Tsuyoshi Shirakawa

Human Nanog pseudogene8 promotes the proliferation of gastrointestinal cancer cells

There is emerging evidence that human solid tumor cells originate from cancer stem cells (CSCs). In cancer cell lines, tumor-initiating CSCs are mainly found in the side population (SP) that has the capacity to extrude dyes such as Hoechst 33342. We found that Nanog is expressed specifically in SP cells of human gastrointestinal (GI) cancer cells. Nucleotide sequencing revealed that NanogP8 but not Nanog was expressed in GI cancer cells. Transfection of NanogP8 into GI cancer cell lines promoted cell proliferation, while its inhibition by anti-Nanog siRNA suppressed the proliferation. Immunohistochemical staining of primary GI cancer tissues revealed NanogP8 protein to be strongly expressed in 3 out of 60 cases. In these cases, NanogP8 was found especially in an infiltrative part of the tumor, in proliferating cells with Ki67 expression. These data suggest that NanogP8 is involved in GI cancer development in a fraction of patients, in whom it presumably acts by supporting CSC proliferation.

Human STEAP3 maintains tumor growth under hypoferric condition.

Iron is essential in cellular proliferation and survival based on its crucial roles in DNA and ATP synthesis. Tumor cells proliferate rapidly even in patients with low serum iron, although their actual mechanisms are not well known. To elucidate molecular mechanisms of efficient tumor progression under the hypoferric condition, we studied the roles of six-transmembrane epithelial antigen of the prostate family member 3 (STEAP3), which was reported to facilitate iron uptake. Using Raji cells with low STEAP3 mRNA expression, human STEAP3-overexpressing cells were established. The impact of STEAP3 expression was analyzed about the amount of iron storage, the survival under hypoferric conditions in vitro and the growth of tumor in vivo. STEAP3 overexpression increased ferritin, an indicator of iron storage, in STEAP3-overexpressing Raji cells. STEAP3 gave Raji cells the resistance to iron deprivation-induced apoptosis. These STEAP3-overexpressing Raji cells preserved efficient growth even in hypoferric mice, while parental Raji cells grew less rapidly. In addition, iron deficiency enhanced STEAP3 mRNA expression in tumor cells. Furthermore, human colorectal cancer tissues exhibited more STEAP3 mRNA expression and iron storage compared with normal colon mucosa. These findings indicate that STEAP3 maintains iron storage in human malignant cells and tumor proliferation under the hypoferric condition.

Efficacy and safety analysis of chemotherapy for advanced colitis-associated colorectal cancer in Japan.

Chemotherapy for advanced colitis-associated colorectal cancer (CAC) has been insufficiently evaluated. The goal of this study was to clarify the efficacy and safety of chemotherapy for CAC in Japan. CAC patients who were treated with chemotherapy between 2005 and 2015 were retrospectively examined. Twenty-nine patients (median age, 48 years; 23 men) were assessed. Eighteen patients had ulcerative colitis, and 11 had Crohn’s disease. Three ulcerative colitis and four Crohn’s disease patients were in the active disease phase. Primary tumors were located in the rectum/anus (n=16), the left colon (n=9), or the right colon (n=4). Palliative or adjuvant chemotherapy was performed in 13 and 16 patients, respectively. First-line palliative chemotherapy regimens were as follows: fluorouracil, leucovorin, and oxaliplatin (FOLFOX; n=6), FOLFOX+bevacizumab (n=3), and others (n=4). Adjuvant chemotherapy regimens were S-1 (n=7), oxaliplatin-based (n=4) and others (n=5). In palliative chemotherapy, the objective response rate was 15%, and the median progression-free survival and overall survival were 182 and 315 days, respectively. In adjuvant chemotherapy, the 5-year relapse-free survival rate was 78%. Grade 3/4 adverse events (AEs) were observed in 16 patients (55%). Active and remission inflammatory bowel disease patients suffered grade 3/4 nonhematological AEs at an incidence of 71 and 23%, respectively (P<0.01). Dose reduction was required in 11 patients (38%), eight of whom required it for hematological AEs. Adjuvant chemotherapy for CAC exhibited sufficient efficacy, whereas modest efficacy was shown for palliative chemotherapy for CAC. AEs, particularly nonhematological AEs, were closely associated with disease activity of colitis.

A phase 2 study of fosaprepitant combined with high-dose dexamethasone for Japanese cancer patients receiving highly emetogenic chemotherapy

Purpose: Combination therapy of fosaprepitant, dexamethasone (DEX) and a serotonin (5-HT3) receptor antagonist is a standard antiemetic prophylaxis for patients receiving highly emetogenic chemotherapy (HEC). However, the appropriate dose of DEX has not been established in Japan. This study determined the efficacy and safety of triplet antiemetic prophylaxis in Japanese patients receiving HEC when administered the same doses of DEX as those given in a previous international phase 3 study on this drug. Methods: To assess the efficacy and safety of a sufficient dose of DEX (12 mg on day 1, 8 mg on day 2, 16 mg on days 3 and 4) in combination with intravenous fosaprepitant and granisetron, we prospectively examined patients receiving HEC including cisplatin (≥50 mg/m2). The primary endpoint was to determine the percentage of patients who had achieved a complete response (CR), which was defined as no vomiting and no rescue therapy during the entire treatment course. Results: Between February 2013 and January 2015, 44 patients were enrolled with a median age of 65 years (range, 30–75). There were 34 males (77.3%) in the study. Most of the patients had upper gastrointestinal cancers. The CR rate during the treatment course was 70% (95% confidence interval [CI]: 55%–83%) in the overall phase and 91% (95% CI: 78%–97%) in the acute phase and 70% (95% CI: 55%–83%) in the delayed phase. Appreciable severe toxicities related to the antiemetic therapy were not observed. Conclusions: These results suggest that a sufficient dose of DEX in combination with fosaprepitant and granisetron is optimal as an antiemetic prophylaxis for Japanese patients receiving HEC.

Complete response to second-line chemotherapy with sunitinib of a gastrointestinal stromal tumor: A case report

Gastrointestinal stromal tumors (GISTs) are a type of sarcoma, and the most common mesenchymal tumor of the gastrointestinal tract. Systemic chemotherapy is recommended for unresectable or metastatic GISTs. Imatinib is an oral multitargeted receptor tyrosine kinase inhibitor that is effective as adjuvant chemotherapy for primary high-risk cases, and as palliative chemotherapy for unresectable or metastatic cases. For imatinib-resistant cases, second-line chemotherapy with sunitinib is recommended due to significantly longer median progression-free survival and higher response rates compared with a placebo. A 54-year-old woman presented with persistent upper abdominal pain and anorexia. An upper gastrointestinal endoscopy and computed tomography revealed a submucosal tumor of the stomach with no apparent metastases. The patient underwent total radical gastrectomy, and was diagnosed histologically with high-risk GIST for recurrence, therefore, the patient received adjuvant chemotherapy with imatinib. However, multiple liver and lymph node metastases were detected, and the patient received sunitinib therapy. After four cycles of sunitinib, the liver and lymph node metastases disappeared, and a complete response (CR) was achieved. To date, there have been no cases of CR in the prospective clinical trials examining the effects of sunitinib, or in case reports worldwide. Therefore, this is a very rare case report of a patient with metastatic GISTs who achieved CR with sunitinib as second-line chemotherapy.

Early tumor shrinkage indicates a favorable response to bevacizumab-based first-line chemotherapy for metastatic colorectal cancer

A close correlation between early tumor shrinkage (ETS) and overall survival (OS) has been shown in antiepidermal growth factor receptor antibody-based chemotherapies for metastatic colorectal cancer (mCRC), but the clinical impact of ETS in bevacizumab-based chemotherapy has not been adequately clarified. Clinical data of mCRC patients who started initial chemotherapy without antiepidermal growth factor receptor antibody from 2005 to 2010 were retrospectively evaluated. The relative change in tumor size after 8 weeks of chemotherapy expected from the first image assessment [estimated ETS (EETS)] and the relative change in the tumor size at the nadir compared with the baseline [depth of response (DPR)] were examined. Seventy-three patients were enrolled and 61 patients were evaluable for survival by simple regression analysis. Bevacizumab-based chemotherapies were administered to 40 (66%) patients. The median EETS, DPR, progression-free survival, and OS were 16.1%, 27.2%, 8.0 months, and 19.5 months, respectively. Progression-free survival showed a positive correlation with OS (R2=0.429), whereas EETS and DPR were less correlated with OS (R2=0.0682, 0.186). EETS was well correlated with DPR (R2=0.659). Patients with EETS greater than 16.12% were predicted to achieve tumor shrinkage of more than 30% at the maximum response. EETS in bevacizumab-treated mCRC showed a close correlation with DPR, which suggested that EETS might be useful, indicating a favorable response in treatment with bevacizumab-based chemotherapy.

Retrospective analysis of cardiovascular diseases related to chemotherapies for advanced solid tumor patients.

Appropriate management of cardiovascular diseases (CVDs) related to chemotherapy for solid tumors is important for safe oncologic treatment. However, prediction of the onset and progression of CVDs has not generally been established in Japan. We carried out a retrospective analysis of advanced or recurrent solid tumor patients who received chemotherapies in a single institution. Patient characteristics, chemotherapy regimens, adverse events, CVDs before chemotherapy, and diagnosis of CVDs in association with chemotherapy were assessed. During the period from April 2006 to March 2012, 394 patients were examined. Cardiac diseases (CDs), hypertension (HT), or arterial thrombosis or venous thromboembolism were prevalent in 37 (9.4%), 22 (5.6%), five (1.3%), and 14 (3.5%) cases, respectively. HT (14.5%) and venous thrombosis (5.8%) were frequent in patients who received bevacizumab-containing chemotherapy. Four cases with left ventricular dysfunction experienced a decrease of ejection fraction and early filling/atrial filling (E/A) and E/A tended to decrease before ejection fraction. Ninety (62.1%) of 145 cases showed an increase in the D-dimer (DD) level before chemotherapy, and a further increase in DD level was found when venous thrombosis occurred. Relative risks of the disease progression of HT, CD, and thromboembolism because of chemotherapy were 1.3, 1.9, and 3.6, respectively. A decrease in E/A and an increase in DD were suggested to be valuable for early diagnosis of the respective onsets of left ventricular dysfunction and venous thrombosis related to chemotherapy. We conclude that patients with previous CD tend to have disease progression of CD during chemotherapy.

Improvement in the Awareness of Palliative Care Nursing Using STAS-J in an Acute Care Hospital

The Japanese version of the Support Team Assessment Schedule (STAS-J) in palliative care units is reliable and widely used in Japan. However, there are few reports showing its impact on palliative care in acute care hospitals (ACHs) treating cancer patients. To verify the usefulness of STAS-J in ACHs, we evaluated changes in the awareness of care for patients among 48 nurses in a university hospital using a questionnaire administered before the introduction of STAS-J, after virtual case assessment, and after assessment of the first five inpatients. Statistical examination was performed by the Mann-Whitney U test. Most of the surveyed items, except noticing the anxiety of the patient’s family and information exchange with medical staff other than doctors, were significantly improved after the introduction of STAS-J (p<0.05). Approximately 60% of the nurses had affirmative opinions of STAS-J. The results suggested STAS-J is useful in improving the awareness of palliative care nursing in ACHs.

Exploratory analysis of a prognosis predictive formula for metastatic colorectal cancer treated with chemotherapy.

757 Background: Progression free survival (PFS) has been recognized as a surrogate outcome in the therapy for metastatic or recurrent colorectal cancer (mCRC). As molecular targeted therapies have become to be widely used, new surrogate outcome such as early tumor shrinkage (ETS; the relative change in the sum of longest diameters of target lesions at week 8 compared to baseline) and deepness of response (DpR; the relative change in the sum of longest diameters of target lesions at the nadir compared to baseline) are proposed. However, their validity has not been fully proven. We conducted to develop a new prognosis predictive formula consisting of the three factors, DpR, ETS and PFS, in the first-line chemotherapy of mCRC. Methods: We retrospectively evaluated mCRC patients who started any chemotherapy from 2005 to 2010. Estimated ETS (eETS), instead of ETS, was defined as the estimated relative change of target lesions at week 8 calculated from first image assessment. DpR was defined as above. Predictiv...

Successful Chemoradiotherapy for Undifferentiated Malignant Neoplasm Arising from the Left Pulmonary Artery

Undifferentiated malignant neoplasms, which occur primarily in the pulmonary artery, are extremely rare and associated with poor outcomes as there is no effective therapy. A 67-year-old woman visited our hospital with complaints of dry cough and dyspnea on exertion. A contrast-enhanced chest computed tomography revealed an intravascular tumor obstructing the left pulmonary artery and a pedunculated lesion extending to the main and right pulmonary artery. Multiple metastases in the lung, bones and bilateral adrenal glands were identified by fluorodeoxyglucose-positron emission tomography. A small sample was obtained by catheter aspiration biopsy of the intravascular tumor, and examination revealed undifferentiated small atypical cells. The tumor was diagnosed as an undifferentiated neoplasm arising from the pulmonary artery based on immunohistochemical findings, including the absence of expressions of organ-specific markers. Systemic chemotherapy (paclitaxel and carboplatin) and concurrent radiation were performed as treatment for the primary tumor. Marked shrinkage of the intravascular tumor was achieved, and no serious adverse events were observed during therapy. Chemotherapy was continued for 5 months, but the patient died because of tumor progression 9 months after the initial diagnosis. Chemoradiotherapy has efficacy against undifferentiated neoplasm of the pulmonary artery.