx.doi.org/10.1007/s10388-019-00709-5DOI Listing
April 2020

Visualization of epithelial-mesenchymal transition in an inflammatory microenvironment-colorectal cancer network.

Sci Rep 2019 11 8;9(1):16378. Epub 2019 Nov 8.

Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan.

Epithelial-mesenchymal transition (EMT) is a biological process by which epithelial cells acquire mesenchymal characteristics. In malignant tumors, EMT is crucial for acquisition of a mesenchymal phenotype with invasive and metastatic properties, leading to tumor progression. An inflammatory microenvironment is thought to be responsible for the development and progression of colorectal cancer (CRC); however, the precise role of inflammatory microenvironments in EMT-related CRC progression remains unclear. Here, we show the spatiotemporal visualization of CRC cells undergoing EMT using a fluorescence-guided EMT imaging system in which the mesenchymal vimentin promoter drives red fluorescent protein (RFP) expression. An inflammatory microenvironment including TNF-α, IL-1β, and cytokine-secreting inflammatory macrophages induced RFP expression in association with the EMT phenotype in CRC cells. In vivo experiments further demonstrated the distribution of RFP-positive CRC cells in rectal and metastatic tumors. Our data suggest that the EMT imaging system described here is a powerful tool for monitoring EMT in inflammatory microenvironment-CRC networks.
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http://dx.doi.org/10.1038/s41598-019-52816-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6841984PMC
November 2019

Photoimmunotherapy for cancer-associated fibroblasts targeting fibroblast activation protein in human esophageal squamous cell carcinoma.

Cancer Biol Ther 2019 11;20(9):1234-1248. Epub 2019 Jun 11.

Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan.

Cancer-associated fibroblasts (CAFs) are strongly implicated in tumor progression, including in the processes of tumorigenesis, invasion, and metastasis. The targeting of CAFs using various therapeutic approaches is a novel treatment strategy; however, the efficacy of such therapies remains limited. Recently, near-infrared photoimmunotherapy (NIR-PIT), which is a novel targeted therapy employing a cell-specific mAb conjugated to a photosensitizer, has been introduced as a new type of phototherapy. In this study, we have developed a novel NIR-PIT technique to target CAFs, by focusing on fibroblast activation protein (FAP), and we evaluate the treatment efficacy and . Esophageal carcinoma cells exhibited enhanced activation of fibroblasts, with FAP over-expressed in the cytoplasm and on the cell surface. FAP-IR700-mediated PIT showed induced rapid cell death specifically for those cells and , without adverse effects. This novel therapy for CAFs, designed as local control phototherapy, was safe and showed a promising inhibitory effect on FAP CAFs. PIT targeting CAFs via the specific marker FAP may be a therapeutic option for CAFs in the tumor microenvironment in the future.
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http://dx.doi.org/10.1080/15384047.2019.1617566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6741582PMC
August 2020

Change in tongue pressure and the related factors after esophagectomy: a short-term, longitudinal study.

Esophagus 2019 07 2;16(3):300-308. Epub 2019 Apr 2.

Department of Preventive Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan.

Background: Dysphagia is a prominent symptom after esophagectomy and may cause aspiration pneumonia. Swallowing evaluation after esophagectomy can predict and help control the incidence of postoperative pneumonia. The aim of this study was to clarify whether the change in tongue pressure was associated with any related factor and postoperative dysphagia/pneumonia in patients with esophageal cancer after esophagectomy.

Methods: Fifty-nine inpatients (41 males and 18 females; 33-77 years old) who underwent esophagectomy participated in this study. Measurement of tongue pressure and the repetitive saliva swallowing test (RSST) was performed before esophagectomy (baseline) and at 2 weeks postoperatively. The general data were collected from patients' medical records, including sex, age, type of cancer, cancer stage, location of cancer, operative approach, history of previous chemotherapy, surgical duration, amount of bleeding during surgery, incidences of postoperative complications, intubation period, period between surgery and initiation of oral alimentation, and intensive care unit (ICU) stay, blood chemical analysis, and lifestyle.

Results: Tongue pressure decreased significantly after esophagectomy (p = 0.011). The decrease of tongue pressure was significantly associated with length of ICU stay and preoperative tongue pressure on multiple regression analysis (p < 0.05). The decrease of tongue pressure in the RSST < 3 or postoperative pneumonia (+) group was significantly greater than in the RSST ≥ 3 (p = 0.003) or pneumonia (-) group (p = 0.021).

Conclusions: The decrease in tongue pressure was significantly associated with the length of ICU stay, preoperative tongue pressure, and the incidence of dysphagia and pneumonia among inpatient after esophagectomy.
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http://dx.doi.org/10.1007/s10388-019-00668-xDOI Listing
July 2019

Flap Reconstruction for Esophageal Perforation Following Anterior Cervical Plate Fixation.

Acta Med Okayama 2019 Feb;73(1):77-80

Department of Plastic and Reconstructive Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama 700-8558, Japan.

Anterior cervical plate fixation is a common surgical treatment for cervical spine trauma, disc herniation, or cervical spondylosis. Esophageal perforation following anterior cervical plate fixation is a rare but serious complication. Management of esophageal perforation is controversial; however, we suggest treating most cases surgically because this condition is slow to heal and often fatal. We managed 2 cases of esophageal perforation following anterior cervical plate fixation by flap reconstruction with the pectoralis major muscle in one case and a jejunal free flap in the other. Here, we report our experience and review the surgical indications.
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http://dx.doi.org/10.18926/AMO/56462DOI Listing
February 2019

[Forefront of perioperative team medicine for esophageal cancer surgery].

Nihon Shokakibyo Gakkai Zasshi 2019;116(2):138-144

Department of Gastroenterological Surgery, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences.

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http://dx.doi.org/10.11405/nisshoshi.116.138DOI Listing
June 2019

A Novel Combination Cancer Therapy with Iron Chelator Targeting Cancer Stem Cells via Suppressing Stemness.

Cancers (Basel) 2019 Feb 3;11(2). Epub 2019 Feb 3.

Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan (Y.K.).

Excess iron causes cancer and is thought to be related to carcinogenesis and cancer progression including stemness, but the details remain unclear. Here, we hypothesized that stemness in cancer is related to iron metabolism and that regulating iron metabolism in cancer stem cells (CSCs) may be a novel therapy. In this study, we used murine induced pluripotent stem cells that expressed specific stem cell genes such as , , , , and , and two human cancer cell lines with similar stem cell gene expression. Deferasirox, an orally available iron chelator, suppressed expression of stemness markers and spherogenesis of cells with high stemness status in vitro. Combination therapy had a marked antitumor effect compared with deferasirox or cisplatin alone. Iron metabolism appears important for maintenance of stemness in CSCs. An iron chelator combined with chemotherapy may be a novel approach via suppressing stemness for CSC targeted therapy.
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http://dx.doi.org/10.3390/cancers11020177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6406536PMC
February 2019

Multicenter retrospective study to evaluate the efficacy and safety of the double-flap technique as antireflux esophagogastrostomy after proximal gastrectomy (rD-FLAP Study).

Ann Gastroenterol Surg 2019 Jan 11;3(1):96-103. Epub 2018 Oct 11.

Department of Gastroenterological Surgery Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama Japan.

Aim: As a result of the difficulty in effective prevention of gastroesophageal reflux, no standard reconstruction procedure after proximal gastrectomy (PG) has yet been established. The double-flap technique (DFT), or Kamikawa procedure, is an antireflux reconstruction procedure in esophagogastrostomy. The efficacy of DFT has recently been reported in several studies. However, these were all single-center studies with a limited number of cases.

Methods: We conducted a multicenter retrospective study in which patients who underwent DFT, irrespective of disease type and reconstruction approach, at each participating institution between 1996 and 2015 were registered. Primary endpoint was incidence of reflux esophagitis at 1-year after surgery, and secondary endpoint was incidence of anastomosis-related complications.

Results: Of 546 patients who were eligible for this study, 464 patients who had endoscopic examination at 1-year follow up were evaluated for reflux esophagitis. Incidence of reflux esophagitis of all grades was 10.6% and that of grade B or higher was 6.0%. Male gender and anastomosis located in the mediastinum/intra-thorax were independent risk factors for grade B or higher reflux esophagitis (odds ratio [OR]: 4.21, 95% confidence interval [CI]: 1.44-10.9, =0.0109). Total incidence of anastomosis-related complications was 7.2%, including leakage in 1.5%, strictures in 5.5% and bleeding in 0.6% of cases. Laparoscopic reconstruction was the only independent risk factor for anastomosis-related complications (OR: 3.93, 95% CI: 1.93-7.80, =0.0003).

Conclusion: Double-flap technique might be a feasible option after PG for effective prevention of reflux, although anastomotic stricture is a complication that must be well-prepared for.
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http://dx.doi.org/10.1002/ags3.12216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6345660PMC
January 2019

Cancer-associated fibroblasts (CAFs) promote the lymph node metastasis of esophageal squamous cell carcinoma.

Int J Cancer 2019 02 3;144(4):828-840. Epub 2018 Dec 3.

Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.

Lymph node metastasis is a pathognomonic feature of spreading tumors, and overcoming metastasis is a challenge in attaining more favorable clinical outcomes. Esophageal cancer is an aggressive tumor for which lymph node metastasis is a strong poor prognostic factor, and the tumor microenvironment (TME), and cancer-associated fibroblasts (CAFs) in particular, has been implicated in esophageal cancer progression. CAFs play a central role in the TME and have been reported to provide suitable conditions for the progression of esophageal cancer, similar to their role in other malignancies. However, little is known concerning the relevance of CAFs to the lymph node metastasis of esophageal cancer. Here, we used clinical samples of esophageal cancer to reveal that CAFs promote lymph node metastasis and subsequently verified the intercellular relationships in vitro and in vivo using an orthotopic metastatic mouse model. In the analysis of clinical samples, FAP CAFs were strongly associated with lymph node metastasis rather than with other prognostic factors. Furthermore, CAFs affected the ability of esophageal cancer cells to acquire metastatic phenotypes in vitro; this finding was confirmed by data from an in vivo orthotopic metastatic mouse model showing that the number of lymph node metastases increased upon injection of cocultured cancer cells and CAFs. In summary, we verified in vitro and in vivo that the accumulation of CAFs enhances the lymph node metastasis of ESCC. Our data suggest that CAF targeted therapy can reduce lymph node metastasis and improve the prognosis of patients with esophageal cancer in the future.
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http://dx.doi.org/10.1002/ijc.31953DOI Listing
February 2019

[The Elucidation of Tumor Immunosuppression Affected by Cancer-Associated Fibroblasts].

Gan To Kagaku Ryoho 2018 Sep;45(9):1279-1281

Dept. of Gastroenterological Surgery, Okayama University Graduate School of Medicine and Dentistry and Pharmaceutical Sciences.

Development of immunotherapy, especially checkpoint inhibitors, dramatically improved the prognosis of some malignancies. However, problems on the occurrence of severe adverse effects and limited responses to these checkpoint inhibitors remain. Recently, tumor infiltrating lymphocytes(TILs)are the predictive markers of immunotherapies based on clinical evidence. The proportion of cytotoxic T cells in the tumor has been reported to affect the antitumor effect. TILs in the tumor are thought to be controlled by the interaction between cancer and tumor microenvironment. As a cause of tumor immunosuppression, cancer-associated fibroblasts(CAFs)play the main role in the tumor microenvironment. We considered the strong involvement of tumor microenvironment, particularly the role of CAFs, and reported the interaction between CAFs and proliferation, invasion, angiogenesis, and resistance in the conventional therapy. The correlation between CAFs and tumor immunity and the immunosuppression promoted by CAFs were also evaluated. Their effects will be reported in our future studies.
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September 2018

New oral hygiene care regimen reduces postoperative oral bacteria count and number of days with elevated fever in ICU patients with esophageal cancer.

J Oral Sci 2018 Dec 30;60(4):536-543. Epub 2018 Aug 30.

Department of Preventive Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences.

Using a controlled pre/post study design, we investigated the effects of professional mechanical cleaning of the oral cavity with benzethonium chloride, interdental brushes, and hydrogen peroxide on the number of oral bacteria and postoperative complications among esophageal cancer patients in an intensive care unit. Before surgery, 44 patients with esophageal cancer were recruited at Okayama Hospital from January through August 2015. The control group (n = 23) received routine oral hygiene care in the intensive care unit. The intervention group (n = 21) received intensive interdental cleaning with benzethonium chloride solution and tongue cleaning with hydrogen peroxide. The number of oral bacteria on the tongue surface and plaque index were significantly lower in the intervention group than in the control group on postoperative days 1 and 2 (P < 0.05). Additionally, the number of days with elevated fever during a 1-week period was significantly lower in the intervention group than in the control group (P = 0.037). As compared with routine oral hygiene, a new oral hygiene regimen comprising benzethonium chloride, interdental brushes, and hydrogen peroxide significantly reduced the number of oral bacteria and days with elevated fever in patients with esophageal cancer.
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http://dx.doi.org/10.2334/josnusd.17-0381DOI Listing
December 2018
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