Significance of genomic instability in breast cancer in atomic bomb survivors: analysis of microarray-comparative genomic hybridization

<p>Abstract</p> <p>Background</p> <p>It has been postulated that ionizing radiation induces breast cancers among atomic bomb (A-bomb) survivors. We have reported a higher incidence of <it>HER2 </it>and <it>C-MYC </it>oncogene amplification in breast cancers from A-bomb survivors. The purpose of this study was to clarify the effect of A-bomb radiation exposure on genomic instability (GIN), which is an important hallmark of carcinogenesis, in archival formalin-fixed paraffin-embedded (FFPE) tissues of breast cancer by using microarray-comparative genomic hybridization (aCGH).</p> <p>Methods</p> <p>Tumor DNA was extracted from FFPE tissues of invasive ductal cancers from 15 survivors who were exposed at 1.5 km or less from the hypocenter and 13 calendar year-matched non-exposed patients followed by aCGH analysis using a high-density oligonucleotide microarray. The total length of copy number aberrations (CNA) was used as an indicator of GIN, and correlation with clinicopathological factors were statistically tested.</p> <p>Results</p> <p>The mean of the derivative log ratio spread (DLRSpread), which estimates the noise by calculating the spread of log ratio differences between consecutive probes for all chromosomes, was 0.54 (range, 0.26 to 1.05). The concordance of results between aCGH and fluorescence in situ hybridization (FISH) for <it>HER2 </it>gene amplification was 88%. The incidence of <it>HER2 </it>amplification and histological grade was significantly higher in the A-bomb survivors than control group (P = 0.04, respectively). The total length of CNA tended to be larger in the A-bomb survivors (P = 0.15). Correlation analysis of CNA and clinicopathological factors revealed that DLRSpread was negatively correlated with that significantly (P = 0.034, r = -0.40). Multivariate analysis with covariance revealed that the exposure to A-bomb was a significant (P = 0.005) independent factor which was associated with larger total length of CNA of breast cancers.</p> <p>Conclusions</p> <p>Thus, archival FFPE tissues from A-bomb survivors are useful for genome-wide aCGH analysis. Our results suggested that A-bomb radiation may affect the increased amount of CNA as a hallmark of GIN and, subsequently, be associated with a higher histologic grade in breast cancer found in A-bomb survivors.</p

Synchronous Total Occlusion of the Celiac Axis and Superior Mesenteric Artery: An Autopsy Case

Acute mesenteric ischemia (AMI) is often caused by superior mesenteric artery (SMA) embolization. We report a rare case of synchronous celiac axis and SMA embolization in an elderly woman with initially mild abdominal pain. Ultimately, a second contrast-enhanced computed tomography revealed extensive necrosis from the stomach to the transverse colon together with liver ischemia due to hours of occlusion. Multiorgan failure made palliation the only option, and she died the following evening. Autopsy revealed a fragile atherosclerosis-asso-ciated thrombus. Careful examination and repeat diagnostic tests should be performed in patients with mild abdominal symptoms at risk for AMI

Differential Expression of Vascular Endothelial Growth Factor (VEGF) and VEGF Receptors in the Sequence of Hyperplastic Polyp, Serrated Adenoma and Adenocarcinoma of Colorectum

AIM: The aim of this study was to investigate the role for vascular endothelial growth factor (VEGF) and its receptors, VEGFR-1 and -2, in the hyperplastic polyp (HP)- serrated adenoma (SA)-adenocarcinoma (AC) sequence of the colorectum.Methods: Thirty-six HPs, 33 SAs and 7 ACs (which contained HP and/or SA) were immunohistochemically examined for the expression of VEGF, VEGFR-1, and VEGFR-2.Results: VEGF protein was expressed in the cytoplasm of SA and AC tumor cells, and VEGFR-1 and VEGFR-2 were expressed both in the cytoplasm and on the membrane of these tumors, while there was faint or no expression of VEGF, VEGFR-1 and VEGFR-2 in HPs. Immunohistochemical staining revealed that 8.3% (3 of 36) HPs, 87.9% (29 of 33) SAs and 100% (7 of 7) ACs were positive for VEGF; 2.8% (1 of 36) HPs, 97.0% (32 of 33) SAs and 100% (7 of 7) ACs were positive for VEGFR-1; 16.7% (6 of 36) HPs, 100% (33 of 33) SAs and 100% (7 of 7) ACs were positive for VEGFR-2. The expression of VEGF, VEGFR-1 or VEGFR-2 was statistically correlated with the sequence of HP, SA and AC (P < 0.0001, respectively) Conclusion: Our results suggest that the VEGF pathway may play an important role in the HP-SA-AC sequence

Üsküdar mesireleri

Taha Toros Arşivi, Dosya No: 63-Salacak-Üsküdarİstanbul Kalkınma Ajansı (TR10/14/YEN/0033) İstanbul Development Agency (TR10/14/YEN/0033

Incidence of multiple primary cancers in Nagasaki atomic bomb survivors: association with radiation exposure.

To assess the effects of atomic bomb radiation on the incidence of multiple primary cancers (MPC), we analyzed the association between the incidence of second primary cancers in survivors of the atomic bombing of Nagasaki, and exposure distance. The incidence rate (IR) of a second primary cancer was calculated and stratified by the distance from the hypocenter and age at the time of bombing for the years 1968 through 1999. The IR of the first primary cancer was also calculated and compared with the second primary cancer to determine whether atomic bomb radiation was associated with the multiplicity of tumors. There were 511 confirmed cases of MPC in the 7572 cancer-bearing survivors. The crude IR was 27.6 per 100,000 person-years. The IR of second primaries decreased significantly with increasing distance from the hypocenter: relative risk, 0.89 per 1.0 km; 95% confidence interval, 0.84-0.94. A significant decrease was also noted for those of older ages at the time of the bombing, based on the attained age of the second primary cancer: relative risk, 0.91 per 1 year; 95% confidence interval, 0.90-0.92. These findings suggest that the radiation has affected the incidence of MPC. Furthermore, when compared with the first primary cancer, a stronger distance effect was suggested on the occurrence of a second primary cancer in the survivors. The present study suggests the significance of atomic bomb radiation on MPC in the survivors. These results on the incidence of MPC in the tumor-bearing survivors and its correlations with the atomic bombing of 62 years ago are described for the first time in this report

Age-dependent effects on radiation-induced carcinogenesis in the rat thyroid

Childhood radiation exposure is a known thyroid cancer risk factor. This study evaluated the effects of age on radiation-induced thyroid carcinogenesis in rats irradiated with 8 Gy X-rays. We analyzed cell proliferation, cell death, DNA damage response, and autophagy-related markers in 4-week-old (4W) and 7-month-old (7M) rats and the incidence of thyroid tumors in 4W, 4-month-old (4M), and 7M rats 18 months after irradiation. Cell death and DNA damage response were increased in 4W rats compared to those in controls at 1 month post-irradiation. More Ki-67-positive cells were observed in 4W rats at 12 months post-irradiation. Thyroid tumors were confirmed in 61.9% (13/21), 63.6% (7/11), and 33.3% (2/6) of irradiated 4W, 4M, and 7M rats, respectively, compared to 0%, 14.3% (1/7), and 16.7% (1/6) in the respective nonirradiated controls. There were 29, 9, and 2 tumors in irradiated 4W, 4M, and 7M rats, respectively. The expression of several autophagy components was downregulated in the area surrounding radiation-induced thyroid carcinomas in 4W and 7M rats. LC3 and p62 expression levels decreased in radiation-induced follicular carcinoma in 4W rats. Radiosensitive cells causing thyroid tumors may be more prevalent in young rats, and abrogation of autophagy may be associated with radiation-induced thyroid carcinogenesis

Operative Outcome of Cardiac Surgery in Patients with Liver Cirrhosis

Introduction: A retrospective study was performed to investigate the relationship between the severity of liver cirrhosis and the outcome of cardiac surgery. Methods and Results: Twenty-one patients with liver cirrhosis underwent cardiac surgery in our institution. According to the Child-Pugh classification, 13 patients were in class A, 7 in class B, and 1 in class C. Coronary artery bypass grafting was performed in 7 patients, surgery for valvular disease in 10 and other procedures in 4. Major postoperative complications occurred in 8%, 29%, and 100% for Child-Pugh class A, B, and C, respectively. Preoperative hemoglobin level was significantly lower in the patients with postoperative complications. None of 4 patients underwent coronary revascularization using off-pump procedure or mini-pump system experienced major complication. The operative mortality was 0%, 14%, and 0% for Child-Pugh class A, B, and C, respectively. Conclusions: Although the overall mortality rate in patients with liver cirrhosis was acceptable in our study, the incidence of severe complications, such as prolonged ventilation, mediastinitis and irreversible hepatic insufficiency was problematic in Child-Pugh class B and class C patients. Application of less invasive cardiac surgery, such as mini-pump system or off-pump procedure will improve the operative outcome in such patient group.長崎大学学位論文 学位記番号:博（医）甲第1,272号学位授与年月日:平成20年7月16

Cutaneous pilomatrical carcinosarcoma: a case report with molecular analysis and literature review

Background: Cutaneous pilomatrical carcinosarcoma (CS) is a very rare biphasic tumor composed of admixed epithelial and mesenchymal malignant cells, with limited information on its pathogenesis. We report a case of pilomatrical CS of the scalp with comparative immunohistochemical and molecular analysis together with a review of the literature. Case presentation: A 74-year-old woman presented with a rapidly growing long-standing tumor of the scalp. The tumor was surgically resected. Histologically, the tumor was 25 mm in diameter, and was composed of carcinoma showing a clear pilomatrical differentiation and sarcoma with pleomorphic spindle cells and giant cells. Both epithelial and mesenchymal components shared focal cytoplasmic and/or nuclear accumulation of β-catenin based on immunohistochemical analysis, although a mutation of exon 3 of the CTNNB1 gene was not detected. Fluorescence in situ hybridization analysis revealed gains of chromosomes 9p21, 3, and 7 in both the epithelial and sarcomatous components. Conclusions: The current case demonstrated characteristic findings of pilomatricoma and further evidence of partial clonality between the carcinomatous and sarcomatous component, suggesting the possibility of malignant transformation of pilomatricoma. Rapid growth of a pilomatrical tumor should warrant the development of a malignant tumor, including CS