Kaori Kameyama

Lymph node metastasis from 259 papillary thyroid microcarcinomas: frequency, pattern of occurrence and recurrence, and optimal strategy for neck dissection.

ObjectiveTo determine the frequency and pattern of lymph node metastasis (LNM) from papillary thyroid microcarcinoma (PTMC) and the results of node dissection, and to establish the optimal strategy for neck dissection in these patients. Summary Background DataMost PTMCs carry a favorable prognosis, but a few present with palpable lymphadenopathy. Patients with LNM are at risk for nodal recurrence, although they do not have higher mortality. The frequency and pattern of LNM from PTMC and the results of node dissection are not well established. MethodsThe frequency and pattern of LNM from 259 PTMCs were analyzed according to the size and location of the primary tumor. Of the 259, 24 with palpable nodes underwent therapeutic node dissection and the other 235 patients without palpable nodes underwent prophylactic node dissection. The authors compared the results of node dissection between the therapeutic group and the prophylactic group, and between PTMCs 5 mm or smaller and PTMCs larger than 5 mm. The authors also compared nodal recurrence between the prophylactic group and a no-lymph-node-dissection group (155 PTMCs). ResultsOverall, 64.1% (166/259) and 44.5% (93/209) had node involvement of the central and ipsilateral lateral compartment, respectively. Pretracheal (43.2%), ipsilateral central (36.3%), and ipsilateral mid-lower (37.8%) jugular were more commonly involved. LNM was more frequent in the therapeutic group than in the prophylactic group (95.8% vs. 60.9% for central compartment, 83.3% vs. 39.5% for ipsilateral lateral compartment). Nodal recurrence was more common in the therapeutic group than in the prophylactic group (16.7% vs. 0.43%), but did not differ between the prophylactic group and the no-dissection group (0.43% vs. 0.65%). The tumor size did not influence nodal recurrence. Nodal recurrence preferentially occurred in ipsilateral mid-lower jugular nodes. ConclusionsPatients who have PTMC presenting with palpable lymphadenopathy should have therapeutic node dissection. Prophylactic node dissection is not beneficial in those without palpable lymphadenopathy.

Gene expression of interstitial collagenase in both progressive and recovery phase of rat liver fibrosis induced by carbon tetrachloride

BACKGROUND/AIMS Liver fibrosis is a dynamic state between matrix production and degradation. Since our report in 1974, many studies have examined collagenase and liver fibrosis, but not the identification of cells responsible for collagenase production in vivo. The aim of this study was to investigate the gene expression of interstitial collagenase in the progressive and recovery phases of experimental rat liver fibrosis by in situ hybridization. METHODS We examined the gene expression of interstitial collagenase (MMP-13) in the progressive and recovery phase of experimental rat liver fibrosis induced by chronic CCl4 intoxication by reverse transcription-polymerase chain reaction (RT-PCR) and in situ hybridization. In order to identify the cells expressing MMP-13 mRNA by in situ hybridization, immunohistochemistry was performed using serial sections. RESULTS In normal rat liver, a faint band for MMP-13 mRNA was observed by RT-PCR, but not by in situ hybridization. The livers of rats treated with CCl4 for 4 weeks showed fatty metamorphosis but no definite fibrosis. Positive signals for MMP-13 mRNA were observed in scattered mesenchymal cells, within lobules which seem to be stellate cells from immunohistochemical staining. Once the fibrosis became prominent, the faint band for MMP-13 mRNA was detected only by RT-PCR and very few signals, if any, by in situ hybridization. On the other hand, in the recovery phase of liver fibrosis, gene expression of MMP-13 was markedly enhanced. Strong positive cells by in situ hybridization were observed mainly at the interface between the resolving fibrous septa and the parenchyma. Overlapping both images of in situ hybridization and immunohistochemical staining with the help of a computer revealed that some positive cells, but not all cells, were stellate cells stained with a-smooth muscle actin antibody. CONCLUSIONS MMP-13 participates in the degradation of newly-formed matrix in the recovery from rat liver fibrosis more than in the remodeling of extracellular matrix for the formation of fibrosis. Hepatic stellate cells play a crucial role in MMP-13 production in the recovery from fibrosis, though not all stellate cells were positive for MMP-13 mRNA. Further investigation into gene expression of MMP-13 in recovery will lead to new strategies for the treatment of liver cirrhosis.

Abdominal radical trachelectomy as a fertility-sparing procedure in women with early-stage cervical cancer in a series of 61 women

OBJECTIVE This retrospective study was conducted as a review of a series of women who had undergone abdominal radical trachelectomy and pelvic lymphadenectomy for early-stage cervical cancer. METHODS We performed a retrospective review of patients who had undergone an abdominal radical trachelectomy. Data regarding tumor size and histology, surgical complications, recurrences, pregnancies and live births were collected and were presented as a percentage of the total number of cases. RESULTS A total of 61 women were followed up for a median of 27 months (range: one month--79 months). There were six recurrences (9.8%); none of the recurrences occurred in patients with a tumor diameter of <20 mm except in one case with adenocarcinoma. Twenty-nine women attempted to conceive; four of these women were successful. All four of these women had live births: two had preterm deliveries, and the remaining two had full-term deliveries. The cumulative pregnancy rate among the women who attempted to conceive was 13.8% (4/29). CONCLUSION Among selected women with early-stage cervical cancer, especially those with a tumor diameter of <20 mm, abdominal radical trachelectomy and pelvic lymphadenectomy is a fertility-sparing treatment option, even though the cumulative conception rate was not particularly high compared with that for women who had undergone a vaginal radical trachelectomy.

Detection of human papillomavirus infection in squamous tumours of the conjunctiva and lacrimal sac by immunohistochemistry, in situ hybridisation, and polymerase chain reaction

BACKGROUND Squamous tumours of the ocular surface, including the lacrimal pathway, range from benign lesions to invasive carcinomas. Some of these tumours are associated with human papillomavirus (HPV) infection, with the types of HPV differing among papillomas and dysplastic or malignant lesions. METHODS The relation between squamous tumours of the conjunctiva and lacrimal sac and HPV infection was investigated in 17 individuals with such tumours. Nine of the 17 tumours were benign, four were dysplastic lesions, and four were carcinomas. RESULTS Eight specimens showed positive immunohistochemical staining with antibodies to HPV; four of these eight were papillomas, three were dysplastic lesions, and one was a carcinoma. Koilocytosis was detected in seven of these eight tumours. Five of the eight specimens positive for immunohistochemical staining were also positive for HPV DNA by in situ hybridisation, and all eight were positive for HPV DNA by the polymerase chain reaction (PCR) method. CONCLUSION Approximately 50% of squamous tumours of the ocular surface and lacrimal sac were associated with HPV infection. This is the first report, to our knowledge, of the detection of HPV in the field of ophthalmology by a combination of immunohistochemistry, in situ hybridisation, and PCR.

Prognostic Factors and Treatment Outcomes of 100 Cases of Anaplastic Thyroid Carcinoma

BACKGROUND Anaplastic thyroid carcinoma (ATC) is a malignancy with one of the highest fatality rates. Here we report a retrospective study of the treatment and other factors associated with its outcomes. MATERIALS AND METHODS The medical records of 100 patients diagnosed with ATC at Ito Hospital between 1993 and 2009 were reviewed and pertinent information was extracted and analyzed. RESULTS There were 80 women and 20 men, and their median age at diagnosis was 68 years (range, 41-90 years). Thirteen patients had a history of well-differentiated thyroid carcinoma. Six patients had a small ATC focus within a differentiated carcinoma. All cases were retrospectively staged according to the Union for International Cancer Control classification system, and the results were stage IVA in 11 cases, stage IVB in 31 cases, and stage IVC in 58 cases. Seventy patients underwent surgical treatment, and complete resection was performed in 24 of them. Seventy-eight patients received radiotherapy, and 58 of them received a total dose of ≥40 Gy. Twenty-seven patients received chemotherapy. Only 15 patients received multimodal therapy (surgery, radiotherapy, and chemotherapy). The 1-year survival rates according to stage were as follows: stage IVA, 72.7%; stage IVB, 24.8%; and stage IVC, 8.2%. Multivariate analysis identified age ≥70 years, white blood cell ≥10,000 mm(3), extrathyroidal invasion, and distant metastasis at the time of diagnosis as prognostic factors. Survival after complete resection was significantly better than after incomplete resection or no resection. The results also suggested that radiation doses of ≥40 Gy were associated with significantly longer survival. CONCLUSION Although the prognosis of most patients with ATC continues to be poor, surgery, radiotherapy, and a combination of both improved the survival of patients with ATC.

Anti-tumour effects of nobiletin, a citrus flavonoid, on gastric cancer include: antiproliferative effects, induction of apoptosis and cell cycle deregulation

Aim:  To demonstrate the antitumour effects of nobiletin (5,6,7,8,3′,4′‐hexamethoxyflavone), a citrus flavonoid extracted from Citrus depressa Hayata, on human gastric cancer cell lines TMK‐1, MKN‐45, MKN‐74 and KATO‐III.

Estrogen Receptors (α and β) and 17β-Hydroxysteroid Dehydrogenase Type 1 and 2 in Thyroid Disorders: Possible In Situ Estrogen Synthesis and Actions

Both epidemiological and experimental findings suggest the possible roles of sex steroids in the pathogenesis and/or development of various human thyroid disorders. In this study, we evaluated the expression of estrogen receptors (ER) α and β in normal thyroid glands (N = 25; female: n = 13, male: n = 10, unknown: n = 2) ranging in age from fetus to adult. Furthermore, using immunohistochemistry, we investigated the expression of ERα and β in 206 cases of thyroid disorders, including 24 adenomatous goiters, 23 follicular adenomas, and 159 thyroid carcinomas. In addition, we also studied the mRNA expression of ERα and β and 17β-hydroxysteroid dehydrogenase Type 1 and 2, enzymes involved in the interconversion between estrone and estradiol, using reverse transcription polymerase chain reaction (RT-PCR), in 48 of these 206 cases (10 adenomatous goiters, 10 follicular adenomas, and 28 papillary thyroid carcinomas) in which fresh frozen tissues were available for examination to further elucidate the possible involvement of intracrine estrogen metabolism and/or actions in thyroid disorders. ERα labeling index, or percentage of cells immunopositive for ERα, was significantly higher in adenomatous goiter (14.2 ± 6.4), follicular adenoma (13.4 ± 5.1), and thyroid carcinoma (16.4 ± 2.1) than in normal thyroid gland (0; P < .05). Few follicular cells were positive for ERα in normal thyroid glands. In papillary carcinoma, ERα labeling index was significantly higher in premenopausal women (28.1 ± 4.5) than in postmenopausal women (14.2 ± 2.9) and in men of various ages (7.6 ± 2.7; P < .05). In other histological types of thyroid carcinoma, no significant correlations were detected. ERβ immunoreactivity was detected in both follicular and C-cells of normal thyroid glands, including those in developing fetal thyroid glands. In addition, ERβ immunoreactivity was detected in the nuclei of various thyroid lesions. But no significant correlations were detected between ERβ labeling index and clinicopathological findings including age, menopausal status, gender, and/or histological type of thyroid lesions. 17β-hydroxysteroid dehydrogenase Type 1 expression was detected in 31/48 (64.0%) of the cases examined, whereas Type 2 was detected only in 3/46 (6.3%) of all the cases examined. These results demonstrated that estrogens may influence the development, physiology, and pathology of human thyroid glands, and these effects, especially through ERα, may become more pronounced in neoplasms, particularly in papillary carcinoma arising in premenopausal women.

Clinicopathological features of 171 cases of primary thyroid lymphoma: A long-term study involving 24553 patients with Hashimoto's disease

There are few large‐scale reports of primary thyroid lymphoma (PTL). This study clinically and pathologically reviewed 171 patients with PTL and 24 553 patients with Hashimoto’s disease at Ito Hospital between January 1990 and December 2004, to investigate the clinical features and the treatment outcomes of PTL. The median age of the patients with PTL was 67 years (range, 27–90 years). The pathological diagnosis of PTL patients included diffuse large B‐cell lymphoma (DLBCL) (n = 74), DLBCL with mucosa‐associated lymphoid tissue (MALT) lymphoma (n = 13), MALT lymphoma (n = 80) and others (n = 4). Of the 167 patients with B‐cell lymphoma, treatment included combined modality therapy (CMT) (n = 95), radiation therapy (RT) alone (n = 60) and chemotherapy alone (n = 6). Information on treatment was not available in six patients. Information on treatment response was available in 154 patients; 149 patients (97%) responded to treatment. According to the institutional treatment strategy of Ito Hospital, 45 of 54 patients with stage IE disease received RT alone, and 87 of 113 stage IIE patients received CMT. The 5‐year overall survival rate was 85% (95% confidence interval, 79–91%). This study demonstrated that PTL showed good response to radiotherapy and chemotherapy and had a favourable prognosis.

Interim Results of Sentinel Node Biopsy during Laparoscopic Gastrectomy: Possible Role in Function-Preserving Surgery for Early Cancer

IntroductionIntraoperative detection of sentinel nodes (SNs) has been used clinically to predict regional lymph node (LN) metastasis in patients with breast cancer and malignant melanoma. Intraoperative lymphatic mapping and SN biopsy can potentially be combined with minimally invasive surgery. However, few reports have demonstrated the validity of SN biopsy during laparoscopic gastrectomy. The aim of this study was to investigate the feasibility and accuracy of laparoscopic lymphatic mapping in predicting LN status in patients with gastric cancer.MethodsA total of 35 patients with gastric cancer diagnosed preoperatively as T1, N0 were enrolled. Endoscopic injection of technetium-99m-radiolabeled tin colloid was completed 16 hours before surgery, and radioactive SNs were identified with a gamma probe intraoperatively. Isosulfan blue dye was injected endoscopically during the operation. Laparoscopy-assisted gastrectomy with LN dissection was performed. All resected LNs were evaluated by routine pathology examination.ResultsSNs were detected in 33 (94.3%) of 35 patients. The mean number of SNs was 3.9, and the diagnostic accuracy according to SN status was 97.0% (32/33), as one patient with a false-negative result was observed. The patient with the false-negative specimen was finally diagnosed as having advanced gastric cancer with invasion into the proper muscular layer and severe lymphatic vessel invasion, causing destruction of normal lymphatic flow by the tumor.ConclusionsRadio-guided SN mapping during laparoscopic gastrectomy is an accurate diagnostic tool for detecting lymph node metastasis in patients with early-stage gastric cancer. Validation of this method requires further studies on technical issues, including indications, tracers, methods of lymph node retrieval, and diagnostic modalities of metastasis.

The citrus flavonoid, nobiletin, inhibits peritoneal dissemination of human gastric carcinoma in SCID mice.

The flavonoid nobiletin (5,6,7,8,3′,4′–hexamethoxyflavone), found in Citrus depressa Rutaceae, a popular citrus fruit in Okinawa, Japan, reportedly inhibits the production of pro–matrix metallo–proteinase (proMMP)–l, 3, and 9 in rabbit synovial fibroblasts in vitro. In the present study, we demonstrated the inhibitory effects of nobiletin on the proliferation of the cancer cell line, TMK–1, and its production of MMPs. In the SCID mouse model, we found that nobiletin inhibited the formation of peritoneal dissemination nodules from TMK–1. The enzymatic activity of MMP–9 expressed in culture medium obtained from a co–culture of TMK–1 and mouse fibroblastic cells was inhibited by nobiletin in a concentration–dependent manner. In the SCID mouse model, total weight of dissemination nodules was significantly lower in the treated group compared with the vehicle control group (0.07 g vs. 0.78 g, P=0.0059). The total number of dissemination nodules was also significantly lower than in the vehicle control group (7.5 vs. 69.3/body, P=0.0001). These results suggest that nobiletin may be a candidate anti–metastatic drug for prevention of peritoneal dissemination of gastric cancer.