Presence of human papillomavirus (HPV) in variable proportions in tonsillar squamous cell carcinoma tissues has been demonstrated by several worldwide studies. Some reports emphasized the significance of HPV in predicting a better prognosis, as well as ethnic differences between Chinese and Caucasians. In order to understand the biological role of HPV and find out clinically accessible methods to determine its prognostic significance in primary tonsillar squamous cell carcinoma, we collected 92 patients with primary tonsillar squamous cell carcinoma diagnosed or treated in National Taiwan University Hospital, for whom archival tumor tissue were available. Immunohistochemical stains of p16(INK4A), high-risk HPV in situ hybridization, and nested polymerase chain reaction (PCR)-based genechips were performed to detect HPV infection and determine its genotype. Clinical data were compared with HPV infection detected by the different methods mentioned above. Real-time PCR was also performed on the HPV16-positive [HPV16(+)] lesions to understand viral integration status. The positive rates of nested PCR-based genechips, overexpression of p16(INK4A), and high-risk HPV in situ hybridization were 75% (69/92), 53% (49/92), and 44% (40/92), respectively. Both overexpression of P16(INK4A) and high-risk HPV in situ hybridization positivity were associated with favorable prognoses (P=0.004 and 0.001, respectively) and also independent prognostic factors in multivariate analyses (P=0.01 and 0.01, respectively). The positivity of nested PCR-based genechips was not statistically significant. From our data, primary tonsillar squamous cell carcinoma with positive immunohistochemical stains of p16(INK4A) and/or high-risk HPV in situ hybridization is associated with a better outcome, and both methods may serve as clinically accessible markers.

Background: In the past two decades, the incidence of breast cancer in young Taiwanese females has been rapidly increasing, approaching the risk level of western countries. As a first step to investigate the possible etiology, we examined the molecular subtypes of female breast cancer in Taiwan.Methods: This study included 1,028 consecutive patients with breast cancer diagnosed in National Taiwan University Hospital between 2004 and 2006. Estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor-2, cytokeratin 5/6, and epidermal growth factor receptor expression and/or gene amplification were analyzed. Results: Younger (≤50 years) breast cancer patients had a higher prevalence of luminal A (67% versus 57%; P < 0.001) and a lower prevalence of basal-like subtype (9% versus 17%; P < 0.001) compared with older (>50

The interplay between histone modifications and promoter hypermethylation provides a causative explanation for epigenetic gene silencing in cancer. Less is known about the upstream initiators that direct this process. Here, we report that the Cystatin M (CST6) tumor suppressor gene is concurrently down-regulated with other loci in breast epithelial cells cocultured with cancer-associated fibroblasts (CAF). Promoter hypermethylation of CST6 is associated with aberrant AKT1 activation in epithelial cells, as well as the disabled INNP4B regulator resulting from the suppression by CAFs. Repressive chromatin, marked by trimethyl-H3K27 and dimethyl-H3K9, and de novo DNA methylation is established at the promoter. The findings suggest that microenvironmental stimuli are triggers in this epigenetic cascade, leading to the long-term silencing of CST6 in breast tumors. Our present findings implicate a causal mechanism defining how tumor stromal fibroblasts support neoplastic progression by manipulating the epigenome of mammary epithelial cells. The result also highlights the importance of direct cell-cell contact between epithelial cells and the surrounding fibroblasts that confer this epigenetic perturbation. Because this two-way interaction is anticipated, the described coculture system can be used to determine the effect of epithelial factors on fibroblasts in future studies. [Cancer Res 2008;68(24):10257-66]

Purpose: We hypothesized that a window period between bevacizumab and cytotoxic agents may enhance drug delivery into tumor tissue through bevacizumab-induced vascular normalization in patients with brain metastases of breast cancer (BMBC).Experimental Design: A single-arm phase II study was conducted in which BMBC patients refractory to whole-brain radiotherapy (WBRT) were enrolled. In a 21-day cycle, patients received bevacizumab (15 mg/kg) on day 1, which, with a 1-day window period, was followed by etoposide (70 mg/m 2 /day; days 2-4) and cisplatin (70 mg/m 2 ; day 2; BEEP regimen). The BEEP regimen was administered for a maximum of 6 cycles. The primary endpoint was the central nervous system (CNS)-objective response rate according to volumetric response criteria.Results: A total of 35 patients were enrolled between January 2011 and January 2013. The median age was 54.3 years (range, 33-75); 19 patients (54.3%) had an Eastern Cooperative Oncology Group performance status of 2 or 3. Twenty-seven patients [77.1%; 95% confidence interval (CI), 59.9-89.6] achieved a CNS-objective response, including 13 patients (37.1%) with a !80% volumetric reduction of CNS lesions. With a median follow-up of 16.1 months, the median CNS progression-free survival and overall survival times were 7.3 months (95% CI, 6.5-8.1) and 10.5 months (95% CI, 7.8-13.2), respectively. Common grade 3 or 4 toxicities included neutropenia (30.8%) and infection (21.3%).Conclusions: By administering bevacizumab 1 day before etoposide and cisplatin, the BEEP regimen appeared highly effective in BMBC refractory to WBRT. Further study of vascular normalization window concept is warranted.

The incidence of breast and genital tract cancers is increasing among Taiwanese women, but the age specificity and histopathological features of these cancers have not been determined. We used a descriptive epidemiological method and data from the Taiwan Cancer Registry (1979Registry ( -2007 to examine secular trends in the age-specific incidences of female breast cancer, three major female genital tract cancers and the histopathological subtypes of these cancers. Age-specific incidence rates in the United States (1978States ( -2002 were used as an external reference, and the incidence rates of all malignancies and of malignant brain tumors were used as internal references. We found that age-adjusted incidence rates of female breast, uterine, and ovarian cancers increased in Taiwan from 1979 to 2007, whereas the incidence of cervical cancer decreased after 1998. The largest increase was observed for ductal and lobular carcinomas of the breast and endometrioid carcinomas of the uterus and ovary in women 55 years, all of these tumors show a high prevalence of hormone receptor expressions. In addition, hormone-receptor-positive rates of breast cancer were uniquely higher in younger, as opposed to older, Taiwanese women. These findings indicate that estrogen-related cancers rapidly emerge in young women in Taiwan and that incidence rates are catching up with that of women living in the United States.The incidences of breast and gynecological cancers are thought to differ significantly between Asians and Caucasians. For example, the frequency of cervical cancer has been reported to be significantly higher among residents of Southeast Asian, when compared to non-Asian, countries. 1-3 In contrast, breast, uterine and ovarian cancer frequencies are reported to be significantly lower in most parts of Asia when compared to other regions. 4 In recent decades, however, the incidences of breast, uterine and ovarian cancer have been increasing in certain rapidly developing Asian countries such as Singapore, Korea, Japan and Taiwan. 5-10 Previous age-period-cohort analyses revealed a much stronger birth cohort effect on the incidence of breast cancer for Taiwanese and Japanese, when compared to Caucasian American, women. 7,8,11 This stronger birth cohort effect was found to correlate directly with a rapid increase in the incidence of early-onset breast cancer in Taiwan and Japan.Similar to that of breast cancer, the incidence of uterine cancer in Japan has increased in women less than 40 years of age. The incidence of ovarian cancer has also increased markedly in Japanese women over 60 years of age, whereas the incidence of cervical cancer has declined significantly among Japanese women aged 40-80 years. 9 Whether the agespecific incidence changes of these cancers exist in other Asian countries, however, remains to be determined.Taiwan has become increasingly industrialized since the 1960s. In our study, the cancer registration system in Taiwan, established in 1979, was utilized to ascertain whether the unique age-specific cha...