Shigeki Minami

Role of Carcinoembryonic Antigen in the Progression of Colon Cancer Cells That Express Carbohydrate Antigen

Carcinoembryonic antigen (CEA) has been reported to promote the metastatic potential in some experimental tumors. Adhesion molecules are known to play an important role in the process of metastasis. Cytokines, including interleukin 1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha), which are produced by Kupffer cells, induce endothelial cells to express adhesion molecules. As a result, the present study was designed to investigate whether the interaction between CEA and Kupffer cells accelerated the metastatic potential of tumors in the liver. Kupffer cells isolated from the liver of male BALB/c mice were cultured with CEA, either with or without the addition of a cytokine inhibitor. The levels of IL-1beta and TNF-alpha were examined in a culture medium. An adhesion assay of colon cancer cell lines to human umbilical vein endothelial cells was also performed. When CEA was added to the Kupffer cell culture medium, cytokines were produced. Elevated levels of cytokines appeared to lead to increased rates of adhesion of cancer cells to endothelial cells. However, these phenomena were blocked by the addition of cytokine inhibitors. CEA stimulated Kupffer cells to produce cytokines. An elevated number of cytokines have been proven to promote the expression of adhesion molecules in endothelial cells. These processes are therefore considered to contribute to the metastasis of malignant cells to the liver. These results suggest that cytokine inhibitors may therefore play an important role in the inhibition of hepatic metastasis.

Treatment of bleeding stomal varices by balloon-occluded retrograde transvenous obliteration.

Although stomal varices are a rare complication, bleeding stomal varices often need to be treated owing to symptoms of hypovolemic shock, recurrence of stomal bleeding, or deterioration in the quality of life. Various treatment strategies for the management of bleeding stomal varices have thus far been reported. We report the case of a 60-year-old woman with refractory recurrent bleeding from varices in a sigmoid stoma, along with nonalcoholic steatohepatitis and marked splenomegaly. A physical examination revealed that the skin was discolored and bluish around the circumference of the sigmoid stoma. The venous phase of a celiac arteriogram revealed an afferent vein from the splenic vein and another from the inferior mesenteric vein, and veins draining into the left superficial epigastric vein. A balloon-occluded retrograde transvenous obliteration (BRTO) procedure was performed. The skin around the stoma, initially discolored bluish, improved markedly. After 10 months of follow-up, the patient has remained well without further episodes of stomal bleeding. To our knowledge, this is the first case of recurrent hemorrhage from stomal varices that was successfully treated by BRTO in a patient with portal hypertension.

The Common Genetic Variant rs944289 on Chromosome 14q13.3 Associates with Risk of Both Malignant and Benign Thyroid Tumors in the Japanese Population

BACKGROUND Several single nucleotide polymorphisms (SNP) have been identified to be associated with the risk for differentiated thyroid cancer in populations of distinct ethnic background. The relationship of these genetic markers to a benign tumor of the thyroid, follicular adenoma (FA), is not well established. METHODS In a multicenter retrospective case-control study, five thyroid cancer-related SNPs-rs966513 (9q22.33, FOXE1), rs944289 (14q13.3, PTCSC3), rs2439302 (8p12, NRG1), rs1867277 (9q22.23, FOXE1), and rs6983267 (8q24, POU5F1B)-were genotyped in 959 cases of histologically verified FA, 535 papillary thyroid carcinomas (PTC), and 2766 population controls. RESULTS A significant association was found between FA and rs944289 (p=0.002; OR 1.176 [CI 1.064-1.316]), and suggestively with rs2439302 (p=0.033; OR 1.149 [CI 1.010-1.315]). In PTC, significant associations were confirmed for rs965513 (p=4.21E-04; OR 1.587 [CI 1.235-2.000]) and rs944289 (p=0.003; OR 1.234 [CI 1.075-1.408]), newly found for rs2439302 (p=0.003; OR 1.266 [CI 1.087-1.493]) and rs1867277 (p=1.17E-04; OR 1.492 [CI 1.235-1.818]), and was not replicated for rs6983267 (p=0.082; OR 1.136 [CI 0.980-1.316]) in this series. A significant correlation between rs2439302 genotype and relative expression of NRG1 was detected in normal and tumor counterparts of PTC (about 10% decrease per each risk allele). NRG1 expression also significantly correlated with that of PTCSC3. CONCLUSIONS Association of rs944289, which was previously known to confer risk for thyroid cancer, with FA, and the correlation between PTCSC3 and NRG1 expression demonstrates that predisposing genetic factors are partly common for benign and malignant thyroid tumors, and imply broader roles of the pathways they underlie in thyroid tumorigenesis, not limited to carcinogenesis.

Treatment and Prognosis of Breast Cancer Patients with Brain Metastases According to Intrinsic Subtype

OBJECTIVE How breast cancer subtypes should affect treatment decisions for breast cancer patients with brain metastases is unclear. We analyzed local brain metastases treatments and their outcomes according to subtype in patients with breast cancer and brain metastases. METHODS We reviewed records and database information for women treated at the National Kyushu Cancer Center between 2001 and 2010. Patients were divided into three breast cancer subtype groups: Luminal (estrogen receptor positive and/or progesterone receptor positive, but human epidermal growth factor receptor 2 negative); human epidermal growth factor receptor 2 positive and triple negative (estrogen receptor negative, progesterone receptor negative and human epidermal growth factor receptor 2 negative). RESULTS Of 524 advanced breast cancer patients, we reviewed 65 (12%) with brain metastases and records showing estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status, as well as outcome data; there were 26 (40%) Luminal, 26 (40%) had human epidermal growth factor receptor 2 and 13 (20%) had triple negative subtypes. There was no statistical difference in the number of brain metastases among subtypes; however, rates of stereotactic radiosurgery or surgery for brain metastases differed significantly by subtype (human epidermal growth factor receptor 2: 81%, Luminal: 42% and triple negative: 47%; P = 0.03). Patients having the human epidermal growth factor receptor 2 subtype, a performance status of ≤1 and ≤4 brain metastases, who underwent systemic therapy after brain metastases and underwent stereotactic radiosurgery or surgery, were predicted to have longer overall survival after brain metastases. Multivariate analysis demonstrated that not having systemic therapy and not having the human epidermal growth factor receptor 2 subtype were independent factors associated with an increased risk of death (hazard ratio 2.4, 95% confidence interval 1.01-5.6; P = 0.05 and hazard ratio 2.9, 95% confidence interval 1.5-5.8; P = 0.003, respectively). CONCLUSION Our study showed that local brain treatments and prognosis differed by subtype in breast cancer patients with brain metastases.

Benign mesenteric schwannoma.

A 54-year-old woman was admitted to our department for an abdominal mass. The 8-cm mass with elastic hard consistency at the upper middle abdomen was found on physical examination, computed tomography (CT) scan, and magnetic resonance (MR) imaging. She had no clinical symptoms or history of von Recklinghausen’s disease. Laboratory studies including tumormarkers showed no abnormal findings. An ultrasonographic examination showed a well-circumscribed 7 × 5-cm mass, including a hypoechoic region, inferior to the pancreas and anterior to the superior mesenteric artery and vein. The mass was found to be mobile on change of position during the ultrasonographic examination. Barium study did not show any abnormality of the duodenum, jejunum, and colon. CT scan demonstrated a well-defined, lowdensity tumor just anterior to the duodenum and the superior mesenteric artery and vein. Enhanced CT scan after intravenous contrast administration showed a locally enhanced round tumor with a cystic component. No calcification was demonstrated. On T1weighted MR images, the tumor was isointense with skeletal muscle, and no high-intensity area was seen (Fig. 1, A). On T2-weighted images, the mass was predominantly hyperintense (Fig. 1, B). There was no evidence of invasion of the adjacent organs. No encasement of vessels or tumor stain was visualized

Parenchymal leiomyoma of the breast : a case report with special reference to magnetic resonance imaging findings and an update review of literature

Parenchymal leiomyomas of the breast are extremely rare, with only 25 cases reported in the literature. We report the 26th case of parenchymal leiomyoma of the breast in a 63-year-old woman who presented to us with a right breast tumor detected on her screening mammography. This tumor was evaluated by mammography, ultrasonography, and MR imaging. To the best of our knowledge, this is the first case of a parenchymal leiomyoma of the breast examined by MR imaging. MR imaging revealed an oval mass with circumscribed margins that appeared as a high-intensity lesion in both T1 and T2. A dynamic MRI study showed a gradual increase pattern on the mass. Excisional biopsy revealed a growth pattern of interlacing fascicles of spindle cells without atypia or mitoses, consistent with parenchymal leiomyoma of the breast. Here we report a case of parenchymal leiomyoma of the breast, and describe the clinical, pathological, and immunohistochemical findings. In addition, we review the literature on parenchymal leiomyoma of the breast with regard to clinical characteristics and pathological features of this entity.

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).

CD8+ tumor‐infiltrating lymphocytes contribute to spontaneous “healing” in HER2‐positive ductal carcinoma in situ

We evaluated the associations between tumor‐infiltrating lymphocytes (TIL) including CD8‐positive [+] lymphocytes in ductal carcinoma in situ (DCIS) and histopathologic factors, particularly spontaneous “healing” and immunohistochemical (IHC)‐based subtypes, to clarify the effects of host immune response to cancer cells proliferation during early carcinogenesis for the breast cancer. This cohort enrolled 82 DCIS patients. We examined the relationships between clinicopathologic factors including age, DCIS architecture, Van Nuys classification, grade, comedo necrosis, apocrine features, TIL, CD8+ lymphocytes, healing, estrogen receptor and HER2 positivity, and IHC‐based subtypes [luminal, luminal‐HER2, HER2‐positive, triple negative (TN)]. The results were analyzed by univariate and multivariate analyses. High numbers of TIL (high‐TIL) and healing were seen in 30.5% and 39.0% of the cohort, respectively. The distributions of luminal, luminal‐HER2, HER2 and TN subtypes were 73.2%, 9.8%, 13.4%, and 3.6%, respectively. High Van Nuys grading, high‐grade, comedo necrosis, apocrine features, high‐TIL, high CD8+ lymphocytes and healing were significantly associated with HER2‐positive (luminal‐HER2, HER2), and TN subtypes. High‐TIL was significantly associated with high‐grade, comedo necrosis, apocrine features, healing, high CD8+ lymphocytes and HER2 and TN subtypes. Healing was significantly correlated with high CD8+ lymphocytes, high‐grade, comedo necrosis, apocrine features, and HER2‐positive and TN subtypes. Logistic regression analysis revealed a strong association between healing and TIL (odds ratio: 11.72, P = 0.024). High CD8+ lymphocytes was also significantly associated with healing (odds ratio: 9.26, P = 0.009). The results of this study suggested that the spontaneous healing phenomenon might be induced by CD8+ high‐TIL associated with high‐grade, comedo necrosis, apocrine features and HER2‐positive DCIS.

Copy Number Alteration and Uniparental Disomy Analysis Categorizes Japanese Papillary Thyroid Carcinomas into Distinct Groups

The aim of the present study was to investigate chromosomal aberrations in sporadic Japanese papillary thyroid carcinomas (PTCs), concomitant with the analysis of oncogene mutational status. Twenty-five PTCs (11 with BRAFV600E, 4 with RET/PTC1, and 10 without mutation in HRAS, KRAS, NRAS, BRAF, RET/PTC1, or RET/PTC3) were analyzed using Genome-Wide Human SNP Array 6.0 which allows us to detect copy number alteration (CNA) and uniparental disomy (UPD), also referred to as copy neutral loss of heterozygosity, in a single experiment. The Japanese PTCs showed relatively stable karyotypes. Seven cases (28%) showed CNA(s), and 6 (24%) showed UPD(s). Interestingly, CNA and UPD were rarely overlapped in the same tumor; the only one advanced case showed both CNA and UPD with a highly complex karyotype. Thirteen (52%) showed neither CNA nor UPD. Regarding CNA, deletions tended to be more frequent than amplifications. The most frequent and recurrent region was the deletion in chromosome 22; however, it was found in only 4 cases (16%). The degree of genomic instability did not depend on the oncogene status. However, in oncogene-positive cases (BRAFV600E and RET/PTC1), tumors with CNA/UPD were less frequent (5/15, 33%), whereas tumors with CNA/UPD were more frequent in oncogene-negative cases (7/10, 70%), suggesting that chromosomal aberrations may play a role in the development of PTC, especially in oncogene-negative tumors. These data suggest that Japanese PTCs may be classified into three distinct groups: CNA+, UPD+, and no chromosomal aberrations. BRAFV600E mutational status did not correlate with any parameters of chromosomal defects.

A Metastatic Jejunal Tumor from Squamous Cell Carcinoma of the Lung Found in an Intestinal Perforation

An 85-year-old male with advanced squamous cell carcinoma of the lung, who was diagnosed about 10 years prior to his current presentation, suddenly complained of abdominal pain and underwent an abdominal computed tomography scan, which revealed free air and massive ascites. He was admitted to our hospital for acute peritonitis and emergency surgery was performed. During the surgical procedure, a perforation of the jejunum was diagnosed and repaired. He was diagnosed to have a metastatic tumor originating from a squamous cell carcinoma of the lung. He improved and was transferred to the former hospital on the 27th postoperative day. Jejunal metastasis from squamous cell carcinoma of the lung is rare, and the prognosis of peritonitis due to a perforated intestinal metastasis from lung cancer is poor. There have been 10 reports of jejunal metastasis of squamous cell carcinoma of the lung reported in Japan between 2000 and 2011. Therefore, when patients with advanced lung cancer present with acute abdomen, it is necessary to keep in mind the possibility of a gastrointestinal metastatic tumor.