Shigeto Maeda

Induction of Thyroid Cancer Cell Apoptosis by a Novel Nuclear Factor κB Inhibitor, Dehydroxymethylepoxyquinomicin

Purpose: The objective of the study was to determine the effects of a novel selective nuclear factor κB (NF-κB) inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), in thyroid carcinoma cells in vitro and in vivo and to additionally elucidate the molecular mechanisms underlying the action of this chemotherapeutic agent. Experimental Design: In the in vitro experiments, the induction of apoptosis by DHMEQ in various human thyroid carcinoma cell types was determined by flow cytometry analysis of annexin-V binding and the caspase activation by Western blotting. For the in vivo study, female nu/nu mice were xenografted with s.c. FRO thyroid tumors. DHMEQ solution was injected i.p. at a dose of 8 mg/kg/day for two weeks. Tumor dimensions were monitored twice weekly, and apoptosis in tumor specimens was determined by terminal deoxynucleotidyl transferase-mediated nick end labeling staining. Results: Treatment with DHMEQ substantially inhibited the translocation of p65 and p50 NF-κB subunits to the nucleus, the DNA-binding activity of the RelA/p65, NF-κB-dependent expression of the inhibitor of apoptosis (IAP)-family proteins, cIAP-1, cIAP-2, and XIAP, and the de novo synthesis of inhibitor of nuclear factor κB α. At concentration levels ranging from 0.1 to 5 μg/ml, DHMEQ induced a caspase-mediated apoptotic response that could be abrogated by the c-Jun NH2-terminal kinase inhibitor SP600125 but not by either mitogen-activated protein/extracellular signal-regulated kinase kinase or p38 inhibitors. In contrast, normal human thyrocytes were resistant to DHMEQ-induced apoptosis. At higher doses of DHMEQ we observed the necrotic-like killing of both normal and malignant thyrocytes, which was resistant to mitogen-activated protein kinase inhibitors. In nude mice DHMEQ substantially inhibited tumor growth without observable side effects, and increased numbers of apoptotic cells were observed in the histologic sections of tumors treated with DHMEQ. Conclusions: Our results show the potential usefulness of the novel NF-κB inhibitor, DHMEQ, in future therapeutic strategies for the treatment of thyroid cancers that do not respond to conventional approaches.

Vacuum-assisted biopsy and steroid therapy for granulomatous lobular mastitis: Report of three cases

We report the cases of three patients with granulomatous lobular mastitis (GLM), who were treated successfully with low-dose steroid therapy. Furthermore, the findings of our review of 271 patients reported in the literature suggest that steroid therapy is the treatment of choice for GLM.

Transient activation of c-Jun NH2-terminal kinase by growth factors influences survival but not apoptosis of human thyrocytes.

Activation of c-Jun NH2-terminal kinase (JNK), a member of the mitogen-activated protein kinase (MAPK) family, is involved in apoptosis or cell proliferation. We have previously demonstrated that ionizing radiation or thyroid-stimulating hormone activated JNK without linking to thyroid cell apoptosis. To clarify the involvement of JNK activation in thyroid cell survival, we investigated the effects of various growth factors on induction of JNK activation in cultured human thyroid cells. JNK activation was observed at 30 minutes after fetal bovine serum (FBS) stimulation and returned to basal level at 240 minutes. Epidermal growth factor (EGF), transforming growth factor-beta (TGF-beta) and hepatocyte growth factor (HGF) also induced JNK activation, but did not trigger apoptotic cell death. Furthermore, we observed high basal activation of JNK in four of five human thyroid cancer cell lines. Overexpression of c-Met, an HGF receptor, was observed in two of the four cell lines with high basal JNK activity. Our results suggest that JNK activation does not induce apoptosis but is associated with survival or transformation of human thyroid cells.

Occult gallbladder carcinoma diagnosed by a laparoscopic cholecystectomy.

AbstractPurpose. A laparoscopic cholecystectomy (LC) has become a common treatment modality. The incidence of occult gallbladder carcinoma (GC) diagnosed by LC has increased; however, the effects of a radical second operation after LC have not yet been demonstrated. In this study we examine the outcome of such further surgical intervention. Methods. We clinicopathologically studied occult GC diagnosed by LC. We analyzed the results to establish a therapeutic protocol for repeated surgical intervention, and to determine whether the incidence of occult GC has increased. Results. GC, which invaded the mucosa and exhibited a noninvading biliary wedge (m+/bm−), did not recur during the follow-up. GC, which invaded the subserosa (ss)+/bm− and thus required a second operation, did not recur, and the patients had a satisfactory prognosis, both short-term and long-term. One of the patients with ss+/bm+ developed peritoneal dissemination after secondary surgical intervention. Conclusion. After evaluating the clinical outcome of a second operation for the treatment of GC, we concluded that, even for advanced stage patients, repeated surgical intervention may improve the prognosis of GC and thus should be considered, when encountering such patients.

Efficacy and safety of eribulin as first- to third-line treatment in patients with advanced or metastatic breast cancer previously treated with anthracyclines and taxanes

OBJECTIVES Despite the survival benefit and acceptable tolerability of eribulin for advanced/metastatic breast cancer (MBC) patients pretreated with anthracyclines and taxanes, there is limited evidence of the clinical benefit of early eribulin use. We investigated the efficacy and safety of first- to third-line eribulin use in patients with MBC. MATERIALS AND METHODS In this phase II, open-label, single-arm study conducted at 14 sites in Kyushu, Japan, women with histologically confirmed human epidermal growth factor receptor 2-negative MBC were enrolled between December 1, 2011 and November 30, 2013 (Data cut-off: November 30, 2014). Objective response rate (ORR; primary endpoint), disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), overall survival (OS), and safety were evaluated. RESULTS Of 53 recruited patients, 47 were enrolled. The ORR was 17.0% (95% confidence interval, 7.6-30.8), DCR was 66.0% (51.2-77.8), median PFS was 4.9 months (3.5-7.0), DOR was 6.6 months (1.9-14.3), and median OS was 17.4 months (10.1-not evaluable). The common grade 3/4 adverse events were neutropenia (25 patients; 53.2%), leucopenia (16 patients; 42.1%) and febrile neutropenia (4 patients; 8.5%). Toxicity did not increase during the long-term treatment. Subgroup analysis indicated that first-line treatment led to higher ORR and prolonged PFS and OS than second-/third-line treatment and that incidence of adverse events in patients of second-/third-line treatment was not higher than that in patients of first-line treatment. CONCLUSION Eribulin exhibited efficacy and manageable tolerability in Japanese women with pretreated MBC in first- to third-line use. (ID: UMIN000007121).

Total thyroidectomy versus thyroid lobectomy for papillary thyroid cancer: Comparative analysis after propensity score matching: A multicenter study

BACKGROUND In patients with papillary thyroid carcinoma (PTC), the role of total thyroidectomy (TT) versus that of thyroid lobectomy (TL) has been controversial. METHODS This retrospective study was approved by our institutional review board, and the requirement to obtain informed consent was waived. In total, 173 patients with 1- to 5-cm stage cN0 and cM0 PTC tumors treated by curative surgery from 1994 to 2008 were evaluated. Clinicopathologic features and adverse events were compared between patients who underwent TT and those who underwent TL. After adjustment for differences in baseline clinicopathologic factors using propensity score matching, we compared recurrence-free survival (RFS) and OS. RESULTS TL was performed in 120 patients and TT in 53 patients. Patients who underwent TT were older; had larger tumors; more frequently had nodal metastasis, multifocal tumors, and extracapsular invasion; and more frequently underwent radioactive iodine ablation than patients who underwent TL. Hypocalcemia requiring medication and recurrent laryngeal nerve paralysis were more frequent in TT than TL. The 10-year RFS and OS of all patients were 93.3% and 96.7%, respectively. There was no significant difference in RFS (90.6% vs 93.0% in TT and TL groups, respectively) or OS (96.2% vs 96.9% in TT and TL groups, respectively) according to the extent of surgical resection after propensity score matching. CONCLUSION Equivalent prognoses were observed for patients with 1- to 5-cm stage cN0 and cM0 PTC tumors treated by TL or TT after propensity score matching. Adverse events occurred less frequently in patients who underwent TL than TT.

Cyclin E Low-Molecular-Weight Isoform as a Predictor of Breast Cancer in Japanese Women

Overexpression of low-molecular-weight isoforms (LMWI) of cyclin E in breast cancer cells is associated with poor prognosis and could serve a novel role in breast cancer progression. LMWI originate from proteolytic processing of cyclin E, which is deregulated and hyperactive. In this study, levels of full-form/LMWI cyclin E were determined with the use of Western blot analysis in 69 Japanese breast cancer patients. LMWI cyclin E levels were significantly correlated with known parameters such as tumor grade and estrogen/progesterone receptor expression. In multivariate analysis, patient survival was significantly correlated with tumor grade but not with either form of cyclin E. LMWI was not as strong a predictor as tumor grade in this study, whereas some cases of early relapse with LMWI overexpression and lower tumor grade were reported. Thus, LMWI might be a good complementary factor to other predictors for early relapse of breast cancer.

Morphological difference in adult thyroid papillary carcinoma between Japan and Ukraine

Geographic differences have been reported to affect the morphological and molecular features of papillary thyroid carcinomas (PTCs). The area around Chernobyl is well-known to be iodine-deficient in contrast to Japan, an iodine-rich country. We reviewed histological differences in adult PTC between Ukraine and Japan. In total, 112 PTCs from age- and sex-matched adults (Ukraine 56, Japan 56) were evaluated histologically for several factors including tumor size, capsulation, tumor components (papillary, follicular, solid, trabecular), lymph node metastasis, extrathyroid invasion, lymphocytic infiltration, oxyphilic metaplasia, and MIB-1 index. We demonstrated that tumors were smaller (1.56 vs. 2.13 cm, p<0.05) and more solid and that lymph node metastasis was less frequent (14.3% vs. 48.2%, p<0.001) in Ukrainian cases. PTC subtype distribution was significantly different between the two groups. Solid variant (8.9% vs. 1.8%) and mixed subtypes with solid components were more frequent in Ukrainian patients. In contrast, classical papillary carcinomas were more frequent in Japanese cases (10.7% vs. 50.0%, p<0.001). Marked oxyphilic metaplasia was more common in Ukrainian cases (33.9 % vs. 8.9 %, p<0.001). MIB-1 index was significantly higher in Ukrainian cases (2.9% vs. 1.8%, p<0.001). However, the frequencies of tumor capsule formation and background lymphoid follicle formation around the tumor were similar between groups. Morphological differences in adult PTCs were similar to those in pediatric PTCs as reported previously, suggesting that morphogenesis of PTC is influenced by environmental factors, especially dietary iodine, as well as genetic factors.

The long-term survival in primary retroperitoneal mucinous cystadenocarcinoma: a case report

BackgroundPrimary retroperitoneal mucinous cystadenocarcinoma (PRMC) is extremely rare, and its biological behavior, pathogenesis, optimum treatments, and prognosis remain to be elucidated. We herein report a case of PRMC with an 80-month follow-up.Case presentationA 29-year-old woman was diagnosed with unknown retroperitoneal tumor with benign right ovarian cyst and uterine fibroids, and she underwent laparotomy. The tumor was completely resected with a subsequent histopathological diagnosis of primary retroperitoneal mucinous cystadenocarcinoma (PRMC). Eighty months after surgery, she remains recurrence-free.ConclusionPRMC is an extremely rare tumor. Only around 60 cases have so far been published in the literature. The preoperative diagnosis of PRMC is difficult, and a definitive diagnosis can usually only be made based on the findings of histopathological examinations after surgery. Presently, only radical resection is useful for both diagnostic and therapeutic purposes. The optimal long-term management after surgery is still not well established. Further studies on PRMC are therefore needed to elucidate the etiology and establish effective treatments.

Change of surgical procedure for thyroid tumor after collaboration with Nagasaki (Japan) and Semipalatinsk (Kazakhstan).

e17590Background: From 1949 to 1989, 456 nuclear tests were conducted by the former Soviet Union at the Semipalatinsk Nuclear Test Site (SNTS) in Kazakhstan. It is very important to assess the clin...