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Purpose: Postoperative pain management is important for enhanced recovery. High-dose oral acetaminophen is effective; however, the safety of its long-term use has not been established in gastrointestinal surgeries. This study aimed to investigate drug-induced liver injury (DILI) in patients with colorectal cancer using high-dose acetaminophen., Methods: One hundred sixty-eight consecutive colorectal cancer using high-dose oral acetaminophen (3600 mg/day between postoperative day 1 and 7) were enrolled., Results: One hundred forty-nine patients (88.7%) completed the administration of high-dose oral acetaminophen. DILI occurred in 58 patients (34.5%), and the cumulative incidence rates were 20.4% and 37.9% on postoperative 6 and 7, respectively. The severity of liver injury was grade 1 in all cases and returned to normal without treatment. Patients with DILI had a higher frequency of dyslipidemia (44.8% vs. 23.6%, P = 0.0047) and M1 staging (10.3% vs. 1.0%, P = 0.0036). A multivariate analysis showed that the presence of dyslipidemia (OR 2.61, P = 0.0067) and M1 stage (OR 12.4, P = 0.0053) were independent risk factors for DILI., Conclusion: The long-term use of high-dose oral acetaminophen in colorectal cancer patients enrolled in enhanced recovery protocols is feasible. Moreover, the presence of dyslipidemia and M status are risk factors for DILI., Competing Interests: Declarations Conflict of interest Dr. Shinya Urakawa, Tatsushi Shingai, Junichiro Kato, Shinya Kidogami, Tadafumi Fukata, Hisashi Nishida, Hiroyoshi Takemoto, Hiroaki Ohigashi, and Takayuki Fukuzaki have no conflicts of interest or financial ties associated with this study., (© 2024. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Background: Robotic gastrectomy(RG)for gastric cancer(GC)has been covered by health insurance since 2018. In this study, we examined the results of RG for GC at our hospital during the initial period of its introduction., Materials and Method: From August 2022 to May 2023, we retrospectively examined the surgical outcomes and short-term postoperative outcomes of the first 9 patients who underwent RG for GC at our hospital., Results: The median patient age was 77(67-82) years, gender was 4 males and 5 females, and distal gastrectomy was performed in all patients. The median operative time was 410(323-486)min, blood loss was 5(1-140)mL, postoperative hospital stay was less than 9 days in all patients, and there was no conversion to laparoscopic or open surgery. There were no postoperative complications of Clavien-Dindo Grade Ⅱ or above., Conclusion: In this study, RG for GC was performed safely without intraoperative or postoperative complications.

A 66-year-old man underwent laparoscopic ileocecal resection for cecal cancer with liver metastasis(cT3N1M1a, cStage Ⅳa). One month later, combination chemotherapy with capecitabine, oxaliplatin, and bevacizumab was administered for liver metastasis. However, during the treatment, peritoneal dissemination and abundant diuretic-resistant ascites was revealed, resulting in poor dietary intake. One year and 11 months after the surgery, the chemotherapy was interrupted and cell-free and concentrated ascites reinfusion therapy(CART)was undergone as palliative care. The initial volume of retrieved ascites was 6,500 mL, and the volume was increased gradually to a maximum of 14,020 mL without hemodynamic instability. Totally CART was administered 10 times during 7 months without any complications: mean volume of retrieved ascites; 9,780 mL/unit, the interval between therapies; 2-3 weeks. Serum albumin level did not decrease since CART administration. His oral intake and daily activities were improved by CART. These clinical outcomes contributed to the readministration of chemotherapy. We present a recent case of safe and periodical CART for abundant refractory ascites in cecal cancer with peritoneal dissemination, resulting in the improvement of QOL and the readministration of chemotherapy.

The case is a female, 50s. She presented to our hospital because of her intestinal obstruction. A CT scan at her visit showed wall thickening of her ascending colon. Colonoscopy revealed type 2 advanced cancer in the ascending colon. The pathological examination was a diagnosis of adenocarcinoma. Laparoscopic right hemicolectomy was performed for cT3N1M0, cStage Ⅲb ascending colon cancer. The pathological result was pT3N1M0, Stage Ⅲb. Contrast-enhanced CT was performed 10 months after the operation. As a result, she was found to have recurrent multiple liver metastases. A laparoscopic partial hepatectomy was performed at the site of recurrence. The pathological result was adenocarcinoma. It was a diagnosis of metastasis recurrence from colorectal cancer. A CT scan 16 months after primary surgery revealed enlarged cardiodiaphragmatic lymph nodes. A PET-CT scan revealed an accumulation of SUVmax 3.0 in the same area. She was diagnosed with lymph node recurrence of colorectal cancer and underwent resection. Histopathological result was adenocarcinoma. It was diagnosed as metastasis from ascending colon cancer.

An 82-year-old man presented with right cervical swelling. Cervical ultrasonography revealed several swollen lymph nodes which were diagnosed with adenocarcinoma by fine needle aspiration cytology. Computed tomography showed right axillary lymph nodes were also swelling. Upper and lower gastrointestinal endoscopy found type 0-Ⅱa gastric cancer located at the posterior wall of the middle region. Pathology was HER2-positive moderately differentiated tubular adenocarcinoma. Doublet chemotherapy with S-1 and cisplatin was administered for unresectable gastric cancer(cT1bN0M1, cStage Ⅳb). One month later, doublet chemotherapy was changed to triplet chemotherapy with trastuzumab, capecitabine, and cisplatin. A month later, complete response(CR)was achieved. After 8 courses of triplet chemotherapy, we changed to doublet chemotherapy with trastuzumab and capecitabine due to impaired kidney function 8 months. Two months later from that, endoscopic mucosal dissection was performed for gastric cancer as local therapy(pathology: well differentiated tubular adenocarcinoma, pT1a, ly0, v0). Two years and 2 months after the beginning of chemotherapy, the right axillary lymph nodes were enlarged again and surgically resected(pathology: HER2-positive poorly differentiated adenocarcinoma). He had CR for 8 years and 2 months, and chemotherapy was canceled due to his decision. During 1 year and 7 months, disease progression was not observed. We present a long-term survival case of HER2-positive gastric cancer with distant lymph node metastasis receiving multidisciplinary therapy.

A 94-year-old woman presented with anorexia, persisting for several months, and marked anemia. An upper gastrointestinal endoscopy revealed type 3 advanced gastric cancer in the antrum. CT imaging indicated a large esophageal hiatus hernia and the elevation of the gastric fornix to the level of the bronchus. Wall thickening in the antrum, surrounded by increased fat tissue density, and swollen lymph nodes along the common hepatic artery, were detected. She was diagnosed with advanced gastric cancer(cT3N1M0, cStage Ⅲ)and a large hiatal hernia. A laparoscopic hiatal hernia repair and distal gastrectomy were performed. The cancer was exposed outside the serosa in the antrum, yet there was no indication of ascites, liver metastasis or peritoneal dissemination. The esophageal hiatus was sutured, and a distal gastrectomy(Billroth-Ⅱ reconstruction)was conducted. To avert hernia recurrence, sutures were applied to the posterior wall of the abdominal esophagus and the crus of the diaphragm, as well as the fornix of the remnant stomach and the diaphragm. Her postoperative course was uneventful, and she was discharged on POD13. There were no instances of gastric cancer recurrence or hiatal hernia 7 months post-operation.

We report a case of recurrent esophageal cancer with long-term survival treated by S-1 monotherapy. A 66-year-old man underwent subtotal esophagectomy, two-field lymphadenectomy after 2 courses of DCF chemotherapy for esophageal cancer 1 year earlier. The final diagnosis was esophageal cancer, Lt, CT-Type 2, ypT3, ypN0(0/62), M0, ypStage Ⅲ. At 6 months after esophagectomy, CT scan revealed mediastinal lymph node metastasis and pleural dissemination, and paclitaxel monotherapy was performed, but lymph node re-enlargement was observed on CT at 12 months after esophagectomy. Chemotherapy with S-1 monotherapy was performed, and 3 months after initiation of S-1 monotherapy, CT showed reduced lymph node metastases and pleural dissemination remained reduced. Adverse events were CTCAE v5.0 Grade 2 thrombocytopenia and diarrhoea, but no Grade 3 or higher adverse events were observed. Long-term survival was achieved with no disease progression for more than 2.5 years after initiation of S-1 monotherapy.

We report a case of colon metastasis from gastric cancer treated by laparoscopic-assisted segmental colectomy. An 81-year-old man was undergone distal gastrectomy, D2 dissection and Billroth Ⅰ reconstruction for gastric cancer 3 years previously, with a final diagnosis of gastric cancer L, Post, Type 2, sig/por2, pT4a(SE), pN3b(30/56), H0, P0, M0, pStage ⅢC. Three years after gastrectomy, CT scan showed an elevated lesion in the transverse colon, which was suspected to be metastatic colorectal cancer on closer examination. As no metastatic lesions were found other than the tumor of transverse colon, we performed laparoscopic-assisted segmental colon resection. A small incision was placed in the umbilical region, and the transverse colon was extracted from the umbilical region after dissection of the adhesions by single-incision laparoscopic surgery. The transverse colon containing the mass lesion was partially resected extracorporeally and reconstructed with a functional end-to-end anastomosis. The postoperative pathological findings revealed tumor cells predominantly below the submucosal layer and partly showing the signet ring cell carcinoma, and the transvers colon tumor was diagnosed as a metastasis from gastric cancer. The postoperative course was uneventful and the patient was discharged 8 days after surgery, and is alive for 10 months after the segmental colon resection followed by chemotherapy.

A 78-year-old man had undergone a laparoscopic sigmoid colon resection; left ureteral resection; and a ureteral reconstruction for sigmoid colon cancer with left ureteral invasion. The patient did not wish to undergo postoperative adjuvant chemotherapy, and he was followed up at fixed intervals. Six months after surgery, CT revealed peritoneal metastasis and liver metastasis(S6). Considering his advanced age and adverse events, the patient was started on capecitabine plus bevacizumab therapy. The patient was able to continue the treatment, even though he had to suspend and reduce the dose due to adverse events of hand-foot syndrome, and achieved CR by CT after 21 courses of treatment. Chemotherapy was discontinued after 24 courses, CR was maintained for 5 years, and the patient is still alive with no evidence of recurrence.

A 60s man was diagnosed with advanced gastric cancer(cT4b[PAN], cN+, cM0, cStage ⅣA). He started first-line chemotherapy consisting of S-1 and cisplatin, but tumor markers remained elevated and CT showed cancer progression. He then started second-line chemotherapy consisting of ramucirumab and paclitaxel. The tumor markers decreased, and CT revealed tumor regression. A distal gastrectomy with D2 lymph node dissection was performed as conversion surgery. The patient had an uncomplicated postoperative course and was discharged early from the hospital. A histological analysis confirmed complete resection of the Grade 1a tumor. The RAM plus PTX regimen was restarted on postoperative day 57. At 15 months postoperative, the patient remained alive and relapse-free.

An 83-year-old man presented with melena and weight loss. Upper gastrointestinal endoscopy showed type 3 advanced gastric cancer with pyloric stenosis. Surgical findings revealed numerous peritoneal dissemination, then gastro-jejunum anastomosis was performed. The oral diet was resumed on POD4, however severe dysphagia occurred immediately on POD6. There were no specific findings on MRI/MRA and nasal endoscopy. Serum antibodies related to neuromuscular diseases and connective tissue diseases were also negative. Despite the rehabilitation, the dysphagia remained. Before total parenteral nutrition on POD16, hypophosphatemia was discovered(1.4 mg/dL). His dysphagia disappeared with the improvement in the serum phosphate level. Hypophosphatemia might be caused by an inadequate intake as urine phosphate, serum calcium and serum PTH levels were normal. We present a recent case of severe dysphagia due to hypophosphatemia in a patient with peritoneal dissemination of gastric cancer.

Background: We analyzed the short-term outcomes and nutritional assessment of gastric cancer surgery patients who underwent exercise intervention after gastrectomy., Materials and Method: Gastric cancer patients who underwent gastrectomy at our department from January 2021 were included in the study. Postoperative exercise intervention(lower limb training) was performed in gastric cancer patients aged 75 years or older(group H: 7 patients)and compared retrospectively with gastric cancer patients younger than 75 years(group L: 10 patients)who did not receive exercise intervention. The rate of decrease in each index after 1 week was compared between the 2 groups., Results: Postoperative complications(yes/no) were 3/4(42.8%)in group H and 2/8(20.0%)in group L(p=0.59); postoperative hospital stay was 11.5(10.8-21.3) days in group H and 11.0(9.0-14.0)days in group L(p=0.37). The percentage decrease in each index was as follows: for BMI in groups H/L: 2.9/5.6%(p=0.17), grip strength in groups H/L: 2.4/－7.6%(p=0.07), skeletal muscle mass in groups H/L: －2.3/7.0%(p=1.00), PNI in groups H/L: 26.6/18.1%(p=0.12)., Conclusion: In this study, no significant differences were noted in postoperative complication rates or postoperative hospital stay between groups H and L.

We report a case of early gastric cancer with Adachi Type Ⅵ vascular anomaly treated by laparoscopic distal gastrectomy. An 81-year-old woman was admitted because of anorexia, and was diagnosed with early gastric cancer. Preoperative MDCT revealed Adachi Type Ⅵ vascular anomaly, where the hepatic artery does not appear at the superior border of the pancreas. The patient was treated successfully with laparoscopic distal gastrectomy with D1+lymph node dissection. At surgery, we identified the portal vein, then, dissection of No. 8a lymph nodes was performed. The postoperative course was uneventful and the patient was discharged 10 days after surgery. The final pathology result showed gastric cancer, M, Less, Type 0-Ⅱc+Ⅲ, 58×50 mm, tub1>pap, pT1a(M), Ly0, V0, pN0(0/40), H0, P0, M0, pStage ⅠA. We understand the arterial running pattern before surgery by using MDCT, and performed laparoscopic surgery safely.

Background: Chemotherapy-induced nausea and vomiting(CINV)are typical side effects caused by chemotherapy. We analyzed CINV during first-line chemotherapy for gastric cancer., Materials and Method: Thirty-one patients who received first-line chemotherapy for gastric cancer were retrospectively assessed for CINV., Results: The median age was 70 years, and the gender(male/female)was 23/8 cases. NK1 receptor antagonist, 5-HT3 receptor antagonist, and dexamethasone were used as antiemetic agents in 29 patients(94%). Sixteen patients(52%)had Grade 1 or higher nausea, and 6 patients (19%)had Grade 1 or higher vomiting, and complete control of nausea and vomiting was achieved in 21 patients(68%). Nausea was significantly more frequent in patients with liver metastasis(p=0.0008), but there was no significant difference in vomiting(p=1.0000). There was no significant difference in the occurrence of CINV between chemotherapy regimens or combination of olanzapine., Conclusion: During first-line chemotherapy for gastric cancer, 3 antiemetic agents were used in 94% of cases, and the complete control rate of CINV was 67.8%.

A 71-year-old male had repeated resection and transcatheter arterial chemo-embolization(TACE)for hepatocellular carcinoma(HCC). Treatment with lenvatinib was started due to multiple liver recurrences and peritoneal disseminations. Since only the disseminated lesion had increased, it was decided to perform laparoscopic resection. Indocyanine green(ICG) was intravenously injected the day before surgery. Disseminated lesions could be easily detected with intraoperative fluorescence imaging, and we could completely resect disseminated lesions. The ICG fluorescence could be considered to be useful in laparoscopic resection for peritoneal dissemination of HCC.

A 67-year-old woman with a pancreatic cancer diagnosed by endoscopic ultrasound with fine needle aspiration(EUS- FNA)was underwent distal pancreatectomy. Two years and 10 months after the operation, a computed tomography scan revealed a tumor in the posterior wall of the lower body of the stomach. Upper gastrointestinal endoscopy showed a 15 mm-sized submucosal tumor on the posterior wall of the angular region, and its biopsy showed tubular adenocarcinoma that it was resembling the resected pancreatic cancer. Needle tract seeding(NTS)of the pancreatic cancer to the gastric wall was suspected. After 5 courses of chemotherapy with gemcitabine and nab-paclitaxel, the tumor shrank and there were no other signs of metastasis, we performed distal gastrectomy. The pathological findings of the resected specimen showed a tubular adenocarcinoma, consistent with the primary pancreatic tumor. We finally diagnosed as the NTS of the pancreatic cancer to the gastric wall. In the case of EUS-FNA for the body or tail tumor of pancreas, it should be paid attention to the recurrence due to NTS because the surgical resection does not include the needle tract site.

We report a case of advanced gastric cancer that was successfully treated with mFOLFOX6 therapy. A 78-year-old man presented to our hospital with a chief complaint of weight loss. Esophagogastroduodenoscopy(EGD)and computed tomography( CT)revealed the presence of type 3 advanced gastric cancer with distant lymph node metastasis and peritoneal dissemination. Biopsy specimen examination revealed moderately differentiated adenocarcinoma with a HER2 score of 1. Chemotherapy comprising 5-fluorouracil, Leucovorin, and oxaliplatin(mFOLFOX6)was administered because of renal failure. Subsequently, the gastric lesion, distant lymph node metastasis, and peritoneal dissemination were seen to be reduced on EGD and CT. After 7 courses, the regimen was changed to 5-fluorouracil and Leucovorin(5-FU/l -LV)chemotherapy because of thrombocytopenia. For more than 10 months, he has continued to receive chemotherapy without the recurrence of metastasis.

This is the first report of the double primary cancer of esophageal cancer (EC) and myelodysplastic syndromes (MDS) treated without esophagectomy. Previously reported cases of the double cancer mostly describe secondary MDS arising after treatment for EC. The double primary cancer was manageable with close follow-ups for possible recurrence., Competing Interests: The authors declare that we have no competing interests., (© 2021 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.)

A 74‒year‒old man was diagnosed with advanced gastric cancer with para‒aortic lymph node metastasis and ascites. He has been treated with S‒1 plus oxaliplatin as the primary treatment, paclitaxel plus ramucirumab as the secondary treatment and CPT‒11 as the third‒line treatment, but the effect of all treatments were temporary and left adrenal metastasis appeared during the course. Nivolumab was started as the fourth‒line treatment. Two months later, para‒aortic lymph nodes and left adrenal metastasis were markedly shrank and ascites disappeared. A 79 years old woman was performed proximal gastrectomy for advanced gastric cancer of the upper stomach. S‒1 therapy was started as adjuvant chemotherapy, but tumor markers have been increased and para‒aortic lymph node recurrence was observed 4 months after the operation. After ramucirumab as the primary treatment was ineffective, nivolumab was started as the secondary treatment. Two months later, para‒aortic lymph nodes shrank below the significant size and tumor markers were normalized.

Background: Since delirium has various adverse effects in patients with malignant tumors, it is important to eliminate the cause. We investigated delirium in patients with malignant tumors., Method: Seventy seven malignant tumor patients who admitted to palliative care unit from May 2015 to March 2016 were subjected to a retrospective analysis of delirium., Results: Delirium was present in 17 patients(22.1%)on admission, and in 38 patients(49.4%)before discharge. After hospitalization, delirium improved without relapse in 5 patients(29%)and the onset of delirium was avoided in 34 patients(57%). Factors of delirium at admission were nausea and day/night reversal, factors of delirium at discharge were dementia, pain, and day/night reversal., Conclusions: In the present study, we investigated the causes and course of delirium in patients with malignant tumors.

We report a case of gastrointestinal submucosal tumor with an intraluminal growth pattern resected by laparoscopic wedge resection. A 62-year-old man was admitted because of melena. Upper gastrointestinal endoscopy revealed gastrointestinal submucosal tumor with an intraluminal growth pattern just below the gastric junction, and the pathological diagnosis was GIST. A laparoscopic wedge resections(percutaneous endoscopic intragastric surgery)was performed by a single access port. After laparotomy 5 cm above the umbilicus, the anterior wall of the middle part of the stomach was incised and fixed to the skin, and the tumor was dissected with a linear stapler. The final pathology result showed a high risk GIST of 70×40 mm with 110 mitotic images/50 HPF, and the patient was treated with imatinib mesylate adjuvant chemotherapy. There were no complications, including postoperative transit disturbances, and there were no local or distant metastatic recurrences.

A 76-year-old man had undergone right lobectomy after transcatheter arterial chemoembolization(TACE)for hepatocellular carcinoma(HCC)in segment 5/6 of the liver. He had undergone TACE for intrahepatic recurrence in segment 1 eight months after the operation. Abdominal CT revealed intrahepatic recurrence in segment 2 and segment 3 and a hepatic portal lymph node swelling 13 months after the operation, he underwent TACE and radiofrequency ablation for intrahepatic lesions. There was neither intrahepatic recurrences nor new extrahepatic lesions, and the hepatic portal lymph node resection was performed. He was discharged on postoperative day 8, and there has been no subsequent recurrence over 42 months after initial treatment. The lymph node metastasis of HCC is rare and systemic chemotherapy such as molecular targeted argent is the standard treatment, but its prognosis is poor. When a patient has a resectable metastasis with controlled intrahepatic lesions, lymph node resection appears to be an effective option.

Generally, the first treatment plan for anal canal squamous cell carcinoma(SCC)is chemo-radiation therapy(CRT). We experienced an extremely rare surgery case of anal canal SCC after prostate brachytherapy. A man in his 70s who had undergone brachytherapy for prostate cancer 8 years before visited our hospital because of blood in feces. A tumor prolapsed from the anal verge, and biopsy revealed SCC. Contrast-enhanced computed tomography showed front-wall thickness in the lower rectum, but we could not evaluate it in detail because of the halation by brachytherapy seeds. We performed laparoscopic abdominoperineal resection to avoid an overdose of radiation for the rectum. Pathological staging was pT2N1aM0, pStage ⅢA. These findings might suggest radiation-induced cancer after brachytherapy.

A 96-year-old woman was brought to our hospital for epigastric pain. Abdominal contrast-enhanced CT and MRCP showed wall thickness of the fundus and extravasation in the gallbladder. With a diagnosis of gallbladder hemorrhage from the tumors, we performed laparoscopic cholecystectomy. The histopathological diagnosis was gallbladder cancer. Herein, we report on this case and also provide a literature review.

A 65-year-old male received the positive result of fecal occult blood. Colonoscopy was performed to reveal a tumor in the ascending colon. The result of biopsy was neuroendocrine carcinoma. Under the preoperative diagnosis of neuroendocrine carcinoma in the ascending colon, cT3N0M0, cStage Ⅱ, laparoscopic ileocecal resection with D3 lymph node dissection was performed. The pathological result was neuroendocrine carcinoma in the ascending colon, pT4aN2M0, pStage Ⅲc. The R0 resection was achieved. As adjuvant chemotherapy, the regimen of cisplatin plus irinotecan was administered for 4 courses. No recurrence was seen until 9 months after the operation, when multiple peritoneal and hepatic metastasis were detected on CT scan. The chemotherapy regimen of etoposide plus carboplatin was started and is now ongoing. The patient is now alive 13 months after the operation.

We report a case of laparoscopic repair of a diaphragmatic hernia after left hepatectomy for liver cancer. A woman in her 70s had undergone left hepatectomy for liver cancer 9 months earlier, and she was admitted because of epigastric pain after vomiting immediately following contrast-enhanced CT. On the next day, contrast-enhanced CT revealed an incarcerated diaphragmatic hernia, for which laparoscopic diaphragmatic hernia repair was performed. The incarcerated stomach was pushed back into the abdominal cavity, and the diaphragm was closed with 2-0 proline sutures. Gastric resection was not performed because the blood flow gradually improved. The postoperative course was good; the patient was discharged on the 7th postoperative day and is under outpatient follow-up.

We report a case of early gastric cancer in the remnant stomach after successful treatment with endoscopic submucosal dissection(ESD). A 64-year-old woman had undergone distal gastrectomy, D2 dissection, and Billroth Ⅰ reconstruction for advanced gastric cancer 11 years previously. During a routine upper gastrointestinal endoscopy, an elevated lesion was detected at the lesser curvature of the upper gastric body of the remnant stomach, and biopsy indicated a Group 4 tumor. Curative en bloc resection of the lesion was achieved via ESD, although there was severe fibrosis along the suture line. The pathological result was 0-I, pT1a, tub1, 3×3 mm, UL(－), ly(－), v(－), HM0(8 mm), VM0(800 μm), indicating curative resection. Surveillance of the upper gastrointestinal tract 5 years after gastric cancer surgery enabled the early detection of the gastric cancer and curative resection with ESD.

Background: Peritoneal dissemination (PD) frequently occurs in gastric cancer (GC) and is incurable. In this study, we aimed to identify novel PD-associated genes and clarify their clinical and biological significance in GC., Materials and Methods: We identified LOXL1 as a PD-associated candidate gene by in silico analysis of GC datasets (highly disseminated peritoneal GC cell line and two freely available GC datasets, GSE15459 and TCGA). Next, we evaluated the clinical significance of LOXL1 expression using RT-qPCR and immunohistochemistry staining (IHC) in a validation cohort (Kyushu cohort). Moreover, we performed gene expression analysis, including gene set enrichment analysis (GSEA) with GSE15459 and TCGA datasets. Finally, we performed a series of in vitro experiments using GC cells., Results: In silico analysis showed that LOXL1 was overexpressed in tumor tissues of GC patients with PD and in highly disseminated peritoneal GC cells, relative to that in the control GC patients and cells, respectively. High expression of LOXL1 was a poor prognostic factor in the TCGA dataset. Next, IHC showed that LOXL1 was highly expressed in GC cells. High LOXL1 mRNA expression was associated with poorly differentiated histological type, lymph node metastasis, and was an independent poor prognostic factor in the Kyushu validation cohort. Moreover, LOXL1 expression was positively correlated with the EMT (epithelial-mesenchymal transition) gene set in GSEA. Finally, LOXL1-overexpressing GC cells changed their morphology to a spindle-like form. LOXL1 overexpression reduced CDH1 expression; increased the expression of VIM, CDH2, SNAI2, and PLS3; and promoted the migration capacity of GC cells., Conclusions: LOXL1 is associated with PD in GC, possibly through the induction of EMT., Competing Interests: I have read the journal's policy and the author (Koshi Mimori) of this manuscript has the following competing interests: [Eli Lilly Japan K.K. Grant]. No authors of this manuscript received funding in the form of salary. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There were no patents, products in development or marketed products to declare in this study.

Background: Due to the development of diagnostic imaging technology, we have increased chance of detecting multiple primary cancers. However, simultaneous triple cancer is still a very rare finding whose frequency is not yet known. Treatment of simultaneous triple cancer is a clinical challenge because it requires multimodal strategies including surgery, chemotherapy and radiotherapy., Case Presentation: Here, we present the case of a 74-year-old male with triple cancer involving esophageal and pancreatic cancer, and rectal carcinoma. Each cancer was surgically resectable, but simultaneous resection of all cancers seemed to cause too much surgical stress for the patient. First, we performed a laparoscopic Hartmann's operation for rectal cancer to minimize the risk of postoperative complications. Then treatment for pancreatic cancer was initiated by administering neoadjuvant chemotherapy with gemcitabine plus nab-paclitaxel. The pancreatic tumor shrank in size, so pancreatoduodenectomy was performed. We chose S-1 as adjuvant chemotherapy. The esophageal cancer showed regression during the treatment of the other two cancers, likely because the chemotherapeutic agents administered for pancreatic cancer had some effect on the esophageal cancer. Definitive chemoradiotherapy was selected instead of esophagectomy because the patient had already undergone two major surgeries. The patient is still alive nine months after the whole course of treatment with no sign of recurrence., Conclusions: The treatment of triple cancer requires an elaborate strategy to determine which cancer has to be dealt with first and which can be treated later. An aggressive multimodal treatment strategy may be an important option for a patient with triple cancer.

Background/aim: The spliceosome pathway, including Splicing Factor 3b Subunit 4 (SF3B4), plays an important role in carcinogenesis and progression in various cancers; however, the clinical relevance of SF3B4 in esophageal squamous cell carcinoma (ESCC) remains unknown., Patients and Methods: SF3B4 expression was evaluated by real-time reverse transcription polymerase chain reaction in 80 ESCC patients. In order to explore the mechanism of SF3B4 in ESCC, the mRNA expression and copy number of SF3B4 were obtained from TCGA and we also implemented gene set enrichment analysis (GSEA)., Results: The high SF3B4 expression group (n=33) showed significantly more lymphatic permeation and poorer prognosis than the low SF3B4 expression group (n=47). GSEA revealed that high SF3B4 expression was correlated with genes associated with the transcription factor E2F and the G 2 /M checkpoint. SF3B4 expression was positively correlated with SF3B4 DNA copy number., Conclusion: Over-expression of SF3B4 may play a crucial role in the lymphatic progression of ESCC., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

A 71-year-old man underwent laparoscopic lower anterior resection(D3 dissection)for rectal cancer and bilateral lung metastases. Histopathological findings indicated Ra, type 2, tub2, ly0, v2, pN0, pM1(PUL1), pStage Ⅳ. The lung metastases had disappeared after postoperative chemotherapy and the patient entered cCR. Two years after the surgery, the patient's anal fistulas appeared sclerotic. Biopsy revealed recurrent rectal cancer. We performed an abdominoperineal resection and rectus abdominis muscle flap. Currently, the patient is alive at 9 months after surgery with no re-recurrence.

We report a case ofadvanced colon cancer, stage cT4bN0M0 in the descending colon with formation ofabscesses in the retroperitoneal space ofa 66-year-old woman. After constructing a transverse colostomy and percutaneous abscess drainage, chemotherapy was initiated with CAPOX. After 4 courses of CAPOX, the tumor had significantly regressed; therefore, the regimen was switched to a triplet combination called CAPOXIRI. After 3 courses of CAPOXIRI, the tumor had become smaller and had separated from the iliopsoas muscle, which led us to perform surgical resection. Left hemicolectomy was performed with R0 resection, and the tumor was pathologically diagnosed as ypT3N0M0. The patient is alive 12 months after the surgery, with no signs of recurrence.

A 73-year-old man underwent a subtotal stomach preserving pancreaticoduodenectomy(SSPPD)for biliary carcinoma without regional lymph node metastasis. Although S-1 was administrated as adjuvant chemotherapy after the operation, the serum CA19-9 level was gradually elevated, and a liver metastasis of 27mm in diameter was detected in Couinaud's segment 8 during chemotherapy. We administrated gemcitabine(GEM)and cisplatin(CDDP)combination therapy(GC therapy). The liver tumor was immediately shrunk to 6mm and kept up the PR state after 15 courses of GC therapy. A stereotactic body radiation therapy(SBRT)was performed 1 year 8 months after the operation. The patient has been alive without recurrence for 4 years since the SBRT. Although systemic chemotherapy is the standard treatment for the recurrence of biliary carcinoma, a loco-regional therapy such as SBRT may be an effective alternative when a patient has a solitary metastasis to the liver with no other evidence of recurrence.

A 60-year-old man was diagnosed with advanced gastric cancer(cT4a, N1, M1[No. 16LYM], cStage Ⅳ). He was treated with a neoadjuvant chemotherapy of a regimen consisting of capecitabine plus oxaliplatin, followed by distal gastrectomy with D2 and No. 16lymph node dissection and partial hepatectomy of S3 and S6. He had an uncomplicated postoperative course and was discharged early from hospital. Capecitabine was started at POD 40 as an adjuvant chemotherapy. Postoperatively, the histological effect was determined to be Grade 2, and hepatic tumors and lymph nodes showed no residual cancer. He started capecitabine monotherapy as adjuvant chemotherapy. At 10 months postoperatively, the patient was alive and relapse-free.

In general, distant metastasis is uncommon in colorectal submucosal(SM)invasion without lymph node metastasis. We experienced an extremely rare case of synchronous pulmonary metastases for colon cancer in SM invasion. A man in his 70s was seen at the hospital for a positive fecal occult blood test. Colonoscopy revealed 3 lesions in the sigmoid colon and endoscopic mucosalresection revealed 2,000 mm SM invasion in all 3 lesions. Computed tomography showed no signs of distant lymph node or liver metastasis but showed small nodules in both lungs. Radical treatment included laparoscopic anterior resection with lymph node dissection. Histological examination showed no residual tumor in the colon and no lymph node metastasis. Two years after surgery, the number of lung nodules gradually increased and we performed partial resection of the left lung, which was diagnosed as pulmonary metastasis from colon cancer by histological examination. Therefore, we resected the opposite-side pulmonary metastases. The patient has exhibited no other signs of recurrence in the 2 years since the last operation.

The patient was a man in his 70s who visited our hospital to undergo an examination for fecal occult blood, which detected a 20 mm, Ⅱa lesion in the lower rectum on colonoscopy. He was diagnosed with SM-invasive cancer and was planned to undergo trans-anal local excision. After the surgery, he had a good postoperative course without complications. The pathological findings were Ⅱa, tub1, 22×16 mm, pT1a(950 mm), int, INF a, ly0, v0, pHM0, pVM0(300 mm). He was followed up after the surgery, but was diagnosed with lateral lymph node recurrence 4 years after a local surgery. The surgery involved right-sided lateral lymphadenectomy with resection of the ureter, spermatic duct, seminal vesicle, and piriformis muscle. He was diagnosed with lymph node metastasis with invasion of the spermatic duct based on pathology. Eight courses of adjuvant chemotherapy containing CapeOX was administered. Unfortunately, primary squamous cell lung cancer was detected, and he died after surgery for recurrence in the second year. It is suggested that it is necessary to note lateral lymph node recurrence on postoperative follow-up for lower rectal cancer at any stage.

Background: In gastric cancer (GC), peritoneal dissemination (PD) occurs frequently and is incurable. In this study, we aimed to identify PD-associated genes in GC., Methods: We identified a PD-associated gene using three GC datasets: highly disseminated peritoneal GC cell lines, the Singapore dataset and The Cancer Genome Atlas (TCGA) dataset. We assessed the clinicopathological significance of the gene expression using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and performed immunohistochemical analysis for the gene in our patient cohort. We also performed survival analyses of the gene in our patient cohort, the Singapore dataset and the GSE62254 datasets. Moreover, gene set enrichment analysis (GSEA) was performed using the Singapore and TCGA datasets. Finally, in vitro experiments such as invasion/migration assays, immunofluorescence staining of actin filaments, epidermal growth factor (EGF) treatment analysis, and gene expression analysis were conducted using three gene-knockdown GC cell lines (AGS, 58As9, MKN45)., Results: ADP-ribosylation factor-like 4c (ARL4C) was identified as a PD-associated gene, and immunohistochemical analysis showed that ARL4C was overexpressed in GC cells. High ARL4C expression was associated with the depth of invasion (p < 0.01) and PD (p < 0.05) and was a poor prognostic factor (p < 0.05) in our patient cohort, the Singapore dataset and the GSE62254 dataset. ARL4C expression positively correlated with the epithelial-mesenchymal transition (EMT) gene set in GSEA. Moreover, ARL4C knockdown reduced invasion/migration capacity, SLUG expression, and the formation of lamellipodia or filopodia in AGS and 58As9 cells. Finally, EGF treatment increased ARL4C expression in MKN45 cells., Conclusions: ARL4C was associated with PD and was a poor prognostic factor in GC, possibly through promoting invasive capacity by activation of both EMT and motility.

Objective: The involvement of epithelial-mesenchymal transition (EMT) in esophageal squamous cell carcinoma (ESCC) has not been fully elucidated. Here, we aimed to identify EMT-related genes associated with TGF-β in ESCC and to clarify the role of these genes in the progression of ESCC., Methods: EMT-related genes associated with TGF-β expression were identified in patients with ESCC using microarray analysis and public datasets. The effects of ubiquitin-like with PHD and ring finger domains 2 (UHRF2) expression were analyzed in ESCC cell lines. Cell proliferation and invasion were measured using MTT and invasion assays, respectively. UHRF2 mRNA expression was also analyzed in 75 ESCC specimens to determine the clinical significance of UHRF2 in ESCC., Results: Treatment of ESCC cell lines with TGF-β increased UHRF2 expression. UHRF2 overexpression increased CDH1 (E-cadherin) expression and decreased invasive capacity. The 75 ESCC specimens were divided into the UHRF2 high-expression group (n = 61) and the UHRF2 low-expression group (n = 14). Low UHRF2 expression was significantly correlated with vascular invasion (p = 0.034) and was an independent prognostic factor for poor prognosis (p = 0.005)., Conclusion: UHRF2 may be a negative regulator of EMT and a novel prognostic biomarker for ESCC., (© 2018 S. Karger AG, Basel.)

The present authors previously identified a novel candidate tumor suppressor gene, zinc finger protein 750 ( ZNF750 ), in esophageal squamous cell carcinoma (ESCC) (1). The present study aimed to clarify the clinical significance of ZNF750 expression in ESCC. The association between ZNF750 DNA mutation status and the mRNA expression was examined by whole exome sequence analysis and quantitative reverse transcription polymerase chain reaction (RT-qPCR). The expression of ZNF750 in 76 patients with ESCC (Kyushu University Beppu Hospital) was measured using immunohistochemistry and RT-qPCR. Using this dataset, the association between ZNF750 mRNA expression and clinicopathological factors was examined. Additionally, survival analysis was performed using datasets from the Kyushu University Beppu Hospital and The Cancer Genome Atlas (TCGA). The biological effects of ZNF750 expression were explored using gene set enrichment analysis (GSEA) and were validated using datasets from the Cancer Cell Line Encyclopedia (CCLE) and the Kyushu University Beppu Hospital. ZNF750 expression analyses demonstrated that ZNF750 mRNA expression was lower in patients with the DNA mutations compared with those without the mutations (P<0.05), and ZNF750 expression was downregulated in tumor tissues compared with normal tissues (P<0.00005). In the clinicopathological analysis, the low ZNF750 expression group exhibited a higher incidence of undifferentiated histology (P<0.05) compared with the high expression group. The low ZNF750 expression group exhibited a poorer prognosis in the Kyushu and TCGA datasets (P<0.0005 and P<0.05, respectively). GSEA indicated that ZNF750 expression was significantly correlated with epithelial differentiation in ESCC. This was confirmed using the datasets from CCLE and the Kyushu University Beppu Hospital by analyzing the levels of small proline rich protein 1A mRNA, an epithelial differentiation-associated gene. In conclusion, the results of the present study suggested that ZNF750 serves a role as a tumor suppressor; potentially via regulating epithelial differentiation and that it may be a promising biomarker of poor outcomes in ESCC.

Background/aim: Amplification of chromosome 7p (Ch.7p) is common in colorectal cancer (CRC). The aim of this study was to identify potential driver genes on Ch.7p that are overexpressed due to DNA copy number amplification and determine their clinical significance in CRC., Materials and Methods: We identified phosphoserine phosphatase (PSPH) as a potential driver gene using a CRC dataset from The Cancer Genome Atlas (TCGA) using a bioinformatics approach. The expression of PSPH in 124 primary CRCs was examined by quantitative reverse transcription polymerase chain reaction (PCR) and immunohistochemistry. The biological effect of PSPH expression was explored by Gene Set Enrichment Analysis (GSEA) using the TCGA dataset., Results: PSPH was overexpressed in tumor tissues and PSPH positively correlated with depth of invasion and distant metastasis. On multivariate analysis, high PSPH expression was an independent poor prognostic factor. These results were supported by GSEA., Conclusion: PSPH could be a novel prognostic biomarker with malignant potential on Ch.7p in CRC., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: The RND1 gene encodes a protein that belongs to the Rho GTPase family, which regulates various cellular functions. Depletion of RND1 expression activates the oncogenic Ras signaling pathway. In this study, we aimed to clarify the clinical significance of RND1 expression in predicting prognosis and to investigate its biological role in human hepatocellular carcinoma (HCC)., Methods: The association between RND1 expression and clinical outcomes in patients with HCC was analyzed in three independent cohorts: 120 cases resected in our hospital; 370 cases in The Cancer Genome Atlas (TCGA); and 242 cases in GSE14520. Gene set enrichment analysis (GSEA) was also conducted. Finally, knockdown experiments were performed using small interfering RNA (siRNA) in vitro., Results: In all cohorts, RND1 expression was decreased as cancer progressed, and was affected by promoter methylation. In our HCC cases, the 5-year overall survival (OS) and recurrence-free survival of patients with low RND1 expression was significantly poorer than those of patients with high RND1 expression. TCGA and GSE14520 analyses provided similar results for OS. Multivariate analysis indicated that RND1 expression was an independent prognostic factor for OS in all three cohorts. Additionally, GSEA showed an inverse correlation between RND1 expression and the Ras signaling activity. In vitro, knockdown of RND1 expression resulted in significant increases in proliferation, invasion, and chemoresistance to cisplatin in HCC cells., Conclusions: Reduced RND1 expression in HCC was associated with cancer progression, likely through regulation of the Ras signaling pathway, and may serve as a novel clinical biomarker for predicting prognosis in patients with HCC.

miR-146a plays important roles in cancer as it directly targets NUMB, an inhibitor of Notch signaling. miR-146a is reportedly regulated by a G>C polymorphism (SNP; rs2910164). This polymorphism affects various cancers, including colorectal cancer (CRC). However, the clinical significance of miR-146a polymorphism in CRC remains unclear. A total of 59 patients with CRC were divided into 2 groups: a CC/CG genotype (n = 32) and a GG genotype (n = 27), based on the miR-146a polymorphism. cDNA microarray analysis was performed using 59 clinical samples. Significantly enriched gene sets in each genotype were extracted using GSEA. We also investigated the association between miR-146a polymorphism and miR-146a, NUMB expression or migratory response in CRC cell lines. The CC/CG genotype was associated with significantly more synchronous liver metastasis (p = 0.007). A heat map of the two genotypes showed that the expression profiles were clearly stratified. GSEA indicated that Notch signaling and JAK/STAT3 signaling were significantly associated with the CC/CG genotype (p = 0.004 and p = 0.023, respectively). CRC cell lines with the pre-miR-146a/C revealed significantly higher miR-146a expression (p = 0.034) and higher NUMB expression and chemotactic activity. In CRC, miR-146a polymorphism is involved in liver metastasis. Identification of this polymorphism could be useful to identify patients with a high risk of liver metastasis in CRC., Competing Interests: The authors have declared that no competing interests exist.

Background/aim: Homeobox B7 (HOXB7) gene is involved in various cellular functions. We investigated the clinical significance of HOXB7 expression in hepatocellular carcinoma (HCC)., Materials and Methods: HOXB7 mRNA expression in 103 HCC samples and 58 matched non-cancerous liver tissues were examined by quantitative real-time polymerase chain reaction (qRT-PCR). HOXB7 protein expression was also examined by immunohistochemistry. Gene set enrichment analysis (GSEA) was performed using a public dataset., Results: HOXB7 expression was significantly higher in HCC tissues than in liver parenchyma. Ten-year overall survival (OS) and 5-year recurrence-free survival (RFS) of cases with higher HOXB7 expression were significantly poorer than those with lower HOXB7 expression. HOXB7 expression was significantly associated with larger tumor size and higher rate of biliary invasion and constituted an independent prognostic factor for OS by multivariate analysis. These results were supported by GSEA., Conclusion: HOXB7 expression in HCC could be a novel biomarker for long-term prognosis after tumor resection., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background/aim: Defects in alternative splicing contribute to carcinogenesis, cancer progression and chemoresistance. The spliceosome pathway, including SF3B4, a component of spliceosomal complex is suggested to play a role in progression of hepatocellular carcinoma (HCC); however, the clinical relevance of SF3B4 in HCC remains unknown., Patients and Methods: SF3B4 expression was evaluated by real-time reverse transcription polymerase chain reaction in 72 HCC samples and non-cancerous liver samples. The relationship between the DNA copy number and SF3B4 expression levels was investigated using TCGA datasets., Results: SF3B4 expression was significantly higher in cancerous than in non-cancerous tissues and positively correlated with SF3B4 DNA copy number. High SF3B4 expression is significantly associated with intrahepatic metastasis and poor prognosis. These results were consistent with data from the public datasets., Conclusion: Overexpression of SF3B4, that is due to DNA copy number increase, is suggested to play a role in progression of HCC., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: The nephroblastoma overexpressed (NOV) gene, which belongs to the cysteine-rich, angiogenic inducer 61/connective tissue growth factor/nephroblastoma overexpressed (CCN) family, is located in the 8q24 region and promotes migration and invasiveness in several types of malignancies. We explored the clinical significance of NOV expression in colorectal cancer (CRC)., Materials and Methods: NOV expression in CRC specimens and CRC cell lines were evaluated. The association between the clinicopathlogical factors and NOV mRNA expression of tumor tissues was assessed in 126 patients with CRC. We assessed the relationships between NOV expression and overall survival in public databases. We performed overexpression experiments in vitro., Results: CRC specimens and CRC cell lines showed high NOV expression. High NOV mRNA expression was correlated with poorer overall survival and higher Union for International Cancer Control (UICC) T factor. In public databases, high NOV expression was associated with poorer prognoses. Overexpression of NOV promoted invasiveness of CRC cells., Conclusion: NOV may be an indicator of poor prognosis and a therapeutic target in CRC., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

A 66-year-old man was diagnosed with advanced gastric cancer (cT4a, N0, M1[ADR], cStage Ⅳ). He was treated with a triplet neoadjuvant chemotherapy regimen including docetaxel, cisplatin, and S-1, followed by totally laparoscopic total gastrectomy with D2+16a2lat lymph node dissection and adrenalectomy. He had an uncomplicated, good postoperative course and was discharged early from the hospital. S-1 plus cisplatin was started on POD42 as adjuvant chemotherapy. In such cases of solitary left adrenal metastasis from gastric cancer, multidisciplinary treatment comprising perioperative chemotherapy and radical surgery is required. In this report, we demonstrated that totally laparoscopic radical surgery with an uneventful postoperative course allowed the patient to initiate adjuvant chemotherapy in the early postoperative period.

Purpose: Esophageal squamous cell carcinoma (ESCC) frequently shows a poor prognosis because of the occurrence of systemic metastasis, mainly via lymphatic vessels. Valosin-containing protein (VCP) has been shown to be associated with antiapoptotic function and metastasis via activation of the nuclear factor-kappaB signaling pathway. In the present study, we examined the association of VCP with the recurrence and prognosis of ESCC., Experimental Design: VCP expression in 156 ESCC patients [139 males and 17 females; age range, 38-82 (median, 60) years] was analyzed by immunohistochemistry. Staining intensity in tumor cells was categorized as weaker (level 1) or equal to or stronger (level 2) than that in endothelial cells. The correlation of VCP expression between the mRNA and protein levels was examined in 12 patients., Results: Fifty-seven (37.3%) cases showed level 1 and 96 (62.7%) level 2 VCP expression. Quantitative reverse transcription-PCR analysis revealed greater VCP mRNA expression in level 2 (n = 6) than level 1 cases (n = 6; P < 0.05). ESCC with level 2 expression showed higher rates of lymph node metastasis (P < 0.01) and deep tumor invasion (P < 0.01), and poorer disease-free and overall survival rates (P < 0.001 for both analyses) than ESCC with level 1 expression. Multivariate analysis revealed that VCP expression level is an independent prognosticator for disease-free and overall survival. Furthermore, VCP level was an indicator for disease-free survival in the early (pT1) and the advanced (pT2-pT4) stage groups., Conclusion: This study demonstrated the prognostic significance of VCP expression in ESCC.