Influence of XRCC4 expression in esophageal cancer cells on the response to radiotherapy.

DNA double-strand break (DSB) is one of the most serious forms of damage induced by ionizing irradiation and is mainly repaired by the non-homologous end joining (NHEJ) repair. Immunohistochemical analysis of proteins involved in NHEJ, such as XRCC4 (X-ray repair cross-complementing protein 4), Ku86 and DNA-PKcs (DNA-dependent protein kinase, catalytic subunits), may be useful for predicting tumor radiosensitivity. We examined 92 patients with esophageal squamous cell carcinoma (ECSS) who were treated by radiotherapy between 1999 and 2008. Immunohistochemical examination of tumor tissue for Ki-67 and DSB-related proteins, including XRCC4, Ku86, and DNA-PKcs, was performed using pretreatment biopsy specimens. Low expression of XRCC4 was detected in 31 of 92 examined samples (33.7 %). The 5-year overall survival (OS) rate was 67.7 % in the low expression group and 31.0 % in the high expression group (P = 0.00). Multivariate analysis confirmed that advanced T-stage (HR 3.24, P = 0.01), radiation dose less than 66 Gy (HR 2.23, P = 0.02), absence of systemic chemotherapy (HR 2.59, P = 0.05), and high expression of XRCC4 (HR 12.0, P = 0.02) were independent prognostic factors for predicting poor OS. Other DSB-related proteins and Ki-67 were not predictive factors. XRCC4 expression might have an influence on results of radiotherapy for patients with ESCC.


Targeting Notch-1 positive acute leukemia cells by novel fucose-bound liposomes carrying daunorubicin.

Complete remission by induction therapy in acute myelogenous leukemia (AML) can be achieved due to improvements in supportive and optimized therapy. However, more than 20% of patients will still need to undergo salvage therapy, and most will have a poor prognosis. Determining the specificity of drugs to leukemia cells is important since this will maximize the dose of chemotherapeutic agents that can be administered to AML patients. In turn, this would be expected to lead to reduced drug toxicity and its increased efficacy. We targeted Notch-1 positive AML cells utilizing fucose-bound liposomes, since activation of Notch-1 is required for O-fucosylation. Herein, we report that intravenously injected, L-fucose-bound liposomes containing daunorubicin can be successfully delivered to AML cells that express fucosylated antigens. This resulted in efficient tumor growth inhibition in tumor-bearing mice and decreased proliferation of AML patient-derived leukemia cells. Thus, biological targeting by fucose-bound liposomes that takes advantage of the intrinsic characteristics of AML cells could be a promising new strategy for Notch-1 positive-AML treatment.


BAK is a predictive and prognostic biomarker for the therapeutic effect of docetaxel treatment in patients with advanced gastric cancer.

Preoperative chemotherapy is a promising strategy for downstaging advanced gastric cancer before radical resection, although severe adverse events can occur and clinical outcomes are often unsatisfactory. To identify predictive biomarkers of drug sensitivity, we used a well-designed functional apoptosis assay and assessed the correlations between chemosensitivity and clinical outcomes. Drug sensitivity to docetaxel, cisplatin, and 5-fluorouracil was examined in 11 gastric cancer cell lines. BCL2-homology domain 3 (BH3) profiling was performed and assessed for correlations with drug sensitivity. Immunohistochemical staining of clinical gastric cancer specimens was performed before preoperative chemotherapy, and correlations with histopathological responses and clinical outcomes were assessed. BIM (BCL2L11)-BH3 profiling results correlated with docetaxel sensitivity and BAK protein expression, whose knockdown caused docetaxel resistance. The BAK expression indexes of 69 gastric cancer specimens before preoperative chemotherapy (including docetaxel treatment) were determined by multiplying numerical values describing the degrees of BAK positivity and staining intensity observed. Patients whose specimens showed good chemotherapeutic histopathological responses had higher BAK indexes than those with poor responses. Patients with BAK index values 3 showed improved progression-free survival (HR, 2.664; 95 % CI, 1.352-5.248; P = 0.005) and overall survival (HR, 3.390; 95 % CI, 1.549-7.422; P = 0.002). BH3 profiling clearly showed that BIM expression, which depends on BAK expression, correlated with docetaxel sensitivity. BAK expression in gastric cancer is thus predictive of chemotherapeutic responses to docetaxel and clinical prognosis in patients treated with preoperative chemotherapy.


Isoform D of vascular endothelial growth factor in systemic capillary leak syndrome: a case report.

In our patient, isoform D of vascular endothelial growth factor (instead of vascular endothelial growth factor) may have been a causative factor of hypotensive crises, since isoform D contributes to vascular endothelial growth factor receptor-2 signaling, which is the major mediator of the permeability-enhancing effects of vascular endothelial growth factor. We suggest the measurement of isoform D of vascular endothelial growth factor in patients with systemic capillary leak syndrome in whose serum vascular endothelial growth factor is not elevated.


A Phase 1/2 Study of Definitive Chemoradiation Therapy Using Docetaxel, Nedaplatin, and 5-Fluorouracil (DNF-R) for Esophageal Cancer.

Patient survival in esophageal cancer (EC) remains poor. The purpose of this study was to investigate a regimen of definitive chemoradiation therapy (CRT) that exerts good local control of EC. We performed a phase 1/2 study to assess the safety and efficacy of CRT with docetaxel, nedaplatin, and 5-fluorouracil (DNF-R). Eligible patients presented with stage IB to IV EC. Patients received 2 cycles of docetaxel (20, 30, or 40 mg/m(2)) and nedaplatin (50 mg/m(2)) on days 1 and 8 and a continuous infusion of 5-fluorouracil (400 mg/m(2)/day) on days 1 to 5 and 8 to 12, every 5 weeks, with concurrent radiation therapy (59.4 Gy/33 fractions). The recommended dose (RD) was determined using a 3 + 3 design. In the phase 1 study, the dose-limiting toxicities were neutropenia and thrombocytopenia. The RD of docetaxel was determined to be 20 mg/m(2). In the phase 2 study, grade 3 to 4 acute toxicities included neutropenia (42.8%), febrile neutropenia (7.14%), thrombocytopenia (17.9%), and esophagitis (21.4%). Grade 3 to 4 late radiation toxicity included esophagostenosis (10.7%). The complete response rate was 82.1% (95% confidence interval: 67.9-96.3%). Both the median progression-free survival and overall survival were 41.2 months. DNF-R showed good tolerability and strong antitumor activity, suggesting that it is a potentially effective therapeutic regimen for EC.

International Journal of Radiation Oncology*Biology*Physics


A Phase I/II Study of Fixed-dose-rate Gemcitabine and S-1 with Concurrent Radiotherapy for Locally Advanced Pancreatic Cancer

This study was conducted to identify the maximum-tolerated dose (MTD) of fixed-dose-rate gemcitabine (FDR-gem) administered concurrently with S-1 and radical radiation for locally advanced pancreatic cancer (LAPC) and to provide efficacy and safety data. Patients with unrespectable pancreatic cancer confined to the pancreatic region were treated with FDR-gem (300-400 mg/m(2), 5 mg/m(2)/min) on days 1, 8, 22, and 29 and 60 mg/m(2) of S-1 orally on days 1-14, 22-35. A total radiation dose of 50.4 Gy (1.8 Gy/day, 28 fractions) was delivered concurrently. Twenty-five patients were enrolled; all were evaluable for toxicity assessment. In phase I, eight patients were treated in sequential cohorts of three to five patients per dose level. The MTD was reached at level 2, and dose-limiting toxicities were neutropenia and thrombocytopenia. The recommended doses were 300 mg/m(2) of gemcitabine and 60 mg/m(2) of S-1 daily. The overall response rate was 25% and disease control rate (partial response plus stable disease) was 92%. The progression-free survival was 11.0 months. The median overall survival and 1-year survival rates were 16.0 months and 73%, respectively. The combination of FDR-gem and S-1 with radiation is a feasible regimen that shows favorable antitumor activity with an acceptable safety profile in patients with LAPC.


[A Case of Fanconi Syndrome Induced by Zoledronic Acid in a Metastatic Colorectal Cancer Patient].

A 60s-year-old woman with metastatic colorectal cancer was treated using mFOLFOX6 plus bevacizumab. Zoledronic acid was also administered owing to the presence of bone metastasis. The patient was admitted to our hospital with progressive hypokalemia, hypocalcemia, hypophosphatemia, and proximal renal tubular dysfunction. A diagnosis of Fanconi syndrome was made, and was believed to be induced by zoledronic acid treatment. This treatment was discontinued, and the patient's renal tubular function recovered. Denosumab was subsequently administered to treat the bone metastasis, and no renal tubular dysfunction occurred. It was possible to continue chemotherapy, and a complete response was obtained. Fanconi syndrome induced by zoledronic acid is rare, but it may hinder chemotherapy. Therefore, monitoring renal tubular function is recommended during therapy with zoledronic acid.

Japanese Journal of Cancer and Chemotherapy


Trastuzumab in combination with docetaxel/cisplatin/S-1 (DCS) for patients with HER2-positive metastatic gastric cancer: feasibility and preliminary efficacy.

We previously reported that a triplet combination of docetaxel, cisplatin, and S-1 (DCS) is active against metastatic gastric cancer with a very high response rate of 87.1 % in a phase II study. Recently, the efficacy of trastuzumab (T-mab) for the treatment of HER2-positive gastric cancer has been reported. Therefore, we investigated the feasibility and preliminary efficacy of DCS + T-mab (DCS-T) for unresectable HER2-positive metastatic gastric cancer. Patients received oral S-1 (40 mg/m(2) b.i.d.) on days 1-14, intravenous cisplatin (60 mg/m(2)), docetaxel (50 mg/m(2)), and T-mab (8 mg/kg in the first cycle and 6 mg/kg in the second cycle and thereafter) on day 8 every 3 weeks. The study included 16 patients: median age, 60 (34-76) years; males/females, 11:5; intestinal-type/diffuse-type histology, 11:5; and HER2 3+/2+(FISH+), 13:3. The completion rate until the third cycle was 87.5 % (14/16) (95 %CI 71.3-103.7 %). Adverse events of grade 3/4 severity during the first 3 cycles were: leukopenia/neutropenia, 50.0:75.0 %; febrile neutropenia, 12.5 %; diarrhea, 12.5 %; and stomatitis, 12.5 %. All of these side effects were manageable and well controlled. There were no treatment-related deaths. The overall response rate was 93.8 % (15/16), and the response rate in patients with measurable lesions was 100 % (15/15). The median cycle to response was only 1 (1-3 cycles). Non-curative factors disappeared in 56.3 % (9/16) of patients, and conversion surgery (R0 resection) was performed in all these cases. Pathological response rates in primary and metastatic lesions were 88.9 % (8/9) and 100 % (9/9), respectively. The median PFS and OS were not reached during the median follow-up time of 18.3 months ranged from 11.0 to 34.3 months. DCS-T was feasible in patients with unresectable HER2-positive metastatic gastric cancer. The observed response was very promising and warrants further investigation. UMIN000005603.


Evaluation of the validity of chemotherapy-induced nausea and vomiting assessment in outpatients using the Japanese version of the MASCC antiemesis tool.

The results of the study showed that the Japanese version of MAT is a highly reliable tool for CINV assessment, indicating that it is valid for assessing CINV in outpatients.


Increased duodenal iron absorption through up-regulation of divalent metal transporter 1 from enhancement of iron regulatory protein 1 activity in patients with nonalcoholic steatohepatitis.

In spite of elevation of serum hepcidin, iron absorption from the GI tract increased through up-regulation of DMT1 by IRP1 activation by humoral factor(s) in sera of patients with NASH.

Increased hepatic iron accumulation is thought to be involved in the pathogenesis of nonalcoholic steatohepatitis (NASH). Hepatic iron accumulation, as well as oxidative DNA damage, is significantly increased in NASH livers. However, the precise mechanism of iron accumulation in the NASH liver remains unclear. In this study, 40 cases with a diagnosis of NASH (n = 25) or simple steatosis (SS; n = 15) by liver biopsy were enrolled. An oral iron absorption test (OIAT) was used, in which 100 mg of sodium ferrous citrate was administered to each individual. The OIAT showed that absorption of iron from the gastrointestinal (GI) tract was increased significantly in NASH patients, compared to SS and control subjects. Iron reduction therapy was effective in patients with NASH, who exhibited iron deposition in the liver and no alanine aminotransferase improvement after other therapies (n = 9). Serum hepcidin concentration and messenger RNA (mRNA) levels of divalent metal transporter 1 (DMT1) also were significantly elevated in patients with NASH. OIAT results were correlated with grade of liver iron accumulation and DMT1 mRNA levels. Then, we demonstrated that DMT1 mRNA levels increased significantly in Caco-2/TC7 cell monolayers cultured in transwells with serum from NASH patients. An electrophoresis mobility shift assay showed activation of iron regulatory protein (IRP) in those cells, and IRP1 small interfering RNA clearly inhibited the increase of DMT1 mRNA levels.


Effect of duloxetine in Japanese patients with chemotherapy-induced peripheral neuropathy: a pilot randomized trial.

Our data suggests that duloxetine has a beneficial effect on CIPN caused by oxaliplatin, paclitaxel, vincristine, or bortezomib in Japanese patients.

International Journal of Clinical Oncology


Phase I trial of oral S-1 combined with hepatic arterial infusion of gemcitabine in unresectable biliary tract cancer.

The MTD of oral S-1 in GS therapy is 80 mg/m(2). Furthermore, HAI of gemcitabine may reduce the rate of grade 3 and 4 neutropenia in BTC patients receiving GS therapy.


EUS-guided celiac plexus neurolysis by using highly viscous phenol-glycerol as a neurolytic agent (with video).


A dose-escalation study of oxaliplatin/capecitabine/irinotecan (XELOXIRI) and bevacizumab as a first-line therapy for patients with metastatic colorectal cancer.

The aim of this study was to determine the recommended dose (RD) of a triweekly capecitabine, oxaliplatin, irinotecan, and bevacizumab (XELOXIRI/bevacizumab) regimen that was easier to administer than FOLFOXIRI/bevacizumab, using capecitabine instead of 5-fuorouracil (5-FU), in patients with metastatic colorectal cancer (mCRC).

XELOXIRI/bevacizumab is a feasible regimen for patients with mCRC, neutropenia was the DLT, and the RD of irinotecan is 150 mg/m(2). The response rate observed is very promising and warrants further investigation.


A long-term survival case of hepatic epithelioid hemangioendothelioma with lung metastases treated with recombinant interleukin-2

Recombinant interleukin-2を投与し6年間経過観察している肺転移を伴う肝類上皮血管内皮腫の1例

A 37-year-old woman was found in a medical checkup to have liver dysfunction. Abdominal CT scan images demonstrated multiple liver tumors. She was referred to our hospital for examination and treatment. Abdominal enhanced CT scan images showed irregularly spreading hypovascular tumors located in the surface of both hepatic lobes. Needle liver biopsy revealed many atypical cells with positive staining for factor VIII-related-antigen and CD34. The tumor was diagnosed as an hepatic epithelioid hemangioendothelioma (HEHE). She has received intravenous administration of recombinant interleukin-2 (rIL-2) for six years with a reduction in tumor volume. HEHE is a rare tumor which has low malignant potential, also is often unresectable due to multifocal tumors involving both hepatic lobes at the time of diagnosis. There was no generally accepted therapy except surgical resection and liver transplantation. The long-term survival observed in the present case may indicate the effectiveness of rIL-2 for HEHE.

症例は37歳女性．2009年1月，健診で肝機能障害を指摘され近医を受診し，単純CTにて肝および肺に多発結節病変を認められたため精査加療目的に当科紹介となった．造影CTでは肝被膜下を中心に境界明瞭な低吸収域が多発し癒合している所見を肝両葉に認めた．肝生検で豊富な硝子様の線維性間質内に腫瘍細胞を認め，免疫染色にて第VIII因子関連抗原，CD34陽性であり肝原発の類上皮血管内皮腫(hepatic epithelioid hemangioendothelioma:HEHE)と診断した．同年4月よりrecombinant interleukin-2(rIL-2)の投与を開始し，6年間外来通院にて治療を継続し，病変体積の減少が得られている．HEHEの生物学的悪性度は低いとされるが，既に腫瘍が肝全体を占めるように多発した切除不能例として発見されることが多い．本疾患の長期間の臨床経過を示した報告が少ないことから，本症例について報告する．


Therapy-related myelodysplastic syndrome as a late adverse event of definitive chemoradiotherapy for esophageal and oropharyngeal cancer

食道癌および中咽頭癌に対する根治的化学放射線併用療法の晩期有害事象と考えられたtherapy-related myelodysplastic syndromeの1例

The risks of myelodysplastic syndrome (MDS) and acute leukemia are increased in patients previously treated for other malignancies. Therapy-related MDS (t-MDS) occurs after exposure to certain cytotoxic agents or radiation used for cancer treatment. We report a case of t-MDS following curative chemoradiotherapy (CRT) for esophageal and oropharyngeal cancer. An 80-year-old male diagnosed with double cancers of the esophagus and oropharynx underwent definitive CRT and achieved a complete response. Six years later, he became anemic, and bone marrow examination showed 3.4% blast cells with fine chromatin structures and basophilic cytoplasm. Cytogenetic analysis indicated a complex karyotype that included chromosome 5 and 7 abnormalities. These findings were consistent with t-MDS. Subsequently, he developed acute myeloid leukemia and died 8 months later. This case indicates that long-term surveillance is needed to closely monitor the risk of t-MDS in patients treated with CRT.

症例は80歳男性．中咽頭癌および胸部上部食道癌の重複癌にて根治的化学放射線療法を2コース施行し，CRを得た．6年後徐々に進行する貧血を認め，骨髄検査と経過よりtherapy-related myelodysplastic syndrome(t-MDS)と診断した．晩期有害事象としてまれだが，t-MDSは極めて予後不良であり，治療前の十分な説明と終了後の慎重な経過観察が必要である．

The Japanese Journal of Gastro-enterology


A CASE OF DUODENAL BRUNNER'S GLAND HAMARTOMA IN WHICH MAGNIFYING ENDOSCOPY WAS USEFUL FOR PREOPERATIVE DIAGNOSIS

拡大内視鏡観察が術前診断に有用であった十二指腸Brunner腺過誤腫の1例

A 70-year-old man was referred to our hospital to treat a polyp in the duodenal bulb. Endoscopic examination showed that the polyp was composed of Yamada type IV lesions with thick stems and a head that was reddish. Magnifying endoscopy revealed a small opening and gastric epithelial metaplasia in the head of the polyp. We performed polypectomy for therapeutic diagnosis. Histologically, the lesion was a duodenal Brunner's gland hamartoma with abundant mature adipose tissue and gastric metaplasia. Brunner's gland hamartoma is composed of hyperplastic Brunner's glands mixed with elements such as adipose tissue, and is often accompanied by gastric epithelial metaplasia. Because diagnosis by biopsy is not possible, preoperative diagnosis of the disease is difficult. However, magnifying endoscopy enabled us to detect some characteristic findings of the disease, such as a small opening and gastric epithelial metaplasia. As a result, preoperative diagnosis might be possible by magnifying endoscopy. This case suggested that magnifying endoscopy is useful for the diagnosis of Brunner's gland hamartoma.

症例は70歳男性．十二指腸球部にポリープを認め，精査加療目的に当科紹介．上部消化管内視鏡検査では，十二指腸球部に基部を持ち，頭部は発赤調で茎部は頭部と同等の太さの，茸状の外観を呈した山田IV型病変を認めた．拡大観察では，頭部に胃上皮化生または異所性胃粘膜と考えられる所見と微小な開口部を認めた．診断的治療目的にpolypectomyを施行したところ，組織学的には表層粘膜に胃上皮化生を伴う成熟脂肪組織の豊富な十二指腸Brunner腺過誤腫であった．Brunner腺過誤腫は，過形成性のBrunner腺に脂肪組織など他の要素が混在するもので，しばしば胃上皮化生を伴う1)とされる．本例では，拡大内視鏡観察によりBrunner腺由来病変に特徴的な所見の指摘が可能であった．

日本消化器内視鏡学会雑誌


Multiple hepatocellular adenomas: a case report

肝生検で高分化型肝細胞癌との鑑別が困難であった多発肝細胞腺腫の1切除例

We report a rare case of multiple hepatocellular adenomas difficulty in ruling out well-differentiated hepatocellular carcinomas prior to resection. A 40s female was admitted to the hospital for examination of multiple liver tumors. CT and Gd-EOB-MRI showed that tumors were located in segment 2 and 5. We conducted a percutaneous tumor biopsy and tumor showed low atypical cells containing fat deposit. As the possibility of multiple hepatocellular carcinomas could not be denied, partial hepatectomy and RFA were done. All resected tumors showed a decreased expression of the liver fatty acid binding protein (L-FABP), and were finally diagnosed as multiple HNF1-inactivated type hepatocellular adenomas. Multiple hepatocellular adenomas are rare tumors, so we report this case with review of the literatures.

症例は40歳代女性．検診の腹部超音波検査で肝血管腫が疑われ当科を紹介受診．造影CT検査で肝血管腫以外に多発肝腫瘍を認め，精査目的に入院となった．Gd-EOB-MRI検査では，S2, S5に腫瘤像が認められ，T1WIで低信号，動脈相で等信号，門脈相，平衡相及び肝細胞相で低信号であった．画像検査では確定診断に至らず，腫瘍生検を施行した．細胞密度の高い異型の乏しい腫瘍細胞で，肝細胞腺腫や高分化型肝細胞癌が疑われ，肝部分切除術と術中RFAを施行した．摘出標本の免疫染色にてliver fatty acid binding protein(L-FABP)の発現低下を認め，Hepatocyte nuclear factor 1α-inactivated type(HNF1α-inactivated type)の多発肝細胞腺腫と診断した．多発肝細胞腺腫は稀であり文献的考察を加え報告する．


RNAi-mediated gene silencing of ST6GalNAc I suppresses the metastatic potential in gastric cancer cells.

ST6GalNAc I may regulate the gene expression of IGF-1 through STAT5b activation in gastric cancer cells and may be a potential target for treatment of metastasizing gastric cancer.


Efficacy of Enteral Supplementation Enriched with Glutamine, Fiber, and Oligosaccharide on Mucosal Injury following Hematopoietic Stem Cell Transplantation.

The combination of glutamine, fiber and oligosaccharides (GFO) is thought to be beneficial for alleviating gastrointestinal mucosal damage caused by chemotherapy. A commercial enteral supplementation product (GFO) enriched with these 3 components is available in Japan. We performed a retrospective study to test whether oral GFO decreased the severity of mucosal injury following hematopoietic stem cell transplantation (HSCT). Of 44 HSCT patients, 22 received GFO and 22 did not. Severity of diarrhea/mucositis, overall survival, weight loss, febrile illness/documented infection, intravenous hyperalimentation days/hospital days, engraftment, acute and chronic GVHD, and cumulative incidence of relapse were studied. Sex, age, performance status, diagnosis, disease status, and treatment variables were similar in both groups. There were fewer days of diarrhea grade 3-4 in patients receiving GFO than in those who did not (0.86 vs. 3.27 days); the same was true for days of mucositis grade 3-4 (3.86 vs. 6.00 days). Survival at day 100 was 100% in the GFO group, but only 77.3% for the patients not receiving GFO (p = 0.0091, log-rank test). Weight loss and the number of days of intravenous hyperalimentation were better in the GFO group (p < 0.001 and p = 0.0014, respectively). Although not significant, less gut bacterial translocation with Enterococcus species developed in the GFO group (p = 0.0728) than in the non-GFO group. Other outcomes were not affected. To the best of our knowledge, this is the first comparative clinical study of GFO supplementation to alleviate mucosal injury after allo-HSCT. We conclude that glutamine, fiber and oligosaccharide supplementation is an effective supportive therapy to decrease the severity of mucosal damage in HSCT.


Radiation-induced leiomyosarcoma of the prostate after brachytherapy for prostatic adenocarcinoma.

Radiation therapy (RTx) has been employed as a curative therapy for prostatic adenocarcinoma. RTx-induced sarcomas (RISs) are rare, late adverse events, representing less than 0.2% of all irradiated patients. RISs are more aggressive tumors than prostatic adenocarcinomas. Herein, we present a case with RTx-induced prostatic leiomyosarcoma after permanent brachytherapy for prostatic adenocarcinoma. A 69-year-old male presented with dysuria and gross hematuria. Six years previously, he had been diagnosed with localized prostate cancer and was treated by permanent brachytherapy. Urethroscopy showed stenosis by a tumor at the prostate. Transurethral prostatectomy was performed for a diagnosis. Based on pathological findings, the diagnosis was leiomyosarcoma of the prostate. He was treated with three cycles of neoadjuvant chemotherapy (CTx) that consisted of doxorubicin and ifosfamide (AI), followed by a prostatocystectomy with intrapelvic lymphadenectomy. The tumor extended from the prostate and infiltrated the bladder wall and serosa with lymphatic and venous invasion. The surgical margin was negative, and no residual prostatic adenocarcinoma was observed. The proportion of necrotic tumor cells by neoadjuvant CTx was around 50%. Subsequently, adjuvant CTx was offered, but the patient chose a follow-up without CTx. Local recurrence and lung metastasis were detected by computed tomography 3 months after the surgery. He was treated again with AI. However, CTx was not effective and he died 6 months after the operation. In conclusion, an effective treatment strategy for prostatic sarcoma should be developed in the near future, although the clinical feature of prostatic sarcoma remains unclear due to its rare incidence.


Successful treatment with entecavir for reactivation of hepatitis B virus following systemic chemotherapy in a hepatitis B surface antigen-negative patient with colorectal cancer.

Reactivation of hepatitis B virus (HBV) has recently been reported as a fatal complication in patients undergoing cytotoxic chemotherapy. We herein describe a case of reactivation in a 76-year-old man who had undergone pelvic exenteration for colorectal cancer (CRC). He was treated with a modified FOLFOX6 chemotherapy regimen after the operation. Thirteen months later, his laboratory data showed severe liver dysfunction. His hepatitis B surface antigen (HBsAg) test was positive, and his HBV-DNA level was elevated. We diagnosed the patient with HBV reactivation as his HBsAg test was negative before starting chemotherapy. His liver dysfunction improved after administration of entecavir. This is the first report describing HBV reactivation following chemotherapy for an HBsAg-negative CRC patient.


Phenol-based endoscopic ultrasound-guided celiac plexus neurolysis for East Asian alcohol-intolerant upper gastrointestinal cancer patients: a pilot study.

Phenol had similar pain-relieving effects to ethanol in EUS-CPN. Comparing the incidences of inebriation and burning pain, phenol may be superior to ethanol in EUS-CPN procedures.


[Effective treatment of metastatic rhabdomyosarcoma with pazopanib].

Pazopanib, an oral tyrosine kinase inhibitor, is the first molecular-targeted agent approved for the treatment of advanced soft tissue sarcoma(STS). Rhabdomyosarcoma in adults is rare, accounting for less than 3%of all adult STS cases. A 57-year old woman presented with cervical lymphadenopathy. Computed tomography revealed a heterogeneous mass in the retroperitoneum, replacing the entire right kidney. On the basis of the above findings, the patient was diagnosed with alveolar rhabdomyosarcoma. She was first treated with 4 courses of vincristine, actinomycin D, and cyclophosphamide(VAC), which resulted in a partial response. Dose reduction and delay occurred owing to hematological toxicity and febrile neutropenia. As second-line chemotherapy, the patient was administered a single daily dose of 800 mg of pazopanib. Because of an episode of hand-foot syndrome and hepatic impairment, the 800-mg daily dose of pazopanib was reduced to a daily dose of 600 mg, which had to be further reduced to a daily dose of 400 mg owing to fatigue and anorexia. The patient maintained a partial response for a total of 4.3 months when treated with pazopanib. Therefore, this drug may be a new treatment option for patients showing metastatic STS after previous chemotherapy.

Japanese Journal of Cancer and Chemotherapy


Activated hepatic stellate cells are dependent on self-collagen, cleaved by membrane type 1 matrix metalloproteinase for their growth.

Stellate cells are distributed throughout organs, where, upon chronic damage, they become activated and proliferate to secrete collagen, which results in organ fibrosis. An intriguing property of hepatic stellate cells (HSCs) is that they undergo apoptosis when collagen is resolved by stopping tissue damage or by treatment, even though the mechanisms are unknown. Here we disclose the fact that HSCs, normal diploid cells, acquired dependence on collagen for their growth during the transition from quiescent to active states. The intramolecular RGD motifs of collagen were exposed by cleavage with their own membrane type 1 matrix metalloproteinase (MT1-MMP). The following evidence supports this conclusion. When rat activated HSCs (aHSCs) were transduced with siRNA against the collagen-specific chaperone gp46 to inhibit collagen secretion, the cells underwent autophagy followed by apoptosis. Concomitantly, the growth of aHSCs was suppressed, whereas that of quiescent HSCs was not. These in vitro results are compatible with the in vivo observation that apoptosis of aHSCs was induced in cirrhotic livers of rats treated with siRNAgp46. siRNA against MT1-MMP and addition of tissue inhibitor of metalloproteinase 2 (TIMP-2), which mainly inhibits MT1-MMP, also significantly suppressed the growth of aHSCs in vitro. The RGD inhibitors echistatin and GRGDS peptide and siRNA against the RGD receptor V1 resulted in the inhibition of aHSCs growth. Transduction of siRNAs against gp46, V1, and MT1-MMP to aHSCs inhibited the survival signal of PI3K/AKT/IB. These results could provide novel antifibrosis strategies.


Combination Chemotherapy of Azacitidine and Cetuximab for Therapy-Related Acute Myeloid Leukemia following Oxaliplatin for Metastatic Colorectal Cancer.

Therapy-related leukemia (TRL) has been reported to occur after treatment with alkylating agents and/or topoisomerase II inhibitors. Oxaliplatin (OXP) is used as a key drug for the treatment of colorectal cancer (CRC). Cisplatin and carboplatin have been linked with TRL, but the involvement of OXP is questionable. A 74-year-old male was diagnosed with peritoneal metastasis from CRC in July 2011. The patient received nine cycles of 5-fluorouracil (5-FU), leucovorin (LV), and OXP (mFOLFOX-6 regimen) and three cycles of 5-FU and LV only, resulting in a clinical complete response. However, recurrence of CRC was detected by CT within 3 months after the last course of chemotherapy. In April 2013, laboratory tests showed pancytopenia and 15% blast cells. A bone marrow examination revealed multilineage dysplasia and 20.4% myeloblasts. Cytogenetic analysis indicated a complex karyotype that included chromosome 5 and 7 abnormalities. The patient was diagnosed with TRL and treated with a combination of azacitidine (AZA) and cetuximab (Cmab) for both cancers. AZA might be useful in TRL when a patient needs to be treated simultaneously for more than one primary cancer because of its low toxicity. Moreover, Cmab is an effective therapeutic tool in TRL patients with metastatic CRC with the wild-type K-ras gene.


Clinical utility of capsule endoscopy with flexible spectral imaging color enhancement for diagnosis of small bowel lesions.

FICE is most useful for improving CE image quality and detection in cases of angioectasia and erosion/ulceration of the small intestine.

In the assessment of visibility in the 152 vascular lesion images, the ∆E and VAS of FICE set 1, 2, and BM images were significantly higher than that of WL images. In 88 erosion/ulceration images, the ∆E and VAS of FICE set 1 and 2 images were significantly higher than that of WL images. In 21 tumor images, there were no significant differences in ∆E among these modalities. When analyzed on a per-patient basis, FICE settings 1 and 2 had the highest sensitivity (100 %) and specificity (97.3 - 100 %) for vascular lesions. As for erosive/ulcerative lesions, FICE setting 2 had the highest sensitivity (100 %) and specificity (97.2 %). For tumors or polyps, WL had the highest sensitivity (90.9 %) and specificity (87.1 %). In per-lesion analysis, FICE settings 1 and 2 showed significantly superior detection ability over WL for vascular lesions. In the detection of erosive/ulcerative lesions, FICE setting 2 was significantly superior to WL. In tumor images, there was no significant improvement with any of the settings relative to WL images.


Narrowband ultraviolet B phototherapy ameliorates acute graft-versus-host disease by a mechanism involving in vivo expansion of CD4+CD25+Foxp3+ regulatory T cells.

Narrowband ultraviolet B phototherapy (NB-UVB) is a therapeutic alternative for haematopoietic stem cell transplantation-related skin graft-versus-host disease (GVHD). The beneficial effects of this intervention may be induced by direct irradiation of inflammatory cells in the skin; however, the putative involvement of indirect effects on systemic immunity has not been elucidated. To address this issue, 11 acute skin GVHD patients refractory to standard corticosteroid treatment and with no gut/liver involvement were treated with NB-UVB irradiation. The median number of treatments was 10 times, with a mean cumulative exposure of 6.36 J/cm(2). No other immunosuppressive therapy was initiated during irradiation. Eight patients achieved an objective complete response, two had a partial response, and one showed no change. None of the patients experienced progressive skin GVHD or newly diagnosed gut/liver GVHD. NB-UVB was well tolerated, with no patients discontinuing irradiation due to toxicity. We additionally demonstrated by flow cytometry that NB-UVB irradiation induces the increment of the proportion of regulatory T cell (Tregs) in patients' peripheral blood. These results suggest that NB-UVB may exert beneficial effects on steroid-refractory skin GVHD through the expansion of Tregs.


A novel strategy inducing autophagic cell death in Burkitt's lymphoma cells with anti-CD19-targeted liposomal rapamycin.

Relapsed or refractory Burkitt's lymphoma often has a poor prognosis in spite of intensive chemotherapy that induces apoptotic and/or necrotic death of lymphoma cells. Rapamycin (Rap) brings about autophagy, and could be another treatment. Further, anti-CD19-targeted liposomal delivery may enable Rap to kill lymphoma cells specifically. Rap was encapsulated by anionic liposome and conjugated with anti-CD19 antibody (CD19-GL-Rap) or anti-CD2 antibody (CD2-GL-Rap) as a control. A fluorescent probe Cy5.5 was also liposomized in the same way (CD19 or CD2-GL-Cy5.5) to examine the efficacy of anti-CD19-targeted liposomal delivery into CD19-positive Burkitt's lymphoma cell line, SKW6.4. CD19-GL-Cy5.5 was more effectively uptaken into SKW6.4 cells than CD2-GL-Cy5.5 in vitro. When the cells were inoculated subcutaneously into nonobese diabetic/severe combined immunodeficiency mice, intravenously administered CD19-GL-Cy5.5 made the subcutaneous tumor fluorescent, while CD2-GL-Cy5.5 did not. Further, CD19-GL-Rap had a greater cytocidal effect on not only SKW6.4 cells but also Burkitt's lymphoma cells derived from patients than CD2-GL-Rap in vitro. The specific toxicity of CD19-GL-Rap was cancelled by neutralizing anti-CD19 antibody. The survival period of mice treated with intravenous CD19-GL-Rap was significantly longer than that of mice treated with CD2-GL-Rap after intraperitoneal inoculation of SKW6.4 cells. Anti-CD19-targeted liposomal Rap could be a promising lymphoma cell-specific treatment inducing autophagic cell death.


The preventive effects of low-dose enteric-coated aspirin tablets on the development of colorectal tumours in Asian patients: a randomised trial.

Low-dose, enteric-coated aspirin tablets reduced colorectal tumour recurrence in an Asian population. The results are consistent with those obtained from other randomised controlled trials in Western countries. THE CLINICAL TRIAL REGISTRY WEBSITE AND THE CLINICAL TRIAL NUMBER: http://www.umin.ac.jp (number UMIN000000697).


Pancreatic metastasis from a solitary fibrous tumor of the central nervous system.

Histological findings and immunohistochemical profile obtained by EUS-FNA are invaluable for the correct diagnosis to avoid excessive surgical procedures.


Fucosylated TGF- receptors transduces a signal for epithelial-mesenchymal transition in colorectal cancer cells.

Fucosyltransferase 3/6 has an essential role in cancer cell adhesion to endothelial cells by upregulation of sialyl Lewis antigens and also by enhancement of cancer cell migration through TGF--mediated EMT.


[Successful treatment with rituximab in a patient with refractory mixed-type autoimmune hemolytic anemia].

The evidence that rituximab is effective therapy for refractory warm or cold autoimmune hemolytic anemia (AIHA) has been accumulating; however, the efficacy of rituximab for mixed-type AIHA is not evident. Herein, we report a case of mixed-type AIHA refractory to corticosteroids and splenectomy, but successfully treated with rituximab (375 mg/m(2)/day, once weekly, four times). She achieved a complete response, which has been maintained for 16 months, to date, despite steroid tapering. Our case suggests that rituximab therapy should be considered for refractory AIHA even of mixed-type.

The Japanese Journal of Clinical Hematology


A case of idiopathic encapsulating peritoneal sclerosis with intractable ileus successfully treated by surgery and steroid therapy.

Encapsulating peritoneal sclerosis (EPS) occurring without a history of peritoneal dialysis is rare. We report on a patient with idiopathic EPS following intractable ileus who was successfully treated by surgery and postoperative steroid therapy without any sign of recurrence. A 67-year-old woman was referred to our department for further treatment of intractable ileus. Abdominal CT scanning revealed wall thickening of the proximal jejunum. Double-balloon enteroscopy disclosed stenosis of the jejunum at 20 cm anally from the Treitz ligament, although the intestinal mucosa appeared normal without specific biopsy findings. In addition, FDG-PET showed no abnormal accumulation, thus discounting a malignant lesion. Since conservative therapy failed to improve the ileus, we performed an operation on her in order to release the ileus and make a histological diagnosis. Surgical findings included a whitish thickening of the serosa extending to the intestine and the whole mesentery. Accordingly, we made a diagnosis of idiopathic encapsulating peritoneal sclerosis because of her negative history of peritoneal dialysis, laparotomy or peritonitis, in addition to the above-noted findings. Postoperative oral administration of steroid has suppressed EPS recurrence. In patients with intractable ileus, EPS should be added to the list of differential diagnoses, even if they have not undergone peritoneal dialysis.


Rapid on-site evaluation by endosonographer during endoscopic ultrasound-guided fine needle aspiration for pancreatic solid masses.

This cytological grading system used in ROSE by endosonographers is invaluable for the diagnosis of pancreatic solid masses.

Journal of Gastroenterology and Hepatology


A phase II study of neoadjuvant combination chemotherapy with docetaxel, cisplatin,and S-1 for locally advanced resectable gastric cancer: nucleotide excision repair (NER) as potential chemoresistance marker

The combination of docetaxel, cisplatin, and S-1 (DCS) chemotherapy is expected to be a promising regimen for advanced gastric cancer. This study was performed to evaluate the efficacy and safety of neoadjuvant DCS chemotherapy for locally advanced resectable gastric cancer. Patients with locally advanced gastric cancer received 2 courses of preoperative chemotherapy with S-1 (40 mg/m(2) b.i.d.) on days 1-14 and docetaxel (60 mg/m(2)) plus cisplatin (60 mg/m(2)) on day 8 every 3 weeks, followed by standard curative surgery within 4-8 weeks. The primary endpoint was R0 resectability. Expression of damage DNA binding protein complex subunit 2 (DDB2)/excision repair cross-complementing 1 (ERCC1) in the pretreated tumor tissues was examined by immunohistochemistry. A total of 43 patients received neoadjuvant chemotherapy. The response rate was 74.4%, and disease control ratio was 100%. Grade 4 neutropenia developed in 53.5% of patients and febrile neutropenia in 16.3%. Non-hematological grade 3/4 adverse events were anorexia (23.3%), nausea (14.0%), and diarrhea (23.3%), but these were generally transient and manageable. The proportion of R0 resections in the 43 eligible patients was 90.7%, and a pathological response was found in 65.9% of patients. There were no treatment-related deaths and no major surgical complications. The accuracy of the combination of DDB2 and ERCC1 expression for predicting chemoresistance was 82.5%. Preoperative treatment with DCS combination for locally advanced gastric cancer demonstrated a sufficient R0 resection rate and a good pathological response with manageable toxicities. The DDB2/ERCC1-high phenotype, as determined by immunohistochemistry, may be useful predictor of resistance to DCS chemotherapy.


Increased hepatic oxidative DNA damage in patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma.

8-OHdG content in liver tissue may serve a marker of oxidative stress and could be a particularly useful predictor of hepatocarcinogenesis.

The 8-OHdG content in the liver tissue of NASH-HCC patients was significantly different from that in the other patients. The median immunostaining intensity was 8.605 in the NASH-HCC cases, which was significantly higher than that in the cases of NASH without HCC (4.845; P = 0.003). Multivariate analysis using hepatic 8-OHdG content as a factor in addition to age and fasting blood sugar revealed a significant difference in clinicopathological factors between NASH-HCC and NASH without HCC cases. Old age (P = 0.015) and high relative immunostaining intensity for intrahepatic 8-OHdG (P = 0.037) were identified as independent factors.


Diagnostic validity of CT gastrography versus gastroscopy for primary lesions in gastric cancer: evaluating the response to chemotherapy, a retrospective analysis.

There was good concordance between the evaluations of GS and CT gastrography. CT gastrography exhibited favorable results in accuracy as well as 100 % PD predictability, which implied the possibility of using CT gastrography as a substitute for endoscopic assessments at post-chemotherapy assessments.


Treatment of pancreatic fibrosis with siRNA against a collagen-specific chaperone in vitamin A-coupled liposomes.

These data suggest the therapeutic potential of the present approach for reversing pancreatic fibrosis.


Stromal cells expressing hedgehog-interacting protein regulate the proliferation of myeloid neoplasms.

Aberrant reactivation of hedgehog (Hh) signaling has been described in a wide variety of human cancers including cancer stem cells. However, involvement of the Hh-signaling system in the bone marrow (BM) microenvironment during the development of myeloid neoplasms is unknown. In this study, we assessed the expression of Hh-related genes in primary human CD34(+) cells, CD34(+) blastic cells and BM stromal cells. Both Indian Hh (Ihh) and its signal transducer, smoothened (SMO), were expressed in CD34(+) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS)-derived cells. However, Ihh expression was relatively low in BM stromal cells. Remarkably, expression of the intrinsic Hh-signaling inhibitor, human Hh-interacting protein (HHIP) in AML/MDS-derived stromal cells was markedly lower than in healthy donor-derived stromal cells. Moreover, HHIP expression levels in BM stromal cells highly correlated with their supporting activity for SMO(+) leukemic cells. Knockdown of HHIP gene in stromal cells increased their supporting activity although control cells marginally supported SMO(+) leukemic cell proliferation. The demethylating agent, 5-aza-2'-deoxycytidine rescued HHIP expression via demethylation of HHIP gene and reduced the leukemic cell-supporting activity of AML/MDS-derived stromal cells. This indicates that suppression of stromal HHIP could be associated with the proliferation of AML/MDS cells.


Intermittent administration of recombinant human soluble thrombomodulin successfully controlled chronic disseminated intravascular coagulation in a patient with dissecting aortic aneurysm on an outpatient basis.

Chronic disseminated intravascular coagulation (DIC) is a rare but life-threatening complication of dissecting aortic aneurysm. Although anticoagulant therapy may often proves effective for controlling DIC itself, patients would have to be hospitalized for a long period due to continuous infusion therapy. Subcutaneous injection of a highly concentrated preparation of heparin calcium may offer one alternative treatment for DIC; however, daily subcutaneous use of heparin for the treatment of DIC has impaired quality of life (QOL). The other alternative therapy is intravenous administration of recombinant human soluble thrombomodulin (rTM), which includes the active extracellular domain of thrombomodulin. Reportedly, rTM effectively resolves DIC by only 6 consecutive days of administration; however, how frequently rTM should be administered after the resolution of chronic DIC to have good control of it has been unclear. We report herein a case of chronic DIC complicated with dissecting aortic aneurysm, whose resolution of chronic DIC achieved by 6 consecutive days of rTM has been maintained by once a week administration of rTM on an outpatient basis.


Successful treatment by fibrin glue sealant for pneumothorax with chronic GVHD resistant to autologous blood patch pleurodesis.

Pneumothorax associated with chronic graft-versus-host disease (cGVHD) after stem cell transplantation is a rare complication. Autologous blood has been used successfully for pleurodesis, which was less toxic than chemical agents. However, when pneumothorax is resistant to pleurodesis, no other procedure is more effective and conservative. Here, we describe a case of myelodysplastic syndromes complicated with cGVHD-related pneumothorax. His pneumothorax has been resistant to pleurodesis using autologous blood and was treated successfully with fibrin glue sealant. In our limited experience, we believe the best success could be achieved when this method is used to treat persistent pneumothorax with cGVHD.


Targeting anticancer drug delivery to pancreatic cancer cells using a fucose-bound nanoparticle approach.

Owing to its aggressiveness and the lack of effective therapies, pancreatic ductal adenocarcinoma has a dismal prognosis. New strategies to improve treatment and survival are therefore urgently required. Numerous fucosylated antigens in sera serve as tumor markers for cancer detection and evaluation of treatment efficacy. Increased expression of fucosyltransferases has also been reported for pancreatic cancer. These enzymes accelerate malignant transformation through fucosylation of sialylated precursors, suggesting a crucial requirement for fucose by pancreatic cancer cells. With this in mind, we developed fucose-bound nanoparticles as vehicles for delivery of anticancer drugs specifically to cancer cells. L-fucose-bound liposomes containing Cy5.5 or Cisplatin were effectively delivered into CA19-9 expressing pancreatic cancer cells. Excess L-fucose decreased the efficiency of Cy5.5 introduction by L-fucose-bound liposomes, suggesting L-fucose-receptor-mediated delivery. Intravenously injected L-fucose-bound liposomes carrying Cisplatin were successfully delivered to pancreatic cancer cells, mediating efficient tumor growth inhibition as well as prolonging survival in mouse xenograft models. This modality represents a new strategy for pancreatic cancer cell-targeting therapy.


Improvement of iron-mediated oxidative DNA damage in patients with transfusion-dependent myelodysplastic syndrome by treatment with deferasirox.

Myelodysplastic syndrome (MDS) is characterized by dysplastic and ineffective hematopoiesis, peripheral blood cytopenias, and a risk of leukemic transformation. Most MDS patients eventually require red blood cell (RBC) transfusions for anemia and consequently develop iron overload. Excess free iron in cells catalyzes generation of reactive oxygen species that cause oxidative stress, including oxidative DNA damage. However, it is uncertain how iron-mediated oxidative stress affects the pathophysiology of MDS. This study included MDS patients who visited our university hospital and affiliated hospitals (n=43). Among them, 13 patients received iron chelation therapy when their serum ferritin (SF) level was greater than 1000 ng/mL or they required more than 20 RBC transfusions (or 100 mL/kg of RBC). We prospectively analyzed 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in peripheral blood mononuclear cells (PBMC) obtained from MDS patients before and after iron chelator, deferasirox, administration. We showed that the 8-OHdG levels in MDS patients were significantly higher than those in healthy volunteers and were positively correlated with SF and chromosomal abnormalities. Importantly, the 8-OHdG levels in PBMC of MDS patients significantly decreased after deferasirox administration, suggesting that iron chelation reduced oxidative DNA damage. Thus, excess iron could contribute to the pathophysiology of MDS and iron chelation therapy could improve the oxidative DNA damage in MDS patients.


Prognostic significance of serum ferritin level at diagnosis in myelodysplastic syndrome.

Myelodysplastic syndrome (MDS) is characterized by peripheral blood cytopenias and risk of progression to acute myeloid leukemia. Elevated serum ferritin (SF), due to ineffective erythropoiesis and increased iron absorption from the gut, is often observed in non-transfused MDS patients, suggesting involvement of iron overload in its pathogenesis. However, the prognostic value of the baseline SF is unclear. We evaluated baseline SF levels in non-transfused MDS patients. The SF level was significantly higher in the 47 MDS patients in this study than in the healthy controls (P < 0.001). The SF level of higher-risk MDS patients (int-2/high) was significantly higher than that of the lower-risk MDS patients (low/int-1) (467 ± 354 vs. 277 ± 372 ng/ml, P < 0.001). The SF level in MDS patients with chromosomal abnormality was significantly higher than that in patients with normal karyotype. When patients were divided into the low SF group (<500 ng/ml) and high SF group (500 ng/mL), the survival time was significantly longer in the former group than the latter group (118.8 vs. 10.2 M, P = 0.002). Further, leukemia-free survival (LFS) was significantly longer in the low SF group than the high SF group (P = 0.010). Baseline SF level may, therefore, be a prognostic factor for overall survival and LFS in MDS patients.


A mechanism for abnormal angiogenesis in human radiation proctitis: analysis of expression profile for angiogenic factors

Radiation proctitis is an increasingly prevalent problem, with many patients being treated with radiotherapy for pelvic cancers. However, the mechanisms by which radiation proctitis develops in humans are not well understood. In this study, the expression profiles of angiogenic factors were analyzed to clarify their role in the etiology of radiation proctitis. Rectal biopsies were taken from 8 patients with radiation proctitis and 8 normal subjects. Protein lysates of the tissues were applied to an antibody array for angiogenesis-related factors. The mRNA level of each factor was evaluated by Taqman real-time PCR. Immunohistochemistry was performed using the labeled streptavidin biotin method. Antibody array analysis revealed 2.12- to 7.31-fold higher expression levels of angiogenin, fibroblast growth factor 1 (FGF1), endoglin, matrix metalloproteinase (MMP)-8, urokinase-type plasminogen activator (uPA) and maspin in radiation proctitis tissues compared with normal rectal mucosa. The mRNA level of each factor in radiation proctitis tissue was significantly higher than in normal rectal mucosa, suggesting their transcriptional activation. Immunohistochemical staining showed strong expression of angiogenin and maspin in rectal epithelia, MMP-8 and uPA in infiltrating lymphocytes, FGF1 in fibroblasts and endoglin in endothelial cells. The expression of VEGF was not evident. Our results suggest that in radiation proctitis, MMP-8 and uPA cooperatively degrade the extracellular matrix and basement membrane to provide space for angiogenesis. Simultaneously, angiogenin and FGF1 promote endothelial cell proliferation, and endoglin induces vessel formation, culminating in angiogenesis. Inhibitors of angiogenic factors such as angiogenin and FGF1 may be effective for treating radiation proctitis.


A phase I trial of arterial infusion chemotherapy with gemcitabine and 5-fluorouracil for unresectable biliary tract cancer.

This regimen of gemcitabine and 5-fluorouracil is tolerable and warrants further investigation in biliary tract cancer.

International Journal of Clinical Oncology


A case of pancreatic abscess associated with colonic fistula successfully treated by endoscopic transgastric drainage using a metallic stent.

A 64-year-old man, who had been treated conservatively for acute pancreatitis in another hospital 6 months previously, was admitted to our hospital with abdominal pain and fever. CT scan showed an air-containing fluid collection extending from the pancreatic tail to areas around the descending colon, leading to a diagnosis of pancreatic abscess associated with colonic fistula. We performed EUS-guided placement of a naso-cystic tube and an internal drainage tube stent, through which irrigation with saline was started. Because these tubes did not effectively relieve the symptoms, a covered EMS was placed to facilitate drainage to the stomach. Both the symptoms and signs of infection improved, and a contrast study confirmed disappearance of the abscess and closure of the fistula. He has been well without recurrence of the pancreatic abscess for half a year.


A case of ulcerative colitis accompanied with myelodysplastic syndrome successfully treated by cyclosporine.

A 64-year-old man had been admitted to a previous hospital because of melena and a diagnosis of ulcerative colitis (UC, pancolitis type) had been made. He had received prednisolone and 5-ASA but steroid-induced hyperamylasemia had developed. Prednisolone had been tapered and halted, but it had resulted in UC relapse and thrombocytopenia. Then, he was referred to our hospital due to severe melena with hypovolemic shock. However, he was also positive for CMV antigen. Thus, we attempted to treat him with ganciclovir for CMV and intravenous cyclosporine (CsA) for UC. According to his clinical course, a reduction of CsA blood concentration induced leukocytopenia. Myelodysplastic syndrome (MDS, RAEB-1) was then revealed after bone marrow biopsy. A high blood CsA concentration may cause the improvement of UC and MDS conditions.

The Japanese Journal of Gastro-enterology


Iron chelator deferasirox rescued mice from Fas-induced fulminant hepatitis.

These findings indicated that the iron chelation exerted a hepatoprotective effect by scavenging ROS upstream of caspase-3 and that iron chelation with deferasirox is a potential treatment for patients with fulminant hepatitis.


Novel missense mutation in the TMPRSS6 gene in a Japanese female with iron-refractory iron deficiency anemia.

Iron-refractory iron deficiency anemia (IRIDA) is a rare autosomal-recessive disorder hallmarked by hypochromic microcytic anemia, low transferrin saturation, and unresponsiveness to oral iron with partial recovery after parenteral iron administration. The disease is caused by mutations in TMPRSS6 (transmembrane protease serine 6) that prevent inactivation of membrane-bound hemojuvelin, an activator of hepcidin transcription. To date, 38 cases have been characterized and reported in European countries and the United States. In this paper, we describe the first case of a Japanese female with IRIDA, who carried a novel mutation (K253E) in the CUB (complement factor C1r/C1s, urchin embryonic growth factor and bone morphogenetic protein 1) domain of the TMPRSS6 gene.


Establishment of a simple test for iron absorption from the gastrointestinal tract.

Recent studies on iron metabolism have begun to reveal the molecular mechanisms underlying iron absorption, which is dramatically affected in several disorders. In the clinical setting, the ability to determine the status of iron absorption would aid in the diagnosis of pathological conditions. Efforts to develop an oral iron absorption test (OIAT) date back to at least 60 years. However, previous procedures were associated with a number of problems, such as radiation exposure and low reproducibility. In an attempt to resolve these issues, we employed sodium ferrous citrate (SFC), by which the influence of various nutrients and drugs on iron absorption was markedly reduced. We found that OIAT using SFC was simple to perform in both hospitalized patients and outpatients. The increment of serum iron and % transferrin saturation at 120 min after SFC administration was useful in distinguishing iron absorption between healthy volunteers, patients with iron-deficiency anemia, and patients with anemia secondary to chronic disorders, which are respectively characterized by normal, enhanced, and reduced iron absorption. Thus, the SFC-based OIAT may represent a viable screening test for the evaluation of gastrointestinal iron absorption.


Randomized double-blind trial of sulindac and etodolac to eradicate aberrant crypt foci and to prevent sporadic colorectal polyps.

On the basis of the results of our preliminary trial suggesting that aberrant crypt foci (ACF) could be eradicated by short-term administration of sulindac, in the present study, we explored the feasibility of using ACF as surrogate markers for chemoprevention of colorectal cancer. Experimental design: Randomly assigned to sulindac (300 mg daily), etodolac (400 mg daily), and placebo groups were 189 subjects without polyps or who had undergone polypectomy. Drugs were administered for 2 months. ACF in the rectal region were counted by magnifying endoscopy. Occurrence of polyps was evaluated at 12 months. A planned interim analysis was conducted. ACF number at 2 months was significantly suppressed in the sulindac group (P = 0.0075), but not in the etodolac group (P = 0.73). In the sulindac group, the numbers of adenomas plus hyperplastic polyps (total polyps) and adenomas at 12 months were significantly (P = 0.02) and marginally (P = 0.064) lower, respectively, in comparison with the placebo group; no such difference was observed in the etodolac group. In analysis of only polypectomized subjects, the numbers of total polyps and adenomas in the sulindac group were even more markedly lower, with P values of 0.014 and 0.034, respectively. A similar tendency was confirmed by analyses of the incidence of polyps at 12 months. Suppression rates of total polyps and adenomas in ACF responders to sulindac were significantly greater than in nonresponders. In all groups, compliance was more than 90% and no intolerable adverse effects were observed. ACF may be useful as surrogate lesions for chemoprevention of colorectal cancer.


[Tuberculous pleuritis with onset of refractory pleural effusion after chemoradiotherapy for esophageal cancer].

A 75-year-old man received chemoradiotherapy (CRT) for stage IVa esophageal cancer and complete response (CR) was obtained. However, he was referred to our department for recurrence in an area of esophagus not included in the previously irradiated field. Left pleural effusion increased after admission. Tuberculous pleuritis was eventually diagnosed by thoracoscopic pleural biopsy. It is necessary to accurately diagnose the cause of pleural effusion after CRT, because treatment strategies greatly depend on it. It is also necessary to consider the possible onset of tuberculous pleuritis, in particular, in patients with a history of tuberculosis infection.


Argon plasma coagulation treatment of hemorrhagic radiation proctopathy: the optimal settings for application and long-term outcome.

No standard treatment exists for hemorrhagic radiation proctopathy (HRP). Recently it was reported that argon plasma coagulation (APC) is effective for HRP. However, previous studies documented complications such as ulcers, strictures, and perforations in as many as 20% of APC-treated patients. The aim of this study was to determine the optimal parameters for APC by using swine rectum and to assess the safety and effectiveness of APC in HRP patients. Prospective case series. University teaching hospital. Sixty-five patients with HRP were prospectively enrolled between 2000 and 2010. APC for HRP. Optimal APC parameters, number of treatments, success rate, complications, clinical remissions. APC in swine rectal wall ex vivo was optimal with a 40-W current, 1.2-L/min gas flow rate, and 2-second application, which was sufficient to treat the submucosal telangiectasia but did not adversely affect the muscle layer. Sixty-five patients (46 men, 19 women; median age 72 years) with HRP occurring at a mean of 20 months after radiotherapy were studied. Proctopathy was classified as grade A (mild) in 7 patients (10.8%), grade B (moderate) in 41 (63.1%), and grade C (severe) in 17 (26.2%). The treatment success rate was 98.5% after a median of 2 (range 1-5) APC sessions. The median clinical score for rectal bleeding was significantly decreased after APC (P < .0001), and the hemoglobin level was significantly increased (P < .0001). APC was well tolerated, and no significant side effects or complications occurred. During a mean follow-up of 34.6 months (range 3.6 -121.1 months), 4 patients (6.3%) had minor recurrent rectal bleeding and 60 (93.8%) remained in remission. Nonrandomized study. HRP treatment with optimal APC settings yields a high success rate and long-lasting clinical remission with no significant complications.


A case of severe acute pancreatitis and ischemic gastropathy caused by acute aortic dissection.

A 49-year-old man presented with chest pain and was given a diagnosis of aortic dissection based on computed tomography (CT) findings. Two days later the dissection reached the origin of the celiac artery and there was poor blood flow from the body to the tail of the pancreas and fundus of the stomach wall. Severe acute pancreatitis developed. Endoscopy showed a near-circumferential gastric ulcer in the gastric cardia and we diagnosed ischemic gastropathy. A fistula between the area of infected pancreatic necrosis and the stomach had formed spontaneously and the necrotic tissue was draining into the stomach. His recovery was uneventful.


Endoscopic findings of enteropathy-type T-cell lymphoma by double-balloon enteroscopy and capsule endoscopy.

Enteropathy-type T-cell lymphoma (ETL) is a rare primary intestinal disorder, particularly in Japan, and there have been few reports on the endoscopic findings of the disease. Here we report detailed endoscopic findings of ETL based on double-balloon enteroscopy and capsule endoscopy. Double-balloon enteroscopy and capsule endoscopy may be useful tools for diagnosing and monitoring the effects of therapy in patients with ETL.


[Evaluation of the efficacy of liposomal amphotericin B].

A retrospective study was performed to evaluate the efficacy and safety of liposomal amphotericin B (L-AMB) in a total of 32 cases who were among patients hospitalized at the Fourth Department of Internal Medicine, Sapooro Medical University from December 2006 to April 2008. Primary diagnoses were hematologic diseases in 87.5% of subjects. The most common hematologic diseases included acute myelogenous leukemia in 50% of the subjects, followed by malignant lymphoma in 12.5% of the subjects. The mean administration period was 14.2 +/- 12.9 days, and the mean cumulative dose was 1,786 +/- 2,181 mg. L-AMB improved 21 of 29 cases (72.4%) with some fungal infections or fever-associated neutropenia. Adverse events occurred in 9 cases to a slight degree, in 7 cases to a moderate degree, and in no case to a severe degree. Hypokalemia and hypercreatininemia were seen in 7 cases (21.9%) and 4 cases (12.5%), respectively, but these adverse reactions were so mild that the treatment did not need to be discontinued. Any adverse reactions for which treatment administration was discontinued were confirmed to have disappeared at the end of the study. These results support the efficacy and safety of L-AMB in accordance with previous foreign reports. It was noteworthy that early use of L-AMB prior to established diagnosis sometimes better therapeutic outcomes. It was also suggested that L-AMB could be safely administered while controlling electrolyte balance, such as serum potassium concentration, with sufficient fluid replacement, including physiological saline infusion. There are limitations in the use of the conventional form of amphotericin B because of its renal toxicity and other reasons. However, L-AMB had fewer side effects, so the agent was considered useful for the treatment of hematologic disease patients who either had mycosis or carried a risk for fungal infection.


[Cholangiocarcinoma with bile duct adenoma and hamartoma-like lesion in the bile duct].

A 76-year-old man presented with fever of unknown origin. Diagnostic imaging showed a liver tumor measuring 3cm in maximum dimension. The tumor was subsequently resected, and histopathology showed a moderately differentiated adenocarcinoma. This showed a number of bile ductules with variable amounts of stroma, well circumscribed but not encapsulated, so the lesion was diagnosed as a cholangiocarcinoma. Within the tumor there was also a cholangiolocarcinoma-like lesion. In addition, cystically dilated ductules resembling bile duct hamartoma and bile duct adenoma adjacent to the tumor were found, but with no area of transition among them. In the Glisson's capsule around the tumor, there was also a bile duct hamartoma.

The Japanese Journal of Gastro-enterology


[A case of solitary fibrous tumor of the pancreas].

A 58-year-old woman without any clinical symptoms had a routine health check-up, during which a mass in the head of the pancreas was detected by US. Abdominal US showed a round, hypoechogenic nodule of the pancreatic head. The tumor measured 3cm in diameter and contained an anechoic area. CT revealed a well-demarcated tumor in the pancreatic head. The tumor was partially enhanced by contrast medium, but the left portion of the tumor, which US had shown to be an anechoic area was not enhanced. Imaging findings suggested an endocrine tumor with cystic changes. A pylorus-preserving pancreatoduodenectomy was performed. The tumor was composed of spindle-shaped cells. There was a typical patternless growth of short fascicles and a short storiform arrangement of cells in the stroma with varying degrees of collagenization. Immunohistochemically, the tumor cells were positive for CD34 and Bcl-2. Based on the light microscopic morphology and immunostaining profile, the tumor was classified as a solitary fibrous tumor (SFT) of the pancreas.


Drug resistance is dramatically restored by hedgehog inhibitors in CD34+ leukemic cells.

Aberrant reactivation of hedgehog (Hh) signaling has been described in a wide variety of human cancers and in cancer stem cells. However, the contribution of Hh signaling to leukemic cell regulation has remained unclear. In this study, we assessed the possibility that Hh pathway activation contributes to the survival and drug resistance of cluster of differentiation (CD)34+ leukemia cells. Hh signaling in leukemic cell lines and primary leukemic cells was screened by reverse transcription - polymerase chain reaction (RT-PCR) and a Hh signaling reporter assay. We found that Hh signaling is active in several human acute myeloid leukemia (AML) cells, especially primary CD34+ leukemic cells and cytokine-responsive CD34+ cell lines such as Kasumi-1, Kasumi-3 and TF-1. These CD34+ cells express the downstream effectors glioma-associated oncogene homolog (GLI)1 or GLI2, indicative of active Hh signaling. Moreover, inhibition of Hh signaling with the naturally derived Smoothened antagonist cyclopamine, endogenous Hh inhibitor hedgehog-interacting protein or anti-hedgehog neutralizing antibody induced apoptosis after 48 h of exposure, although these CD34+ cell lines exhibited resistance to cytarabine (Ara-C). In contrast, cyclopamine failed to affect growth or survival in U937 and HL-60 cell lines that lack expression of Hh receptor components, confirming that the effect of Hh inhibition is specific. Furthermore, combination with 10 microM cyclopamine significantly reduced drug resistance of CD34+ cell lines and primary CD34+ leukemic cells to Ara-C. These results suggest that aberrant Hh pathway activation is a feature of some CD34+ myeloid leukemic cells and Hh inhibitors may have a therapeutic role in the treatment of AML.


Successful treatment for gastro-intestinal bleeding of Osler-Weber-Rendu disease by argon plasma coagulation using double-balloon enteroscopy.


[Effective CDDP arterial infusion with DSM for liver metastasis of malignant melanoma complicating DIC due to intratumoral hemorrhage--a case report].

A 65-year-old male, who had been diagnosed with melanoma of stage IIB and treated by chemotherapy since 2003 at the Dermatology Department, was referred to our department for liver metastasis of melanoma that had become resistant to chemotherapeutic agents. In 2006, he started receiving hepatic arterial infusion of CDDP. He was admitted to the hospital on an emergency basis for general fatigue the next May. Blood tests revealed anemia and thrombocytopenia. Contrast CT showed aggravation of liver metastasis. Contrast ultrasonography revealed nodular contrast enhancement at the margin of the tumor. On the basis of image findings and blood test results, DIC due to intratumoral hemorrhage was diagnosed. CDDP arterial infusion with DSM resulted in improved DIC, and he was able to be discharged. Taken together, attention has to be paid to the potential for emergency complications of DIC due to liver metastasis of melanoma with intratumoral hemorrhage. Moreover, it was shown that arterial infusion with DSM was effective for liver metastasis of melanoma.

Japanese Journal of Cancer and Chemotherapy


[A case of hepatosplenic gammadelta T-cell lymphoma associated hemophagocytic syndrome].

A 56-year-old woman was admitted to our hospital for examination of high fever, liver dysfunction, pancytopenia, elevated lactate dehydrogenase (LDH) and ferritin, which were not improved by methylprednisolone pulse therapy. Although bone marrow aspiration revealed hypocellularity with no apparent activated macrophages, all other data strongly suggested hemophagocytic syndrome (HPS). She was then treated with chemotherapy consisting of etoposide, prednisolone and cyclosporine, which resulted in transient improvement and allowed her to undergo whole-body fluorine-18fluorodeoxyglucose positron emission tomography (FDG-PET) analysis. FDG uptake was elevated especially in the spleen and liver. A liver biopsy was performed and the examination of the specimen with immunohistochemical staining and PCR analysis revealed monoclonal infiltration of gammadelta T-cell. Despite the repeated chemotherapy, she deteriorated rapidly and succumbed to multi-organ failure. A postmortem examination revealed massive infiltration of activated macrophages with hemophagocytosis in the spleen, liver, bone marrow and perisplenic lymph nodes.


Treatment of hepatocellular carcinoma by AdAFPep/rep, AdAFPep/p53, and 5-fluorouracil in mice.

Although conditionally replicable adenovirus (CRAd) has been used in the clinical treatment of hepatocellular carcinoma (HCC), it suffers from the inherent drawback of having relatively low antitumor activity. Here, we have sought to overcome this drawback. First, we combined CRAd (AdAFPep/Rep) driven by alpha-fetoprotein enhancer/promoter (AFPep) with a replication-incompetent adenovirus carrying a p53 transgene that is also driven by AFPep. The synergism of this combination produced a significantly improved tumoricidal effect on the human HCC cell line Hep3B, which has a relatively short doubling time in comparison with other human HCC cell lines, through the transactivation of p53 by early region 1A transcribed by AdAFPep/Rep. This synergistic interaction was augmented by the addition of a subtumoricidal dose (0.5 microg/mL) of 5-fluorouracil (5-FU), which enhanced p53 expression and facilitated the release of virions from tumor cells. When relatively large (10-mm-diameter) Hep3B tumors grown in nude mice were injected with the two viruses in combination, they showed significantly impaired growth in comparison with those treated with each virus separately. The growth suppression effect of the virus combination was enhanced by a low dose (600 microg) of 5-FU. Survival of the tumor-bearing mice treated with these three agents was significantly longer than that of control mice. Moreover, the tumor completely disappeared with the repeated injection of these agents. CONCLUSION: This combination strategy holds promise for the treatment of relatively large and rapidly growing HCCs that may be encountered clinically.


Apoptosis supercedes necrosis in mitochondrial DNA-depleted Jurkat cells by cleavage of receptor-interacting protein and inhibition of lysosomal cathepsin.

In the present study, we used mitochondrial DNA-depleted Jurkat subclones (rho0 cells) to demonstrate that Fas agonistic Ab (CH-11), at the concentrations that evoke apoptotic death of the parental Jurkat cells, induced necrosis mainly through generation of excess reactive oxygen species, lysosomal rupture, and sequential activation of cathepsins B and D, and in minor part through activation of receptor-interacting protein (RIP). In the rho0 cells treated with CH-11, ATP supplementation converted necrosis into apoptosis by the formation of the apoptosome and subsequent activation of procaspase-3. In these ATP-supplemented rho0 cells (ATP-rho0), generation of excess ROS and lysosomal rupture were still seen, yet cathepsins B and D were inactivated and RIP was degraded. The conversion of necrosis to apoptosis, RIP degradation, and cathepsin inactivation in ATP- rho0 cells were blocked by caspase-3 inhibitors. Activities of cathepsins B and D in the lysate of necrotic rho0 cells were inhibited by the addition of apoptotic parental Jurkat cell lysate. Thus, apoptosis may supercede necrosis.


Case report of a focal nodular hyperplasia-like nodule present in cirrhotic liver.

An 81-year-old female was referred to Sapporo Medical University Hospital because of a nodular lesion 20 mm in diameter found in the liver S8 during follow-up for type C liver cirrhosis. Abdominal ultrasonography showed a capsule-like structure, and contrast computed tomography revealed hypervascularity at the early phase and inner pooling of the contrast medium with ring enhancement at the late phase. Magnetic resonance T2-weighted imaging (T2WI) demonstrated a hyperintensity nodule with further hyperintensity signals in some parts of the nodule, and the signal pattern differed from that of typical fibrosis. SPIO-magnetic resonance imaging showed partial hypointensity signals by T2WI, which indicated the presence of Kupffer cells. Angiography did not show a spoke-wheel pattern. The results by imaging modalities indicated that the nodule was atypical for hepatocellular carcinoma (HCC) and focal nodular hyperplasia (FNH), and liver nodule biopsy was performed for histological diagnosis. Compared with the background liver, the nodule revealed high cellular density, cellular dysplasia at the periphery, a pseudo-crypt structure and irregular hepatic cord arrangement in some parts of the nodule. Among them, there was immature fibrous tissue containing arterioles with muscular hypertrophy. There has been no report of well-differentiated HCC with a central scar, and this case was presumed to be an FNH-like nodule with dysplasia physically associated with cirrhotic tissue.


Ex vivo large-scale generation of human red blood cells from cord blood CD34(+) cells by co-culturing with macrophages.

We generated red blood cells (RBC) from cord blood (CB) CD34+ cells using a four-phase culture system. We first cultured CB CD34+ cells on telomerase gene-transduced human stromal cells in serum-free medium containing stem cell factor (SCF), Flt-3/Flk-2 ligand, and thrombopoietin to expand CD34+ cells (980-fold) and the total cells (10,400-fold) (first phase). Expanded cells from the first phase were liquid-cultured with SCF, interleukin-3 (IL-3), and erythropoietin (EPO) to expand (113-fold) and differentiate them into erythroblasts (second phase). To obtain macrophages for the next phase, we expanded CD34+ cells from a different donor using the same coculture system. Expanded cells from the first phase were liquid-cultured with granulocyte-macrophage colony stimulating factor, macrophage-colony stimulating factor (M-CSF), IL-3, and SCF to generate monocytes/macrophages (75-fold), which were incubated with type AB serum and M-CSF to fully differentiate them into macrophages. Erythroblasts were then co-cultured with macrophages in the presence of EPO to expand (threefold) and fully differentiate them (61% orthochromatic erythroblasts plus 39% RBC) (third phase). RBC were purified from erythroblasts and debris through a deleukocyting filter to generate 6.0 x 10(12) RBC from 1.0 unit of CB (3.0 transfusable units). Qualitatively, these RBC showed a hemoglobin content, oxygenation of hemoglobin, and in vivo clearance similar to those of adult peripheral RBC. Finally, an almost complete enucleation of orthochromatic erythroblasts (99.4%) was achieved by the cultivation method recently described by Miharada et al. in the absence of macrophages and cytokines (fourth phase). RBC were purified from remnant erythroblasts and debris by passage through a deleukocyting filter to generate 1.76 x 10(13) RBC from 1.0 unit of CB (8.8 transfusable units), the highest yield ever reported. Thus, this method may be useful for generating an alternative RBC supply for transfusions, investigating infectious agents that target erythroid cells, and as a general in vitro hematopoietic model system.


Resolution of liver cirrhosis using vitamin A-coupled liposomes to deliver siRNA against a collagen-specific chaperone.

There are currently no approved antifibrotic therapies for liver cirrhosis. We used vitamin A-coupled liposomes to deliver small interfering RNA (siRNA) against gp46, the rat homolog of human heat shock protein 47, to hepatic stellate cells. Our approach exploits the key roles of these cells in both fibrogenesis as well as uptake and storage of vitamin A. Five treatments with the siRNA-bearing vitamin A-coupled liposomes almost completely resolved liver fibrosis and prolonged survival in rats with otherwise lethal dimethylnitrosamine-induced liver cirrhosis in a dose- and duration-dependent manner. Rescue was not related to off-target effects or associated with recruitment of innate immunity. Receptor-specific siRNA delivery was similarly effective in suppressing collagen secretion and treating fibrosis induced by CCl(4) or bile duct ligation. The efficacy of the approach using both acute and chronic models of liver fibrosis suggests its therapeutic potential for reversing human liver cirrhosis.


A Phase I trial of arterial infusion chemotherapy with gemcitabine and 5-fluorouracil for unresectable advanced pancreatic cancer after vascular supply distribution via superselective embolization.

Arterial infusion chemotherapy using 1000 mg/m(2) gemcitabine on Day 1 and 300 mg/m(2)/day 5-fluorouracil on Days 1-5 every 2 weeks warrants a Phase II study.


[An advanced metastatic breast cancer patient successfully treated with combination therapy including docetaxel, doxorubicin and cyclophosphamide (TAC) as salvage therapy].

We reported here a case of advanced breast cancer successfully treated with combination therapy including docetaxel, doxorubicin and cyclophosphamide (TAC) as salvage therapy. A 56-year-old male was referred to our hospital for treatment of recurrent metastatic breast cancer. When he was admitted, his general condition was poor due to massive intraperitoneal metastasis. We administered TAC chemotherapy (docetaxel 75 mg/m(2), doxorubicin 50 mg/m(2), and cyclophosphamide 500 mg/m(2), every 3 weeks). During chemotherapy, he showed no major adverse effects except grade 3 neutropenia, which could be easily managed with G-CSF administration. Metastatic lesions almost disappeared after 4 cycles of TAC. TAC therapy was considered to be acceptable as salvage therapy for a metastatic male breast cancer patient.

Japanese Journal of Cancer and Chemotherapy


Aberrant Crypt Foci as Precursors of the Dysplasia-Carcinoma Sequence in Patients with Ulcerative Colitis.

Long-standing ulcerative colitis (UC) predisposes patients to the development of colorectal cancer, but surveillance of colitis-associated cancer by detecting the precancerous lesion dysplasia is often difficult because of its rare occurrence and normal-looking appearance. In sporadic colorectal cancer, aberrant crypt foci (ACF) have been reported by many investigators to be precursor lesions of the adenoma-carcinoma sequence. In the present study, we analyzed the genetic background of ACF to determine whether they could be precursors for dysplasia, and we examined the usefulness of endoscopic examination of ACF as a surrogate marker for surveillance of colitis-associated cancer. ACF were examined in 28 UC patients (19 patients with UC alone and 9 patients with UC and dysplasia; 2 of those patients with dysplasia also had cancer) using magnifying endoscopy. K-ras, APC, and p53 mutations were analyzed by two-step PCR RFLP, in vitro--synthesized protein assay, and single-strand conformation polymorphism, respectively. Methylation of p16 was analyzed by methylation-specific PCR. ACF that appeared distinct endoscopically and histologically were identified in 27 out of 28 UC patients. They were negative for K-ras, APC, and p53 mutations but were frequently positive for p16 methylation (8 of 11; 73%). In dysplasia, K-ras and APC mutations were negative but p53 mutation (3 of 5; 60%) and p16 methylation (3 of 5; 60%) were positive. There was a significant stepwise increase in the number of ACF from patients with UC alone to patients with dysplasia and to patients with cancer. Univariate and multivariate analyses showed significant correlations between ACF and dysplasia. We have disclosed an ACF-dysplasia-cancer sequence in colitis-associated carcinogenesis similar to the ACF-adenoma-carcinoma sequence in sporadic colon carcinogenesis. This study suggests the use of ACF instead of dysplasia for the surveillance of colitis cancer and warrants further evaluation of ACF as a surveillance marker in large-scale studies.


Long-term phlebotomy with low-iron diet therapy lowers risk of development of hepatocellular carcinoma from chronic hepatitis C.

We have previously demonstrated that in patients with chronic hepatitis C (CHC), iron depletion improves serum alanine aminotransferase (ALT) levels as well as hepatic oxidative DNA damage. However, it has not been determined whether continuation of iron depletion therapy for CHC favorably influences its progression to hepatocellular carcinoma (HCC). We conducted a cohort study on biopsy-proven CHC patients with moderate or severe liver fibrosis who failed to respond to previous interferon (IFN) therapy or had conditions for which IFN is contradicted. Patients were divided into two groups: subjects in group A (n = 35) underwent weekly phlebotomy (200 g) until they reached a state of mild iron deficiency, followed by monthly maintenance phlebotomy for 44-144 months (median, 107 months), and they were advised to consume a low-iron diet (5-7 mg iron/day); group B (n = 40) comprised CHC patients who declined to receive iron depletion therapy. In group A, during the maintenance phase, serum ALT levels decreased to less than 60 IU/l in all patients and normalized (<40 IU/l) in 24 patients (69%), whereas in group B no spontaneous decrease in serum ALT occurred. Hepatocarcinogenesis rates in groups A and B were 5.7% and 17.5% at the end of the fifth year, and 8.6% and 39% in the tenth year, respectively. Multivariate analysis revealed that iron depletion therapy significantly lowered the risk of HCC (odds ratio, 0.57) compared with that of untreated patients (P = 0.0337). Long-term iron depletion for CHC patients is a promising modality for lowering the risk of progression to HCC.


Phase I study of S-1, docetaxel and cisplatin combination chemotherapy in patients with unresectable metastatic gastric cancer.

The aim of this dose escalation study was to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs) and preliminary efficacy of docetaxel, S-1 and cisplatin combination chemotherapy in patients with unresectable metastatic gastric cancer. Seventeen patients received oral S-1 (40 mg m(-2) bid) on days 1-14, intravenous cisplatin (60 mg m(-2)) and docetaxel (60, 70 or 80 mg m(-2) depending on DLT) on day 8 every 3 weeks. The MTD of this combination was presumed to be docetaxel 70 mg m(-2). At this dose level, 40% of the patients (two of five) developed grade 4 neutropenia and 20% (one of five) exhibited grade 3 nausea during the first course. Therefore, the recommended dose of docetaxel was defined as 60 mg m(-2). The DLT was neutropenia. The response rate (RR) was 88.2% (15 of 17), consisting of one complete response and 14 partial responses. There were two stable diseases but no progressive disease. Of these 15 responders, four (23.5%) with high VEGF expression showed rapid tumour regression and achieved downstaging, leading to subsequent curative gastrectomy. Three of these have been disease free for about 3 years, suggesting a complete cure. In conclusion, this regimen was tolerable and showed a quite high RR, with an appreciable downstaging rate in metastatic gastric cancer.


[Reactivation of hepatitis B virus due to rituximab plus CHOP after preemptive lamivudine administration in a patient with diffuse large B-cell lymphoma].

A 59-year-old woman received eight cycles of R-CHOP for diffuse large B-cell lymphoma from July, 2004. Pretreatment HBV serological tests were positive, however, the transaminases were within normal limits, and she remained asymptomatic. Lamivudine (LAM) was administered orally from the start of R-CHOP. HBV-DNA levels gradually decreased and were not detected until December, 2004. LAM was administered until 3 months after the end of chemotherapy, with the entire treatment lasting less than 1 year. Two months after the cessation of treatment, she was re-admitted for general malaise. A liver function test revealed severe abnormalities, and HBVDNA levels were increased. Clinically, she was experiencing acute hepatitis due to HBV reactivation. She was then treated with LAM and interferon-beta immediately. Her HBV-DNA levels soon decreased, and liver function improved.


[A case of resection of synchronous multiple liver metastases from colorectal cancer after hepatic infusion chemotherapy and systemic chemotherapy].

A 70-year-old man was admitted for tranverse colon cancer with multiple liver metastases. Hepatic arterial infusion chemotherapy and systemic chemotherapy (FOLFOX 4) were conducted postoperatively. Thirteen months after the first surgery, liver metastases became resectable and hepatectomy was performed. Though multiple liver metastases were unresectable at the time of the first examination, hepatectomy was possible followed by hepatic arterial infusion chemotherapy and systemic chemotherapy.


[Fifth-line chemotherapy for metastatic gastric cancer--a case responding to modified FOLFOX 6].

According to the National Comprehensive Cancer Network (NCCN) clinical practice guideline for gastric cancer (2006, the first edition), 5-FU/Leucovorin (LV), 5-FU-based, cisplatin (CDDP)-based, oxaliplatin (L-OHP)-based, taxane-based, and irinotecan (CPT-11)-based, ECF are recommended. We used modified FOLFOX 6 (mFOLFOX 6) for pretreatment, that is oxaliplatin-based chemotherapy, for a patient who had received 5-FU-based, CDDPbased, taxane-based, and CPT-11-based treatment for an unresectable gastric cancer case responding to mFOLFOX 6. A 73-year-old male admitted to our hospital for treatment of advanced gastric cancer was diagnosed to be inoperable. A combination chemotherapy docetaxel and CDDP and S-1 as first-line treatment, CPT-11 and CDDP as second-line treatment, weekly paclitaxel treatment as third-line treatment, and MTX and 5-FU as fourth-line treatment were performed. He had progressed after 5-FU-based, CDDP-based, taxane-based, and CPT-11-based chemotherapy. There are no effective approved drugs for gastric cancer in Japan. Oxaliplatin was reportedly effective for metastatic gastric cancer, but it is still non-approved in Japan. After receiving an explanation of oxaliplatin-based therapy, he gave informed consent. Oxaliplatin-based therapy for this patient was then evaluated and approved under an institutional review board of Higashi Sapporo Hospital. mFOLFOX 6 used for the oxaliplatin-based therapy. After 2 courses of mFOLFOX 6, he showed a partial response. Oxaliplatin-based treatment was thought to be promising for previously CDDP-treated patients with unresectable gastric cancers.


Report of an autopsy case of colon cancer with amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a degenerative disease involving both upper and lower motor neurons and the pathogenesis of this disorder is still unknown. To date, few reports have suggested that motor neuron diseases may have a paraneoplastic origin. However, it is still under discussion whether ALS occurring in cancer patients is paraneoplastic. A 60-year-old man with rectal cancer (Stage IV) having multiple lung, liver and para-aortic lymph node metastases underwent anterior resection of the rectum as palliative surgery. He was referred to our hospital for adjuvant chemotherapy. Lung and lymph node metastases decreased after 2 courses of chemotherapy using CPT-11 and 5-FU/LV but liver metastases were enlarged, following up increase in CEA. Thereafter, he suffered from muscle weakness in hands, arms, and legs and results of neurophysiologic studies were compatible with primary lateral sclerosis (ALS). For second line chemotherapy, he was treated with low-dose CDDP/5-FU over 6 courses. As a result, the size the of metastatic lesions markedly reduced and CEA was decreased to the normal level. Although significant tumor reduction was observed, his neurological symptoms rapidly progressed. He died of aspiration pneumonia 8 months after onset of the disease. Autopsy revealed that his neuropathological findings were compatible with ALS, and it was thought to be the primary cause of death in the because of absence of cancer progression. In this case the neurological syndrome was not affected by cancer therapy. Thus our case does not support the hypothesis that ALS in associated with cancer and the relationship between both disorders remains uncertain.

The Japanese Journal of Gastro-enterology


[Factor XI deficiency caused by a mutation of Gly400Val].

The patient described herein is a 69-year-old Japanese woman with a history of excessive bleeding after left heminephrectomy for a malignant renal tumor at 31 years of age. Her parents, who do not have abnormal bleeding, are first cousins. Her factor XI activity was less than 1% of normal with an prolonged activated partial thromboplastin time (APTT) of 74.3 seconds. Analysis of the patient's factor XI genes revealed homozygosity for a valine substituting for the wild-type glycine at amino acid 400 (Gly400Val). The patient has two children, neither of whom has abnormal bleeding and whose factor XI activities are 62% and 57% of normal, with APTT levels within normal limits in both cases. We herein report on a Japanese family with factor XI deficiency caused by Gly400Val mutation.

The Japanese Journal of Clinical Hematology


[Gastric relapse of stage I ocular adnexal mucosa-associated lymphoid tissue lymphoma].

A 57-year-old male with right ocular adnexal mucosa-associated lymphoid tissue lymphoma (MALT lymphoma) was successfully treated with local radiation therapy. The gastroendoscopic examination revealed a slight inflammatory change of the gastric mucosa, and the urease test was positive. Eradication therapy against Helicobacter pylori was successfully done, however, the patient developed gastric MALT lymphoma two years after the initial treatment. Southern blot analysis of the immunoglobulin heavy chain gene rearrangement revealed that the lymphoma cells from the ocular adnexal and gastric MALT lymphomas were identical, indicating that the gastric MALT lymphoma was not the primary but the metastatic region from the ocular adnexal MALT lymphoma. Further, immunohistochemical staining demonstrated the expression of integrin alpha4beta 7 on ocular adnexal MALT lymphoma cells, which is essential for the adhesion of lymphocytes to gastrointestinal mucosa. These results indicate that ocular adnexal MALT lymphoma cells can metastasize to the stomach, depending on the adhesional function of integrin alpha4 beta7.


[Anaphylactic reaction to oxaliplatin--a case of colon cancer].

Oxaliplatin (L-OHP) is a new third-generation platinum which is efficacious in treating advanced unresectable recurrent colorectal cancer as a first-line regimen. The marketing authorization was given in Japan in March, 2005. Its increased use has resulted in rare serious adverse effects, including anaphylactic shock. We experienced a case that developed anaphylactic shock by L-OHP. We report a 69-year-old man who was treated for recurrent colorectal cancer who underwent systemic chemotherapy with FOLFOX 4. After eight cycles he developed severe L-OHP associated neuropathy and lung metastases was a progressive tendency. The FOLFOX 4 regimen was discontinued and another modality, FOLFIRI regimen, was used. After eight cycles of FOLFIRI regimen, lung and liver metastases showed progressive disease for response assessment by RECIST criteria. Although a patient was stopped L-OHP for neurotoxicity, neuropathy was disappeared after 4 months interval. Therefore, we reintroduced L-OHP, FOLFOX 4 regimen. Anaphylactic shock occurred in the second cycle of reintroduction of the FOLFOX 4 regimen (total 10 cycles), 30 minutes after infusion of L-OHP. L-OHP infusion was immediately withdrawn and he was treated with intravenous hydroxyzine hydrochloride and methylprednisolone. The anaphylaxis symptoms resolved in 30 minutes. Chemotherapy based on L-OHP for unresectable recurrence colorectal cancer causes anaphylactic shock as a rare severe complication. The prediction factor is not proved. We should take steps for early detection of anaphylactic reaction and perform the appropriate treatment.

Japanese Journal of Cancer and Chemotherapy


[Peripheral T-cell lymphoma presenting with eosinophilia due to interleukin-5 produced by lymphoma cells].

A 72-year-old male was admitted to our hospital to determine the cause of neck lymphadenopathies. He was diagnosed pathologically by a lymph node biopsy as having peripheral T-cell lymphoma (PTCL). He also had developed eosinophilia and his serum concentration of Interleukin-5 (IL-5) was extremely high. Immunostaining of a resected lymph node revealed that there were lymphoma cells which were stained with anti-IL-5 antibody. After 2 courses of CHOP therapy, the lymphadenopathies and eosinophilia disappeared and the concentration of serum IL-5 was normalized. It was suggested that IL-5 produced by lymphoma cells had induced his eosinophilia.


[A case of recurrent biliary cystadenocarcinoma successfully treated with 5FU/CDDP systemic chemotherapy].

We report a case of biliary cystadenocarcinoma which recurred 41 months postoperatively. A 60-year-old woman was admitted for further examination of multiple metastatic tumors and a large amount of ascites. Systemic administration of 5FU and CDDP caused her CEA level to decrease gradually and abdominal computed tomography revealed considerable reduction of the metastatic tumors and ascites. Since her general condition had improved, chemotherapy was continued in the outpatient clinic.


Ex vivo large scale generation of human platelets from cord blood CD34+ cells.

In the present investigation, we generated platelets (PLTs) from cord blood (CB) CD34(+) cells using a three-phase culture system. We first cultured 500 CB CD34(+) cells on telomerase gene-transduced human stromal cells (hTERT stroma) in serum-free medium supplemented with stem cell factor (SCF), Flt-3/Flk-2 ligand (FL), and thrombopoietin (TPO) for 14 days. We then transferred the cells to hTERT stroma and cultured for another 14 days with fresh medium containing interleukin-11 (IL-11) in addition to the original cytokine cocktail. Subsequently, we cultured the cells in a liquid culture medium containing SCF, FL, TPO, and IL-11 for another 5 days to recover PLT fractions from the supernatant, which were then gel-filtered to purify the PLTs. The calculated yield of PLTs from 1.0 unit of CB (5 x 10(6) CD34(+) cells) was 1.26 x 10(11) - 1.68 x 10(11) PLTs. These numbers of PLTs are equivalent to 2.5-3.4 units of random donor-derived PLTs or 2/5-6/10 of single-apheresis PLTs. The CB-derived PLTs exhibited features quite similar to those from peripheral blood in morphology, as revealed by electron micrographs, and in function, as revealed by fibrinogen/ADP aggregation, with the appearance of P-selectin and activated glycoprotein IIb-IIIa antigens. Thus, this culture system may be applicable for large-scale generation of PLTs for future clinical use.


[Enteropathy-type T-cell lymphoma with CD8 and CD56 expression].

A 54-year-old male presented at a previous hospital with abdominal pain, where the patient was diagnosed as having abdominal and retroperitoneal lymphadenopathies by CT scan, then, he was referred to our hospital for further examination. Upper gastrointestinal endoscopy showed a tumor formation in the second portion of the duodenum, and there were medium sized atypical lymphocytes in biopsy specimens of the tumor. Since the atypical lymphocytes in the biopsy specimens were positive for CD3, CD8, CD56 and CD103 by immunostain, and had a rearrangement of the T-cell receptor 7-chain, the patient was diagnosed as having enteropathy-type T-cell lymphoma (ETL). Although ETL usually occurs as a complication of celiac disease, malabsorption and anti-gliadin antibodies, which are normally present in celiac disease, were not observed in this patient.

The Japanese Journal of Clinical Hematology