[Multimodal therapy improved carcinoid syndrome secondary to liver metastases of an atypical lung carcinoid tumor:a case report].

A 69-year-old male presented for an annual medical examination, and his chest X-ray showed an abnormal shadow. He presented to our hospital, and was diagnosed with typical carcinoid tumor of the lung by bronchoscopy. We recommended surgery, however the patient did not agree to the operation. One year later, two masses were detected in the liver. Ultrasound guided biopsy revealed that they were metastases from the atypical carcinoid tumor of the lung. We recommended chemotherapy, but he refused. Six months later, he was admitted to our hospital for symptoms of flushing, fever, watery diarrhea, and palpitations. We diagnosed this combination of symptoms as carcinoid syndrome, and started the administration of a long acting release (LAR) octreotide. The patient's symptoms improved, but did not resolve completely. We then performed a hepatic artery embolization for the liver metastases, and the symptoms resolved. However, viable lesions of the liver metastases slowly grew and caused a carcinoid crisis. By increasing the dosage of octreotide up to a continuous intravenous infusion of 1500µg/day, as well as LAR 30mg/4weeks, the patient recovered from the crisis. Hepatic artery embolization was performed shortly afterward. Because it was difficult to control the carcinoid syndrome by hepatic artery embolization alone, he underwent a resection of the liver metastases. After the hepatic resection, he has had no recurrence of carcinoid syndrome while still being treated with octreotide LAR.

[Long-Term Survival of a Patient with Advanced Recurrent Rectal Cancer Treated with a Multidisciplinary Therapy including Five Operations-A Case Report].

A 68-year-old female with rectal cancer underwent low anterior resection with regional lymph node dissection. The final pathological diagnosis was Stage Ⅲa, and an adjuvant therapy(S-1)was provided for 6 months. One year after the surgery, an anastomotic recurrence was detected. Therefore, pelvic chemoradiotherapy with folinic acid and 5-fluorouracil(FL)was provided, and resection was performed with the Hartmann procedure. Following the second surgery, chemotherapy with bevacizumab(BV)and capecitabine plus oxaliplatin(CapeOX)was provided, and the patient showed no signs of recurrence for several years. However, lung metastasis appeared, which was resected. A year later, the patient underwent hepatectomy and radiofrequency ablation for liver metastasis. Another year later, she underwent lung resection again because of new lung metastasis. During the periods between the surgeries, various chemotherapy regimens were followed continuously, however, the patient died of progressive recurrence 8 years and 4 months after the initial surgery. Recurrences and distant metastases are poor prognostic factors for rectal cancers. However, combined effective chemotherapy and radiotherapy with surgery may improve the patient's chances of survival.

[A Case Report of Gastric Cancer Excised after Neoadjuvant Chemotherapy and Long-Term Survival Achieved after NivolumabAdministration for Peritoneal Dissemination].

The patient was a 64-year-old man with Type 3 advanced cancer in the upper body of the stomach. The preoperative tumor marker value of CA19-9 was abnormally high, but there was no proof of distant metastasis or peritoneal dissemination. The first operation was an exploratory laparotomy due to direct tumor invasion to the pancreas. Systemic chemotherapy was performed for tumor reduction. First, S-1 plus cisplatin therapy was administered for 4 courses but discontinued because of renal dysfunction and thrombocytopenia. In the second-line therapy, ramucirumabplus paclitaxel therapy was administered for 7 courses. Since the tumor invasion to the pancreas turned to be clear based on a CT scan, total gastrectomy with regional lymphadenectomy was performed. However, 5 months after surgery, a single nodule appeared in the upper abdomen that was suspected to be peritoneal dissemination. Nivolumab therapy was administered for 16 months without tumor enlargement or any adverse effect. Recently, there has been a marked development in chemotherapy for gastric cancer. Unresectable cases became operable after the administration of appropriate chemotherapy. In our case, nivolumab therapy had no adverse effect. However, serious adverse effects have been reported by several authors which suggests that regular examinations for interstitial pneumonia, hypothyroidism, and other adverse effects are important.

[A Case Report of P0CY1 Gastric Cancer Achieved Long-Term Survival after Treated with Ramucirumab Monotherapy].

The patient was a woman in her early 60s with type 4 advanced cancer which spread throughout the entire stomach. Total gastrectomy with regional lymphadenectomy was performed. She was diagnosed as Stage Ⅳ scirrhous gastric cancer with positive lavage cytology pathologically without any macroscopic peritoneal metastasis(P0CY1). S-1 plus cisplatin therapy was carried out as first-line therapy, but must be stopped after 2 courses because of appetite loss. As the second-line, ramucirumab monotherapy was administered, due to the patient's denial of alopecia and numbness as side effects of paclitaxel. Tumor marker value of CA19-9 remained high 24 months after ramucirumab chemotherapy, but gradually decreased near the normal level with no proof of distant metastasis or peritoneal dissemination. However, after 74 courses, CA19-9 value was elevated and peritoneal dissemination was detected from CT scan. Nivolumab therapy was started as third-line, but only for 5 courses because of indefinite complaints. Afterwards, no chemotherapy has been performed as the patient's request until almost 5 years after surgery. The prognosis of patients with P0CY1 gastric cancer is generally poor, but in our case long-term survival was obtained from ramucirumab therapy only. Recently, ramucirumab monotherapy is administered for advanced HCC patients and expect to be effective in AFP producing gastric cancer. There is an urgent need to elucidate potential predictive biomarkers of ramucirumab efficacy.

[A Case Report of Gastric Cancer with Positive Peritoneal Lavage Cytology and Metachronous Schnitzler's Metastasis Treated with Multimodality Therapy].

A69 -year-old male patient with type 3 gastric cancer in pyloric antrum underwent distal gastrectomy with regional lymphadenectomy. Serosal infiltration of cancer tissue was found in the anterior wall of antrum, and the evaluation of peritoneal lavage cytology were positive. Pathological analysis showed the tumor was mainly consist of moderately tubular adenocarcinoma and strongly positive for HER2 stain. Postoperatively, combined therapy of capecitabine and trastuzumab was carried out, but cisplatin was excluded because of the patient's rejection. However, nine months after drug withdrawal, singular tumor located at left anterior side of rectum was detected by abdominal CT scan. Colonoscopy revealed its mucosal invasion and the result of biopsy was metastasis of gastric cancer, also known as Schnitzler's metastasis. Local radiation therapy aimed at the tumor was performed, followed by capecitabine and oxaliplatin therapy for 18 months. After the therapy, Schnitzler's metastatic lesion was disappeared and biopsy from colonic mucosa revealed there was no tumor tissue left. The patient has been in good health 5 years after surgery. This case suggests that multimodality therapy including radiation and chemotherapy might improve survival of gastric cancer patient with positive peritoneal lavage cytology and metachronous metastasis.

[Recurrence of a Giant Retroperitoneal Leiomyosarcoma Six Years after the Initial Surgery].

A 51-year-old man came to our department because of a large abdominal mass. CT, MRI, and sonography revealed a large tumor adjacent to the retroperitoneal area. A resection was performed, and histologically we confirmed the diagnosis as a leiomyosarcoma originating from the retroperitoneum. Six years after the initial surgery, the patient came to our outpatient department with a complaint of nausea. A relatively large tumor was seen on a CT scan that was causing obstruction of the duodenum. Another surgery was performed with the final diagnosis as a recurrence of the leiomyosarcoma. After 3 courses of adjuvant chemotherapy with eribulin, the patient presented with abdominal distension. CT revealed a very large tumor with massive invasion to the ileum and colon. This time, we considered the tumor unresectable, and administered chemotherapy with a combination of doxorubicin and ifosfamide. However, after 1 course, the patient's condition worsened and he died of the disease 3 months after the chemotherapy.

Dominant Expression of DCLK1 in Human Pancreatic Cancer Stem Cells Accelerates Tumor Invasion and Metastasis.

Patients with pancreatic cancer typically develop tumor invasion and metastasis in the early stage. These malignant behaviors might be originated from cancer stem cells (CSCs), but the responsible target is less known about invisible CSCs especially for invasion and metastasis. We previously examined the proteasome activity of CSCs and constructed a real-time visualization system for human pancreatic CSCs. In the present study, we found that CSCs were highly metastatic and dominantly localized at the invading tumor margins in a liver metastasis model. Microarray and siRNA screening assays showed that doublecortin-like kinase 1 (DCLK1) was predominantly expressed with histone modification in pancreatic CSCs with invasive and metastatic potential. Overexpression of DCLK1 led to amoeboid morphology, which promotes the migration of pancreatic cancer cells. Knockdown of DCLK1 profoundly suppressed in vivo liver metastasis of pancreatic CSCs. Clinically, DCLK1 was overexpressed in the metastatic tumors in patients with pancreatic cancer. Our studies revealed that DCLK1 is essential for the invasive and metastatic properties of CSCs and may be a promising epigenetic and therapeutic target in human pancreatic cancer.

[A Case of Brain Metastasis from Rectal Cancer with Synchronous Liver and Lung Metastases after Multimodality Treatment--A Case Report].

We report a case of brain metastasis from rectal cancer a long time after the initial resection. A 62-year-old woman, diagnosed with lower rectal cancer with multiple synchronous liver and lung metastases, underwent abdominoperineal resection after preoperative radiochemotherapy (40 Gy at the pelvis, using the de Gramont regimen FL therapy: 1 kur). The histological diagnosis was a moderately differentiated adenocarcinoma. Various regimens of chemotherapy for unresectable and metastatic colorectal cancer were administered, and a partial response was obtained; thereby, the metastatic lesions became resectable. The patient underwent partial resection of the liver and lung metastases. Pathological findings confirmed that both the liver and lung lesions were metastases from the rectal cancer. A disease-free period occurred for several months; however, there were recurrences of the lung metastases, so we started another round of chemotherapy. After 8 months, she complained of vertigo and dizziness. A left cerebellar tumor about 3 cm in diameter was revealed by MRI and neurosurgical excision was performed. Pathological findings confirmed a cerebellar metastasis from the rectal cancer. Twenty months after resection of the brain tumor, the patient complained of a severe headache. A brain MRI showed hydrocephalia, and carcinomatous meningitis from rectal cancer was diagnosed by a spinal fluid cytology test. A ventriculo-peritoneal shunt was inserted, but the cerebrospinal pressure did not decreased and she died 20 months after the first surgery. Although brain metastasis from colorectal cancer is rare, the number of patients with brain metastasis is thought to increase in the near future. Chemotherapy for colorectal cancer is effective enough to prolong the survival period even if multiple metastases have occurred. However, after a long survival period with lung metastases such as in our case, there is a high probability of developing brain metastases.

[A Case of Squamous Cell Carcinoma of the Anal Canal with a Perianal Abscess].

A 72-year-old female patient was referred to our department because she felt pain at the anus with pus discharge. Physical examination revealed a tumor on the left side of the anus, and a subcutaneous induration near the tumor. Abdominal CT scan revealed an irregularly shaped tumor with abscess formation. There were no enlarged lymph nodes or distant metastasis. Anal canal carcinoma (cStage Ⅱ) with a complication of perianal abscess was suspected, so we performed surgical incision and drainage. A biopsy of the tumor led to the diagnosis of squamous cell carcinoma. However, because surgical drainage alone was not effective for treatment of the abscess, colostomy of the sigmoid colon was carried out 14 days after admission. After chemoradiation therapy (5-FU 800 mg/m2/day on days 1-4 and 29-32, mitomycin C [MMC] 10 mg/m2 on days 1 and 29, and radiation with a total dose 54 Gy), the tumor disappeared completely, considered to be a complete response. Twenty months after chemoradiation, there were no signs of recurrence.

[Curative resection of stage IV advanced gallbladder cancer following combined treatment with gemcitabine and CDDP].

A 74-year-old woman was referred to our hospital following the diagnosis of advanced gallbladder cancer with para-aortic lymph node metastasis. Combination treatment involving gemcitabine(1,000mg/m / 2 body surface area)and CDDP(50mg/ m2 body surface area)was initiated and repeated for 4 courses; gemcitabine was administrated on day 1 and day 8, whereas CDDP was administrated on day 8, followed by 1 week of no treatment. After 4 courses, abdominal computed tomography (CT)indicated a reduction in size of the main lesion and disappearance of para -aortic lymph nodes. The remarkable response to the chemotherapy, which resulted in tumor downstaging, enabled us to perform the curative surgery procedure. Thus, cholecystectomy with resection of the hepatic bed and lymph node dissection were performed. The resected specimens indicated papillary adenocarcinoma of the gallbladder infiltrating the muscular wall of the gallbladder. In addition, the resected para-aortic lymph nodes indicated hyalinization and fibrosis as a result of the chemotherapy. Moreover, the pericholedocal lymph nodes were necrotic and no viable tumor was noted, thus indicating the excellent response to the chemotherapy.

Visualization of stem cell features in human hepatocellular carcinoma reveals in vivo significance of tumor-host interaction and clinical course.

UNLABELLED: Hepatocellular carcinoma (HCC) is one of the most aggressive malignancies because of recurrence and/or metastasis even after curative resection. Emerging evidence suggests that tumor metastasis and recurrence might be driven by a small subpopulation of stemness cells, so-called cancer stem cells (CSCs). Previous investigations have revealed that glioma and breast CSCs exhibit intrinsically low proteasome activity and that breast CSCs also reportedly contain a lower reactive oxygen species (ROS) level than corresponding nontumorigenic cells. Here we visualized two stem cell features, low proteasome activity and low intracellular ROS, in HCC cells using two-color fluorescence activated cell sorting to isolate cells with stem cell features. These cells were then analyzed for their division behavior in normoxia and hypoxia, expression of stem cell markers, tumorigenicity, metastatic potential, specific gene expression signatures, and their clinical implications. A visualized small subpopulation of HCC cells demonstrated asymmetric divisions. Their remarkable tumorigenicity in nonobese diabetic/severe combined immunodeficient mice suggested the cancer initiation potential of these HCC CSCs. Comprehensive gene expression analysis revealed that chemokine-related genes were up-regulated in the CSCs subpopulation. Our identified HCC CSCs facilitated the migration of macrophages in vitro and demonstrated metastatic potential by way of recruitment of macrophages in vivo. In patients who undergo curative operation for HCC, the CSC-specific gene signature in the liver microenvironment significantly correlates with recurrence. CONCLUSION: Based on these findings, the stem cell feature monitoring system proposed here is a promising tool to analyze the in vivo significance of CSC microenvironments in human HCCs.

Identification of pancreatic cancer stem cells and selective toxicity of chemotherapeutic agents.

BACKGROUND & AIMS: Identification and purification of cancer stem cells (CSCs) could lead to new therapeutic targets, but their heterogeneous expansion is an obstacle to their study. We investigated whether it is possible to monitor pancreatic CSCs in real time, based on their intrinsic low level of proteasome activity. METHODS: We engineered human pancreatic adenocarcinoma cells (PANC1, MIAPaCa2, BxPC3, and KLM1) to express a green fluorescent molecule fused to the degron of ornithine decarboxylase (Gdeg) from a retroviral vector; the fluorescent Gdeg accumulates in CSCs as a result of low activity of the 26S proteasome. Cells with high and low levels of fluorescence (Gdeg(high) and Gdeg(low)) were isolated by flow cytometry; tumor growth was analyzed in immunocompromised mice. We performed a screen for agents that were specifically toxic to pancreatic CSCs, in a synthetic lethal manner. RESULTS: Gdeg(high) cells, but not Gdeg(low) cells, formed spheres and underwent asymmetric division-features of CSCs. Injection of as few as 10 Gdeg(high) cells led to tumor formation in mice. Gemcitabine was toxic to cultured Gdeg(low) cells, whereas Gdeg(high) cells were resistant. We observed that quercetin was toxic to Gdeg(high) cells in culture and in pre-established tumors grown from these cells in mice. Nuclear accumulation of ß-catenin was detected in Gdeg(high), but not Gdeg(low), and lost after exposure to quercetin. CONCLUSIONS: We used a fluorescence marker system for level of proteasome activity to identify pancreatic cancer cells with features of cancer stem cells. We identified quercetin as a compound that is specifically toxic to pancreatic CSCs.

Analogy between sphere forming ability and stemness of human hepatoma cells.

Increasing evidence suggests that cancers contain a small subset of cancer-initiating cells, so-called cancer stem cells (CSCs) that are capable of regenerating a tumor after chemoradiation therapy. Sphere forming ability is known to be one of properties of CSCs, but the significance remains unclear. The present study focused on sphere formation of human hepatoma cells in three-dimensional culture in order to evaluate the analogy between sphere forming ability and stemness of cancer cells in vitro. Under three-dimensional culture condition, HepG2, Hep3B and PLC/PRF/5 cells demonstrated the sphere formation while SK-Hep1 and Huh-7 cells did not. The population of G0/G1 phase increased in the spheres compared with the monolayer (67 vs. 38%). In spite of no significant difference in stem cell surface markers (CD44, CD90, CD133, EpCAM and ABCG2), remarkable up-regulation of p27 CDK inhibitor was observed in sphere forming cells. Immunofluorescence analysis revealed the nuclear expression of p27 in the whole of the sphere, but weak expression of p21 only at the peripheral area. The spheres acquired chemoresistance to cisplatin compared with the monolayers (58.9 vs. 16.2 µM in IC50). This model was useful for assessment of the role of cell-cycle quiescence in the stemness and chemoresistance of cancer cells.