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Background/aim The prognosis of cholangiolocarcinoma, a rare malignant liver tumor derived from hepatic progenitor or stem cells, is considered relatively good; however, it frequently recurs. We herein present the diagnosis, histological findings, and treatment of cholangiolocarcinoma. Case report A 65-year-old woman with a large liver tumor (70 mm in diameter) was referred. Hepatocellular carcinoma was suspected based on strong early enhancement and delayed washout by enhanced computed tomography. The patient underwent curative left tri-sectionectomy. Histologically, she was diagnosed with pure cholangiolocarcinoma in a slightly fibrous liver. Three metachronous recurrent lesions (all ≤10 mm in diameter) were found between fifteen and twenty months after the initial hepatectomy. One lesion and the remaining two lesions were treated with hepatectomy and radiofrequency ablation, respectively. Two years after the initial diagnosis, she was doing well without recurrence. Conclusion Repeated hepatectomy and radiofrequency ablation might be useful for small intrahepatic recurrences of cholangiolocarcinoma.

Aim To assess the utility of the perioperative use of direct oral anticoagulants for patients with hepatocellular carcinoma (HCC) with cancer-associated thrombosis. Case report An 83-year-old woman was admitted with a solitary HCC (10-cm diameter), as well as with multiple sites of venous thromboembolism and macroscopic portal vein tumor thrombosis. She had appropriate liver function without viral hepatitis, triple-positive tumor markers, and secondary polycythemia. Edoxaban at 30 mg was initiated 10 days before surgery to remove HCC. Complete remission of the pulmonary embolism and stability of the deep vein thrombosis and massive superior mesenteric vein thrombosis were recognized preoperatively. An extended left hepatectomy was successfully performed. To avoid hemorrhage complications, we used intravenous administration of nafamostat mesylate for 2 days, thereafter we restarted edoxaban. Superior mesenteric vein thrombosis resolved 5 months after surgery. Conclusion Perioperative oral administration of edoxaban was useful in multidisciplinary treatment for a patient with advanced HCC with cancer-associated thrombosis.

Background Lenvatinib, a newly developed oral multi-tyrosine kinase inhibitor, has amazing potential in the multidisciplinary treatment of advanced or metastatic hepatocellular carcinoma. Thrombocytopenia is a serious adverse event that causes drug dose reduction or withdrawal. Partial splenic embolization is currently being used as a non-surgical treatment for thrombocytopenia caused by various pharmacotherapies. Case report Partial splenic embolization was performed for three patients with hepatocellular carcinoma receiving lenvatinib therapy with/without transarterial chemoembolization. Partial splenic embolization was advantageous for various situations, including the induction of lenvatinib for patients with thrombocytopenia, application of lenvatinib after multiple transarterial chemoembolization using cisplatin and radiotherapy, and re-administration of lenvatinib after lenvatinib therapy-induced thrombocytopenia. In all cases, lenvatinib therapy was completed without need for cessation due to thrombocytopenia. Conclusion We strongly recommend the new concept of combining partial splenic embolization and lenvatinib therapy for hepatocellular carcinoma.

Background Colorectal cancer is the third most commonly diagnosed cancer in both men and women, and one of the more widely recognized preventable cancers. Adenosquamous carcinoma (ASC) of the colon/rectum is an uncommon disease that consists of both glandular and squamous components, and the most common site of ACS is the right and transverse colon. Case report Here, we present the case of a 78-year-old woman, who complained of abdominal pain. Colonoscopy revealed a circumscribed tumor in the ascending colon, and no specific lesion was detected in the other areas of the colon or rectum. ASC (pT3N0M0) was diagnosed from right hemicolectomy specimens. Three months after the first surgery, the serum levels of tumor markers had gradually increased, and a new tumor was subsequently detected in the sigmoid colon 2 months later. The sigmoid lesion was surgically resected and diagnosed as ASC (pT3N3M0). Strong PD-L1 expression was also found in the squamous component. Conclusion To our knowledge, this is the first report of a recurrent sigmoid colon ASC that likely originated from the ascending colon, and PD-L1/PD-1 signaling was likely involved in the immune escape mechanism.

Background Hepatic inflammatory pseudotumor (HIPT) is an uncommon benign tumor-like mass that mimics malignant tumors. Case report A 73-year-old man was admitted with severe epigastric pain and high fever. He had received choledocojejunostomy. Enhanced computed tomography showed a 76 mm, heterogeneous, gradual enhanced low-density mass in the caudate lobe and hyperdense fluid was detected around the mass. Based on the diagnosis of hemorrhage from a hypervascular malignant liver tumor, chemoembolization was conducted. Antibiotics (Meropenem) were administered for 2 weeks, and methylprednisolone (125 mg) was administered twice as a premedication for chemoembolization. After the 2nd chemoembolization, rapid tumor shrinkage was observed and the inflammatory changes gradually disappeared. The tumor was finally diagnosed as fibrohistiocytic type HIPT with an ultrasound-guided percutaneous tumor biopsy. The diameter of the liver tumor decreased to 15 mm and intra-abdominal hemorrhage disappeared in 3 months. Conclusion Development of HIPT can be associated with intra-abdominal hemorrhage.

Multidisciplinary treatment is recommended for the management of patients with advanced hepatocellular carcinoma (HCC). Some operative decollateralization of extrahepatic feeding arteries with laparotomy have been introduced for HCC. We herein newly develop laparoscopic devascularization (LDEV) to continue transarterial chemoembolization (TACE) for HCC with extrahepatic collateral arteries. A 74-year-old man with multiple huge HCC (4 tumors, 18 cm in diameter) and poor liver function (non-alcoholic steatohepatitis, Child–Pugh score 7) was treated with 6 times of chemoembolization in combination with LDEV, 3 times of ablation therapies, and lenvatinib therapy. His tumor markers were triple positive (AFP, 12,906.5 ng/ml; PIVKA-II, 491,743 mAU/ml; AFP-L3, 91.8%) before treatments; however, they all returned to normal limits. Complete response was achieved according to the modified RECIST criteria. Unfortunately, he died 6 months after the final treatment with no recurrence of HCC due to the postoperative complication of primary lung cancer. LDEV is a useful tool to continue effective TACE, and multidisciplinary treatment including chemoembolization and LDEV can cure advanced HCC patients with extrahepatic collaterals and impaired liver function.

Aim Our aim was to confirm the utility of Indocyanine green (ICG) fluorescence imaging for intraoperative detection of adrenal hepatocellular carcinoma (HCC) metastasis. Case report An 83-year-old man with a right adrenal HCC metastasis was admitted after complete remission of primary HCC and a metachronous left adrenal metastasis. He was treated with ICG fluorescence-guided limited resection to preserve adrenal function. ICG was administered intravenously at a dose of 0.5 mg/kg, 6 days before the operation. After removal of the entire suspicious metastatic HCC, ICG fluorescence imaging clearly demonstrated two illuminated lesions. The lesions were separately resected using an energy device. Finally, there were no ICG fluorescent lesions which meant residual tumor. Histopathological examination confirmed adrenal metastasis of moderately differentiated HCC in the initial specimen and the additional resected specimens. Three months after the operation, adrenal function was well preserved without recurrence of HCC. Conclusion ICG fluorescence imaging is essential for complete resection of adrenal HCC metastasis.

Hepatic sclerosed hemangioma is a rare benign liver tumor that originated from hepatic cavernous hemangioma; however, the process of its formation has been unclear. We herein present the patient of a histologically proven hepatic sclerosed hemangioma that showed drastic changes in diagnostic images in a short period. A 56-year-old man was referred to our hospital for the treatment of suspicious hepatocellular carcinoma with hepatitis C, approximately 2 cm in diameter in liver segment 8. Initially, the tumor manifested as early entire enhancement with mildly delayed washout in contrast-enhanced ultrasonography; however, it manifested as continuous peripheral enhancement with the central non-enhanced area after 1 month in various diagnostic images. He completely quit drinking and smoking 1 month preoperatively. No special symptoms and signs were found to suggest tumor ischemia. Anatomical resection of segment 8 was completed. Histological examination confirmed the final diagnosis of common type hepatic sclerosed hemangioma, derived from atypically enhancing cavernous hemangioma. No signs of impaired blood flow were observed in both diagnostic images and histological examination. Sclerosing changes in hepatic cavernous hemangioma may be completed in a relatively short time with no apparent reason.

Large tumor size and arterioportal shunt are poor prognostic factors for hepatocellular carcinoma. Lenvatinib is a novel and potent multi-tyrosine kinase inhibitor developed in Japan. A 66-year-old woman with hepatocellular carcinoma and untreated hepatitis C was referred to our hospital. She was judged as unresectable and was treated with four sessions of transarterial chemoembolization; however, the therapeutic effect was unsatisfactory because of major arterioportal shunt. Lenvatinib was sequentially administered for 4 months. Thereafter, we observed tumor shrinkage, complete disappearance of arterioportal shunt, and obvious improvement in liver function. A curative conversion hepatectomy was successfully accomplished. The extremely high levels of tumor markers almost normalized; the pretreatment levels were 1,008,021 ng/ml for alpha-fetoprotein. At 1 year after the primary treatment, the patient has not experienced recurrence. To our knowledge, this is the first case of a patient with initially unresectable hepatocellular carcinoma with arterioportal shunt who underwent conversion hepatectomy after multidisciplinary treatment, including lenvatinib.

Great effort has been paid to decrease blood loss during hepatectomy. Excessive blood loss and/or allogeneic blood transfusion can cause an increased risk of perioperative morbidity and mortality and may lead to a greater risk of early tumor recurrence (1-4). Hepatic steatosis or steatohepatitis is present in 30–50% of patients in the Western countries and can increase blood loss and morbidity in patients undergoing hepatectomy for colorectal liver metastases (5-7). Steatotic livers are hypertrophic and delicate and are therefore more difficult to mobilize or transect compared to nonsteatotic livers.

Gastric cancer with portal vein tumor thrombosis (GC-PVTT) is a rare condition with a very poor prognosis. A 64-year-old man with GC-PVTT was admitted to our hospital. His carcinoembryonic antigen level was slightly elevated (17.4 ng/ml). Upper gastrointestinal endoscopy showed a type-2 gastric lesion (45 mm × 40 mm) in the gastric antrum. The PVTT originated from the main gastric tumor and continued to the superior mesenteric vein. Fluorodeoxyglucose-positron emission tomography showed high uptake both by the main tumor and PVTT. A distal gastrectomy with D2 lymphadenectomy was performed with simultaneous removal of the PVTT. Pathological examination showed a poorly differentiated adenocarcinoma with neuroendocrine differentiation. Adjuvant chemotherapy with S-1 was administered for 1 year. The patient survived for >5 years with no recurrence. Surgical gastrectomy and complete removal of the PVTT followed by S-1 chemotherapy could be a treatment option that offers improved long-term survival for patients with GC-PVTT.

Background Various pathological elbow lesions are often complicated with ulnar neuropathy at the elbow (UNE), although the precise pathology, incidence, and clinical and neurological features of these lesions have not been identified. We therefore investigated elbow pathology and neurological severity in Japanese patients with UNE. Methods The medical records of 457 Japanese UNE patients who were surgically treated among 6 hospitals were retrospectively examined. Eligible patients had UNE diagnosed by physical findings and nerve conduction studies according to the criteria of the American Association of Electrodiagnostic Medicine. The elbows were analyzed with regard to age, gender, occupation, pathology at the elbow, and severity of nerve palsy. Results A total of 398 patients with 413 UNE elbows of a mean age of 63 years (range: 15–87) met the inclusion criteria. UNE elbows were predominantly in male patients (69.0%). Overall, 310 elbows (75.1%) had 1 or more elbow lesions: 238 elbows (76.8%) had a single lesion and 72 elbows (23.3%) had 2 or more lesions. The most common lesion was primary elbow osteoarthritis (EOA) occurring in 54.5% of elbows, followed next by medial elbow ganglion in 8.5% and cubitus valgus in 6.5%. Most elbows with medial elbow ganglion or cubitus valgus were associated with EOA. Entrapment sites were at the cubital tunnel in 84.5%–91.3% of UNE elbows, regardless of an association with elbow lesion. The incidence of McGowan grade III lesion was 50.8% in elbows with primary EOA, which was higher than the 35.0% in elbows with no lesion. Conclusions This study revealed that UNE had various isolated or combined elbow lesions. In Japanese UNE, primary or secondary EOA was found in 62.2% of cases and severe motor weakness was noted in 47.2%. The incidences of EOA and severe ulnar nerve palsy in the Japanese UNE are higher than those in Caucasians. Level of evidence Level IV; Prognostic—Investigating the effect of a patient characteristic on the outcome of a disease; Case series.

In this paper, a dynamometer for measurement of the force of each finger is developed, newly. Four pressure sensors are attached to the grip part of the dynamometer that is a smedley type. And, the developed dynamometer is able to measure the normal grip strength, when the grip strength of each finger is measured. Using the dynamometer, the grip strength of each finger of some subjects that are healthy and young are measured. It is clear that maximum grip strength is obtained by middle finger, and that the finger that obtains second maximum grip strength is different. Moreover, the grip strength of each finger of patients with with the carpal tunnel syndrome are measured. It is clear that the patterns of the patients are similar with the patterns of the implicit knowledge of the medical doctor.

Osteoarthritis (OA) is a group of common, chronic, and painful inflammatory joint diseases. One important finding in OA patients is a remarkable decrease in the molecular weight of hyaluronic acid (HA) in the synovial fluid of affected joints. Therapeutic HA is available to patients in most parts of the world as a viscosupplementation product for the treatment of OA. Previous clinical reports show that high molecular weight HA (HMWHA) more effectively relieves pain than low molecular weight HA (LMWHA). However, the mechanism behind this finding remains unclear. In this study, we investigated whether a LMWHA (Low-0.9 MDa) and two types of HMWHA (High-1.9 MDa and 6 MDa) differentially affected chondroregulatory action. We tested this using ATDC5 cell, a murine chondrocytic cell line widely used in culture systems to study chondrogenic differentiation. We found that HMWHA, especially hylan G-F 20 (High-6 MDa), significantly induced aggrecan and proteoglycan accumulation, nodule formation, and mRNA expression of chondrogenic differentiation markers in a time- and dose-dependent manner. In addition, we showed that HMWHA prevented TNF-α induced inhibition of chondrogenic differentiation, with no effect on cell proliferation or viability. These results reveal that HMWHA significantly promotes chondrogenic differentiation of ATDC5 cells in vitro, and suggest that HMWHA plays a significant chondroregulatory role in vivo. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:1619–1627, 2014.

Laparoscopic liver resection (LLR) has become a standard procedure for hepatocellular carcinoma (HCC) as well as liver metastases and other benign and malignant liver tumors (1-3). Numerous cohort studies and their reviews or meta-analyses comparing LLR with open liver resection (OLR) for HCC frequently have serious selection biases in terms of the differences in the size, number, tumor location, and malignancy degree (4-6).

The CellSearch system (Veridex, LLC) is useful for detecting circulating tumor cells (CTCs) in various carcinomas, including colorectal cancer (CRC); however, there are some problems associated with its clinical use. A transcription–reverse transcription concerted reaction (TRC) method, which is a PCR-based technique producing more stable and reliable results, because it is a more simplified process compared with the conventional techniques, has been introduced for detecting micrometastasis in some carcinomas. We aimed to demonstrate the effectiveness of TRC method in the CTC detection. We compared the two methods for the sensitivity for CTC detection using the colon cancer cell line and 42 whole-blood samples from patients with advanced or metastatic CRC. Furthermore, 25 patients with metastatic CRC were enrolled to investigate the correlation between CTC detection and prognosis in both methods. The sensitivity of the TRC method was similar to that of the CellSearch system. The overall survival rate was significantly worse in the patients diagnosed as CTC-positive by the TRC method than in those diagnosed as CTC-negative; this finding was similar to the prognosis indicated by the CellSearch system. However, clinically, the TRC method could detect CTCs more rapidly and at a reduced cost compared with the CellSearch system. The TRC method seems to be a useful alternative to the CellSearch system for clinically detecting CTCs in patients with metastatic CRC.

Background: Despite improvements in the surgical management of esophageal cancer, the prognosis of patients with lymph node metastases is still unsatisfactory. Recently, survival benefit of neoadjuvant or induction chemotherapy for patients with esophageal cancer has been highlighted. Methods: Efficacy and toxicity of induction chemotherapy for esophageal cancer were reviewed. In addition, our experience on modified docetaxel/cisplatin/5-FU (DCF) as induction chemotherapy was also demonstrated. The modified DCF consisted of 60 mg/m2 of docetaxel on day 1, and 350 mg/m2 of 5-FU and 6 mg/m2 of cisplatin on days 1–5. Two courses have been administered as induction chemotherapy in 51 patients with node-positive esophageal cancer. Response was evaluated by RECIST v1.0 and changes in standardized uptake value by 18F-fluorodeoxyglucose positron emission tomography. Results: Induction chemotherapy may be beneficial for node-positive esophageal cancer, although the consensus has not yet been established. A regimen of induction chemotherapy should have a high response rate and cisplatin/5-FU may be underpowered as an induction setting. DCF can be a candidate for the regimen of induction chemotherapy for esophageal cancer, although severe adverse events have been reported. Several modified regimens to reduce the toxicity have been reported. The response rate of our series was 61% and a significant decrease in standardized uptake values was observed after the induction chemotherapy. Although high-grade neutropenia was still observed with this regimen, neither treatment-related death nor delay in the following treatment was observed. Conclusions: Modified DCF can be a regimen of induction chemotherapy for node-positive esophageal cancer because of its high efficacy, although an adequate care for severe neutropenia is needed.

Laparoscopic liver resection (LLR) has become the standard treatment for various tumors of the liver including hepatocellular carcinoma (HCC) (1-3). LLR for liver tumors are considered to possess several perioperative advantages compared with conventional open liver resection (OLR). The Oslo-CoMet is the only randomized-controlled trial (RCT) to provide solid evidence that LLR is safer, less invasive, and cost-effective compared with OLR in patients with colorectal liver metastases (4).

Background and Objectives The aim of this study is to clarify the extent of lymphatic spread of cancer cells using a novel genetic test to examine patients with thoracic esophageal squamous cell carcinoma (ESCC). Methods A total of 35 patients who underwent an esophagectomy with three-field lymph node (LN) dissection were eligible. The regional LN stations were categorized into the cervical (C), recurrent nerve (RN), paraesophageal (PE), tracheo-bronchial (TB), and perigastric (PG) nodes. Lymphatic spread was pathologically diagnosed with Hematoxylin-Eosin (HE) and anti-cytokeratin immunohistochemistry (IHC) staining, and CEA-mRNA expression was examined using the transcription-reverse transcription concerted (TRC) reaction. Results The rates of lymphatic spread with HE, IHC, and TRC were 7.2%, 10.1%, and 55.5%, respectively. The number of CEA-mRNA(+) LN stations significantly correlated with tumor depth, LN metastasis diagnosed by HE, and vascular invasions. CEA-mRNA expression was observed in 42.9%, 94.3%, 77.1%, 80.0%, and 82.9% of C, RN, TB, PE, and PG nodes, respectively. Conclusions The high frequency of CEA-mRNA expression suggests that systemic therapy is necessary in addition to esophagectomy with adequate LN dissection. Conversely, a relatively low frequency of CEA-mRNA expression in the C node does not support the routine dissection of the LNs in this area. J. Surg. Oncol. 2010;102:509–515. © 2010 Wiley-Liss, Inc.

Peritoneal dissemination of gastric cancer is often refractory to systemic therapies. Although adenoviral gene therapy has been reported to be a potentially useful therapeutic modality, the adenovirus itself has a dose-limiting toxicity. A novel system was constructed using adenoviral oncolytic suicide gene therapy targeting carcinoembryonic antigen (CEA), and its therapeutic effect and the possibility to reduce the total viral dose while still preserving the antitumor effect were assessed.Three types of adenoviruses were prepared for this novel system: (A) Ad/CEA-Cre, (B) Ad/lox-CD::UPRT for a Cre/loxP system, and (C) Ad/CEA-E1 for conditionally replicating adenovirus. The antitumor effect of the oncolytic suicide gene therapy (A + B + C) was then evaluated in vitro. Mice bearing peritoneal dissemination of human gastric cancer were treated with either this system (A + B + C) or with a tenfold viral dose of suicide gene therapy (A + B). The adverse effects in terms of hepatotoxicity were then evaluated between the two groups.The current system (A + B + C) demonstrated significantly better cytotoxic effect for CEA-producing cell lines than did suicide gene therapy (A + B) at the same viral dose in vitro. The effect of oncolytic suicide gene therapy was almost equal to that of the tenfold viral dose of suicide gene therapy in vivo. The hepatotoxicity of the two treated groups was also found to be equivalent.It was possible to reduce the total adenoviral dose of oncolytic suicide gene therapy while still preserving the antitumor effect.

症例は86歳の男性で, 下血を主訴に精査を行い, 直腸内腔全体を占める全周性のRb直腸癌と診断された. 手術前の検討では肛門機能温存が不可能な低位直腸癌と診断され, 腹会陰式直腸切断術が予定されたが, 手術中に直腸癌による腸重積が判明し, これを解除することにより超低位前方切除術を行うことができた. 下部直腸癌で内腔全体を占める腫瘍の場合, 直腸癌による腸重積を考慮に入れ, 慎重な術式の選択をする必要があることが示唆された. 直腸癌による腸重積は極めてまれであり, 若干の文献的考察を加え報告する.

Surgical resection is the most effective therapy for colorectal liver metastases, subsequently there are chemotherapy and thermal destruction technique using microwave coagulation therapy (MCT) and radiofrequency ablation therapy (RFA). As the surgical approach is generally guided by these criteria (cancer factors : Tumor staging, differentiation of tumor, recurrence free interval, node status and transition of CEA. patient factors : age, liver function and performance status) and these criteria are intricated, the majority of patients present practically with unresectable. The thermal destructive therapy is well acceptable for hepatocellular cancer but not for colorectal liver metastases. We review the patients of colorectal liver metastases that we performed the thermal destructive therapy.

Objective Aldosterone plays an important role in the pathogenesis of atherosclerosis; however, the significance of mineralocorticoid receptor blockade for atherosclerosis has not been fully elucidated. In this study, the effect of add-on eplerenone on the degree of arterial stiffness was examined in patients with uncontrolled hypertension. Methods Forty-seven uncontrolled hypertensive patients who had previously been treated with anti-hypertensive drugs were examined retrospectively. Thirty-two patients received add-on therapy consisting of eplerenone (Group E) and 15 patients received add-on therapy with a Calcium channel blocker (CCB) or an increased dose of CCB (Group C) in addition to their baseline medications. Both the systolic blood pressure (SBP) and diastolic blood pressure (DBP) values were significantly decreased at two and 12 months in Group C. In contrast, neither the SBP nor DBP values were significantly changed at two months and eventually decreased at 12 months in Group E. The degree of arterial stiffness, as evaluated according to the cardio-ankle vascular index (CAVI), did not improve at either two or 12 months in Group C, whereas the CAVI values improved as early as at two months and the improvement was sustained at 12 months in Group E. The extent of change in the CAVI was not associated with the level of changes in the SBP or DBP values in Group E. Conclusion Treatment with eplerenone added to the patient's baseline medications improves the degree of arterial stiffness as early as at two months after the beginning of treatment, independent of the blood pressure-lowering actions of these drugs in patients with uncontrolled hypertension.

Chondroblastoma is a benign tumor that typically arises in the epiphysis of a long bone. There have been only 2 reported cases of chondroblastoma involving the capitate. This is the first report of chondroblastoma with secondary aneurysmal bone cyst involving the capitate. A 33-year-old man presented with a 3-year history of pain and swelling of the right wrist. Radiography as well as computed tomography showed a radiolucent area and no matrix calcification within the capitate. Magnetic resonance imaging revealed a homogeneous signal that was low on T1-weighted images and high on T2-weighted images and showed only slight enhancement. On the basis of imaging findings, the authors chose excisional biopsy. The bone tumor in the capitate was explored through a dorsal approach by dividing the extensor tendons. After repeated curettages, bone graft substitute using allograft bone was packed into the capitate. Histologically, the authors diagnosed this tumor as a chondroblastoma with a secondary aneurysmal bone cyst. At the final 2-year follow-up, there was evidence of bone union, full range of motion, and recovery and no evidence of recurrence. Although the recurrence of chondroblastoma is occasionally reported, the principal treatment is intralesional curettage and bone graft. High-speed burring, phenol, bone cement, and cryosurgery have been reported to reduce local recurrence. Complete excision of the carpal bone seems to be overtreatment.

Introduction Rapamycin is an mTOR inhibitor with anti-tumor activity in several human cancers. However, the efficacy of this compound in osteosarcoma has not been fully elucidated. It acts downstream in the PI3K pathway and impedes cell growth, cell proliferation, cell motility, cell survival, protein synthesis and transcription. Here, we assessed the anti-tumor activity of rapamycin. We had previously reported that gemcitabine reduced viability, growth and metastasis of osteosarcoma cell lines. In this study, we investigated whether gemcitabine could enhance the anti-tumor effects of rapamycin in the murine osteosarcoma cell line LM8 in vitro and in vivo. Results In the LM8 cell line, rapamycin synergized with gemcitabine to reduce cell proliferation as determined by the WST assay and to induce apoptosis as analyzed by flow cytometry using the annexin V and 7AAD staining method. Rapamycin at doses >10 μM showed significant cytotoxicity. By combining with gemcitabine, the amount of rapamycin required for apoptosis was reduced to 1 μM. Autophagy was evaluated with the Cyto-ID® Autophagy detection kit. Not only rapamycin but also gemcitabine induced autophagy in the LM8 cell line. However, no synergistic effects were observed. Cell mobility was evaluated by migration assay using a trans-well system (LM8 cells in the upper layer and conditioned medium in the lower chamber). Rapamycin synergized with gemcitabine to reduce LM8 cell mobility. In C3H mice inoculated subcutaneously with LM8, we observed frequent metastasis to the lung. Treatment of the mice with rapamycin reduced the size of the primary tumor; elevated levels of apoptosis were observed. Moreover, rapamycin in combination with gemcitabine had additive effects on the primary tumor and almost no metastatic lesions in the lung were seen. Consequently, combination therapy prolonged the overall survival of tumor-bearing mice. Conclusions Rapamycin synergized with gemcitabine to reduce cell proliferation, and to induce apoptosis, autophagy and cell mobility of the LM8 murine osteosarcoma cell line in vitro. Rapamycin in combination with gemcitabine exhibited synergistic antitumor effects. The combination prolonged overall survival and reduced the number of lung metastases in osteosarcoma-bearing mice. Rapamycin has been used to treat osteosarcoma in clinical trials and gemcitabine combined with docetaxel chemotherapy has shown good clinical results. Rapamycin combined with gemcitabine chemotherapy might be a novel and promising therapeutic approach to the treatment of osteosarcoma. Citation Format: Takashi Ando, Jiro Ichikawa, Nobutaka Sato, Tetsuro Ohba, Kensuke Koyama, Tetsuo Hagino, Hirotaka Haro. Rapamycin in combination with gemcitabine reduced viability, growth and metastasis of the murine osteosarcoma cell line LM8 in vitro and in vivo. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3536.

The mammalian target of rapamycin (mTOR) plays central roles in the regulation of cell growth and proliferation by monitoring nutrient availability, cellular energy level, oxygen level, and mitogenic signals. The aberrant activation of mTOR in relation to clinical outcome has been reported in several types of cancers. mTOR is increasingly important as a potential target for anticancer therapy. Nonetheless, a prognostic feature of mTOR activation in esophageal squamous cell carcinoma (ESCC) remains uncertain.First, in order to validate phospho-specific mTOR antibody (Ser2448), phosphorylated mTOR (p-mTOR) expression levels in five ESCC cell lines under cultural conditions with or without everolimus (mTOR inhibitor, also known as RAD001) were evaluated by in vitro immunohistochemistry and immunoblotting. Second, we examined p-mTOR expression by immunohistochemistry using 143 resected ESCC specimens. Prognostic significance of p-mTOR expression was examined by Cox regression and Kaplan-Meier analyses.Among 143 patients, 71 (49.7%) were classified into p-mTOR-positive and 72 (50.3%) were classified into p-mTOR-negative. Compared with p-mTOR-negative patients, p-mTOR-positive patients experienced high overall mortality [hazard ratio (HR) 2.44; 95% confidence interval (CI), 1.24-4.83; P = 0.008], which persisted in multivariate analysis (multivariate HR 2.92; 95% CI, 1.48-5.78; P = 0.002). A similar finding was observed for esophageal cancer-specific mortality. p-mTOR expression was not related with any clinical or pathologic variables including age, sex, tumor location, histological grading, operative procedure, T classification (tumor invasion), or lymph-node metastasis.p-mTOR overexpression was independently associated with poor prognosis in ESCC, supporting the potential for mTOR as a therapeutic target for ESCC.

p12 CDK2-associating protein 1 (p12CDK2-AP1) is a growth suppressor that negatively regulates cyclin-dependent kinase 2 (CDK2) activities. In addition, p12CDK2-AP1 has also been shown to interfere in DNA replication. A reduction of p12CDK2-AP1 expression is known to be a negative prognostic indicator in patients with oral squamous cell carcinoma. To elucidate the role of p12CDK2-AP1 expression in esophageal squamous cell carcinoma (ESCC), we immunohistochemically examined the expression of p12CDK2-AP1 protein in 120 resected ESCC specimens and determined its association with the clinicopathological characteristics and prognosis. Of the 120 ESCCs, 79 (65.8%) showed positive staining (>or=25% of cancer cells showing p12CDK2-AP1 expression), while 41 (34.2%) lacked the staining (

Purpose: MicroRNAs are ∼22 nucleotide noncoding RNA molecules that posttranscriptionally regulate gene expression. The aim of this study was (a) to determine a role of microRNA-21 in esophageal squamous cell carcinoma and (b) to elucidate the regulation of the programmed cell death 4 (PDCD4) gene by microRNA-21. Experimental Design: MicroRNA-21 expression was investigated in 20 matched normal esophageal epitheliums and esophageal squamous cell carcinomas and seven esophageal squamous cell carcinoma cell lines (TE6, TE8, TE10, TE11, TE12, TE14, KYSE30) by TaqMan quantitative real-time PCR and in situ hybridization. To evaluate the role of microRNA-21, cell proliferation and invasion were analyzed with anti–microRNA-21–transfected cells. In addition, the regulation of PDCD4 by microRNA-21 was elucidated to identify the mechanisms of this regulation. Results: Of 20 paired samples, 18 cancer tissues overexpressed microRNA-21 in comparison with matched normal epitheliums. Specifically, patients with lymph node metastasis or venous invasion showed significantly high expression of microRNA-21. In situ hybridization for microRNA-21 showed strong positive staining in paraffin-embedded esophageal squamous cell carcinoma tissues. All seven esophageal squamous cell carcinoma cell lines also overexpressed microRNA-21, and anti–microRNA-21–transfected cells showed significant reduction in cellular proliferation and invasion. The PDCD4 protein levels in esophageal squamous cell carcinoma cells have an inverse correlation with microRNA-21 expression. Anti–microRNA-21–transfected cells increased PDCD4 protein expression without changing the PDCD4 mRNA level and increased a luciferase-reporter activity containing the PDCD4-3′ untranslated region construct. Conclusions: MicroRNA-21 targets PDCD4 at the posttranscriptional level and regulates cell proliferation and invasion in esophageal squamous cell carcinoma. It may serve as a novel therapeutic target in esophageal squamous cell carcinoma.

We experienced a case of diaphragmatic hernia which occurred six years after a trauma. A 21-year-old woman underwent appendectomy under a diagnosis of acute appendicitis at a nearby hospital 3 days before. However, the patient complained of lasting abdominal pain and vomiting, was found to have a stricture of the large intestine, and was referred to our hospital. On admission tenderness of the epigastric region and weakness in breathing at lower segment of the left lung were recognized. Chest X-ray showed intestinal gas shadow in the left pleural cavity and lifting of left diaphragm.Under a diagnosis of incarceration of diaphragmatic hernia, an emergency operation was performed. Some part of the transverse colon was protruding into the left pleural cavity via the central part of the diaphragmatic tendon and was necrotic. The necrotic part of the colon was resected, and the defect of the diaphragm was sutured directly.As the patient had a history of chest and abdominal contusion by a traffic accident six years ago, she was diagnosed as traumatic diaphragmatic hernia.This case shows us a possibility that a delayed diaphragmatic hernia can occur in a certain period after chest and abdominal trauma.

Background: Owing to refinement of an immunomagnetic separation technology method for count and characterization of circulating tumor cells (CTCs) in patients with epithelial malignancies has been established. CellSearch System (CSS) is a device using this technology and the significance of CSS has been reported in various carcinoma. On the other hand, as a novel PCR based techniques, the amplification system with transcription-reverse transcription concerted reaction (TRC) method was introduced for detecting a few cancer cells. This method amplifies a cancer-specific messenger RNA (mRNA) directly in a single tube at a constant temperature without thermal cycling in three steps for PCR: denaturing, annealing, and extension. Accordingly, this method may produce a more stable and reliable result because of its simplified process compared to conventional PCR-based techniques. Another advantage of TRC method over CSS is the cost. It takes 30 dollars per sample in TRC method, while the cost of CSS is 800 dollars per sample. Object: In this study, we have investigated the utility of TRC method which targeted CEA-mRNA in detecting CTCs of patients with colorectal cancer. Materials and Methods: Between Nov. 2008 and May 2009, 42 samples from metastatic and/or recurrent colorectal cancer patients (mCRC) were enrolled. We compared the detection rate of CTCs between TRC method and CSS. In CSS, CTC was considered as positive when at least one cancer cell was detected. On the other hand, in TRC method, CTCs was considered as positive when the result of TRC method was positive. The statistical significance was evaluated by chi-square test. Differences were considered to be statistically significant when the p-value was less than 0.05. Results: In CSS, 27 samples (64.3%) were CTC positive, while 16 samples (38.1%) were CTC positive by TRC method. All of samples which are CTC positive by TRC method were also CTC positive by CSS. In order to compensate the lower sensitivity of TRC method, we have taken serum CEA value into account. As a result, all samples negative for TRC method but positive for CSS were from the patients whose serum CEA value was more than 20 ng/ml. In contrast, when serum CEA value of the patients was less than 20 ng/ml, all samples negative for TRC method demonstrated CTC negative for CSS. These results indicate that CSS should be done only when the sample from patients whose serum CEA value is more than 20 ng/ml is negative for TRC method. Conclusions: In conclusion, combination with TRC method and serum CEA evaluation can reduce the necessity of CSS analysis and thus reduce the cost of detecting CTCs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3749.

Background: The retina may be involved in patients with acquired immunodeficiency syndrome (AIDS). Progressive outer retinal necrosis (PORN) is a liability. Case: A 46-year-old female had repeated exacerbations of pulmonary tuberculosis since 2 years before. Herpes zoster developed in her right trigeminal nerve area 2 weeks before, leading to a diagnosis of AIDS. She was referred to us for ophthalmological evaluation. Findings: Both eyes showed numerous yellowish white patches in the deeper retinal layers. The anterior chamber and the vitreous were almost intact. Herpes zoster virus was identified in the aqueous by the polymerase chain reaction method. Systemic acyclovir or ganciclovir failed to prevent rapid extension of fundus lesions, resulting in whole-layer necrosis of the retina. Retinal detachment with multiple breaks developed in both eyes within eleven days after the patient was first seen by us. The clinical course was different from acute retinal necrosis and was characteristic of PORN. Conclusion: This case illustrates that PORN may develop in patients affected by AIDS.