The combination of the low immunohistochemical expression of peroxiredoxin 4 and perilipin 2 predicts longer survival in pancreatic ductal adenocarcinoma with peroxiredoxin 4 possibly playing a main role.

Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease with poor prognosis. Therefore, indicators that can be used for the early prediction of the prognosis of PDAC are needed. Peroxiredoxin (PRDX) 4 is a secretion-type antioxidant enzyme located in the cytoplasmic endoplasmic reticulum. Recent studies have reported that it is closely related to the development and prognosis of many types of cancer. Perilipin (PLIN) 2 is a lipid droplet coating protein. The high expression of PLIN2 is known to be an indicator of some types of cancer and oxidative stress management. It is highly suggestive of the interplay between PRDX4 and PLIN2 to some degree. In this study, we collected 101 patients' clinical data and paraffin-embedded specimens with PDAC and analyzed them with immunohistochemical staining of PRDX4 and PLIN2. We found that the low expression of PRDX4 predicts longer survival and a better clinical condition in PDAC patients. Moreover, when the low expression of PRDX4 is combined with the low expression of PLIN2, the 3-year survival is significantly improved. Univariate and multivariate Cox proportional hazard analyses showed that the PRDX4 expression in PDAC was an independent prognostic factor for survival. Taken together, between PRDX4 and PLIN2, PRDX4 plays a main role in prognosis and has the potential to become a clinical prognostic indicator of PDAC.

Bleeding Risk Factors after Endoscopic Submucosal Dissection in Early Gastric Cancer and the Necessity of "Second-Look" Endoscopic Examination on the following Day.

BACKGROUND AND AIM: Hemorrhage is often encountered after endoscopic submucosal dissection (ESD). In addition to active bleeding after resection, exposed blood vessels and blood clots without active bleeding on the post-dissection ulcer floor have been recognized within our department. We consider exposed and/or observable vessel findings and clots on the ulcer floor after re-section as important risk factors for hemorrhage. Here, we compared and examined the active bleeding frequency and "post-resection ulcer at risk of bleeding" on the day following ESD, in relation to their risk factors. METHOD: We retrospectively examined 447 patients who underwent second-look endoscopy in our department between August 2008 and March 2018. Logistic regression analyses were performed to determine the hazard ratio and 95% confidence interval. We compared the association of each factor mentioned above with active bleeding on the day after ESD and the presence of ulcers at risk of bleeding after resection. RESULTS: Our retrospective analysis revealed that the risk factors were larger ulcer sizes and the administration of antithrombotic drugs. Additionally, the risk was low for upper body lesions but high for antral lesions. CONCLUSION: Our results may help determine whether second-look endoscopy should be performed to minimize active bleeding after ESD, reduce postoperative complications, and improve medical safety.

nPTD classification: an updated classification of gastric cancer location for function preserving gastrectomy based on physiological lymphatic flow.

BACKGROUND: The correlation between tumor location and lymphatic flow distribution in gastric cancer has been previously reported, and PTD (Proximal - Transitional - Distal) classification was proposed. Our group updated and developed the nPTD classification. METHOD: We retrospectively studied gastric cancer patients who underwent the dye method sentinel node biopsy from 1993 to 2020. The inclusion criteria were a single lesion type 0 cancer of ≤5 cm in the long axis, clinically node-negative, and invasion within the proper muscle layer pathologically. In this study, the distribution of dyed lymphatic flow was evaluated for each occupied area of the tumor. RESULTS: We included 416 patients in this study. The tumors located in the watershed of the right and left gastroepiploic arteries near greater curvature had extensive lymphatic flow; therefore, a newly circular region with a diameter of 5 cm is set on the watershed of the greater curvature between P and T zone as the 'n' zone. In addition, for cancers located in the lesser P curvature, lymphatic flow to the greater curvature was not observed. Therefore, the P zone was divided into two: the lesser curvature side (PL) and the greater curvature side (PG). CONCLUSIONS: The advantage of the nPTD classification is that it provides not only proper nodal dissection but also adequate function-preserving gastrectomy. If the tumor is localized within the PL, the proximal gastrectomy resection area can be further reduced. In contrast, for cancers located in the 'n' zone, near-total gastrectomy is required because of the extensive lymphatic flow.

Examination of Endoscopic Ultrasonographic Diagnosis for the Depth of Early Gastric Cancer.

BACKGROUND: Endoscopic ultrasonography (EUS) is one of the helpful tools to diagnose depth of early gastric cancer (EGC). In this study, we examined efficiencies of EUS for EGC such as overall accuracy, risk factors of over/under-staging, and accuracies of each invasive distance. METHODS: A total of 403 EGC lesions that could be investigated by EUS during pre-operation and histological diagnosis after endoscopic submucosal dissection (ESD) or surgery were enrolled in this study. For the 403 cases, we analyzed the accuracies of depth by conventional endoscopy (CE) and EUS retrospectively. We evaluated the clinical survey items of CE and EUS which will be described later to compare the differences between "accuracy group" and "over-staging group", and between "accuracy group" and "under-staging group", retrospectively. Additionally, 78 EGC lesions which were confined to the submucosa and for which it was possible to measure accurate invasive distance from the muscularis mucosae were examined for the relationship between preoperative diagnosis of depth by CE and EUS and invasive distance retrospectively. RESULTS: The overall accuracies of both CE and EUS in predicting EGC invasion depth were 87.3%. For CE staging, histological classification was the factor which influenced over-staging. Gastric regions and tumor area were the factors which influenced under-staging of CE. For EUS staging, tumor area was the factor which influenced over-staging, and gastric regions were the factors which influenced under-staging. Both CE and EUS were not sufficient for predicting the lesions confined to < 500 µm from the muscularis mucosae because the accuracies of both in predicting depth were less than 50%. However, EUS has a higher accuracy than CE for the lesions confined to 500 - 2,000 µm. CONCLUSIONS: The overall accuracies of both CE and EUS in predicting EGC invasion depth were equal, but the contributing factors for over/under-staging were different. Both CE and EUS are not sufficient at present to predict the lesions confined to < 500 µm from the muscularis mucosae. However, the accuracy of EUS in predicting them may increase if high-performance EUS systems are developed in the future.

A Case of Refractory Esophageal Ulcer Caused by Radiotherapy for Hepatocellular Carcinoma.

A 77-year-old man who underwent radiotherapy for hepatocellular carcinoma 6 months prior consulted for esophageal obstruction. Esophagogastroduodenoscopy revealed an esophageal ulcer caused by radiotherapy for hepatocellular carcinoma. He was treated with dietary counseling and vonoprazan. After 9 months, the ulcer improved but a moderate stenosis remained. Several factors such as high fraction size, history of chemotherapy, and stress associated with food intake might involve in the development of a radiation-associated ulcer. Opportunities to choose radiotherapy for hepatocellular carcinoma may increase, so we hypothesize that esophageal ulcers might be a complication that should be noted associated with this therapy.

Life prognosis of sentinel node navigation surgery for early-stage gastric cancer: Outcome of lymphatic basin dissection.

BACKGROUND: Lymphatic basin dissection is a sentinel node biopsy method that is specific for gastric cancer. In this method, the dyed lymphatic system is dissected en bloc, and sentinel nodes are identified at the back table (ex vivo). Even with lymphatic basin dissection, blood flow to the residual stomach can be preserved, and function-preserving curative gastrectomy can be performed. The oncological safety of function-preserving curative gastrectomy combined with lymphatic basin dissection has not yet been fully investigated. We hypothesized that the oncological safety of sentinel node navigation surgery (SNNS) is not inferior to that of the guidelines. AIM: To investigate the life prognosis of SNNS for gastric cancer in comparison with guidelines surgery. METHODS: This was a retrospective cohort study. Patients were selected from gastric cancer patients who underwent sentinel node biopsy from April 1999 to March 2016. Patients from April 1999 to August 2008 were from the Department of Surgery II, Kanazawa University Hospital, and patients from August 2009 to March 2016 were from the Department of Surgical Oncology, Kanazawa Medical University Hospital. Patients who were diagnosed with gastric cancer, which was preoperatively diagnosed as superficial type (type 0), 5 cm or less in length, clinical T1-2 and node negative, and underwent various gastrectomies guided by sentinel node navigation were retrospectively collected. The overall survival (OS) and relapse-free survival (RFS) of these patients (SNNS group) were investigated. Patients with gastric cancer of the same stage and who underwent guidelines gastrectomy with standard nodal dissection were also selected as the control group. RESULTS: A total of 239 patients in the SNNS group and 423 patients in the control group were included. Pathological nodal metastasis was observed in 10.5% and 10.4% of the SNNS and control groups, respectively. The diagnostic abilities of sentinel node biopsy were 84% and 98.6% for sensitivity and accuracy, respectively. In the SNNS group, 81.6% of patients underwent modified gastrectomy or function-preserving curative gastrectomy with lymphatic basin dissection, in which the extent of nodal dissection was further reduced compared to the guidelines. The OS rate in the SNNS group was 96.8% at 5 years and was significantly better than 91.3% in the control group (P = 0.0014). The RFS rates were equal in both groups. After propensity score matching, there were 231 patients in both groups, and the cumulative recurrence rate was 0.43% at 5 years in the SNNS group and 1.30% in the control group, which was not statistically different. CONCLUSION: The oncological safety of patients who undergo gastrectomy guided by sentinel node navigation is not inferior to that of the guidelines surgery.

Relationship Between Gastroesophageal Reflux Disease and Endoscopic Finding "Iodine-Unstained Streak".

BACKGROUND: Esophagogastroduodenoscopy (EGD) with iodine stain is a useful and diffused method for diagnosing esophageal cancer. We can perform the procedure easily with endoscopic system which does not comprise image-enhanced endoscopy. Several studies advocated that iodine-unstained streaks are a characteristic finding of gastroesophageal reflux disease (GERD). However, there are only a few reports about the subject. In this study, we investigated the usefulness of iodine chromoendoscopy for GERD consultation. METHODS: The study was conducted with 154 GERD cases in which EGD with iodine stain to the esophagus was performed. For the 154 cases, we analyzed the existence of reflux esophagitis finding and iodine-unstained streaks. In 47 GERD cases (proton pump inhibitor (PPI): 45 cases, histamine H2-receptor antagonist (H2-RA): two cases) where medication was started after EGD, we examined predictive factors of the symptom improvement such as sex, age, weight, reflux esophagitis finding, and iodine-unstained streak. RESULTS: An iodine-unstained streak was observed in 50/154 cases (32.5%). For 50 cases with iodine-unstained streak, there were only 24/50 cases (48.0%) that had both reflux esophagitis findings (≥ Los Angeles classification: grade M) and an iodine-unstained streak. For 47 cases in which medication was started, 34 cases showed improvement in their symptoms, and 13 cases did not show improvement. An iodine-unstained streak was observed more often in "Improved" group rather than in "Not improved" group (P < 0.01). When we supposed an iodine-unstained streak to be the predictive factor of the medication effect for GERD, sensitivity was 61.8% and specificity was 84.6%. CONCLUSIONS: No erosion was often found in the GERD cases without reflux esophagitis, and iodine-unstained streak was observed more often in "Improved" group rather than in "Not improved" group. We think that iodine-unstained streak can be useful for diagnosing of GERD and predictive factor of the medication effect.

[A case of gastric antral vascular ectasia improved by splenorenal shunt embolization].

An 80-year-old man with chronic renal failure and a splenorenal shunt was admitted because of progressive anemia. Gastrointestinal endoscopy revealed bleeding from a gastric antral vascular ectasia (GAVE). Despite treatment with argon plasma coagulation and blood transfusions on multiple occasions, anemia caused by GAVE bleeding recurred frequently. The GAVE improved after splenorenal shunt embolization, and the patient did not require further blood transfusions for anemia. In this case, we inferred that some humoral factor (e.g., gastrin) in the portal blood caused the GAVE.

Sealed endoscopic full-thickness resection for gastric cancer: a pilot study in an ex vivo and in vivo porcine model.

Background and study aims Endoscopic full-thickness resection (EFTR) is a useful procedure that allows minimal resection of the gastric wall because the tumor can be located endoscopically. However, the procedure carries a risk of peritoneal infection or dissemination. Thus, we devised a new EFTR technique in which the serosa is sealed using a silicone sheet to prevent the escape of gastric juice. Materials and methods Three whole stomachs were harvested from pigs for an ex vivo experiment, and seven pigs were used for an in vivo experiment. In both experiments, silicone sheets and gauze were pasted to the serosa using a fibrinogen-thrombin solution. A seromuscular incision was then made endoscopically using a HookKnife. We then evaluated whether stomach collapse could be prevented using this technique. Furthermore, the method was compared with conventional laparoscopic-assisted EFTR (LA-EFTR) in terms of resection time and quality of endoscopic view. Results In the ex vivo experiment, stomach collapse was suppressed and the seromuscular layer could be incised layer by layer. In the in vivo experiment, the time required for seromuscular incision with the new EFTR technique was significantly shorter than that with the conventional method. All layers of the stomach were smoothly resected under good endoscopic view. Conclusions Sealed EFTR is a potentially useful technique for the minimally invasive resection of gastric tumor. All layers of the stomach could be incised while confirming the incision line from the inside of the stomach and avoiding exposure of the tumor to the abdominal cavity.

Findings of the margin around lesions by magnifying endoscopy with narrow-band imaging in early gastric carcinoma and intestinal metaplasia.

OBJECTIVE: Many endoscopists have reported their own classifications of early gastric carcinoma (EGC) using magnifying narrow-band imaging (M-NBI). However, few reports on classifying the margin around lesions by M-NBI have been published. The aim of this study was to advocate the usefulness of the demarcation area classification for the diagnosis of EGC. METHODS: Altogether 197 lesions that could be investigated by M-NBI were included in this study, consisting of 115 EGC and 82 intestinal metaplasias (IM). We hypothesized that the changes in white zone (fusion and erasure signs) and blood vessel (extend and draw sign) were the indications of EGC and we retrospectively investigated this hypothesis. RESULTS: For the investigation of the white zone in the demarcation area, both fusion (P < 0.0001) and erasure signs (P < 0.0001) were observed more often in EGC than in IM, with an accuracy of 80.7%. For the investigation of blood vessel in the demarcation area, both the extend (P < 0.001) and the draw sign (P < 0.0001) were observed more often in EGC than in IM, with an accuracy of 59.9%. CONCLUSION: Estimations of the white zone and blood vessels in the demarcation area are useful for the diagnosis of EGC.

A case of primary small cell carcinoma of the breast.

We report a rare case of primary small cell carcinoma of the breast. A 44-year-old woman was admitted to our hospital with a mass in her left breast. Fine-needle biopsy revealed small cell carcinoma with neuroendocrine differentiation resembling small cell carcinoma of the lung. Systemic computed tomography (CT) and magnetic resonance imaging (MRI) revealed no primary site in the lung or any other organ. A modified radical mastectomy with removal of the axillary lymph node (Bt + Ax, R2) was performed. Histological examination revealed that the tumor was composed of small round to oval cells with a large nuclear-cytoplasmic ratio. The tumor cells were positive for neuroendocrine differentiation markers such as synaptophysin, CD56, and neuron-specific enolase (NSE), but negative for thyroid transcription factor-1 (TTF-1), leukocyte common antigen (LCA), estrogen receptor (ER), and progesterone receptor (PR). Interestingly, the tumor cells lacked immunoreactivity for epithelial markers, including cytokeratin AE1/3, CAM5.2, and epithelial membrane antigen (EMA). The patient was given adjuvant chemotherapy for axillary lymph node metastasis. There were no signs of recurrence 22 months after surgery.

Adjuvant immunochemotherapy with protein-bound polysaccharide K for colon cancer in relation to oncogenic beta-catenin activation.

PURPOSE: Protein-bound polysaccharide K is an immunotherapeutic agent that promotes apoptosis by inhibiting nuclear factor-kappaB activation in cancer cells. We previously showed that oncogenic beta-catenin activates nuclear factor-kappaB and inhibits apoptosis by up-regulating beta-transducin repeat-containing protein. We investigated whether the activation state of beta-catenin in the primary tumor is associated with differences in survival rates of patients with colon cancer undergoing immunochemotherapy with 5-fluorouracil plus polysaccharide K vs. chemotherapy with 5-fluorouracil alone. METHODS: We assessed the activation states of beta-catenin and nuclear factor-kappaB in the primary tumors of 202 colon cancer patients, and analyzed the data in terms of the clinicopathologic characteristics and survival of patients undergoing the two forms of adjuvant therapy. RESULTS: We found two distinct patterns of nuclear accumulation of activated beta-catenin in the tumor cells: diffuse nuclear accumulation in 89 cases (44 percent) and selective nuclear accumulation at the tumor invasion front in 18 cases (9 percent). Nuclear factor-kappaB activation was found in 64 cases (32 percent). In patients with diffuse nuclear accumulation-type beta-catenin activation, immunochemotherapy significantly improved recurrence-free survival, cancer death survival, and overall survival rates compared with patients receiving chemotherapy alone. No survival benefit was found in cases with nuclear accumulation at the tumor invasion front-type beta-catenin activation or no activation. Similarly, immunochemotherapy favored the survival of patients with nuclear factor-kappaB activation. Multivariate analysis established the TNM stage and administration of polysaccharide K as independent prognostic factors in the patients with diffuse nuclear accumulation-type beta-catenin activation. CONCLUSIONS: The presence of diffuse nuclear accumulation-type beta-catenin activation identifies patients with colon cancer who respond better to immunotherapy with polysaccharide K.

[Combination chemotherapy of TS-1, docetaxel and CDDP produces a remarkable response in a patient with advanced esophageal cancer].

We report a patient with advanced esophageal cancer who achieved a complete response to combination chemotherapy of TS-1, docetaxel and CDDP. A 74-year-old man was admitted to our hospital for advanced esophageal cancer with a complaint of dysphagia. He received chemotherapy, consisting of TS-1 100 mg/body, docetaxel 35 mg/m(2), and CDDP 10 mg/m(2), every 3 weeks. TS-1 was administered for 14 days followed by 7 days rest; docetaxel and CDDP were administered by intravenous infusion at day one and day 8 after beginning TS-1. After three cycles of chemotherapy, his dysphagia disappeared, and endoscopic examination of the primary esophageal tumor showed a complete response. Endoscopic examination with biopsy confirmed the disappearance of the esophageal cancer. No severe side effects were observed during this chemotherapy. Combination chemotherapy of TS-1, docetaxel, and CDDP can thus be effective for advanced esophageal cancer.

Pilot study of low-dose, divided maximum tolerated dose of CPT-11 in 21 consecutive patients with metastatic colorectal or gastric cancer.

PURPOSE: We devised a new treatment regimen, delivering a frequent low dose of CPT-11, calculated by dividing the maximum tolerated dose (MTD) to reduce its toxicity without impairing its efficacy. METHODS: CPI-11, 25 mg/m2, determined by dividing the MTD dose per month by 12, was given on days 1, 2, and 3 of every week, to 21 consecutive patients; 12 with metastatic colon cancer and 9 with metastatic gastric cancers. RESULTS: The total delivered dose of CPI-11 per patient was more than 1,000 mg in 17 (80.1%) of the 21 patients. Grade 3 marrow depression developed in 3 (14.3%) patients, and although nausea, vomiting, alopecia, and diarrhea developed in some patients, these side effects were all categorized as grade 2 or milder. The antitumor effect was evaluated in 18 patients with measurable lesions, who had received CPI-11 according to our regimen for at least 3 weeks. Of these 18 patients, 10, 7, and 1, respectively, had a found to have partial response, no change, or progression of disease, demonstrating a 55.6% efficacy rate [colon 6/10 (60.0%) and stomach 4/8 (50.0%)]. Moreover, time to progression (TTP) was greater than 90 days in 12 (75.0%) of these 18 patients. CONCLUSION: These results show that our low-dose, divided MTD of CPI-11 regimen is a promising method of reducing toxicity and strengthening the antitumor effect, justifying further large-scale comparative clinical studies to verify this potential.

Essential roles of tumor necrosis factor receptor p55 in liver metastasis of intrasplenic administration of colon 26 cells.

Intrasplenic administration of a colon adenocarcinoma cell line, colon 26, induced tumor necrosis factor (TNF) alpha protein expression around the central and portal veins of the liver at 3 days, and liver metastases by 24 days after the tumor injection, in 90% of wild-type (WT) mice. To explore the roles of TNF-alpha in the process, we administered colon 26 cells into tumor necrosis factor receptor p55 (TNF-Rp55) knockout (KO) mice. Less than 50% of TNF-Rp55 KO mice developed liver metastasis with significantly lower liver weights and the volumes of metastatic foci. These observations suggest the critical roles of TNF-Rp55-mediated signals in this liver metastasis model. The intrasplenic tumor injection induced mRNA expressions of vascular endothelial growth factor, heparin-binding epidermal growth factor, matrix metalloproteinase-9, and tissue inhibitor of matrix metalloproteinase-1 at similar levels in the livers of both WT and TNF-Rp55 KO mice. Immunohistochemical analyses of the livers of WT mice after tumor injection demonstrated the enhanced expression of vascular cell adhesion molecule (VCAM)-1 and E-selectin on sinusoidal endothelial cells. Enhanced E-selectin expression was similarly observed in the liver of TNF-Rp55 KO mice after tumor injection. However, the enhancement in VCAM-1 mRNA expression and its protein production was significantly attenuated in the liver of TNF-Rp55 KO mice when compared with WT mice. Collectively, these observations suggest that TNF-Rp55-mediated signals can up-regulate both VCAM-1 expression in the liver and subsequent liver metastasis after intrasplenic tumor injection.