Prognostic factors and significance of postoperative adjuvant chemotherapy in patients with advanced gastric cancer undergoing neoadjuvant chemotherapy followed by gastrectomy.

PURPOSE: In Japan, gastrectomy with D2 lymph node dissection and postoperative adjuvant chemotherapy are the standard treatments for locally advanced gastric cancer. Neoadjuvant chemotherapy (NAC) is not affected by postgastrectomy syndromes or postoperative complications. This multicenter retrospective study investigated the prognostic factors and significance of postoperative adjuvant chemotherapy in patients with advanced gastric cancer who underwent NAC followed by gastrectomy. METHODS: Consecutive patients (n = 221) with advanced gastric cancer who underwent NAC followed by curative surgery were enrolled in this study. Prognostic factors including postoperative adjuvant chemotherapy were investigated using univariate and multivariate analyses. RESULTS: A multivariate analysis revealed that pathological lymph node metastasis (ypN) status and postoperative adjuvant chemotherapy were independent prognostic factors for the overall and relapse-free survival. Forty-five patients (20.4%) did not receive postoperative adjuvant chemotherapy. There were no significant differences between patients with and without adjuvant chemotherapy for all factors, except age. The most common reason for not undergoing postoperative adjuvant chemotherapy was a poor condition (n = 23). CONCLUSIONS: ypN status and postoperative adjuvant chemotherapy were independent prognostic factors in gastric cancer patients who underwent NAC followed by curative gastrectomy. It is important to maintain the patient's condition during NAC and the perioperative period so that they can receive postoperative adjuvant chemotherapy.

Long-Term Outcomes of Pylorus-Preserving Gastrectomy for Early Gastric Cancer.

BACKGROUND: In the short term, pylorus-preserving gastrectomy (PPG) has been reported to have advantages over distal gastrectomy (DG) with regard to postprandial symptoms and dumping syndrome. We aimed to evaluate the quality of life after PPG for early gastric cancer in the long term in comparison to that after DG. METHODS: Twenty-six patients who underwent gastrectomy (11 PPG, 15 DG) for early gastric cancer at Osaka University Hospital participated and were followed for more than 4 years. Body weight changes, nutritional status, dual-phase scintigraphy findings, endoscopic survey results, and questionnaire responses after gastrectomy were examined. RESULTS: There were significantly lower ratios of weight changes in PPG than in DG, 5 years after surgery. There were no differences in the clinicopathological characteristics, nutritional parameters, questionnaire responses, and endoscopic findings between the two groups. Based on gastric scintigraphy, although the gastric emptying of liquids showed similar curves in the two groups, gastric emptying of solids was significantly slower in the PPG group than in the DG group (P = .039). DISCUSSION: PPG had advantages with regard to long-term outcomes over DG in terms of weight maintenance and the prevention of rapid gastric emptying. PPG might be efficient in patients with early gastric cancer.

Phenotypic and molecular characterization of novel pulmonary adenocarcinoma cell lines established from a dog.

Canine pulmonary adenocarcinoma (PAC) resembles human lung tumors in never-smokers, but it is rarer than human pulmonary adenocarcinoma. Therefore, research on canine PAC is challenging. In the present study, we successfully established various novel canine PAC cell lines from a single lesion in a dog, including two parent cell lines and fourteen cloned cell lines, and characterized their cellular properties in vitro. Several of these cell lines showed epithelial-mesenchymal transition (EMT)-like and/or cancer stem cell (CSCs)-like phenotypes. We additionally assessed the sensitivity of the cells to vinorelbine in vitro. Three clonal lines, two of which showed EMT- and CSC-like phenotypes, were resistant to vinorelbine. Furthermore, we evaluated the expression and activation status of EGFR, HER2, and Ras signaling factors. The findings indicated that the cell lines we established preserved the expression and activation of these factors to varying extents. These novel canine PAC cell lines can be utilized in future research for understanding the pathogenesis and development of treatments for canine PAC.

[A Case of Gastric Submucosal Tumor at Esophagogastric Junction Resected by Endoscopic Intragastric Surgery].

We report a case in which a gastric submucosal tumor at the esophagogastric junction was resected by endoscopic intragastric surgery with minimally invasive and function-preserving. A 30s-year-old man was referred to our hospital because of an abnormal findings pointed by a barium examination at a health check up. Upper gastrointestinal endoscopy and endoscopic ultrasound revealed a submucosal tumor approximately 60 mm in size on the posterior wall of the gastric fundus. Endoscopic ultrasound-fine needle aspiration was carried out and pathological result was a leiomyoma. The tumor was an intraluminal and extraluminal growth extending from the dorsal esophagus to the cardiac region, but considering the patient's young age, we decided to perform endoscopic intragastric surgery to preserve the function of stomach. A 30 mm median incision was made above the umbilicus, and the anterior wall of the gastric body was incised and the intragastric surgery was started using the double protector method. The mucosal surface of the tumor was located at the fundus, but the tumor developed into the dorsal aspect of the lower esophageal muscle layer. The tumor was carefully dissected and resected by intragastric manipulation. Postoperative oral contrast examination revealed no obvious stenosis, and gastric peristalsis was normal.

Expression profile of immunoregulatory factors in canine tumors.

Cancers utilize a variety of molecules to escape host immune responses. Better understanding the immune environment surrounding cancer may facilitate application of innovative cancer immunotherapies, such as immune checkpoint inhibitors, to dogs as well as humans. In this study, we screened the expression of 20 immune regulatory molecules in diverse canine tumors (n = 59). Quantitative RT-PCR (qPCR) analysis revealed that some immune regulatory molecules, such as LGALS9 (coding Galectin-9) and CD48, were expressed in most canine tumors, but other molecules, such as CD274 (coding PD-L1), IL4I1, PVR, TNFSF18, ICOSLG, and TNFSF4, were rarely expressed. NECTIN2 was highly expressed in epithelial tumors but was low in non-epithelial tumors. In contrast, VSIR and CD200 expressions were low in epithelial tumors but high in non-epithelial tumors. Interestingly, several tumors expressed distinctive immunoregulatory factors. Hepatocellular carcinomas expressed FGL1, mast cell tumors expressed PDCD1LG2 (coding PD-L2), transitional cell carcinomas expressed VTCN1 (coding B7x), and lymphomas and squamous cell carcinomas expressed CD70. Consistent with qPCR results, immunofluorescence staining confirmed that hepatocellular carcinomas expressed FGL-1 protein. Thus, this study reveals the expression profile of immunoregulatory molecules in canine tumors and opens the door to better understanding the relationship between canine tumors and host immunity.

Exome Sequencing Reveals De Novo Variants in Congenital Scoliosis.

Congenital scoliosis (CS) is a lateral curvature of the spine characterized by the presence of vertebral anomalies. Pathogenic genetic variants in the TBX6 gene are one of the causes of CS. However, since many clinically diagnosed cases of CS are without known TBX6 gene variations, this study aims to uncover new genes related to disease susceptibility of CS by exome sequencing (ES). This study employed ES in a cohort of 5 Japanese patients with CS and their healthy parents or a sister for a total of 16 samples among 5 families. Variant interpretation was performed using SIFT, PolyPhen-2, Mutation Taster, and CADD. Four de novo variants were identified by ES and confirmed by Sanger sequencing: 1 frameshift variant ( SHISA3 ) and 3 missense variants ( AGBL5 , HDAC4 , and PDE2A ). ES also uncovered 1 homozygous variant in the MOCOS gene. All of these variants were predicted to be deleterious by SIFT, PolyPhen-2, Mutation Taster, and/or CADD. The number of de novo variants identified in this study was exactly what would be expected by chance. Additional functional studies or gathering matched patients using Gene Matcher are needed.

Inhibitor of protein kinase N3 suppresses excessive bone resorption in ovariectomized mice.

INTRODUCTION: The long-term inhibition of bone resorption suppresses new bone formation because these processes are coupled during physiological bone remodeling. The development of anti-bone-resorbing agents that do not suppress bone formation is urgently needed. We previously demonstrated that Wnt5a-Ror2 signaling in mature osteoclasts promoted bone-resorbing activity through protein kinase N3 (Pkn3). The p38 MAPK inhibitor SB202190 reportedly inhibited Pkn3 with a low Ki value (0.004 µM). We herein examined the effects of SB202190 on osteoclast differentiation and function in vitro and in vivo. MATERIALS AND METHODS: Bone marrow cells were cultured in the presence of M-csf and GST-Rankl to differentiate into multinucleated osteoclasts. Osteoclasts were treated with increasing concentrations of SB202190. For in vivo study, 10-week-old female mice were subjected to ovariectomy (OVX). OVX mice were intraperitoneally administered with a Pkn3 inhibitor at 2 mg/kg or vehicle for 4 weeks, and bone mass was analyzed by micro-CT. RESULTS: SB202190 suppressed the auto-phosphorylation of Pkn3 in osteoclast cultures. SB202190 significantly inhibited the formation of resorption pits in osteoclast cultures by suppressing actin ring formation. SB202190 reduced c-Src activity in osteoclast cultures without affecting the interaction between Pkn3 and c-Src. A treatment with SB202190 attenuated OVX-induced bone loss without affecting the number of osteoclasts or bone formation by osteoblasts. CONCLUSIONS: Our results showed that Pkn3 has potential as a therapeutic target for bone loss due to increased bone resorption. SB202190 is promising as a lead compound for the development of novel anti-bone-resorbing agents.

[A Case of Giant Mesenteric Lymphangioma in an Adult].

A 26-year-old man with left inguinal pain and frequent urination was examined. An abdominal ultrasound revealed a cystic lesion. In further examinations, CT and MRI showed a large cystic lesion of about 20 cm in size, connected to mesenteric- derived blood vessels. We suspected a huge mesenteric lymphangioma and decided to perform a laparotomy. A tumor was seen in the mesentery of the jejunum and adhered to the duodenum widely. The tumor could be removed safely without resection of the duodenum by first sucking the contents and shrinking the tumor. The final pathological diagnosis was mesenteric lymphangioma. Adult mesenteric lymphangiomas measuring larger than 20 cm are relatively rare. We review the case in the context of the relevant literature.

[A Case of Gastric Anisakiasis That Required Differentiation from Scirrhous Gastric Cancer].

A 36-year-old woman visited a previous doctor with lower abdominal pain and nausea. Her former doctor's upper gastrointestinal endoscopy and CT scan showed giant folds and wall thickening of the lower body of the stomach, and she was referred on suspicion of scirrhous gastric cancer. Similar findings were found on enhanced CT at our hospital. Endoscopic findings performed several days later showed red and thickened mucosa at the cardia, but no wall thickening and giant fold, and there were no findings suggestive of scirrhous gastric cancer. Biopsy showed no atypical cells, and a large number of eosinophils appeared in the lesion at the cardia. Eosinophilia and anisakis IgE antibody were positive and a diagnosis of gastric anisakiasis was made. She was eating grilled horse mackerel the day before her stomachache. At the same time, pruritus and edema around her right knee also appeared, and a dermatologist diagnosed her with anisakis-related eosinophil edema. One month later, CT scan and endoscopy were almost normal. A young woman referred on suspicion of scirrhous gastric cancer experienced a rare case diagnosed with gastric anisakiasis.

[Radical Resection Was Achieved Using a Liver-First Approach for Simultaneous Liver Metastasis from Rectal Cancer-A Case Report].

The patient was a 70s male. A fecal occult blood test showed a positive reaction, and colonoscopy was performed. Under a diagnosis of rectal cancer, he was referred to our hospital. Detailed examination revealed solitary liver metastasis measuring 60 mm and involving the S4 to S1 areas of the liver. A strategy to perform systemic chemotherapy in advance was adopted. Five courses of FOLFOXIRI therapy were conducted, and a partial response(PR)was achieved, suggesting that the tumor is resectable. Extended left/caudal lobectomy was performed. There was no complication, and the patient was discharged. After 4 months, laparoscopic low anterior resection and temporary ileostomy were conducted. According to the TNM staging, the grade was evaluated as ypT2N0. On histological response evaluation, the grade was evaluated as 1a. The stoma was closed. During the 1.5-year follow-up after initial treatment, there has been no relapse. We encountered a patient with simultaneous liver metastasis from rectal cancer in whom the use of a liver-first approach(LFA)after systemic chemotherapy facilitated radical resection. The present case suggested that the LFA contributes to a rise in the resection rate, further improving the prognosis.

[Laparoscopic Abdominoperineal Resection with the Trans-Perineal Approach for Anal Canal Cancer in a Patient with Situs Inversus Totalis-A Case Report].

Situs inversus totalis(SIT)is a rare congenital condition that causes complete transposition of thoracic and abdominal viscera. Due to associated anatomical abnormalities and low frequency, surgery for affected patients is considered to be difficult. A 72-year-old man was referred to our hospital with a chief complaint of narrow stools. The diagnosis was anal canal cancer(cT1bN0M0)accompanied by SIT. A trans-perineal minimally invasive surgical procedure with laparoscopic abdominoperineal resection(Tp-APR)was performed. When mobilizing the sigmoid colon, the surgeon changed their position in consideration of anatomical abnormalities. On the other hand, manipulation around the rectum was possible using the same technique as in patients with normal anatomy. The postoperative course was uneventful, and he had no recurrence 18 months after surgery. This is the first case that showed Tp-APR for anal canal cancer with SIT performed safely and feasibly. Preoperative simulation of associated abnormal anatomical structures is considered crucial for a case of SIT.

Robotic-assisted proximal gastrectomy using the double-flap technique for early gastric cancer with situs inversus totalis: a case report.

BACKGROUND: The robotic system has been applied in the treatment of gastric cancer (GC), and the procedure has been found to be safe and feasible. Situs inversus totalis (SIT) is a relatively rare autosomal recessive congenital anomaly. We successfully performed robot-assisted proximal gastrectomy (RAPG) and handsewn double-flap esophagogastrostomy for GC in a patient with SIT. CASE PRESENTATION: A 71-year-old woman was referred to us with an asymptomatic ulcerative lesion in the upper body of the stomach. Computed tomography revealed that she had SIT. She was diagnosed with cT1bN0M0, cStageIA gastric cancer. RAPG with lymph node dissection and handsewn double-flap esophagogastrostomy was performed. Robotic surgery enabled the surgeon to perform the surgery without changing his position and experiencing any confusion resulting from the patient's reversed anatomy. It took 448 min, and no intraoperative complications occurred. Her postoperative course was uneventful; she was discharged on postoperative day 10. The final pathologic report showed pT1b1N0M0, pStage IA. CONCLUSIONS: This is the first case describing RAPG with handsewn double-flap esophagogastrostomy for a SIT patient with early GC.

Deciphering OPDA Signaling Components in the Momilactone-Producing Moss Calohypnum plumiforme.

Jasmonic acid (JA) and its biologically active form jasmonoyl-L-isoleucine (JA-Ile) regulate defense responses to various environmental stresses and developmental processes in plants. JA and JA-Ile are synthesized from α-linolenic acids derived from membrane lipids via 12-oxo-phytodienoic acid (OPDA). In the presence of JA-Ile, the COI1 receptor physically interacts with JAZ repressors, leading to their degradation, resulting in the transcription of JA-responsive genes by MYC transcription factors. Although the biosynthesis of JA-Ile is conserved in vascular plants, it is not recognized by COI1 in bryophytes and is not biologically active. In the liverwort Marchantia polymorpha, dinor-OPDA (dn-OPDA), a homolog of OPDA with two fewer carbons, and its isomer dn-iso-OPDA accumulate after wounding and are recognized by COI1 to activate downstream signaling. The moss Calohypnum plumiforme produces the antimicrobial-specialized metabolites, momilactones. It has been reported that JA and JA-Ile are not detected in C. plumiforme and that OPDA, but not JA, can induce momilactone accumulation and the expression of these biosynthetic genes, suggesting that OPDA or its derivative is a biologically active molecule in C. plumiforme that induces chemical defense. In the present study, we investigated the biological functions of OPDA and its derivatives in C. plumiforme. Searching for the components potentially involving oxylipin signaling from transcriptomic and genomic data revealed that two COI1, three JAZ, and two MYC genes were present. Quantification analyses revealed that OPDA and its isomer iso-OPDA accumulated in larger amounts than dn-OPDA and dn-iso-OPDA after wounding. Moreover, exogenously applied OPDA, dn-OPDA, or dn-iso-OPDA induced the transcription of JAZ genes. These results imply that OPDA, dn-OPDA, and/or their isomers potentially act as biologically active molecules to induce the signaling downstream of COI1-JAZ. Furthermore, co-immunoprecipitation analysis showed the physical interaction between JAZs and MYCs, indicating the functional conservation of JAZs in C. plumiforme with other plants. These results suggest that COI1-JAZ-MYC mediated signaling is conserved and functional in C. plumiforme.

Safety and efficacy of laparoscopic repeat liver resection and re-operation for liver tumor.

Laparoscopic liver resection (LLR) has been reported as a safe, minimally invasive, and effective surgery for the management of liver tumor. However, the efficacy and safety of laparoscopic repeat liver resection (LRLR) for recurrent liver tumor are unclear. Here, we analyzed the surgical results of LRLR. From June 2010 to May 2019, we performed 575 LLR surgeries in our department, and 454 of them underwent pure LLR for the single tumor. We classified the patients who received pure LLR for the single tumor into three groups: LRLR (n = 80), laparoscopic re-operation after previous abdominal surgery (LReOp; n = 136), and laparoscopic primary liver resection (LPLR; n = 238). We compared patient characteristics and surgical results between patients undergoing LRLR, LReOp and LPLR. We found no significant differences between LRLR and LPLR in the conversion rate to laparotomy (p = 0.8033), intraoperative bleeding (63.0 vs. 152.4 ml; p = 0.0911), or postoperative bile leakage rate (2.50 vs. 3.78%; p = 0.7367). We also found no significant difference in the surgical results between LReOp and LPLR. However, the number of patients undergoing the Pringle maneuver was lower in the LRLR group than the LPLR group (61.3 vs. 81.5%; p = 0.0004). This finding was more pronounced after open liver resection than laparoscopic liver resection (38.9 vs. 67.7%; p = 0.0270). The operative time was significantly longer in patients with proximity to previous cut surface than patients with no proximity to previous cut surface (307.4 vs. 235.7 min; p = 0.0201). LRLR can safely be performed with useful surgical results compared to LPLR.

Augmentation of Stimulator of Interferon Genes-Induced Type I Interferon Production in COPA Syndrome.

OBJECTIVE: Coatomer subunit alpha (COPA) syndrome, also known as autoinflammatory interstitial lung, joint, and kidney disease, is caused by heterozygous mutations in COPA. We identified a novel COPA variant in 4 patients in one family. We undertook this study to elucidate whether and how the variant causes manifestations of COPA syndrome by studying these 4 patients and by analyzing results from a gene-targeted mouse model. METHODS: We performed whole-exome sequencing in 7 family members and measured the type I interferon (IFN) signature of the peripheral blood cells. We analyzed the effects of COPA variants in in vitro experiments and in Copa mutant mice that were generated. RESULTS: We identified a heterozygous variant of COPA (c.725T>G, p.Val242Gly) in the 4 affected members of the family. The IFN score was high in the members carrying the variant. In vitro analysis revealed that COPA V242G, as well as the previously reported disease-causing variants, augmented stimulator of interferon genes (STING)-induced type I IFN promoter activities. CopaV242G/+ mice manifested interstitial lung disease and STING-dependent elevation of IFN-stimulated gene expression. In CopaV242G/+ dendritic cells, the STING pathway was not constitutively activated but was hyperactivated upon stimulation, leading to increased type I IFN production. CONCLUSION: V242G, a novel COPA variant, was found in 4 patients from one family. In gene-targeted mice with the V242G variant, interstitial lung disease was recapitulated and augmented responses of the STING pathway, leading to an increase in type I IFN production, were demonstrated.

[A Case of Pancreatic Neuroendocrine Tumor(p-NET)with Long-Term Survival with Multidisciplinary Treatment].

Pancreatic neuroendocrine tumor(p-NET)is a relatively rare disease, and treatment is multidisciplinary with resection, local therapy, radiotherapy, and chemotherapy. We report on a case in which long-term survival was achieved by multidisciplinary treatment. The case is a 47-year-old male. He was referred to our hospital because of the diagnosis of pancreatic tail tumor and underwent distal pancreatectomy in May 2008. And he was diagnosed as p-NET G1 by the pathological results. After 3 TACE treatments and 1 partial liver resection for recurrent liver metastasis, multiple liver metastases and lymph node metastases were found in August 2014. As a result of the everolimus treatment, the determination of efficacy to lymph nodes was CR and liver lesions were CR with the addition of TACE treatment. In July 2017, he had multiple liver metastases and right humeral metastases, and has been treated with radiotherapy for bone metastases and has maintained CR. After TACE in November 2017, he received 9 rounds of lanreotide treatment. In December 2018, he again had liver metastases and lymph node recurrence. He has been treated with everolimus treatment again and is maintaining SD in outpatient treatment.

[A Case of GIST That Recurred More Than 30 Years after Surgery and Could Be Resected].

The patient was a 77-year-old woman. She underwent a partial gastrectomy at the age of 40, and a partial colectomy at the age of 75 following a diagnosis of a carcinoid. In November 2019, a 1.5 cm mass with a clear boundary was found in the pancreatic tail, which was strongly stained uniformly. And furthermore, multiple masses between 2 cm and 3 cm with a clear boundary was found inside liver segment S1 and S6 and S7 and S8 on CT, which was strongly stained at the edge in the early phase and was seen as a low density area in the late phase. At a result of image examination, it was diagnosed as a pancreatic tail neuroendocrine tumor and its multiple liver metastases. The distal pancreatectomy, posterior segmentectomy, and partial S1 lt and S8 liver resection were performed. With postoperative pathological diagnosis, the pancreatic tumor was accessory spleen, and liver tumor were epithelioid type GIST which were positive for CD34 and PDGFRA and negative for c- kit. The pathology specimen of colectomy was re-examined, and the diagnosis from the previous surgery was changed to GIST from a carcinoid. Epithelioid type GIST was associated with a PDGFRA gene mutation and was known to have many gastric origins. Based on the clinical course, it was diagnosed as recurrence of gastric GIST at 40 years after 30 years or more.

[Deviation of Peripherally Inserted Central Catheter(PICC)during Total Parenteral Nutrition(TPN)for a Gastric Cancer Patient-A Case of Report].

A 90s woman was diagnosed as having cT4aN2M0, cStage ⅢA, advanced gastric cancer. As she was severely malnourished owing to pyloric stenosis, a peripherally inserted central catheter (PICC)was placed in her left arm, and total parenteral nutrition(TPN)was initiated. She complained of dyspnea, and radiography revealed right pleural effusion on day 4 of TPN. Contrast computed tomography revealed that the tip of the catheter had perforated the vessel wall of the superior vena cava and had migrated into the mediastinal space. After thoracocentesis, the catheter was removed under fluoroscopic guidance after hemostasis was achieved. Thus, the possibility of catheter deviation should be considered in case of dyspnea and pleural effusion during TPN.

[A Curatively Resected Case of Quadruple Cancer including Synchronous Gastric and Superficial Esophageal Cancers with Metachronous Sigmoid Colon Cancer and Hepatocellular Carcinoma].

A 80s year old man was referred to our hospital with melena. Colonoscopy revealed an elevated lesion in the sigmoid colon. Laparoscopic sigmoidectomy(D2)was performed in August 2011. Postoperative diagnosis was advanced sigmoid colon cancer(pT2N1M0 and pStage Ⅲa, UICC). In January 2015, He suffered from epigastric discomfort after meals. Gastrointestinal endoscopy revealed advanced gastric cancer and superficial esophageal cancer. For esophageal cancer, endoscopic submucosal dissection was performed with a diagnosis of cStage 0-Ⅱa(UICC). Laparoscopic distal gastrectomy with Billroth Ⅰ reconstruction was performed for gastric cancer with a diagnosis of pT1bN0M0 and pStage ⅠA(UICC). Follow up CT and MRI images in October 2016 showed a liver tumor in S4/S5. Laparoscopic partial liver resection was performed. Postoperative pathological diagnosis was hepatocellular carcinoma pT1N0M0, pStage Ⅰ(UICC). We finished following up period of the sigmoid colon cancer. Gastric cancer and esophageal cancer are followed up by gastrointestinal endoscopy once a year. Hepatocellular carcinoma is followed up every 3 months. He has no recurrence until now.