Urinary microRNA-210-3p as a novel and non-invasive biomarker for the detection of pancreatic cancer, including intraductal papillary mucinous carcinoma.

BACKGROUND: This study aims to explore novel microRNAs in urine for screening and predicting clinical characteristics in pancreatic cancer (PC) patients using a microRNA array-based approach. METHODS: We used the Toray® 3D-Gene microRNA array-based approach to compare urinary levels between PC patients and healthy volunteers. RESULTS: (1) Four oncogenic microRNAs (miR-744-5p, miR-572, miR-210-3p, and miR-575) that were highly upregulated in the urine of PC patients compared to healthy individuals were identified by comprehensive microRNA array analysis. (2) Test-scale analysis by quantitative RT-PCR for each group of 20 cases showed that miR-210-3p was significantly upregulated in the urine of PC patients compared to healthy individuals (P = 0.009). (3) Validation analysis (58 PC patients and 35 healthy individuals) confirmed that miR-210-3p was significantly upregulated in the urine of PC patients compared to healthy individuals (P < 0.001, area under the receiver operating characteristic curve = 0.79, sensitivity: 0.828, specificity: 0.743). We differentiated PC patients into invasive ductal carcinoma (IDCa) and intraductal papillary mucinous carcinoma (IPMC) groups. In addition to urinary miR-210-3p levels being upregulated in IDCa over healthy individuals (P = 0.009), urinary miR-210-3p levels were also elevated in IPMC over healthy individuals (P = 0.0018). Urinary miR-210-3p can differentiate IPMC from healthy individuals by a cutoff of 8.02 with an AUC value of 0.762, sensitivity of 94%, and specificity of 63%. (4) To test whether urinary miR210-3p levels reflected plasma miR-210-3p levels, we examined the correlation between urinary and plasma levels. Spearman's correlation analysis showed a moderate positive correlation (ρ = 0.64, P = 0.005) between miR-210-3p expression in plasma and urine. CONCLUSIONS: Urinary miR-210-3p is a promising, non-invasive diagnostic biomarker of PC, including IPMC. TRIAL REGISTRATION: Not applicable.

Effects of forest bathing (shinrin-yoku) on serotonin in serum, depressive symptoms and subjective sleep quality in middle-aged males.

BACKGROUND: We previously found that a forest bathing (shinrin-yoku) program significantly reduced the scores for depression, anxiety, anger, fatigue, and confusion and increased the score for vigor in the profile of mood states (POMS) test and showed a potential preventive effect on the depressive status in both males and females. In the present study, we investigated the effects of a forest bathing program on the level of serotonin in serum, depressive symptoms and subjective sleep quality in middle-aged males. METHODS: Twenty healthy male subjects aged 57.3 ± 8.4 years were selected after obtaining informed consent. These subjects took day trips to a forest park, the birthplace of forest bathing in Japan named Akasawa Shizen Kyuyourin, Agematsu, Nagano Prefecture (situated in central Japan), and to an urban area of Nagano Prefecture as a control in June 2019. On both trips, they walked 2.5 km for 2 hours each in the morning and afternoon on Saturday and Sunday, respectively. Blood was sampled in the afternoon before and after each trip. Concentrations of serotonin and lactic acid in serum were measured. The POMS test and a questionnaire for subjective sleep quality were conducted before and after the trips. Ambient temperature and humidity were monitoring during the trips. The Ethics Committees of the Nippon Medical School and Nagano Prefectural Kiso Hospital approved this study. RESULTS: The forest bathing program significantly increased level of serotonin in serum, and significantly increased the score for vigor and decreased the score for fatigue in the POMS test. The forest bathing program also improved the sleepiness on rising and feeling refreshed (recovery from fatigue) in the Oguri-Shirakawa-Azumi sleep inventory MA version (OSA-MA). CONCLUSIONS: Taken together, the present study suggests that forest bathing may have potential preventive effects on depression (depressive status).

[Clinical Features and Treatment for Cholangiolocellular Carcinoma(CoCC)-Report of Three Cases].

We report 3 cases of cholangiolocellular carcinoma(CoCC)experienced from April 2017 to March 2021 in our hospital. The average age of the cases is 74.3 years old, 2 males and 1 female respectively. Hepatectomy was performed in 2 cases, and transcatheter arterial embolization(TAE)and radiofrequency ablation(RFA)therapy was performed in 1 case because of old age and his wishes as the background liver disease. Chronic hepatitis C was found in 1 case, fatty liver in 1 case, and alcoholic liver disease in 1 case. Two patients who underwent hepatectomy had good long-term prognosis, but another patient who underwent TAE and RFA developed early recurrence at bone and died in 3 months after treatment. Therefore, we consider that the risk of recurrence should be examined and the treatment should be performed accordingly.

Oligometastasis scoring system for predicting survival of patients with colorectal liver metastasis after hepatectomy.

BACKGROUND: Oligometastasis, the presence of a small number of resectable metastatic tumors, usually has favorable outcomes. Here we examined whether the novel oligometastatic score (OLGS), which divides the number of colorectal liver metastases (CRLMs) by the time from colorectal resection to liver recurrence, better predicts CRLM patient survival than the commonly used clinical risk score. METHODS: A total of 143 patients who underwent curative hepatectomy for CRLMs between 2007 and 2018 were analyzed. We investigated their clinical characteristics and outcomes using OLGS. RESULTS: Of the 143 CRLM patients, 70 had synchronous CRLMs and 73 had metachronous CRLMs. Patients with metachronous CRLMs were divided into OLGS-low (n = 59) and OLGS-high (n = 14) subgroups. The 5-year overall survival (OS) rates after hepatectomy differed significantly between the subgroups (p < .001). In the multivariate Cox model, a high OLGS was an independent predictor of 5-year OS (p < .001), and the hazard ratio (HR) of the OLGS-high group (HR = 7.171) was higher than that of the high clinical risk score group (HR = 4.337). CONCLUSION: The OLGS, a simple and handy scoring system, better predicts the 5-year OS of patients with CRLMs after hepatectomy and warrants prospective validation.

[Case of a 5mm Rectal Neuroendocrine Tumor(G1)with Lymph Node Metastasis].

Screening colorectal endoscopy revealed a 5mm rectal neuroendocrine tumor(NET: G1)in a 72-year-old man. Endoscopic mucosal resection(EMR)was performed, and the histopathological examination demonstrated lymphatic and vessel invasion with a possible positive vertical margin. Therefore, we performed laparoscopic low anterior resection, lymphadenectomy, and ileostomy as additional surgical resections. No residual tumor was found in the specimen, but 3 metastatic lymph nodes were identified. The rate of lymph node metastasis in rectal NETs of diameter<10mm is low, and additional surgery can reduce the patient's quality of life affected due to impaired anorectal function. However, in the Japanese guidelines for NET, additional surgery is adopted in cases with high-risk factors for lymph node metastasis. Therefore, it is necessary to select between additional surgery and careful follow-upfor rectal NETs of diameter<10mm with high-risk factors because of possible lymph node metastasis.

[Curative Resection of Advanced Rectal Cancer with Direct Invasion of the Prostate and Extra-Regional Lymph Node Metastases after Chemotherapy].

A-69-year-old man presented with an obstructed defecation. He was diagnosed as having advanced lower rectal cancer with direct invasion of the prostate and metastases to regional and para-aortic lymph nodes. Biopsy examination of the tumor showed RAS wild-type expression and negative BRAF V600E mutation. The patient received 13 courses of mFOLFOX6 and panitumumab(Pmab)in combination and 1 course of mFOLFOX6 alone. After the chemotherapy, the size of the primary tumor and lymph node metastases decreased remarkably. 18F-fluorodeoxyglucose-positron emission tomography(18F-FDG- PET)showed no 18F-FDG accumulation in the tumor and lymph nodes. We performed laparoscopic abdominoperineal resection with D3LD2 lymph node dissection and left external iliac lymph node(293-lt)sampling. Pathological examination revealed no residual cancer at the primary tumor location and only a few malignant cells remained in the 293-lt lymph node. The patient has shown no recurrence for 1 year without adjuvant chemotherapy. We conclude that mFOLFOX6 and Pmab in combination is an effective preoperative chemotherapy against advanced RAS wild-type rectal cancer. This strategy may reduce surgical invasion and save the surrounding organs while maintaining curability.

[Successful curative resection after chemotherapy for initially unresectable advanced gallbladder cancer with rectal metastasis:a case report].

A 42-year-old male was referred to our hospital with bloody feces and lower back pain. He was diagnosed with unresectable gallbladder cancer with rectal metastasis (T3aN1M1, Stage IVB). The patient was administered gemcitabine plus cisplatin (GC). After nine courses of GC, computed tomography showed regression of the tumor and the patient's tumor marker levels had decreased. Therefore, curative resection was performed. Ten months after the operation, recurrence was observed in the rectal margin and GC was restarted. Because the total dose of cisplatin was 1040mg, we stopped cisplatin and continued to administer only gemcitabine (at the same dose). A follow-up examination 2 years after the operation showed no evidence of recurrence. Conversion therapy might be an effective multidisciplinary treatment for advanced gallbladder cancer that is initially unresectable. Herein, we report the case of a patient with advanced gallbladder cancer and rectal metastasis who was successfully treated by curative resection after chemotherapy;we also review the relevant literature.

[Neoadjuvant FOLFIRINOX for Unresectable Adenocarcinoma of the Pancreas - A Case Report].

A 38-year-old male presented to our hospital with complaint of vomiting. A CT demonstrated a mass sized 42mm in the pancreatic head invading to the duodenum and a liver mass sized 15mm in the medial segment. Biopsy revealed adenocarcinoma. Due to liver metastasis, he was deemed surgically unresectable. He was started on FOLFIRINOX therapy after gastrojejunum bypass operation. After 15 courses of the therapy, restaging showed a decrease in pancreatic tumor size and a disappearance of a liver mass along with PET-CT revealing no FDG-avid uptake. A serum value of DUPAN-2 was also normalized. He was offered resection as a potentially curative treatment. He underwent curative pancreaticoduodenectomy(PD), which was difficult to perform because of adhesion and hard fibrous tissues. Operating time and blood loss were 600 minutes and 1,933 mL, respectively. Histologic examination revealed Grade 1a histological chemotherapy effect. His cancer recurred 11 months after PD. He received nab-paclitaxel and gemcitabine regimen at out-patients clinic.

[Long-Term Survival of a Patient with Metastatic Liver and Para-Aortic Lymph Node Cancer from Colon Cancer Treated with Regorafenib].

A 54-year-old man was presented at our hospital with weight loss.He diagnosed with colorectal cancer, multiple liver metastases and para-aortic lymph node metastasis.After undergoing colostomy, he was treated sequentially with mFOLFOX6 plus bevacizumab(Bmab), FOLFIRI plus Bmab or Pmab, according to the guideline.Since these chemotherapy resulted in progressive disease, regorafenib was administered as a salvage-line treatment.PET -CT showed only para-aortic lymph node swelling with high FDG uptake.Severe adverse effects were developed shortly after regorafenib treatment so he requireda reduction in dose.Three years after treatment with regorafenib, the response of the target lesion was stable disease according to the RECIST criteria.Tumor growth had been controlled for a long time.

[A Successful Curative Resection Case of Metastatic Hepatocellular Carcinoma to the Kidney Which Extended into the Renal Vein].

A 78-year-old woman underwent partial hepatectomy for the treatment of hepatocellular carcinoma(HCC).After surgery, she was further treated with radiofrequency ablation(RFA)and transcatheter arterial embolization(TAE)for the intrahepatic reccurence of HCC.Thirty months after surgery, her tumor marker levels increased and computed tomography (CT)revealed an intrahepatic mass and right renal tumor which extended into the renal vein.We therefore suspected a reccurence of HCC and right renal cell carcinoma which extended into the renal vein, and thus performed right nephrectomy before again performing TAE to treat the reccurence of HCC.The pathological findings showed HCC metastasis in the kidney. Nephrectomy should be performed as soon as possible in patients with a renal vein tumor thrombus in order to prevent the occurrence of a pulmonary embolism.We herein describe a very rare oncologic emergency case and review the relevant literature.

[A Case Report of an Elderly Patient's Intrahepatic Cholangiocellular Carcinoma with Cholangitis].

We report a case of an elderly patient diagnosed with intrahepatic cholangiocellular carcinoma with cholangitis.An 88- year-old woman presented with fever.Computed tomography examination showed a hepatic tumor and dilation of the peripheral bile duct.Cholangiocarcinoma was diagnosed.Biliary tract drainage and palliative care were suggested because of her age.However, her family asked for a second opinion about operative management and consulted our hospital.Radical operations for intrahepatic cholangiocellular carcinoma that has spread to the left lobe are usually accompanied by widespread lymph node dissection and extensive hepatectomy with biliary tract reconstruction.However, in this case, the patient was very elderly and was able to safely undergo an operation by reduction of the excision range and by omitting lymph node dissection.We conclude that appropriate surgery and postoperative care to prevent complications are necessary when performing very invasive surgery in elderly patients.

Plasma level of metastasis-associated lung adenocarcinoma transcript 1 is associated with liver damage and predicts development of hepatocellular carcinoma.

Recent studies have shown that metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) was overexpressed in many human solid cancers, however, its roles in plasma of hepatocellular carcinoma (HCC) patients were unclear. The aim of this study was to investigate the significance of plasma MALAT1 levels in HCC patients. Plasma samples were collected from pre-operative HCC, hepatic disease patients, and healthy controls, and tissue samples from HCC patients and colorectal cancer patients with liver metastasis. Plasma and tissue MALAT1 levels were measured. Plasma MALAT1 levels were progressively and significantly higher in HCC patients than hepatic disease patients, and higher in hepatic disease patients than healthy controls. The expression of MALAT1 in HCC tissue was slightly higher than that in paired non-cancerous liver tissue, but not significant. The expression of MALAT1 in the non-cancerous liver tissue of 20 HCC patients was significantly higher than that in normal liver tissue of 13 colorectal cancer patients. In contrast, plasma MALAT1 levels were significantly low in HCC patients with hepatitis B infection, and significantly high in patients with liver damage B or liver cirrhosis. In a receiver-operator curve analysis of HCC and hepatic disease patients, the cut-off value of plasma MALAT1 was 1.60 and the area under the curve was 0.66. Plasma MALAT1 levels were not correlated with α-fetoprotein or protein induced by vitamin K absence II, whereas sensitivity and specificity for the detection of HCC with the combination of MALAT1, α-fetoprotein, and protein induced by vitamin K absence II were 88.6% and 75%, respectively. In conclusion, the plasma MALAT1 level is associated with liver damage, and has clinical utility for predicting development of HCC.

Modified high dorsal procedure for performing isolated anatomic total caudate lobectomy (with video).

BACKGROUND: Isolated anatomic total caudate lobectomy is indicated in patients who have liver tumors limited to the caudate lobe. However, isolated caudate lobe resection is a challenging surgical procedure that required safe and reliable techniques. All portal and hepatic veins that connect this area originate from the first branch of the portal vein or vena cava; therefore, the operator must be cautious of the potential for massive bleeding. METHODS: The important points regarding the safety of our procedure include creating an optimal surgical view and preparing for accidental bleeding before parenchymal dissection. Sufficient mobilization and removal of Spiegel's lobe from the left to the right side of the vena cava allows the operator to perform parenchymal dissection under a right- or front-side view. RESULTS: We have performed this technique in two patients with HCC and one patient with primary cystadenocarcinoma. The average operative time and amount of blood loss were 435 min and 1137 ml, respectively. No operative mortalities or postoperative complications were observed in any of the patients. Our three patients are currently doing well without any recurrence. CONCLUSION: Our modified high dorsal resection procedure can be used to safely remove the entire caudate lobe.

[A Case Report of Early Gastric Cancer with Submucosal Heterotopic Gastric Glands].

We reported a case of early gastric cancer with submucosal heterotopic gastric glands.A 62-year-old woman presented with poor appetite, weight loss, and epigastric pain.Endoscopy examination identified giant gastric folds and a gastric ulcer on the posterior wall of the upper-middle stomach.Biopsy specimen analysis showed adenocarcinoma.We preoperatively diagnosed the lesion as type II c-like advanced cancer and performed a total gastrectomy.Pathologically, the lesion was diagnosed as gastric cancer(non-solid type poorly differentiated adenocarcinoma)located in the mucosal layer and accompanied by submucosal heterotopic gastric glands.Submucosal gastric gland heterotopia is a relatively rare disease, and it is difficult to diagnose the glands before surgery is performed.However, endoscopic ultrasonography helps to demonstrate diffuse cystic lesion preoperatively.It is often associated with multiple gastric cancers.Therefore, we must diagnose and treat the disease with great care.

[A Case of Bismuth III b Hilar Cholangiocarcinoma Resected with Extended Left Hepatic Lobectomy after ERCP Induced Pancreatitis].

Endoscopic retrograde cholangiopancreatography(ERCP)is widely accepted as the standard therapy before surgery for hilar cholangiocarcinoma. The patient is a 68-year-old man who presented with liver dysfunction. Computed tomography (CT)revealed abnormal lesions in his liver. He was referred to our hospital for therapy. We present a rare case of expansion of left lobectomy for Bismuth III b hilar cholangiocarcinoma after grade 2 severe pancreatitis caused by ERCP. He received arterial infusion therapy and endoscopic necrosectomy 6 times and percutaneous transhepatic biliary drainage(PTBD). The surgical procedure could be performed after the severe pancreatitis resolved. His postoperative course was uneventful.

Plasma microRNA profiles: identification of miR-744 as a novel diagnostic and prognostic biomarker in pancreatic cancer.

BACKGROUND: This study aims to explore novel microRNAs in plasma for screening cancer and predicting clinical outcomes in pancreatic cancer (PCa) patients using a microRNA array-based approach. METHODS: We used the Toray 3D-Gene microRNA array-based approach to compare plasma levels between PCa patients and healthy volunteers. RESULTS: (1) Six oncogenic microRNAs (miR-615-5p, -744, -575, -557, -675, and -550a) with high expression in plasma were selected. (2) By quantitative RT-PCR using plasma samples from 94 PCa patients and 68 healthy volunteers, a significantly higher level of plasma miR-744 in PCa patients than in healthy volunteers was validated in small-scale analysis (P=0.0038), two independent cohort analyses, and large-scale analysis (P<0.0001, AUC 0.8307). (3) miR-744 expression was significantly higher in PCa tissues (P=0.0069) and PCa cell lines (P=0.0074) than in normal tissues and fibroblasts, respectively. Preoperative plasma level of miR-744 was significantly reduced in postoperative samples (P=0.0063). (4) A high level of plasma miR-744, which was correlated with lymph node metastasis (P=0.0407) and recurrences (P=0.0376), was an independent poor prognostic factor of PCa patients after pancreatectomy (P=0.0007, HR 21.2 (3.17-436)). Furthermore, a high level of plasma miR-744 contributed to poorer progression-free survival of non-operable PCa patients who underwent gemcitabine-based chemotherapy (P=0.0533). Overexpression of miR-744 in PCa cells induced significant chemoresistance to gemcitabine in vitro. CONCLUSIONS: Plasma miR-744 might be useful biomarker for screening PCa, monitoring, and predicting poor prognosis and chemoresistance in PCa patients.

[Successful Treatment of Stenosis of the Portal Vein Using an Expandable Metallic Stent after Extended Right Hepatectomy--A Case Report].

We report successful treatment of stenosis of the portal vein caused by enlargement of the remnant liver after extended right hepatectomy with interventional radiology using an intraportal expandable metallic stent (EMS). A 75-year-old man underwent extended right hepatectomy after percutaneous transhepatic right portal embolization for advanced gallbladder cancer. His portal vein branched out into the anterior, posterior, and left branches. The main portal vein and left branch formed a sharp angle by nature. We ligated the posterior branch and sutured the cut line of the anterior branch during surgery. Several days after the surgery, icterus and massive ascites developed. Computed tomography (CT) and portography showed thrombi and stenosis of the cut line of the right branches due to enlargement of the remnant liver. A covered EMS was placed at the stenosis with interventional radiology. After stent placement, the icterus and massive ascites resolved. The patient remains well and EMS has caused no difficulty for 19 months. Intraportal EMS placement is effective in treating perioperative portal venous complications.

[A Case of Retroperitoneal Lymphangioma that Was Difficult to Differentiate from Pancreatic Tumor].

We report a rare case of retroperitoneal lymphangioma that was difficult to differentiate from pancreatic tumor. The patient was a 38-year-old woman. In June 2011, CT detected a pancreatic tail tumor. She was expected to undergo radical surgery and was referred to our hospital. The tumor was 55×43×40 mm in size and was described as a multilocular cystic lesion with a partition on CT. MRI demonstrated the tumor as a high-intensity area on T2-weighted images. Sonazoid-enhanced US showed a contrast effect of the partition wall. Therefore, the lesion was diagnosed as a mucinous cystic neoplasm, and the patient underwent surgery. Intraoperatively, the tumor was a white multilocular cystic lesion with a capsule. The cystic lesion was exfoliated from the pancreatic parenchyma. Histologically, the tumor was diagnosed as a cavernous lymphangioma without malignancy. The surgery achieved good progress and the patient was discharged 12 days postoperatively. She is attending our clinic without any recurrence.

[A Case of Adult Invagination Caused by Rectal Cancer].

An 87-year-old man visited our hospital with a chief complaint of melena. Invagination caused by rectal cancer or sigmoid colon cancer was suspected as a result of physical and radiological examinations. Since there were no subjective symptoms, laparoscopic surgery was planned electively. As an operative finding, a tumor was found in the rectosigmoid colon and caused invagination. The invagination was released during an operation, and high anterior resection with D3 dissection was performed laparoscopically. The operation time was 108 minutes and the amount of blood loss was 22 mL. Although anastomotic leakage occurred as a postoperative complication, recovery was achieved conservatively by percutaneous drainage. In many cases, invagination of adults is caused by a solid tumor such as bowel carcinoma, which commonly occurs at the cecum or sigmoid colon. Although invagination of the rectosigmoid colon fixed to the retroperitoneum is relatively rare, the fragility of the supporting tissues in the pelvis accompanied by aging is considered to be a cause. In cases of a large tumor occupying the lumen of the intestine, appropriate preoperative diagnosis is needed and the method of operation should be chosen carefully.

[The Clinical Efficacy of Neoadjuvant Chemotherapy for Borderline Resectable Pancreatic Carcinoma--Report of Two Cases Treated by Curative Pancreatectomy with Portal Vein Resection after Neoadjuvant Chemotherapy].

We report 2 cases of curative resection of pancreatic cancer after neoadjuvant chemotherapy. A 60-year-old woman was diagnosed as having borderline resectable pancreatic ductal adenocarcinoma with invasion of the nerve plexus covering the superior mesenteric artery. The preoperative chemotherapy, 4 courses of gemcitabine and S-1, reduced the volume of tumor; pancreaticoduodenectomy with portal vein resection after chemotherapy resulted in R0 resection. Pathological examination of the resected specimen showed fibroid tissue with myxoid degeneration and mucinous lake surrounded by differentiated adenocarcinoma. A 40-year-old woman was diagnosed as having borderline resectable pancreatic ductal adenocarcinoma with invasion of the common hepatic artery and splenic artery. The preoperative chemotherapy, 4 courses of gemcitabine and S-1, reduced the tumor volume; distal pancreatectomy with portal vein resection after chemotherapy obtained R0 resection. Pathological examination of the resected specimen revealed that the majority of the tumor was fibrotic and necrotic tissue, and few cancer cells remained viable. Neoadjuvant chemotherapy has a potential to increase the rate of R0 resection. Furthermore, preoperative chemotherapy can help avoid unnecessary surgery by allowing time for potential metastasis to become obvious.