Roles of voltage­gated potassium channels in the maintenance of pancreatic cancer stem cells.

The targeting of membrane proteins that are activated in cancer stem cells (CSCs) represents one of the key recent strategies in cancer therapy. The present study analyzed ion channel expression profiles and functions in pancreatic CSCs (PCSCs). Cells strongly expressing aldehyde dehydrogenase 1 family member A1 (ALDH1A1) were isolated from the human pancreatic PK59 cell line using fluorescence­activated cell sorting, and PCSCs were identified based on tumorsphere formation. Microarray analysis was performed to investigate the gene expression profiles in PCSCs. ALDH1A1 messenger RNA levels were higher in PCSCs compared with non­PCSCs. PCSCs were resistant to 5­fluorouracil and capable of redifferentiation. The results of the microarray analysis revealed that gene expression related to ion channels, including voltage­gated potassium channels (Kv), was upregulated in PCSCs compared with non­PCSCs. 4­Aminopyridine (4­AP), a potent Kv inhibitor, exhibited greater cytotoxicity in PCSCs compared with non­PCSCs. In a xenograft model in nude mice, tumor volumes were significantly lower in mice inoculated with PK59 cells pre­treated with 4­AP compared with those in mice injected with non­treated cells. The present results identified a role of Kv in the persistence of PCSCs and suggested that the Kv inhibitor 4­AP may have potential as a therapeutic agent for pancreatic carcinoma.

[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.

Outcome of a second hepatectomy in octogenarians with hepatocellular carcinoma recurrence: single centre's experience.

BACKGROUND: Physicians rarely select surgery a second time as the treatment for octogenarians with hepatocellular carcinoma (HCC) recurrence. METHODS: We encountered eight male and three female octogenarians underwent surgery a second time as the treatment for HCC recurrence (octo group). We studied these cases clinically and compared them with 25 younger people underwent surgery a second time (young group). All patients of octo group have resectable HCC according to the Japanese guideline, that is HCC patients with Child-Pugh status A or B and who have solitary or only a few HCC nodules, in addition, no serious comorbidities, no serious dementia, a performance status of 0-1 and the will to receive hepatectomy. RESULTS: The average maximum tumour size at the first hepatectomy was significantly larger than that at the second hepatectomy (P < 0.05). The extent of the first hepatectomy was significantly greater than that of the second one (P < 0.05). There were no mortalities at either hepatectomy. The morbidities of the first and the second hepatectomies were 9.1% and 18.2%, respectively. All complications were bile leakage. Furthermore, there were no significant differences in the clinical features, including the prognosis, between the octo and young groups. CONCLUSION: Selected octogenarians who received a second hepatectomy showed a relatively good post-operative course after the first and second hepatectomies. Repeated hepatectomy for octogenarians seems to have same positive influence on the prognosis in comparison to the young group. But on the data analysed, we have not shown repeated hepatectomy is superior to non-surgical treatments.

[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.

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.

[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 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.

Prognostic impact of hepatectomy for patients with non-hepatitis B, non-hepatitis C hepatocellular carcinoma.

UNLABELLED: BACK GROUND/AIM: The purpose of the present study was to clarify the clinicopathological features of non-hepatitis B and -C (NBNC) hepatocellular carcinoma (HCC), the incidence of which has been increasing. PATIENTS AND METHODS: Two hundred and eighty-four patients with HCC were classified into three groups according to viral hepatitis status, namely NBNC, hepatitis B, and hepatitis C. We compared the three groups and studied related risk factors. RESULTS: Patients without cirrhosis who had increased number of platelets and diabetes mellitus, and a serum alpha-feto-protein (AFP) level <100 ng/dl were more common in the NBNC group. The cumulative survival and disease-free survival were better in the NBNC group than in the other groups. The tumor size and hepatitis B or C viral status were found to be independent risk factors of disease-free survival and the presence of multiple lesions was the only independent risk factor of survival. CONCLUSION: Close follow-up of NBNC liver cirrhosis and early detection of NBNC-HCC can improve the prognosis after surgery.

Mesohepatectomy with total caudate lobectomy of the liver for hepatocellular carcinoma.

BACKGROUND: Mesohepatectomy with total resection of the caudate lobe and extrahepatic bile duct is sometimes performed for hilar cholangiocarcinoma or gallbladder carcinoma; however, only a few reports on mesohepatectomy with total caudate lobectomy of the liver for hepatocellular carcinoma are available. METHODS: A 71-year-old woman was preoperatively diagnosed with hepatocellular carcinoma in the central bisections (Couinaud's segments 4, 5, and 8) and the paracaval portion of the caudate lobe. Mesohepatectomy with total caudate lobectomy of the liver permitted the removal of tumors to provide a cancer-free raw surface of the liver. Mobilization of the caudate lobe is an important procedure in this surgery. Before the liver parenchyma was dissected, all short hepatic veins were ligated and divided from the left to the right side as the left lateral section was retracted to the right, and the caudate lobe branches of the portal vein and hepatic artery were ligated and divided. After the liver parenchymal dissection, both between the left lateral and medial sections and between the right anterior and posterior sections, the Glissonean branches of the caudate lobe were ligated and divided as the central bisections were anteriorly retracted. Finally, liver parenchymal dissection was performed between the caudate lobe and the right posterior section, which was along the right side of the inferior vena cava. RESULTS: The surgery time was 538 minutes and blood loss was 1,207 mL. No blood transfusions were required during or after surgery. The postoperative course was uncomplicated. The patient is still alive 25 months after hepatectomy. CONCLUSION: Although mesohepatectomy with total caudate lobectomy of the liver is technically more difficult than mesohepatectomy of the liver because the caudate lobe must be completely detached from the inferior vena cava and the hilar plate, it is a safe and effective treatment method in selected patients with hepatocellular carcinoma located at both the central bisections and the paracaval portion of the caudate lobe.

Anatomical liver segmentectomy 2 for combined hepatocellular carcinoma and cholangiocarcinoma with tumor thrombus in segment 2 portal branch.

BACKGROUND: Hepatic resection is the only effective treatment for combined hepatocellular carcinoma and cholangiocarcinoma. CASE PRESENTATION: A 52-year-old man was preoperatively diagnosed with hepatocellular carcinoma in segment 2 with tumor thrombus in the segment 2 portal branch. Anatomical liver segmentectomy 2, including separation of the hepatic arteries, portal veins, and bile duct, enabled us to remove the tumor and portal thrombus completely. Modified selective hepatic vascular exclusion, which combines extrahepatic control of the left and middle hepatic veins with occlusion of left hemihepatic inflow, was used to reduce blood loss. A pathological examination revealed combined hepatocellular carcinoma and cholangiocarcinoma with tumor thrombus in the segment 2 portal branch. No postoperative liver failure occurred, and remnant liver function was adequate. CONCLUSION: The separation method of the hepatic arteries, portal veins, and bile duct is safe and feasible for a liver cancer patient with portal vein tumor thrombus. Modified selective hepatic vascular exclusion was useful to control bleeding during liver transection. Anatomical liver segmentectomy 2 using these procedures should be considered for a patient with a liver tumor located at segment 2 arising from a damaged liver.

A Case of Neuroendocrine Cell Carcinoma with Sigmoidovesical Fistula.

Colonic neuroendocrine cell carcinoma (NEC), which is a rare subtype of colon epithelial neoplasm, has been reported to show extremely aggressive characteristics with a 1-year survival rate of 20%. We report herein a resected case of NEC that manifested bacterial sepsis due to sigmoidovesical fistula. Staged surgery consisted of resecting the sigmoid colon and part of the bladder four weeks after construction of an ileostomy to alleviate septic shock. The resected specimen was histologically diagnosed as NEC invading the wall of the urinary bladder with metastasis to the regional lymph nodes. The patient underwent four cycles of FOLFOX after surgery for additional treatment of residual metastatic lymph nodes around the abdominal aorta diagnosed preoperatively. Although the patient showed stable disease measured by computed tomography scan for the first three months after surgery, he rejected additional chemotherapy thereafter, and died ten months after the initial admission due to progression of residual tumor in the urinary bladder as well as the lymph nodes. This is the first case report describing colonic NEC manifesting perforation into the urinary bladder. Although the optimal chemotherapeutic regimen for colonic NEC has not yet been established, FOLFOX may be one of the choices.

Results of total gastrectomy with extended lymphadenectomy for gastric cancer in elderly patients.

BACKGROUND AND OBJECTIVES: The incidence of gastric cancer, in people over 70 years of age, has increased remarkably. Aggressive lymphadenectomy with gastrectomy has been reported to improve survival in patients with gastric cancer. Because complication rates following gastrectomy increase with advancing age, we sought to determine whether this procedure was merited in elderly patients with gastric cancer. METHODS: We performed a retrospective analysis of 202 patients who underwent total gastrectomy with extended lymphadenectomy for gastric carcinoma. Postoperative complication rates were compared between patients over and under 70 years of age. RESULTS: The 10-year survival rates of patients under and over 70 years of age following total gastrectomy with extended lymphadenectomy were not significantly different. Although medical comorbidities in each group were similar, pulmonary dysfunction was significantly more common following total gastrectomy in patients over 70 years than in patients under 70 years. Moreover, logistic regression analysis revealed that patient's age was the only variable that independently correlated with the presence of postoperative complications. CONCLUSIONS: The prognosis of the gastric cancer patients over 70 years of age was similar to that of younger patients after total gastrectomy with extensive lymphadenectomy. However, pulmonary dysfunction was significantly more common in patients over 70 years old.

Application of 99mTc labeled chimeric Fab fragments of monoclonal antibody A7 for immunoscintigraphy of pancreatic carcinoma.

BACKGROUND: One of the reasons for the poor prognosis of pancreatic carcinoma is the difficulty of obtaining an early diagnosis of pancreatic carcinoma. One possibility is the application of radioimmunoscintigraphy using radiolabeled monoclonal antibodies (Mabs). METHODS: We labeled chimeric (human/mouse) Fab fragments of Mab A7 (chA7Fab) with (99m)Tc and examined the distribution of (99m)Tc-labeled chA7Fab in nude mice bearing human pancreatic carcinoma. RESULTS: The tumor accumulation of (99m)Tc-labeled chA7Fab was larger than that of (99m)Tc-labeled A7 from 2 to 6 hr after injection. (99m)Tc-labeled chA7Fab disappeared from blood more rapidly than (99m)Tc-labeled A7. For all resected normal tissues except kidney, the accumulation of (99m)Tc-labeled chA7Fab was low and similar to that of (99m)Tc-labeled A7. CONCLUSIONS: Because the half-life of (99m)Tc is short (6 hr), chA7Fab, which accumulates rapidly in tumors, may be a better carrier of (99m)Tc than intact Mab A7.

Local administration of methotrexate bound to activated carbon particles (MTX-CH) for treating cancers in mice.

PURPOSE: A new dosage formulation of methotrexate (MTX-CH) was developed to control cancer growth by local administration. MATERIALS AND METHODS: BALB/c mice received a subcutaneous inoculation with transplantable Colon 26 cancer cells on the back. When cancerous tumor became 7 mm in diameter, MTX-CH or MTX aqueous solution (MTX-sol) was injected into the tumor. The MTX concentration in the tumor was compared between the MTX-CH group and the MTX-sol group. The tumor growth was assessed in single or repeated local administration experiments. RESULTS: The MTX concentrations were significantly higher for longer periods in the MTX-CH group than those in the MTX-sol group. Repeated MTX-CH administration was significantly more effective for suppressing the tumor growth compared with repeated MTX-sol administration. CONCLUSION: MTX-CH is superior to MTX-sol in controlling the tumor growth by local administration because of its long-acting effect.