Metformin suppresses esophageal cancer progression through the radiation­induced cellular senescence of cancer­associated fibroblasts.

Senescent cells are known to secrete proteins, including inflammatory cytokines and damage­associated molecular patterns. This phenomenon is known as the senescence­associated secretory phenotype (SASP). SASP in cancer stromal fibroblasts is involved in cancer growth and progression. Conversely, metformin, an antidiabetic drug, has been reported to inhibit SASP induction by inhibiting the activation of NF­κB, a regulator of SASP. To date, at least to the best of our knowledge, there have been no reports regarding cellular senescence in fibroblasts and tumor progression via the SASP­mediated paracrine pathway. The present study thus aimed to elucidate the induction mechanisms of SASP in radiation­induced fibroblasts and to determine its effects on cancer progression via the paracrine pathway. Furthermore, the present study aimed to determine whether controlling SASP using metformin suppresses cancer progression. A well­differentiated esophageal cancer cell line established by the authors' department and fibroblasts isolated and cultured from the non­cancerous esophageal mucosa of resected esophageal cancer cases were used for the experiments. Fibroblasts were irradiated with 8 Gy radiation, and the changes in the expression of the senescence markers, SA­ß­gal, p21, p16 and NF­κB were evaluated using immunofluorescent staining and western blot analysis in the presence or absence of metformin treatment. The culture supernatants of irradiated fibroblasts treated with metformin and those treated without metformin were collected and added to the cancer cells to evaluate their proliferative, invasive and migratory abilities. Vimentin and E­cadherin expression levels were also evaluated using immunofluorescent staining and western blot analysis. The expression levels of p16, p21 and NF­κB in irradiated fibroblasts were attenuated by treatment with metformin. Supernatants collected from irradiated fibroblasts exhibited the proliferative activity of esophageal cancer cells, and the promotion of migratory and invasion abilities, which may be due to epithelial­mesenchymal transition and changes in cell morphology. These reactions were confirmed to be suppressed by the addition of the supernatant of cultured fibroblasts pre­treated with metformin. On the whole, the present study demonstrates that fibroblasts in the cancer stroma may be involved in tumor progression through cellular senescence.

Noninferiority of additional gastrectomy after endoscopic submucosal dissection compared with surgery alone on long-term prognosis: a propensity score matching analysis.

BACKGROUND: Patients in whom endoscopic submucosal dissection (ESD) has resulted in noncurative resection need further surgical treatment. However, the oncologic outcome of additional gastrectomy after ESD compared with surgery alone remains unclear. METHODS: The clinical data of 778 patients who underwent gastrectomy for early gastric cancer (EGC) from January 2008 to December 2019 in Ishikawa Prefectural Central Hospital were retrospectively analyzed. Of these 778 patients, 187 underwent additional gastrectomy after ESD [ESD (+) group] and 591 underwent surgery alone [ESD (-) group]. We compared the overall survival and disease-free survival between the ESD (+) and ESD (-) groups, using propensity score matching (PSM) to adjust for baseline characteristics. We also assessed early postoperative outcomes. RESULTS: After PSM based on sex (male or female), age, tumor diameter, tumor gross type, and operative procedure, each group comprised 144 patients with no significant differences in clinical background characteristics. After matching, the 5-year overall survival rate in the ESD (+) and ESD (-) group was 90.9% and 87.8%, respectively, with no significant difference (P = .470). In addition, there was no significant difference in the disease-free survival rate (97.6% vs 95.8%, respectively; P = .504). The postoperative complication rate was similar in both groups. CONCLUSION: Additional gastrectomy for patients in whom ESD resulted in noncurative resection did not adversely affect the long-term prognosis. Additional gastrectomy after ESD is oncologically acceptable for EGC.

Importance of duodenal stump reinforcement to prevent stump leakage after gastrectomy: a large-scale multicenter retrospective study (KSCC DELICATE study).

BACKGROUND: The significance of reinforcement of the duodenal stump with seromuscular sutures and the effectiveness of reinforced staplers in preventing duodenal stump leakage remain unclear. We aimed to explore the importance of duodenal stump reinforcement and determine the optimal reinforcement method for preventing duodenal stump leakage. METHODS: This retrospective cohort study was conducted between January 1, 2012 and December 31, 2021, with data analyzed between December 1, 2022 and September 30, 2023. This multicenter study across 57 institutes in Japan included 16,475 patients with gastric cancer who underwent radical gastrectomies. Elective open or minimally invasive (laparoscopic or robotic) gastrectomy was performed in patients with gastric cancer. RESULTS: Duodenal stump leakage occurred in 153 (0.93%) of 16,475 patients. The proportions of males, patients aged ≥ 75 years, and ≥ pN1 were higher in patients with duodenal stump leakage than in those without duodenal stump leakage. The incidence of duodenal stump leakage was significantly lower in the group treated with reinforcement by seromuscular sutures or using reinforced stapler than in the group without reinforcement (0.72% vs. 1.19%, p = 0.002). Duodenal stump leakage incidence was also significantly lower in high-volume institutions than in low-volume institutions (0.70% vs. 1.65%, p = 0.047). The rate of duodenal stump leakage-related mortality was 7.8% (12/153). In the multivariate analysis, preoperative asthma and duodenal invasion were identified as independent preoperative risk factors for duodenal stump leakage-related mortality. CONCLUSIONS: The duodenal stump should be reinforced to prevent duodenal stump leakage after radical gastrectomy in patients with gastric cancer.

A de novo nonsense variant in the DMD gene associated with X-linked dystrophin-deficient muscular dystrophy in a cat.

BACKGROUND: X-linked dystrophin-deficient muscular dystrophy (MD) is a form of MD caused by variants in the DMD gene. It is a fatal disease characterized by progressive weakness and degeneration of skeletal muscles. HYPOTHESIS/OBJECTIVES: Identify deleterious genetic variants in DMD by whole-genome sequencing (WGS) using a next-generation sequencer. ANIMALS: One MD-affected cat, its parents, and 354 cats from a breeding colony. METHODS: We compared the WGS data of the affected cat with data available in the National Center for Biotechnology Information database and searched for candidate high-impact variants by in silico analyses. Next, we confirmed the candidate variants by Sanger sequencing using samples from the parents and cats from the breeding colony. We used 2 genome assemblies, the standard felCat9 (from an Abyssinian cat) and the novel AnAms1.0 (from an American Shorthair cat), to evaluate genome assembly differences. RESULTS: We found 2 novel high-impact variants: a 1-bp deletion in felCat9 and an identical nonsense variant in felCat9 and AnAms1.0. Whole genome and Sanger sequencing validation showed that the deletion in felCat9 was a false positive because of misassembly. Among the 357 cats, the nonsense variant was only found in the affected cat, which indicated it was a de novo variant. CONCLUSION AND CLINICAL IMPORTANCE: We identified a de novo variant in the affected cat and next-generation sequencing-based genotyping of the whole DMD gene was determined to be necessary for affected cats because the parents of the affected cat did not have the risk variant.

Impact of Arteriosclerosis on Reconstruction-related Complications After Esophagectomy and Usefulness of Tailor-made Reconstruction Technique.

BACKGROUND/AIM: Anastomotic leakage is one of the most common and serious postoperative complications following esophagectomy. This study analyzed the effect of risk factors, such as the degree of arteriosclerosis, comorbidities, and patient characteristics on the incidence of reconstruction-related complications including anastomotic leakage. Furthermore, the usefulness of tailor-made reconstruction methods was clarified using wide gastric conduit. PATIENTS AND METHODS: Patients who underwent esophagectomy with a gastric conduit for esophageal cancer between 2011 and 2018 were enrolled. In the initial group that underwent esophagectomy between August 2011 and February 2016, gastrointestinal reconstruction was performed using a narrow gastric conduit. In the latter group, reconstruction using subtotal gastric conduit was selected for high-risk patients between March 2016 and March 2018. Postoperative complications including reconstruction-related complications were assessed. RESULTS: The occurrence of anastomotic leakage was significantly associated with the patient's risk in the initial group. The rates of anastomotic leakage and reconstruction-related complications were significantly lower in the latter group than in the initial group (3.2% vs. 23.0%, p=0.001; 27.0% vs. 44.3%, p=0.044). The incidence of all complications was significantly lower in the latter group than in the initial group (28.6% vs. 59.0%, p=0.001). The change in bodyweight loss one year after the operation was significantly lower in the latter group than in the initial group (p=0.042). CONCLUSION: Tailor-made reconstruction using wide gastric conduit for high-risk cases of esophageal cancer could reduce the occurrence of anastomotic leakage and promote a better quality of life after surgery.

Multidisciplinary treatment of advanced cervical esophageal adenocarcinoma derived from a gastric inlet patch: A case report.

A gastric inlet patch (GIP) is an ectopic gastric mucosal lesion usually arising at the cervical esophagus that may rarely cause esophageal adenocarcinoma (EAC). To the best of our knowledge, this is the first case of a GIP-derived EAC that was successfully treated using a multidisciplinary treatment approach. A 64-year-old man was referred to the Department of Gastrointestinal Surgery, Kanazawa University Hospital (Kanazawa, Japan) for surgical treatment of refractory recurrent cervical EAC derived from GIP who had previously been treated with induction chemotherapy, definitive chemoradiotherapy and photodynamic therapy (PDT). Esophagogastroduodenoscopy revealed a stenotic tumor at the GIP site in the cervical esophagus and submucosal tumors with suspected multiple intramural metastases in the anal side of the thoracic esophagus. The patient underwent robot-assisted thoracoscopic esophagectomy with laryngopharyngectomy and cervical lymphadenectomy as radical salvage surgery 4 months after the last PDT procedure. After postoperative adjuvant chemotherapy using oral administration of tegafur/gimeracil/oteracil (oral 5-fluorouracil prodrug) for 1 year; at present, the patient is alive without recurrence 3 years after the operation.

Surgical Approach to the Upper Side of the Gastrosplenic Ligament During Laparoscopic Total Gastrectomy for Proximal Gastric Cancer: Operative Techniques and Initial Results.

Background: Laparoscopic gastrectomy for gastric cancer has become widespread as minimally invasive surgical treatment, but use of laparoscopic total gastrectomy (LTG) remains limited because of the technical difficulty and complexity of lymphadenectomy at the splenic hilum. Surgical techniques and initial experiences with the surgical approach to the upper side of the gastrosplenic ligament during LTG are introduced. Materials and Methods: Between January 2019 and December 2022, 57 patients with proximal gastric cancer underwent LTG using this approach. Results: Regarding the extent of lymphadenectomy, D1+, D2, spleen-preserving D2 + 10, and D2 + 10 with splenectomy were performed in 31, 18, 4, and 4 patients, respectively. Operative time was 341 (192-724) minutes, and estimated blood loss was 30 (0-515) g. There were no conversions to laparotomy and no postoperative complications of Clavien-Dindo grade ≥III. Conclusions: The present procedure is safe and feasible and provides an excellent operative view at the splenic hilum, making it easier to determine exactly the extent of lymphadenectomy in accordance with cancer progression.

Successful treatment of nonocclusive mesenteric ischemia in a reconstructed jejunum after esophagectomy and remnant gastric tube resection: a case report.

BACKGROUND: Nonocclusive mesenteric ischemia (NOMI), an ischemic bowel disease without a disruption of the mesenteric blood flow or strangulation of the mesentery or intestine, may cause a lethal clinical course. We report a very rare case of jejunal necrosis caused by NOMI in the pedicled mesentery of the reconstructed jejunum after remnant gastric tube resection for heterochronous gastric tube cancer after esophagectomy. CASE PRESENTATION: An 80-year-old man visited our department with chief complaints of fever and appetite loss after 4 months from gastric tube resection and digestive reconstruction with pedicled jejunum. Contrast-enhanced computed tomography (CT) revealed impaired blood flow without torsion of the mesentery, severe wall thickness, and micro-penetration in the reconstructed jejunum and combined pyothorax in the right thoracic cavity. Esophagogastroduodenoscopy demonstrated extensive mucosal necrosis confined to the jejunum, which was elevated in the thoracic cavity. The jejunal necrosis due to NOMI occurring in the reconstructed jejunum was suspected, and lifesaving small bowel resection with right thoracotomy was considered necessary. However, radical operation with right thoracotomy was considered to be excessively invasive and not valid due to the patient's poor physical status, advanced age, and presence of left adrenal metastasis from the remnant gastric cancer. Therefore, we selected the conservative treatment with fasting, transnasal drainage, and administration of antibiotics due to the patient's intention. CT-guided right thoracic drainage for the intrathoracic abscess was needed 10 days after starting treatment and the inflammatory response rapidly improved. Follow-up CT and esophagogastroduodenoscopy revealed the improvement in the ischemic changes in jejunal mucosa without perforation. Intake was initiated at 20 days after symptom onset, and the patient was discharged at 40 hospital days without any complications and sequelae. CONCLUSIONS: To the best of our knowledge, this is the first case of NOMI occurring in the reconstructed jejunum after remnant gastric tube resection that was successfully treated with a conservative treatment. For NOMI, it is important to make appropriate diagnosis based on imaging findings and perform proper assessment of the patient's condition. Conservative treatments may be also useful depending on the patient's condition.

Impact of preoperative docetaxel, cisplatin, and 5-fluorouracil (DCF) therapy on degree of malignant esophageal stenosis.

BACKGROUND: Malignant esophageal stenosis is a common and severe complication of advanced esophageal cancer that can be a serious problem in the continuation of chemotherapy and other anticancer treatments. The impact of chemotherapy regimens on the degree of improvement in esophageal stenosis is unknown. In this study, we focused on the impacts of chemotherapy on the direct anticancer effects, and in the improvement of malignant stenosis. METHODS: Patients who underwent radical esophagectomy after chemotherapy, either adjuvant 5-fluorouracil and cisplatin (FP) or docetaxel, cisplatin, and 5-fluorouracil (DCF) regimen, were included. We assessed the length of the cancerous stenosis, the width of the narrowest segment, and the size of the intraluminal area in the stenotic segment by fluoroscopy, and compared the differences before and after chemotherapy. In addition, we evaluated the dysphagia score (Mellow-Pinkas scoring system) as the evaluation of patients' symptoms. The antitumor effects of chemotherapy were also investigated. RESULTS: A total of 81 patients were enrolled: 50 were treated with FP, and 31 were treated with DCF. The expansion rate in the length of the narrowest part was significantly increased in the DCF group compared with the FP group. Furthermore, the stenosis index (intraluminal stenotic area/stenotic length) was significantly increased in the DCF group compared with the FP group (112% vs 96%, P = 0.038). Dysphagia score after chemotherapy significantly improved in the DCF group compared to the FP group (P = 0.007). The response rates were 60% in the FP group and 67.7% in the DCF group. Effective histopathological response (improvement to grade 2 or 3) was 24% in the FP group and 38.8% in the DCF group. CONCLUSION: DCF therapy is more effective than FP treatment in the improvement of malignant esophageal stenosis.

Analysis of factors associated with operative difficulty in thoracoscopic esophageal cancer surgery in the left-decubitus position: a single-center retrospective study.

BACKGROUND: The degree of difficulty in the overall procedure and forceps handling encountered by surgeons is greatly influenced by the positional relationship of intrathoracic organs in minimally invasive esophagectomy. This study aimed to identify the anatomical factors associated with the difficulty of minimally invasive esophagectomy assessed by intraoperative injuries and postoperative outcomes. METHODS: Minimally invasive esophagectomy in the left-decubitus position was performed in 258 patients. We defined α (mm) as the anteroposterior distance between the front of the vertebral body and aorta, ß (mm) as the distance between the center of the vertebral body and center of the aorta, and γ (degree) as the angle formed at surgeon's right-hand port site by insertion of lines from the front of aorta and from the front of vertebrae in the computed tomography slice at the operator's right-hand forceps hole level. We retrospectively analyzed the correlations among clinico-anatomical factors, surgeon- or assistant-caused intraoperative organ injuries, and postoperative complications. RESULTS: Intraoperative injuries significantly correlated with shorter α (0.2 vs. 3.9), longer ß (33.0 vs. 30.5), smaller γ (3.0 vs. 4.3), R1 resection (18.5% vs. 8.3%), and the presence of intrathoracic adhesion (46% vs. 26%) compared with the non-injured group. Division of the median values into two groups showed that shorter α and smaller γ were significantly associated with organ injury. Longer ß was significantly associated with postoperative tachycardia onset, respiratory complications, and mediastinal recurrence. Furthermore, the occurrence of intraoperative injuries was significantly associated with the onset of postoperative pulmonary complications. CONCLUSIONS: Intrathoracic anatomical features greatly affected the procedural difficulty of minimally invasive esophagectomy, suggesting that preoperative computed tomography simulation and appropriate port settings may improve surgical outcomes.

Using LAP PROTECTOR™ to prevent subcutaneous emphysema after robotic gastrectomy.

Subcutaneous emphysema (SE), a complication of robotic gastrectomy (RG), occurs when the gas used to establish pneumoperitoneum escapes and enters the soft tissue. SE typically does not result in major clinical problems, but massive SE can have life-threatening consequences. Hence, developing adequate preventive methods against postoperative SE is essential. We aimed to determine whether an existing protective device, the LAP PROTECTOR™ (LP), can be used to reduce the incidence of SE after RG. We analyzed the data of 194 patients who underwent RG at our hospital between August 2016 and December 2022. Since September 2021 (the 102nd patient), we have used the LP (FF0504; Hakko Medical, Hongo, Tokyo, Japan) at the trocar site, as this was expected to reduce the incidence of SE. The primary endpoint of this study was the efficacy of the LP in reducing the incidence of clinically relevant SE (defined as SE extending into the cervical area) a day after RG. Univariate analysis revealed that sex, body mass index (BMI), and LP usage differed significantly between patients with and without postoperative SE. Logistic regression analysis revealed that male sex (odds ratio [OR]: 0.22, 95% confidence interval [CI]: 0.15-0.72, P < 0.001), high BMI (OR: 0.13, 95% CI: 1.23-4.45, P = 0.009), and LP usage (OR: 0.11, 95% CI: 0.04-0.3, P < 0.001) were preventive factors independently associated with a lower incidence of clinically relevant SE. Placing an LP at the trocar site may be a safe and effective method of preventing SE after RG.

Pancreatic thickness as a predictor of postoperative pancreatic fistula after laparoscopic or robotic gastrectomy.

BACKGROUND: Despite technical advances in minimally invasive gastrectomy for gastric cancer, an increased incidence of postoperative pancreatic fistula (POPF) has been reported. POPF can cause infectious and bleeding complications, which could lead to surgery-related death; therefore, reduction of the post-gastrectomy POPF risk is crucial. This study aimed to investigate the importance of pancreatic anatomy as a predictor of POPF in patients undergoing laparoscopic or robotic gastrectomy. METHODS: Data were collected from 331 consecutive patients who underwent laparoscopic or robotic gastrectomy for gastric cancer. The thickness of the pancreas anterior to the most ventral level of the splenic artery (TPS) was measured. The correlation between TPS and POPF incidence was investigated using univariate and multivariate analyses. RESULTS: The cutoff value of TPS was 11.8 mm, which predicted a high drain amylase concentration on postoperative day 1, and patients were categorized into thin (Tn group) and thick TPS groups (Tk group). There was no significant difference in the background characteristics between the two groups, except for sex (P = 0.009) and body mass index (P < 0.001). The incidences of POPF grade B or higher (2% vs. 16%, P < 0.001), all postoperative complications of grade II or higher (12% vs. 28%, P = 0.004), and postoperative intra-abdominal infections of grade II or higher (4% vs. 17%, P = 0.001) were significantly higher in the Tk group. Multivariable analysis identified that high TPS was the only independent risk factor for grade B or higher POPF and grade II or higher postoperative intra-abdominal infectious complications. CONCLUSIONS: The TPS is a specific predictive factor for POPF and postoperative intra-abdominal infectious complications in patients undergoing laparoscopic or robotic gastrectomy. Careful pancreatic manipulation during suprapancreatic lymphadenectomy is necessary for patients with increased TPS (> 11.8 mm) to avoid postoperative complications.

Robot-assisted distal gastrectomy for duodenal gastrointestinal stromal tumors adhering to the pancreas: a case report.

Duodenal gastrointestinal stromal tumors (D-GISTs) are uncommon and account for 3-5% of all GISTs. Currently, no established surgical strategy for D-GISTs exists, which mostly depends on tumor size, relation to the ampulla and invasion of the adjacent organ. We report a case of large D-GIST resected by robotic distal gastrectomy. A 62-year-old woman was diagnosed with a 5-cm D-GIST located at posterior wall of the duodenal bulb. Computed tomography findings indicated possible tumor invasion of the pancreas head. Robot-assisted distal gastrectomy was firstly planned and pancreatoduodenectomy was also considered when the tumor was invading to the pancreas. Although tumor was tightly adherent to the pancreas, it could be dissected from the pancreatic head without capsule damage and resected by robotic distal gastrectomy with no postoperative complication. The large D-GIST tightly adherent to the pancreas could be resected by efficiency of the robotic surgery.

Adipocytes contribute to tumor progression and invasion of peritoneal metastasis by interacting with gastric cancer cells as cancer associated fibroblasts.

BACKGROUND: Peritoneal metastasis (PM) is one of the most common causes of noncurative surgery and the most frequent recurrence pattern in gastric cancer (GC). During the process of PM, GC cells detached from primary tumor interact with human peritoneal mesothelial cells (HPMC) overlapped with adipose tissues such as the omentum or mesentery. Although the interaction with HPMC promotes the malignancy of GC, the role of adipose tissues remains unclear. AIMS: We aimed to clarify how adipose tissue are affected by adjacent primary tumors during the expression of adipokines and to elucidate whether GC cells transform adipocytes into CAFs in vitro. In addition, we investigated whether GC cells are affected by adipocytes in their ability to infiltrate. METHODS: We investigated the phenotypic conversion of adipocytes during the malignant process of GC cells in vivo and in vitro. We evaluated the expression levels of adiponectin in the omental adipose tissue of gastric cancer patients by western blotting. Following adipocytes/gastric cancer cells coculture, adipocyte markers, adiponectin receptors, and inflammatory cytokine markers were detected by real-time PCR and/or western blotting in the single-cultured and co-cultured adipocytes; cancer-associated fibroblast (CAF) markers were detected by immunofluorescence and western blotting in the single-cultured and co-cultured adipocytes; invasion assays were performed in single cultured and co-cultured MKN45 and OCUM. RESULTS: In omental adipose tissues that are situated close to the primary tumors, the expression of adiponectin tended to decrease in patients with subserosal or serosal invasion. By co-culturing with GC cells, adipocytes were dedifferentiated and the expression levels of CAF marker FSP1 and inflammatory cytokines, PAI-1 and IL-6, significantly increased (p < 0.05). Furthermore, GC cells co-cultured with adipocytes showed enhanced invasion ability. CONCLUSION: Our findings suggest that the phenotypic conversion of adipocytes may promote the malignancy of GC in the construction of the cancer microenvironment of PM.

Hypoxia-Induced CD36 Expression in Gastric Cancer Cells Promotes Peritoneal Metastasis via Fatty Acid Uptake.

BACKGROUND: The lipid scavenger receptor cluster of differentiation 36 (CD36) has been shown to have a pro-metastatic function in several cancers. Adipose tissue, a favorable site for peritoneal metastasis (PM) from gastric cancer (GC), promotes this process by providing free fatty acids (FFAs); however, the role of CD36 in PM progression from GC remains to be elucidated. MATERIALS AND METHODS: We evaluated CD36 expression in the GC cells under various conditions. CD36 overexpressing (CD36OE) MKN45 cells were prepared and their migration and invasive properties were assessed. A PM mouse model was used to investigate the biological effects of palmitic acid (PA) and CD36. Furthermore, we examined the clinical role of CD36 expression in 82 human PM samples by immunohistochemical staining. RESULTS: Hypoxia markedly increased CD36 expression in GC cells. In normoxia, only CD36OE MKN45 cells treated with PA showed an increase in migration and invasion abilities. An increased expression of active Rac1 and Cdc42 was observed, which decreased following etomoxir treatment. Conversely, hypoxia increased those capacities of both vector and CD36OE MKN45 cells. In a mouse model transplanted with CD36OE MKN45 cells, more peritoneal tumors were observed in the high-fat diet group than those in the normal diet group. In clinical samples, 80% of PM lesions expressed CD36, consistent with hypoxic regions, indicating a significant association with prognosis. CONCLUSION: Our findings indicate that a hypoxia in the peritoneal cavity induces CD36 expression in GC cells, which contributes to PM through the uptake of FFAs.

Prognostic value of tumor-infiltrating CD163+macrophage in patients with metastatic gastric cancer undergoing multidisciplinary treatment.

BACKGROUND: The multidisciplinary treatment including induction chemotherapy plus conversion surgery (CS) has attracted attention as a new strategy to improve the outcome of metastatic gastric cancer (MGC). However, it is unclear which patients achieve a good response to chemotherapy and successful CS. Tumor-infiltrating immune cells (TIICs) have been reported to be both prognostic and predictive biomarkers not only in immunotherapy but also in chemotherapy in many cancer types. However, there have been no reports on the usefulness of TIICs as biomarkers in conversion surgery for MGC. The aim of the present study was to evaluate the association between the TIICs and treatment outcome for the multidisciplinary treatment in MGC. METHODS: We retrospectively analyzed 68 MGC patients who received docetaxel plus cisplatin plus S-1 (DCS) therapy between April 2006 and March 2019 in our institute. The number of tumor-infiltrating CD4+, CD8+, Foxp3+lymphocytes, CD68+, CD163+macrophages in pre-treatment endoscopic biopsy samples were evaluated to investigate their predictive value for multidisciplinary treatment. RESULTS: Fifty patients underwent CS following DCS therapy (CS group), whereas 18 patients underwent DCS therapy alone (non-CS group). The median survival time (MST) of CS group was 33.3 months, which was significantly longer than the MST of 9.0 months in non-CS group (p < 0.01). The number of CD163+macrophages was extracted as an independent prognostic factor for overall survival in all patients. There were more cases of high infiltration of CD163+macrophages in non-CS group than in CS group. Furthermore, in CS group, pathological responders to DCS therapy showed low infiltration of CD163+ macrophages, and high infiltration of CD8+lymphocyte. CD163 low group showed a significant prolonged survival compared with CD163 high group in patients who underwent CS (p = 0.02). CONCLUSIONS: The pre-treatment CD163+macrophages infiltration would be a pivotal biomarker for predicting prognosis and pathological response to multidisciplinary treatment among TIICs in MGC. Thus, for patients with low CD163+macrophage infiltration in pre-treatment biopsy sample, diagnostic imaging should be performed frequently during chemotherapy to avoid missing the optimal timing for CS, and CS should be aggressively considered as a treatment option if curative resection is deemed feasible.

Usefulness of Prophylactic Administration of Pegfilgrastim for Esophageal Cancer Chemotherapy: A Single-center Retrospective Study.

BACKGROUND/AIM: To evaluate the impact of prophylactic administration of pegfilgrastim in esophageal cancer (EC) patients treated with chemotherapy consisted of docetaxel, cisplatin, and fluorouracil (DCF). PATIENTS AND METHODS: Among 102 patients who received neoadjuvant or induction DCF for primary advanced EC, 65 received prophylactic pegfilgrastim and 37 did not. The association of pegfilgrastim with adverse events and clinicopathological outcomes was retrospectively analyzed. RESULTS: In the pegfilgrastim group, the incidence of grade >3 neutropenia was lower (30.8% vs. 62.2%) and more patients avoided dose reduction or discontinuation of chemotherapy (32.3% vs. 70.3%). The radiological (PR≤) and histopathological (grade 1b≤) response rates were significantly higher (69.2% vs. 43.2% and 59.2% vs. 35.7%). Three-year overall survival and progression-free survival rates were significantly higher (65.0% vs. 48.6%, p=0.033; 56.1% vs. 35.1%, p=0.007, respectively). CONCLUSION: Prophylactic pegfilgrastim in DCF may relieve adverse events and improve the oncologic outcome of EC patients.

Robot-assisted transhiatal lower esophagectomy and proximal gastrectomy for Siewert type II advanced esophagogastric junction cancer with situs inversus totalis: a case report.

BACKGROUND: Situs inversus totalis (SIT) is a rare congenital abnormality in which the thoracic and abdominal organs are reversed or mirrored from their usual positions. We herein report the first case of robot-assisted transhiatal lower esophagectomy and proximal gastrectomy with esophagogastrostomy for treatment of Siewert type II advanced esophagogastric junction (EGJ) cancer with SIT. CASE PRESENTATION: A 62-year-old man with SIT and intestinal malrotation was diagnosed with T3N0M0 Stage IIA EGJ cancer. Three-dimensional reconstruction of a computed tomography angiogram showed that the common hepatic artery was absent, the proper hepatic artery was derived from the superior mesenteric artery through the gastroduodenal artery, and an accessary left hepatic artery arose from the left gastric artery. The patient underwent robot-assisted transhiatal lower esophagectomy and proximal gastrectomy with D2 lymph node dissection, including lower mediastinal lymphadenectomy. Intraoperative examination revealed minor vascular abnormalities, including three branches of the left gastric artery and two left gastric veins, that had not been recognized preoperatively. The surgery was performed safely, and the patient had an uneventful postoperative course. CONCLUSIONS: Robotic-assisted surgery is efficient even for complex conditions, such as Siewert type II advanced EGJ cancer with SIT.