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.

[Three Cases of Preoperative Chemotherapy(FOLFOXIRI plus Bevacizumab)for Locally Advanced Colorectal Cancer with Urinary Bladder Invasion].

Radical cystectomy for locally advanced colorectal cancer with urinary bladder invasion significantly reduces the quality of life in exchange for a cure. We performed preoperative chemotherapy with FOLFOXIRI plus bevacizumab for 3 patients with locally advanced colorectal cancer with urinary bladder invasion to avoid radical cystectomy and to achieve local control for urinary bladder preservation. Grade 3 neutropenia was observed in 2 patients as an adverse reaction to the preoperative chemotherapy, but all 3 patients showed good tumor regression. All 3 patients underwent laparoscopic high anterior rectal resection and partial cystectomy, and all were able to undergo R0 resections with urinary bladder preservation. One patient had anastomotic leakage as a postoperative complication. One patient had local recurrence in the urinary bladder, and 2 had recurrence with peritoneal dissemination during their postoperative courses. Preoperative chemotherapy(FOLFOXIRI plus bevacizumab)for locally advanced colorectal cancer with urinary bladder invasion is considered to be a useful treatment option because of its potential for tumor shrinkage and bladder preservation.

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.

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.

Successful closure of refractory esophago-pulmonary fistula after esophagectomy using a vascular embolization plug under endoscopy: A case report.

Esophago-pulmonary fistula after esophagectomy is a fatal complication of severe respiratory distress. Minimally invasive treatments, such as esophageal stent placement, have been developed to treat esophago-pulmonary fistulae; however refractory fistulae may not be cured by this mode of treatment. We encountered a case in which the esophago-pulmonary fistula did not close even though sealing of polyglycolic acid sheets and fibrin glue was administered three times over 4 mo while the esophageal stent was in place. We successfully closed this refractory esophago-pulmonary fistula using a vascular embolization plug under endoscopy. Our procedure can thus be an effective and less invasive treatment for refractory esophago-pulmonary fistula after esophagectomy.

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.

Verification of Resectability Status for Pancreatic Cancer: Radiological and Pathological Analysis of Patients Undergoing Pancreatoduodenectomy With Combined Resection of the Superior Mesenteric Artery.

OBJECTIVES: Resectability status is considered an important indicator for progression of pancreatic cancer. We verified the superior mesenteric artery (SMA) factors of resectability status by radiological and pathological analysis in patients who underwent pancreatoduodenectomy with combined resection of the SMA. METHODS: We enrolled 22 patients who underwent pancreatoduodenectomy with combined resection of the SMA. Patients were divided into 3 groups according to the contact angle between the tumor and the SMA in preoperative computed tomography images (no contact, R-sma; contact within 180 degrees, BR-sma; contact more than 180 degrees, UR-sma). We pathologically evaluated cancer progression toward the SMA. RESULTS: There were 3 patients with R-sma, 12 with BR-sma, and 7 with UR-sma. The median distance (mm) between the cancer and the SMA was 7.0 with R-sma, 1.0 with BR-sma, and 0 with UR-sma (P = 0.0003). Invasion to the superior mesenteric nerve plexus was positive in none with R-sma, 11 with BR-sma, and 7 with UR-sma (P < 0.0001). Invasion to the SMA was positive in none with R-sma and BR-sma, and 7 with UR-sma (P < 0.0001). CONCLUSIONS: Superior mesenteric artery factors of resectability status are reliable indicator for cancer progression toward the SMA.

A case of primary malignant melanoma of the esophagogastric junction with abscopal effect after nivolumab administration.

BACKGROUND: The abscopal effect is a rare phenomenon in which local irradiation causes tumor regression outside the irradiated area. There have been no reports of abscopal effect in patients with gastrointestinal melanoma with metastasis. Here, we report a case of primary malignant melanoma of the esophagogastric junction with abscopal effect after long-term treatment with nivolumab. CASE PRESENTATION: A 75-year-old woman was referred to our hospital with a gastroesophageal lesion. Upper gastrointestinal endoscopy revealed a raised lesion on the posterior wall of the greater curvature of the cardia and tenderness in the lower esophagus. Immunostaining of the tumor biopsy showed positive staining for Melan-A, human melanoma black-45 (HMB45), and S-100, indicating malignant melanoma of the esophagogastric junction. Contrast-enhanced computed tomography (CT) of the abdomen showed a mildly stained lesion protruding into the cardiac part of stomach and enlarged surrounding lymph nodes. The patient was diagnosed with malignant melanoma of the esophagogastric junction and proximal gastrectomy with lower esophagus resection was performed. Histological examination showed large, round tumor cells with nuclear atypia. Immunostaining was positive for Melan A, HMB45, S-100 protein, and SRY-box transcription factor 10, and the final diagnosis was malignant melanoma of the esophagogastric junction, with regional lymph node metastases. Three months after surgery, follow-up CT indicated left pleural metastasis; therefore, the patient was administered nivolumab, an immune checkpoint inhibitor (ICI). Following three courses of nivolumab, the patient exhibited grade 3 renal dysfunction (Common Terminology Criteria for Adverse Events version 5.0). After that, we have not administered nivolumab treatment. Five months after the development of renal dysfunction, a CT scan demonstrated an unstained nodule within the pancreatic, and the patient was diagnosed with pancreatic metastasis; intensity-modulated radiotherapy was performed. Six months later, CT revealed pancreatic nodule and pleural metastasis was shrunk; after an additional 2 months, pleural metastasis and effusion had disappeared. The patient is alive with no additional lesions. CONCLUSIONS: We report a case of primary malignant melanoma of the esophagogastric junction with an abscopal effect following nivolumab treatment. The findings of this case report suggest that ICIs in combination with radiotherapy may be effective for treating metastatic or recurrent malignant melanoma of the gastrointestinal tract.

Gastrointestinal stromal tumor metastasis to the ovary: A case report.

Gastrointestinal stromal tumors are common mesenchymal tumors of the gastrointestinal tract. The major site of metastasis for gastrointestinal stromal tumors is the liver or peritoneum, while metastasis to the ovary is exceptionally rare. A 53-year-old woman visited the hospital for bloating and anorexia and was diagnosed with a huge gastric gastrointestinal stromal tumor and peritoneal metastasis in the pelvis on upper gastrointestinal endoscopy and abdominal enhanced computed tomography. After administration of imatinib, the tumor was significantly reduced, and we performed laparoscopic pelvic tumor resection and open proximal gastrectomy with transverse colectomy. Intraoperatively, the pelvic tumor was found to be an ovarian tumor. Microscopic examination confirmed a gastric gastrointestinal stromal tumor with ovarian metastasis. In conclusion, we experienced a rare case of gastric gastrointestinal stromal tumor with ovarian metastasis. Preoperative administration of imatinib was successful and radical resection was achieved. Although pelvic tumors are difficult to differentiate preoperatively, the possibility of ovarian metastasis from gastrointestinal stromal tumor should be considered.

[A Case of an Asymptomatic Coagulopathy after Peritoneovenous Shunt Placement for Malignant Ascites of Gastric Cancer].

The patient was a 61‒year‒old man who had an advanced gastric cancer with peritoneal dissemination. After chemotherapy, intraoperative findings during a total gastrectomy revealed the disappearance of the dissemination nodules. Although adjuvant chemotherapy was performed, the presence of massive ascites led to the recurrence of the peritoneal dissemination 5 months after the surgery. While the chemotherapy regimen was altered, we observed no reduction in malignant ascites. The patient complained of abdominal distention and was admitted to our hospital for symptom management. We performed a cell‒free and concentrated ascites reinfusion therapy(CART)several times. However, symptom management proved difficult; therefore, the patient underwent a peritoneovenous shunt(Denver shunt)placement. After the shunting, we observed no organ injury and improved abdominal distention; however, an asymptomatic coagulopathy was present in the course. Additionally, blood examinations showed increased FDP‒DD and thrombin‒antithrombin complex(TAT). However, 6 months after the shunting, coagulopathy improved and the patient reported the absence of abdominal distention. This report describes a patient with an asymptomatic coagulopathy after Denver shunt placement and evaluated the clinical course by using TAT values.

[Four Cases of Surgical Treatment for Radiation Enteritis].

Although radiation therapy for pelvic cancer leads to improved outcomes, it may cause radiation enteritis. Radiation enteritis is classified as early and late reaction. Late reaction indicate progressive and irreversible changes caused by ischemic changes of the intestinal mucosa. Severe cases require a surgical treatment, which is challenging because of severe adhesions and a high risk of suture failure. In addition, the postoperative course may be unfavorable in some cases. We performed surgery for 4 radiation enteritis cases; however, the postoperative course was unfavorable in 2 cases because of impaired absorption and ileus of the remaining short bowel. These patients could not eat adequately after discharge; therefore, we needed to explain and make them understand the benefits and disadvantages of radiation therapy.

High CD8/CD33 ratio in peritoneal metastatic lesions is associated with favorable prognosis in gastric cancer.

BACKGROUND: Tumor-infiltrating lymphocytes (TILs) and other immune cells have been reported as a prognostic factor in several tumors, including gastric cancer, and they play an important role in antitumor effect at the primary site. There were few reports on the immune status in peritoneal metastatic lesions for gastric cancer. AIMS: The aims of this study were to assess the prognostic significance of TILs (CD4, CD8, CD19, regulatory T cells [Tregs]), and myeloid-derived suppressor cells (MDSCs) in peritoneal metastatic lesions. METHODS: We retrospectively investigated 60 patients for gastric cancer with peritoneal metastasis who were treated between 2009 and 2016 in our institute. Immunohistochemistry for CD4, CD8, CD19, FOXP3, and CD33 was performed in the peritoneal metastatic lesions. The absolute numbers of immune cells and ratios were evaluated, and the relationship between immune-related marker and overall survival (OS) was investigated. RESULTS: A high infiltration of CD8+ lymphocytes or high CD8/CD33 ratio was a better prognosis for OS in univariate analysis using all immunologic variables (P = .012, P = .001). In multivariate analysis for clinical and immunologic variables, high CD8/CD33 ratio was identified as an independent prognostic factor for OS (Hazard ratio: 0.291, 95% confidence interval: 0.126-0.670, P = .004). CONCLUSION: High CD8/CD33 ratio and high infiltration of CD8+ lymphocytes in peritoneal metastatic lesions were favorable prognoses for gastric cancer patients with peritoneal metastasis. It is necessary to modify the immune microenvironment result to increase the level of CD8+ lymphocytes in the peritoneal metastatic lesions.

A phase I study of preoperative (neoadjuvant) chemotherapy with gemcitabine plus nab-paclitaxel for resectable pancreatic cancer.

Neoadjuvant chemotherapy (NAC) has become a standard treatment for borderline resectable pancreatic ductal adenocarcinoma (PDAC). The present study examined the maximum tolerated dose of NAC with gemcitabine plus nab-paclitaxel (GnP) in patients with resectable PDAC. Between 2015 and 2019, 39 patients with resectable PDAC were enrolled in the present study. GnP was administered for two 28-day cycles on days 1, 8 and 15. The planned doses for levels 1, 2 and 3 were 75, 100 and 125 mg/m2, respectively, for nab-paclitaxel and 600, 800 and 1,000 mg/m2, respectively, for gemcitabine. Dose-limiting toxicity (neutropenia, anemia, thrombocytopenia and/or liver injury) was observed in 44.4% of patients treated at dose level 1 (21 patients) and 60.0% of those treated at dose level 2 (18 patients). Therefore, the maximum tolerated dose was set as level 1. Six patients withdrew from protocol treatment because of non-hematologic adverse events (skin rash, pancreatitis and biliary tract infection). Among the 31 patients with pathologically confirmed PDAC, partial response, stable disease and disease progression were recorded in 4 (12.9%), 24 (77.4%) and 3 (9.7%) patients, respectively. NAC significantly reduced tumor size according to computed tomography, and CA19-9 levels and the 18F-fluorodeoxyglucose maximum standardized uptake value were decreased in positron emission tomography. No postoperative complications attributable to NAC were recognized. Among the 27 patients with PDAC who underwent resection, the pathological treatment effect was judged as grades Ia, Ib and II in 21 (77.8%), 4 (14.8%) and 2 (7.4%) patients, respectively. R0 resection was performed in 24 out of 27 patients (88.9%). Adjuvant chemotherapy with oral S-1 was administered to 21 out of 27 patients (77.8%). In conclusion, NAC with GnP was safe and feasible for resectable PDAC at dose level 1. In the future, verification of the long-term results of the present study will be necessary, and a phase II clinical trial is anticipated.