Xi Cheng

Recurrence patterns and prognosis of endometrial stromal sarcoma and the potential of tyrosine kinase-inhibiting therapy

OBJECTIVEnEndometrial stromal sarcoma (ESS) is a rare uterine malignancy. The current treatment approaches yield unsatisfactory results, and potential therapeutic targets need exploration.nnnMETHODSnWe reviewed the electronic medical records of 74 patients with low-grade ESS who had been evaluated at the University of Texas MD Anderson Cancer Center between 1995 and 2006. Using immunohistochemistry, we tested the expression of targets in paraffin-embedded tissue samples taken from 13 of the patients.nnnRESULTSnForty-seven patients (64%) had a recurrence, and 16 (22%) had died of their disease at last follow-up. The 10-year progression-free survival (PFS) rate was 43% (median PFS duration, 108months), and the overall survival (OS) rate was 85% (median OS, 288months). Patients who received hormonal therapy had an overall response rate of 27%; another 53% had stable disease, with a median time to progression of 24months. No complete response or partial response was observed among patients who received radiotherapy or chemotherapy. In the paraffin-embedded specimens we tested, c-abl was expressed universally. Expression of PDGF-α, PDGF-β, VEGF, and c-Kit was detected in 33%, 36%, 54%, and 8%, of specimens, respectively. EGFR and HER-2 were not detectable in any specimens.nnnCONCLUSIONSnOur study suggests that ESS is a hormone-dependent malignancy, with hormonal therapy having activity in recurrent disease. Targeted therapy, specifically targeting c-abl may be a potential treatment for this disease.

Surgical treatment for patients with different origins of Krukenberg tumors: outcomes and prognostic factors.

AIMSnWe sought to investigate survival impacts of metastasectomy in women with Krukenberg tumors of the ovary and survival benefits in different origins (gastric cancer, colorectal cancer, or others).nnnMETHODSnAll patients diagnosed with Krukenberg tumors of the ovary who underwent surgical treatment at a single institution between 1997 and 2003 were retrospectively evaluated. Survival analyses and comparisons were performed using Kaplan-Meier method and log-rank test.nnnRESULTSnA total of 54 patients with Krukenberg tumors of the ovary were identified. The estimated 5-year survival was 12.1%. The median survival in patients with microscopic residual disease after metastasectomy was 29.6 months, compared to 10 months in those with visible residual disease (P<0.01). The median survival among patients with Krukenberg tumors of gastric origin, colon and rectum origin, and other origins were 13 months, 29.6 months, and 48.2 months, respectively (P=0.03). There was a significant difference in survival between patients with metastatic disease confined to the ovaries and those with extensive metastases, with an estimated median survival of 30.7 months and 10 months, respectively (P=0.02). Multivariate analysis suggested that the origin of ovarian metastatic carcinoma (P<0.01), residual disease after metastasectomy (P<0.01), and KPS (Karnofsky performance status) (P=0.03) were independent prognostic factors of survival.nnnCONCLUSIONSnPatients with Krukenberg tumors from colorectal cancer experience a better prognosis than those from gastric cancer and benefit more from metastasectomy. And metastasectomy significantly lengthens overall survival in patients with primary colorectal or breast cancer, higher KPS score, and those with optimal metastasectomy.

The Biphasic Role of NF-κB in Progression and Chemoresistance of Ovarian Cancer

Purpose: NF-κB is a transcription factor known to promote tumorigenesis. However, NF-κB is also known to be proapoptotic and may potentially function as a tumor suppressor, although such a functional role has not been extensively investigated in human cancer. Experimental Design: A dominant-negative mutant of IκBα with mutations at S32A and S36A was used to inhibit the function of NF-κB in ovarian cancer cell lines. The transcription ability, tumorigenesis, apoptosis, and drug sensitivity were examined in derivative cell lines in comparison with parental cells. We also analyzed the association of nuclear expression of NF-κB p65 with patient survival in an ovarian cancer tissue array. Results: We show that NF-κB functions as a tumor suppressor in four ovarian cancer cell lines, but it functions as an oncogene in their aggressive chemoresistant isogenic variants. NF-κB can exert its proapoptotic or antiapoptotic effect by activating or repressing mitogen-activated protein kinase (MAPK) phosphorylation in parental or aggressive chemoresistant variant cell lines. We also show that the nuclear accumulation of p65 in epithelial cancer tissue is associated with a good response to chemotherapy and can predict longer overall survival for patients with ovarian cancer. Conclusions: Our data provide strong evidence that NF-κB can function as a biphasic regulator, either suppressing or enhancing ovarian cancer growth through the regulation of MAPK and cellular apoptosis. Clin Cancer Res; 17(8); 2181–94. ©2011 AACR.

Functional variants in TNFAIP8 associated with cervical cancer susceptibility and clinical outcomes.

Tumor necrosis factor-α-induced protein 8 (TNFAIP8) is an anti apoptotic and pro-oncogenic signaling molecule involved in the process of immunity, carcinogenesis and tumor progression. Single nucleotide polymorphisms (SNPs) at microRNA-binding sites may change messenger RNA target gene function, thus leading to cancer susceptibility and tumor progression. In this study of 1584 cervical cancer cases and 1394 cancer-free female controls, we investigated associations between three potentially functional SNPs in TNFAIP8 family genes and cervical cancer risk as well as platinum resistance and clinical outcomes in Eastern Chinese women. We found that the TNFAIP8-rs11064 variant GG genotype was associated with an increased risk of cervical cancer compared with AA/AG genotypes (adjusted odds ratio = 2.16, 95% confidence interval = 1.16-4.03, P = 0.015). Further in vitro and ex vivo functional experiments demonstrated that the TNFAIP8-rs11064 variant G allele weakened the binding affinity of miR-22 to the TNFAIP8 3-untranslated region (UTR) in four cancer cell lines, resulting in increased production of the TNFAIP8 protein in the patients cervical tissues. In the survival subset, the high TNFAIP8 protein expression was significantly associated with both resistance to cisplatin and nedaplatin, recurrence and death from cervical cancer. Taken together, in the absence of information on human papillomavirus (HPV) infection, the TNFAIP8-rs11064 SNP may function by affecting the affinity of miR-22 binding to the 3-UTR of TNFAIP8 and regulating TNFAIP8 expression, thus contributing to cervical cancer risk. Additionally, the increased TNFAIP8 protein expression may predict platinum resistance and clinical outcomes in cervical cancer patients. Larger, prospective studies with detailed HPV infection data are warranted to validate our findings.

Surgery in recurrent epithelial ovarian cancer: Benefits on survival for patients with residual disease of 0.1-1 cm after secondary cytoreduction

Recent retrospective trials stated that a benefit of surgery for recurrent ovarian cancer may be limited to patients in whom a complete cytoreduction (R0) could be achieved. Most of them pointed out there was no difference in survival between residual disease of 0.1–1u2009cm (R1) and >1u2009cm (R2). The aim of this study was to evaluate survival benefits from cytoreduction to R1.

Activation of interleukin-6/signal transducer and activator of transcription 3 by human papillomavirus early proteins 6 induces fibroblast senescence to promote cervical tumourigenesis through autocrine and paracrine pathways in tumour microenvironment

Although it is reported that interleukin (IL)-6/signal transducer and activator of transcription 3 (STAT3) is activated by human papillomavirus (HPV) infection in cervical cancer cells, little is known about the role of IL-6/STAT3 in tumour microenvironment during development of the disease. In this study, we found that cancer-associated fibroblasts (CAF) but not normal fibroblasts (NF) secrete high level of IL-6 with activated STAT3 and appear senescent at early passages in culture or in cervical cancer tissues infected with high-risk HPV, and that treatment of NF with recombinant IL-6 or CAF conditioned medium (CM) induces activation of STAT3 and cellular senescence. IL-6 and STAT3 are either upregulated or activated in Siha and Hela cells infected with HPV 16 or 18, but not in C33A and ME180 cells without HPV 16 or 18 infection. Overexpression of HPV early proteins 6 (E6) activates STAT3, increases IL-6 expression and tumour burden in C33A and ME180 cells, while silencing of HPV E6 by specific shRNA reduces STAT3 activation, IL-6 expression, and tumour formation in Siha and HeLa cells, so does silencing of STAT3 by specific shRNA in HeLa and C33A/E6 cells. The tumour growth of cervical cancer cells reconstituted with CAF or NF is largely affected by inhibition of fibroblast senescence with STAT3 inhibitor or with IL-6 antibody treatment. Thus, we have uncovered a mechanism that fibroblast senescence promotes cervical cancer development through high-risk HPV E6-activated IL-6/STAT3 signalling in tumour microenvironment.

A pri-miR-218 variant and risk of cervical carcinoma in Chinese women

BackgroundMicroRNA (miRNA)-related single nucleotide polymorphisms (SNPs) may compromise miRNA binding affinity and modify mRNA expression levels of the target genes, thus leading to cancer susceptibility. However, few studies have investigated roles of miRNA-related SNPs in the etiology of cervical carcinoma.MethodsIn this case–control study of 1,584 cervical cancer cases and 1,394 cancer-free female controls, we investigated associations between two miR-218-related SNPs involved in the LAMB3-miR-218 pathway and the risk of cervical carcinoma in Eastern Chinese women.ResultsWe found that the pri-miR-218 rs11134527 variant GG genotype was significantly associated with a decreased risk of cervical carcinoma compared with AA/AG genotypes (adjusted OR=0.77, 95% CI=0.63-0.95, P=0.015). However, this association was not observed for the miR-218 binding site SNP (rs2566) on LAMB3. Using the multifactor dimensionality reduction analysis, we observed some evidence of interactions of these two SNPs with other risk factors, especially age at primiparity and menopausal status, in the risk of cervical carcinoma.ConclusionsThe pri-miR-218 rs11134527 SNP was significantly associated with the risk of cervical carcinoma in Eastern Chinese women. Larger, independent studies are warranted to validate our findings.

Polymorphisms of the Interleukin 6 gene contribute to cervical cancer susceptibility in Eastern Chinese women

Interleukin 6 (IL6) encodes a cytokine protein, which functions in inflammation, maintains immune homeostasis and plays important roles in cervical carcinogenesis. Single nucleotide polymorphisms (SNPs) in IL6 that cause variations in host immune response may contribute to cervical cancer risk. In this two-stage case–control study with a total of 1,584 cervical cancer cases and 1,768 cancer-free female controls, we investigated associations between two IL6 SNPs and cervical cancer risk in Eastern Chinese women. In both Study 1 and Study 2, we found a significant association of the IL6-rs2069837 SNP with an increased risk of cervical cancer as well as in their combined data (OR 1.27 and 1.19, 95xa0% CI 1.08–1.49 and 1.04–1.36, Pxa0=xa00.004 and 0.014 for dominant and additive genetic models, respectively). Furthermore, rs2069837 variant AG/GG carriers showed significantly higher levels of IL6 protein than did rs2069837 AA carriers in the target tissues. Using multifactor dimensionality reduction (MDR) and classification and regression tree (CART) analyses, we observed some evidence of interactions of the IL6 rs2069837 SNP with age at primiparity and menopausal status in cervical cancer risk. We concluded that the IL6-rs2069837 SNP may be a marker for susceptibility to cervical cancer in Eastern Chinese women by a possible mechanism of altering the IL6 protein expression. Although lacked information on human papillomavirus (HPV) infection, our study also suggested possible interactions between IL6 genotypes and age at primiparity or menopausal status in cervical carcinogenesis. However, larger, independent studies with detailed HPV infection data are warranted to validate our findings.

The prognosis of women with stage IB1-IIB node-positive cervical carcinoma after radical surgery.

BackgroundPelvic lymph nodes metastasis is an important prognostic factor for patients with cervical carcinoma. However, the relationships between the number of positive nodes, site of metastases nodes, adjuvant therapy and the prognosis is controversial. The purpose of this study was to investigate the influence of positive lymph nodes on the prognosis of Chinese women with stage IB1-IIB cervical carcinoma.Patients and methodsBetween January 1992 and December 1997, 398 women with International Federation of Gynecology and Obstetrics (FIGO) stage IB1-IIB cervical carcinoma underwent radical surgery in Cancer Hospital, Fudan University. Of these sixty-six patients (16.6%) who were histologically confirmed to have positive pelvic lymph nodes were analyzed retrospectively. The survival was estimated using Kaplan-Meier method. The differences in survival were compared with Log-rank test. Multivariate analyses were performed with the Cox proportional hazard model.ResultsThe 5-year survival of the patients with pelvic lymph nodes metastases was 40.7%. Cox proportional hazard model analysis showed that cellular differentiation, the number of positive nodes and adjuvant therapy to be the independent prognostic factors (P < 0.05). The 5-year survival of patients with one positive node was higher than that of those with two or more positive nodes (56.5% vs. 36.4%, P < 0.05). The distant metastasis rate in the former group (5.9%) was lower than the latters (32.7%) (P = 0.05). However, there was no significant difference of pelvic recurrence between the two groups (P > 0.05). The number of positive nodes positively correlated with the level of positive nodes (P < 0.01). The 5-year survival of the patients who had no adjuvant therapy (12.6%) was much lower than that (53.7%) of those with adjuvant therapy (P < 0.05). However, there was no obvious difference between adjuvant radiotherapy, chemotherapy and chemo-radiotherapy (P > 0.05).ConclusionsThe prognosis of patients with stage IB1-IIB node-positive cervical carcinoma who underwent radical surgery alone was very poor. Adjuvant therapy increases the survival rate, decreases the pelvic recurrence and distant metastasis.

RAD52 Variants Predict Platinum Resistance and Prognosis of Cervical Cancer

RAD52 is an important but not well characterized homologous recombination repair gene that can bind to single-stranded DNA ends and mediate the DNA-DNA interaction necessary for the annealing of complementary DNA strands. To evaluate the role of RAD52 variants in the response of tumor cells to platinum agents, we investigated their associations with platinum resistance and prognosis in cervical cancer patients. We enrolled 154 patients with cervical squamous cell carcinoma, who had radical surgery between 2008 and 2009, and genotyped three potentially functional RAD52 variants by the SNaPshot assay. We tested in vitro platinum resistance and RAD52 expression by using the MTT and immunohistochemistry methods, respectively. In 144 cases who had genotyping data, we found that both the rs1051669 variant and RAD52 protein expression were significantly associated with carboplatin resistance (Pu200a=u200a0.024 and 0.028, respectively) and rs10774474 with nedaplatin resistance (Pu200a=u200a0.018). The rs1051669 variant was significantly associated with RAD52 protein expression (adjusted ORu200a=u200a4.7, 95% CIu200a=u200a1.4−16.1, Pu200a=u200a0.013). When these three RAD52 variants were combined, progression-free survival was lower in patients who carried at least one (≥1) variant allele compared to those without any of the variant alleles (Pu200a=u200a0.047). Therefore, both RAD52 variants and protein expression can predict platinum resistance, and RAD52 variants appeared to predict prognosis in cervical cancer patients. Large studies are warranted to validate these findings.