Phase I Dose-Escalation Study of Weekly Paclitaxel and Cisplatin Followed by Radical Hysterectomy in Stages IB2 and IIA2 Cervical Cancer.

PURPOSE: To define the optimal dose of paclitaxel combining cisplatin, as weekly neoadjuvant chemotherapy (NAC) for early-stage bulky squamous cell carcinoma of the uterine cervix. METHODS: A prospective trial was conducted for International Federation of Gynecology and Obstetrics stages IB2 and IIA2 cervical squamous cell carcinoma patients with magnetic resonance imaging or positron emission tomography-defined lymph node negative. Weekly fixed-dose cisplatin (40 mg/m) and 4-level dose escalation of paclitaxel (50, 60, 70, 80 mg/m) for 3 courses was given and followed by radical hysterectomy and pelvic lymph node dissection (RH-PLND) 14 to 28 days later. Postoperative adjuvant therapy was tailored according to pathologic response. RESULTS: No dose-limiting toxicity occurred. Twelve subjects were enrolled without reaching maximum tolerated dose, nor was any RH-PLND procedure delayed for >2 weeks. Pathologic response rate was 50% (complete in 2 and partial in 4). Paclitaxel dose level seemed unrelated to pathologic response. No subjects had grade ≥3 acute adverse events. Seven patients (58.3%) received postoperative radiotherapy or chemoradiation. Patients with human papillomavirus 16-negative tumor and aged 55 years and older had marginally higher risk (100%) of adjuvant radiotherapy or chemoradiation after NAC than those with human papillomavirus 16-positive or age less than 55 (P=0.081). With a median follow-up of 45.5 months, all 12 patients remained alive without disease. CONCLUSIONS: Weekly paclitaxel and cisplatin NAC for 3 courses can be tolerated with excellent short-term outcome. With the caveat of small number of patients, this study supports future phase II trials of weekly paclitaxel and cisplatin NAC for 4 to 5 cycles.

Self-sampling HPV test in women not undergoing Pap smear for more than 5 years and factors associated with under-screening in Taiwan.

BACKGROUND/PURPOSE: Under-utilization of Papanicolaou (Pap) smear causes a gap in the prevention of cervical neoplasms. A prospective population-based study was conducted investigating whether a self-sampling human papillomavirus (HPV) test was feasible for under-users of Pap smear and factors associated with under-screening in Taiwan. METHODS: Women not having Pap smear screening for > 5 years were invited to participate in this study. Invitation letters and educational brochures were mailed to 4% of randomly selected eligible women from Taoyuan City, Taiwan, and responders received an HPV self-sampling kit. Those with HPV-positive results were recalled for a Pap smear and colposcopy. RESULTS: Between March 2010 and June 2012, 10,693 women were invited, 354 responded (3.3%), and 282 (2.6%) gave valid informed consent, answered the questionnaire, and submitted HPV samples. The median age of enrolled women was 48.1 years. Forty-seven women (16.7%) had a positive HPV test, and 14 women accepted further survey to find two CIN2+. Another two cases of CIN2+ were identified from a national registry database. The cost of direct mailing self-samplers was less than that done on request (from NT$434,866 to NT$164,229, response rate of 5% to 15%, respectively, versus NT$683,957 for detecting 1 CIN2+). Reasons for not attending screening included lack of time, embarrassment, assumed low risk, fear of positive results, and perceived potential pain. Among the responders, 90.8% found the method acceptable. CONCLUSION: Our study indicated that different approaches (e.g., direct mailing self-samplers to under-users and/or various educational interventions) must be explored to improve coverage in populations with culture characteristics similar to Taiwan.

Identification of patients with hormone receptor-positive breast cancer who need adjuvant tamoxifen therapy for more than 5 years.

BACKGROUND/PURPOSE: Extended hormonal therapy with tamoxifen for > 5 years has improved disease-free survival (DFS) and overall survival (OS) in hormone receptor (HR)-positive breast cancer patients. The aim of this study was to identify the HR-positive breast cancer women who need adjuvant tamoxifen for > 5 years. METHODS: Between 1990 and 2004, 1104 HR-positive breast cancer patients who had received tamoxifen treatment at our institution and had been disease free for at least 6 years were included in this analysis. Univariate and multivariate analyses of prognostic factors for late recurrence were performed using the binary logistic regression model. RESULTS: During a median follow-up period of 10.9 years after surgery, 70 patients died and 99 showed recurrence. In multivariate analysis, age < 40 years (p < 0.001) and lymph node metastasis (p < 0.001) were associated with higher rates of recurrence. We stratified patients into high-risk (age < 40 years or positive lymph node status, 536 patients) and low-risk (age > 40 years and negative lymph node status, 566 patients) groups. The recurrence rates were 14.6% and 3.5% in the high-risk and low-risk groups, respectively. Patients in the high-risk group had poorer disease-free survival (p < 0.001) and overall survival (p = 0.010) than those in the low-risk group. CONCLUSION: Our findings suggest that HR-positive breast cancer women either aged < 40 years or with positive lymph node status were justified in continuing with tamoxifen therapy for > 5 years.

Percutaneous ultrasound-guided renal biopsy in children: The need for renal biopsy in pediatric patients with persistent asymptomatic microscopic hematuria.

BACKGROUND: Percutaneous renal biopsy (PRB) is essential for the diagnosis, prognosis, and management of children with unknown kidney disease. In this study, the safety and efficacy of PRB is investigated, and also the common etiologies of childhood kidney disease, based on histological findings. In addition, we explored the role of PRBs in the diagnosis of children who presented with persistent asymptomatic hematuria. METHODS: By chart review, from July 2005 to July 2009, a total of 99 PRBs were performed on 91 children (43 girls and 48 boys; mean age, 10.9 ± 4.4 years) under ultrasound (US) guidance, by a doctor, using an automated 18-gauge biopsy needle following the same protocol, at a medical center in northern Taiwan. RESULTS: The accuracy of the histological diagnosis was excellent. The most common post-biopsy complications were perirenal hematoma (11.1%) and asymptomatic gross hematuria (3.0%), respectively. Nevertheless, these complications resolved spontaneously, and none had major bleeding episodes. Histological results showed that lupus nephritis, minimal change disease, and IgA nephropathy (IgAN) could be the current leading causes of childhood kidney diseases in Taiwan. CONCLUSIONS: Automated ultrasound (US)-guided PRB is a safe and reliable method of assessing childhood renal disease. A recent study shows that the presence of persistent asymptomatic isolated microhematuria in adolescents is a predictive marker of future end-stage renal disease. Hence, the emphasis of renal biopsy on children with persistent asymptomatic hematuria is beneficial for the early diagnosis of IgAN or other glomerulonephritis (GN), which tends toward progressive kidney disease in adulthood without prompt therapeutic intervention.

A dual tyrosine kinase inhibitor lapatinib suppresses overexpression of matrix metallopeptidase 1 (MMP1) in endometrial cancer.

UNLABELLED: Endometrial cancers have been recently molecularly characterized; amplifications of human epidermal growth factor receptor 2 (HER2) were seen in 25 % of the serous-like tumors, and mutations in the PI(3)K/AKT pathways were seen in 93 % of endometrioid tumors. These new findings about endometrial cancer suggest a potential for targeted therapy with lapatinib, a dual inhibitor of epidermal growth factor receptor and HER2 tyrosine kinases. However, the clinical efficacy of lapatinib in phase II clinical trials for the treatment of endometrial cancers was only minimal. In this study, we investigated the signaling changes induced by lapatinib in endometrial cancer, which may improve its therapeutic efficacy in molecularly selected patient groups. We identified one of the final molecular targets of lapatinib to be interstitial collagenase, matrix metallopeptidase 1 (MMP1). Lapatinib suppresses MMP1 through EGFR and HER2, and their downstream ERK and AKT signaling pathways. We also found that the activating protein-1 binding site of MMP1 promoter is required for its transcriptional activation, which may be unique for endometrial cancers. Our results also showed that forced expression of active ERK or active AKT mutants rescued MMP1 expression from lapatinib suppression, further suggesting the importance of molecular selection to find appropriate patients with endometrial cancer for future clinical trials with any targeted therapies. KEY MESSAGE: MMP1 expression was high in tissues and sera in patients with endometrial cancer. Lapatinib inhibited MMP1 via both HER2 and EGFR signaling pathways. Both AKT and ERK need to be inhibited for efficient MMP1 suppression by lapatinib. Activating protein-1 (AP-1) binding site of MMP1 promoter is uniquely required for MMP1 activation in endometrial cancer. Suppression of both c-fos and c-Jun bound to AP1 binding site is required for lapatinib inhibition.

Identification of patients with node-negative, triple-negative breast cancer who benefit from adjuvant cyclophosphamide, methotrexate, and 5-fluorouracil chemotherapy.

AIM: Triple-negative breast cancer (TNBC) has a relatively poor prognosis compared to other molecular subtypes of breast cancer. This study aimed to evaluate the role of adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF) in node-negative TNBC and to identify patients who could benefit from this therapy. PATIENTS AND METHODS: We retrospectively reviewed the clinicopathological features and outcomes of patients with node-negative TNBC after surgery followed by either adjuvant chemotherapy with CMF or observation only. RESULTS: Between January 2000 and December 2006, 276 patients with node-negative TNBC were eligible for inclusion in this study. The median follow-up time was 85.0 months by the end of 2010. The CMF (N=211) and observation (N=65) groups did not significantly differ with regard to T-stage, lymphovascular invasion (LVI), and tumour grade, but patients in the former group were on average younger (p<0.01). Adjuvant CMF was associated with favourable disease-free survival (DFS) (p=0.04). The CMF group also had a significantly lower locoregional recurrence rate than the observation group (0.4% vs. 9.2%, p=0.02). Subgroup analysis revealed that patients in the CMF group had significantly better DFS than those in the observation group among those with tumours larger than 2 cm (hazard ratio=0.38, p=0.02) and those who underwent partial mastectomy (hazard ratio=0.28, p=0.01). CONCLUSION: Adjuvant CMF chemotherapy was effective in reducing locoregional recurrence rate and prolong DFS in patients with node-negative TNBC, particularly in those with tumours of more than 2 cm or who had undergone partial mastectomy.

Fertility-preserving treatment in young women with endometrial adenocarcinoma: a long-term cohort study.

OBJECTIVE: Growing evidence suggests that fertility-preserving treatment is feasible for young women with early-stage, low-grade endometrial carcinoma. However, published data on their long-term outcomes and prognostic factors remain scanty. We aimed to investigate the outcomes of young women receiving fertility-preserving treatment. METHODS: Between 1991 and 2010, the outcomes of young women with grade 1 endometrioid endometrial carcinoma at presumed stage IA (without myometrial invasion) who underwent fertility-preserving treatment of megestrol acetate 160 mg/d with or without other hormonal agents were retrospectively analyzed. RESULTS: We identified 37 eligible patients (median age, 32 years; range, 18-40 years). The median follow-up time was 78.6 months (range, 19.1-252.8 months). Complete response (CR) lasting more than 6 months was achieved in 30 (81.1%) women. Responders were significantly younger than nonresponders (P = 0.032). Of the 30 women who had a CR, 15 (50.0%) had disease recurrence. The 5-, 10-, and 15-year cumulative recurrence-free survival rates were 51.0%, 51.0%, and 34.0%, respectively. Notably, those recurred were significantly older (P = 0.003), and the time to CR was significantly longer (P = 0.043) than those without recurrence. One patient developed late recurrences at 156 months, and 2 patients developed ovarian metastasis (6 and 137 months from diagnosis). All the patients are currently alive. CONCLUSIONS: This study demonstrates the feasibility of high-dose megestrol acetate-based therapy for fertility preservation. The substantial risk of late recurrences highlights the need for long-term follow-up studies of large sample sizes with in-depth tumor and host molecular signatures.

Estradiol and tamoxifen induce cell migration through GPR30 and activation of focal adhesion kinase (FAK) in endometrial cancers with low or without nuclear estrogen receptor α (ERα).

Estrogens and tamoxifen (an antiestrogen) exert their actions by activation of estrogen receptor (ER) through genomic and non-genomic mechanisms and are implicated in the development of endometrial cancer. Previous reports have demonstrated that estradiol and tamoxifen induce proliferation of human endometrial cancer cells through GPR30 (non-genomic ER) signaling pathway. Herein, we demonstrate that phosphorylation of focal adhesion kinase (FAK) is involved in cell migration induced by estradiol, tamoxifen and G1 (a GPR30 agonist) through the transmembrane ER (GPR30) in endometrial cancer cell lines with or without ERα (Ishikawa and RL95-2). Additionally, the GPR30-mediated cell migration was further abolished by administration of either specific RNA interference targeting GPR30 or an FAK inhibitor. Moreover, we have validated that the signaling between GPR30 and phosphorylated FAK is indeed mediated by the EGFR/PI3K/ERK pathway. Clinically, a significant correlation between levels of GPR30 and phophorylated FAK (pFAK) observed in human endometrial cancer tissues with low or without ERα further suggested that estrogen-induced phosphorylation of FAK and cell migration were most likely triggered by GPR30 activation. These results provided new insights for understanding the pathophysiological functions of GPR30 in human endometrial cancers.

Clinicopathologic parameters and immunohistochemical study of endometrial stromal sarcomas.

We aimed to investigate the clinicopathologic features, immunohistochemical studies, and prognosis in patients with endometrial stromal sarcoma (ESS). Clinical information was reviewed retrospectively for cases of ESS (1985-2009). A histologic review and immunohistochemical staining for the estrogen receptor, progesterone receptor, c-Kit, CD-10, Ki-67, and m-TOR were performed. Sixty-one patients (median age, 44 y; range, 22-71) were eligible for analysis (1988 International Federation of Gynecology and Obstetrics Stage I, 43; Stage II, 2; Stage III, 11; Sage IV, 4; unstaged, 1). The median follow-up period for survivors was 73 mo. Of those, the patients who underwent an adnexectomy and a pelvic lymphadenectomy, 15% and 13%, respectively, revealed metastasis. There were 20 relapses/persistence, including 13 (65%) in the pelvis and abdomen and 7 (35%) in distant sites. Eight patients died from ESS at a median duration of 14.5 mo (range, 2-50 mo) after relapse. Five- and 10-yr cancer-specific survival (CSS) rates were 88% and 85%, respectively; and 5- and 10-yr progression-free survival rates were 69% and 57%, respectively. Stage, residual disease, and high proliferative index of Ki-67 were significant prognostic factors for both progression-free survival and CSS in a univariate analysis, in addition to mitotic index for CSS. Multivariate analysis selected only residual disease as an independent variable for progression-free survival and stage and residual disease for CSS. Our results support using clinical Stage I, no residual disease, low proliferative index of Ki-67, and estrogen receptor/progesterone receptor overexpression as potential biomarkers to select patients with ESS for fertility-preservation surgery (5 such patients were alive and free).

Potential of an age-stratified CA125 cut-off value to improve the prognostic classification of patients with endometrial cancer.

OBJECTIVE: It is not clear whether the prognostic value of pretreatment serum CA125 levels is independent or through association with other clinicopathological features in endometrial cancer. METHODS: All patients with endometrial cancer treated between 2000 and 2010 were retrospectively reviewed. The correlation of clinicopathological characteristics, CA125 and treatment outcomes was analyzed. Receiver operating characteristics (ROC) curves were used to determine the CA125 cut-off values. Cox proportional hazard regression was used for multivariate analysis. RESULTS: Of the 923 eligible patients, 757 had serum CA125 levels measured before treatment. We identified 264 (34.9%) patients with pretreatment serum CA125>35 U/mL. By multivariate analysis, advanced stage (P=0.001), serous or clear cell carcinoma (P=0.008), positive peritoneal cytology (P=0.042), and lymph node metastases (P=0.004) were significant risk factors for cancer-specific survival (CSS), while serum CA125>35 U/mL (P=0.067) was of borderline statistical significance. Using ROC curve stratified by age, we found that a serum CA125>35 U/mL was significant for CSS (HR=2.34, 95% CI=1.04-5.29) among patients >49 years old. After adjustment for confounding factors, serum CA125>105 U/mL was significant (HR=6.03, 95% CI=1.19-30.63) in patients ≤49 years old. CONCLUSIONS: These results suggest that an age-stratified cut-off level for CA125 (35 U/mL in patients >49 years old and 105 U/mL in patients ≤49 years old) can improve the prognostic stratification of patients with endometrial cancer.

Tumor stress-induced phosphoprotein1 (STIP1) as a prognostic biomarker in ovarian cancer.

Stress-induced phosphoprotein 1 (STIP1) has been recently identified as a released biomarker in human ovarian cancer. In addition, STIP1 secreted by human ovarian cancer cells has been shown to promote tumor cell proliferation by binding to ALK2 (activin A receptor, type II-like kinase 2) and activating the SMAD-ID3 signaling pathways. In this study, a total of 330 ovarian cancer tumor samples were evaluated for STIP1 expression by immunohistochemistry and analyzed for a possible correlation with patient characteristics and survival. The quantification of immunoreactivity was accomplished by applying an immunohistochemical scoring system (histoscore). Patients with high-level STIP1 expression (histoscore ≥169) had a significantly worse survival (high STIP1, mean survival time = 76 months; low STIP1, mean survival time = 112 months; P<0.0001). Moreover, STIP1 histoscores were significantly higher in high-grade tumors (grade 3) than in low-grade (grade 1-2) malignancies (P<0.0001), suggesting that STIP1 may be a proxy for tumor aggressiveness. The results of multivariable analysis revealed that high STIP1 histoscores, advanced stages, histologic types, and the presence of residual disease (≥2 cm) were independent predictors of poor prognosis. The addition of STIP1 histoscores improved the prediction of overall and progression-free survival rates in the multivariable Cox proportional hazard model. The treatment of ovarian cancer cells with recombinant STIP1 stimulated cell proliferation and migration, but co-treatment with anti-STIP1 antibodies abrogated this effect. Our findings suggest that STIP1 expression may be related to prognosis and that the STIP1 pathway may represent a novel therapeutic target for human ovarian cancer.

Estrogen stimulates the proliferation of human endometrial cancer cells by stabilizing nucleophosmin/B23 (NPM/B23).

Unopposed estrogen exposure is an important factor in the tumorigenesis of endometrial cancer. Nucleophosmin/B23 (NPM/B23), a phosphoprotein that has pleiotropic functions in cells, plays an important role in various cancers. However, the regulatory role of NPM/B23 in estrogen signaling in endometrial cancer has not been explored. Here, we report that NPM/B23 was required for estrogen-induced endometrial proliferation, and the increase in NPM/B23 was estrogen receptor α-dependent. Furthermore, estrogen increased NPM/B23 protein levels by repressing its ubiquitination and subsequently stabilizing the protein. The overexpression of the alternate reading frame (ARF) suppressed the estrogen-induced increase in the NPM/B23 protein levels, indicating that ARF inhibited the observed estrogen-mediated NPM/B23 stabilization. Our results suggest that one of the effects of estrogen on endometrial proliferation is the suppression of the NPM/B23-ARF interaction and the subsequent increase in NPM/B23 protein levels. This novel characterization of NPM/B23 in estrogen-mediated cell proliferation may extend our understanding of the tumorigenesis of steroid hormone-related cancers.

Prognostic significance of pituitary tumour-transforming gene-binding factor (PBF) expression in papillary thyroid carcinoma.

BACKGROUND: Pituitary tumour-transforming gene (PTTG)-binding factor (PBF), originally known as PTTG1 interacting protein (PTTG1IP), has been found to be significantly increased in well-differentiated thyroid cancer and independently associated with early tumour recurrence. OBJECTIVE: To assess the prognostic significance of PBF expression in a large cohort of papillary thyroid carcinoma (PTC) patients with a long-term follow-up. DESIGN AND PATIENTS: Retrospective analysis of PBF expression in PTC cases at different stages and correlate it with various clinicopathological parameters and patient survival. Subjects included 153 patients who received a thyroid operation for PTC at Chang Gung Memorial Hospital between 1991 and 2000. All patients had a complete follow-up till the end of 2010. MEASUREMENTS: Immunohistochemical study for PBF expression on tissue sections from tumour specimens. Bond automated machine (Leica Microsystems, Germany) with a polyclonal rabbit anti-PBF antibody (LifeSpan BioSciences, LS-C118942, Seattle, WA, USA) was used. SPSS 13.0 for Windows (SPSS Inc, Chicago, IL, USA) was used for all statistical analyses. RESULTS: High PBF expression was significantly correlated with age (P = 0·0298), distant metastases at diagnosis (P = 0·0139), tumour multicentricity (P = 0·0035), TNM stage (P = 0·0103), locoregional recurrence (P = 0·0410) and disease-specific mortality (P = 0·0064). The expression level of PBF was significantly correlated with disease-specific survival (P = 0·0065). Cox regression analysis showed that age, tumour size and PBF expression were independent prognostic indicators (P = 0·0097, P = 0·0021 and P = 0·0179). CONCLUSION: PBF expression may be a promising biomarker for prognostic and therapeutic purpose. More large-scale studies are needed to clarify its potential usefulness.

Clinical implications of human papillomavirus genotype in cervical adeno-adenosquamous carcinoma.

BACKGROUND: Our aims were to evaluate the genotype distribution of human papillomavirus (HPV) and the correlation between HPV parameters and clinicopathological/treatment variables with prognosis in cervical adeno-adenosquamous carcinoma (AD/ASC). PATIENTS AND METHODS: Consecutive patients who received primary treatment for cervical AD/ASC International Federation of Gynecology and Obstetrics (FIGO) stages I-IV between 1993 and 2008 were retrospectively reviewed. Prognostic models were constructed and followed by internal validation with bootstrap resampling. RESULTS: A total of 456 AD/ASC patients were eligible for HPV genotyping, while 452 were eligible for survival analysis. HPV18 was detected in 51.5% and HPV16 in 36.2% of the samples. Age >50 years old, FIGO stages III-IV and HPV16-negativity were significantly related to cancer relapse, and age >50, FIGO stages III-IV, HPV16-negativity and HPV58-positivity were significant predictors for cancer-specific survival (CSS) by multivariate analyses. HPV16-positivity was also significantly associated with good prognosis in those receiving primary radiotherapy or concurrent chemoradiation (RT/CCRT) (CSS: hazard ratio 0.41, 95% confidence interval 0.21-0.78). Patients with FIGO stages I-II and HPV16-negative AD/ASC treated with primary RH-PLND had significantly better CSS (p<0.0001) than those treated with RT/CCRT. CONCLUSIONS: Age >50 years old, FIGO stages III-IV and HPV16-negativity were significant poor prognostic factors in cervical AD/ASC. Patients with HPV16-negative tumour might better be treated with primary surgery (e.g. radical hysterectomy for stages I-II and pelvic exenteration for stage IVA). Those with unresectable HPV16-negative tumour (stage IIIB) should undergo CCRT in combination with novel drugs. The inferences of a single-institutional retrospective study require prospective studies to confirm.

Reappraisal of TLE-1 immunohistochemical staining and molecular detection of SS18-SSX fusion transcripts for synovial sarcoma.

The aim of the present study was to re-evaluate TLE-1 staining and the molecular detection methods of SS18-SSX transcripts for synovial sarcoma. We analyzed TLE-1 expression in 50 molecularly confirmed synovial sarcomas and 85 other soft tissue tumors with three previously published scoring systems. In the present study, 39 to 43 synovial sarcomas showed TLE-1 nuclear staining, whereas 9-15 of 85 other soft tissue tumors showed TLE-1 staining (P < 0.0001). The specificities of strong TLE-1 staining were 100%, 97.6% and 98.8%. The positive likelihood ratio of moderate and strong TLE-1 nuclear expression was >10 in all three scoring systems. There was no difference in TLE-1 staining between different subtypes of synovial sarcoma (P > 0.05). Based on a comparison between conventional reverse transcription (RT)-polymerase chain reaction (PCR) and fluorescence in situ hybridization (FISH), quantitative RT-PCR is a more sensitive method than conventional RT-PCR and FISH to detect t(X;18). A positive correlation between TLE-1 staining and SS18-SSX translocation was detected by conventional PCR (P < 0.05). In conclusion, although all three scoring systems could differentiate synovial sarcoma from other soft tissue tumors, diffuse moderate to severe intensity tumors showed the highest specificity in the diagnosis of synovial sarcoma.

Phosphorylated mTOR expression correlates with poor outcome in early-stage triple negative breast carcinomas.

The mammalian target of rapamycin (mTOR) plays an important role in cell growth, proliferation, and metabolism. Some studies have associated phosphorylated mTOR (p-mTOR) expression with worse outcome in breast cancers. However, the significance of p-mTOR expression specifically in triple negative breast carcinoma (TNBC) is unknown. In this study, p-mTOR expression was evaluated by immunohistochemistry in 172 TNBCs and the result was correlated with clinicopathologic variables and disease outcome. The majority of tumors (72.1%) were p-mTOR positive; p-mTOR expression did not correlate with age, tumor size, grade, lymph node status, or tumor stage. In patients at stage 1 and 2 disease, those with p-mTOR expression had significantly worse overall as well as recurrence-free survival compared to those without p-mTOR expression. p-mTOR expression appears to be an adverse prognostic indicator in early-stage TNBCs. The assessment of p-mTOR expression in these tumors may also help to stratify patients for future target therapy studies.

Immune responses during healing of massive segmental femoral bone defects mediated by hybrid baculovirus-engineered ASCs.

Baculovirus holds promise for genetic modification of adipose-derived stem cells (ASCs) and bone engineering. To explore the immune responses during bone healing and the cell fate, ASCs were mock-transduced (Mock group), transduced with the baculovirus transiently expressing growth factors promoting osteogenesis (BMP2) or angiogenesis (VEGF) (S group), or transduced with hybrid baculoviruses persistently expressing BMP2/VEGF (L group). After allotransplantation into massive femoral defects in rabbits, these 3 groups triggered similar degrees of transient inflammatory response (e.g. neutrophil proliferation and immune cell infiltration into the graft site), revealing that baculovirus and transgene products did not exacerbate the inflammation. The cells in all 3 groups underwent apoptosis initially, persisted for at least 4 weeks and were eradicated thereafter. The L group prolonged the in vivo BMP2/VEGF expression (up to 4 weeks), extended the antibody responses, and slightly enhanced the cell-mediated cytotoxicity. Nonetheless, the L group led to remarkably better bone healing and remodeling than the Mock and S groups. These data confirmed that the ASCs engineered with the hybrid BV imparted prolonged expression of BMP2/VEGF which, although stimulated low levels of humoral and cell-mediated immune responses, essentially augmented the healing of massive segmental bone defects.

Favorable outcome of secondary axillary dissection in breast cancer patients with axillary nodal relapse.

PURPOSE: Little evidence can be found about the long-term outcome of breast cancer patients after axillary lymph node recurrence (ALNR) and its survival benefit after different kinds of management. The present study intends to evaluate the risk factors associated with axillary recurrence after definite surgery for primary breast cancer. The prognosis after ALNR and particularly outcome of different management methods also were studied. METHODS: We retrospectively reviewed data from 4,473 patients who were diagnosed with primary breast cancer and received surgical intervention in a single institute from January 1990 to December 2002. Medical files were reviewed and data on survival were updated annually. Risk factors and prognosis of patients with axillary recurrence were analyzed. Breast-cancer-specific survival of patients with ALNR and outcomes after different management methods also were studied. RESULTS: After a median follow-up of 70.2 months, axillary recurrence developed in 0.8% of patients. Factors associated with ALNR included: age younger than 40 years, medial tumor location, no initial standard level I & II axillary dissection, and not receiving hormonal therapy. The 5-year breast-cancer-specific survival after ALNR was 57.9%. For patients who received further axillary dissection, the 5-year survival rate was 82.5% compared with 44.9% for patients who did not receive further dissection. CONCLUSIONS: ALNR is a rare event in treating breast cancer. Young age at diagnosis and medially located tumor are associated with higher risk, but standardized initial axillary dissection to level II and adjuvant hormonal therapy is protective against ALNR. In patients with ALNR, the outcome is not dismal and survival may be improved if further axillary dissection is given.

Human papillomavirus in vaginal intraepithelial neoplasia.

There are limited data on the prevalence and distribution of human papillomavirus (HPV) genotypes in vaginal intraepithelial neoplasia (VAIN). We sought to clarify this issue in a series of 450 VAIN cases with a confirmed diagnosis between 1990 and 2006. HPV genotyping was performed using paraffin-embedded specimens and polymerase chain reaction (PCR)-based methods. Multiple HPV types were validated by E6 type-specific PCR and direct sequencing. The HPV genotypes of the vaginal and cervical neoplasms were compared for those with incident VAIN and a history of previous/concomitant cervical neoplasms. Ki-67 was performed for supporting diagnosis of VAIN. Of these 450 VAIN cases (median age, 59 years; range, 19-93), two with missing paraffin blocks and 54 with poor DNA quality were excluded. HPV was detected in 273/394 (69.3%) VAIN, and multiple infections were found in 17.9% of HPV-positive samples. The leading types were HPV16 (35.5%), HPV58 (9.9%), HPV52 (9.9%), HPV39 (8.4%), HPV33 (7.3%) and HPV53 (7.0%). Among the 156 cases with a history of previous cervical neoplasia, 29.0% had concordant HPV genotypes, while synchronous VAIN samples (n = 49) were more likely to harbor concordant genotypes (58.7%) with the concomitant cervical neoplasm (p = 0.0003). Whether those HPV types in the incident VAIN lesions had existed in the vaginal epithelium at the time of the previous cervical neoplasia or a new acquisition needs to be clarified in prospective follow-up studies.