Impact of reduced margin pelvic radiotherapy on gastrointestinal toxicity and outcome in gynecological cancer.

Purpose: To investigate the effect of reduced margin pelvic radiotherapy on gastrointestinal toxicity and outcomes in gynecological cancer. Materials and methods: This retrospective study analyzed data of 590 patients who underwent hysterectomy and adjuvant pelvic radiotherapy between 2010 and 2020 at two tertiary centers. The pelvic nodal region was delineated based on a reduced margin definition or the Radiation Therapy Oncology Group (RTOG) guidelines. All patients were treated with intensity-modulated radiotherapy with imaging guidance. Gastrointestinal toxicity was assessed using the Common Terminology Criteria for Adverse Events (CTCAE) and the Patient-Reported Outcome version (PRO-CTCAE). Results: Overall, 352 (59.7%) and 238 (40.3%) patients underwent RTOG and reduced margin pelvic radiotherapy, respectively. Median follow-up was 6.4 years (IQR: 3.7-9.6). Reduced margin pelvic radiotherapy significantly lowered the radiation dose to the small bowel. For CTCAE grade ≥ 2 or 3, acute gastrointestinal toxicity was lower in the reduced margin group than in the RTOG group (16.4% vs. 33.5%, p < 0.001; 2.9% vs. 8.5%, p < 0.001). The reduced margin group reported less severe acute gastrointestinal toxicity (PRO-CTCAE score ≥ 3) than the RTOG group (12.5% vs. 28.7%, p < 0.001). Late grade 3 gastrointestinal toxicity was lower in the reduced margin group than in the RTOG group (0.8% vs. 4.8%, p = 0.006). The 5-year pelvic recurrence-free survival and disease-free survival in the RTOG and reduced margin pelvic radiotherapy groups were 97.4% and 97.9% (p = 0.55) and 80.7% and 83.5% (p = 0.18), respectively. Conclusion: Reduced margin pelvic radiotherapy decreased acute and late gastrointestinal toxicity and achieved favorable outcomes.

Association of malignant ascites with systemic inflammation and muscle loss after treatment in advanced-stage ovarian cancer.

BACKGROUND: Malignant ascites is prevalent in advanced-stage ovarian cancer and may facilitate identification of the drivers of muscle loss. This study aimed to evaluate the association of ascites with changes in systemic inflammation and muscle after treatment of advanced-stage ovarian cancer. METHODS: We evaluated 307 patients with advanced-stage (III/IVA) ovarian cancer who underwent primary debulking surgery and adjuvant platinum-based chemotherapy between 2010 and 2019. The changes in skeletal muscle index (SMI) and radiodensity (SMD) were measured using pre-surgery and post-chemotherapy portal-venous phase contrast-enhanced computed tomography scans at L3. Systemic inflammation was measured using albumin levels, prognostic nutritional index (PNI), neutrophil-lymphocyte ratio (NLR), and platelet-lymphocyte ratio (PLR). Primary endpoint was the changes in SMI and SMD after treatment. Linear regression analysis was used to test associations between muscle change and other covariates. Mediation analysis was used to determine the mediator. RESULTS: The median (range) age was 53 (23-83) years. The median duration (range) of follow-up was 5.2 (1.1-11.3) years. Overall, 187 (60.9%) patients had ascites. The changes in muscle and systemic inflammatory markers after treatment were significantly different between patients with and without ascites (SMI: -3.9% vs. 2.2%, P < 0.001; SMD: -4.0% vs. -0.4%, P < 0.001; albumin: -4.4% vs. 2.1%, P < 0.001; PNI: -8.4% vs. -0.1%, P < 0.001; NLR: 20.6% vs. -29.4%, P < 0.001; and PLR: 1.7% vs. -19.4%, P < 0.001). The changes in SMI and SMD were correlated with the changes in albumin, PNI, NLR, and PLR (all P < 0.001). In multiple linear regression, ascites and NLR changes were negatively while albumin change was positively correlated with SMI change (ascites: ß = -3.19, P < 0.001; NLR change: ß = -0.02, P = 0.003; albumin change: ß = 0.37, P < 0.001). Ascites and NLR changes were negatively while PNI change was positively correlated with SMD change (ascites: ß = -1.28, P = 0.02; NLR change: ß = -0.02, P < 0.001; PNI change: ß = 0.11, P = 0.04). In mediation analysis, ascites had a direct effect on SMI change (P < 0.001) and an indirect effect mediated by NLR change (indirect effects = -1.61, 95% confidence interval [CI]: -2.22 to -1.08) and albumin change (indirect effects = -2.92, 95% CI: -4.01 to -1.94). Ascites had a direct effect on SMD change (P < 0.001) and an indirect effect mediated by NLR change (indirect effects = -1.76, 95% CI: -2.34 to -1.22) and PNI change (indirect effects = -2.00, 95% CI: -2.79 to -1.36). CONCLUSIONS: Malignant ascites was associated with enhanced systemic inflammation and muscle loss after primary debulking surgery and adjuvant chemotherapy in advanced-stage ovarian cancer. The association between ascites and muscle loss may be mediated by systemic inflammation.

The role of postoperative radiation after radical hysterectomy for women with early-stage neuroendocrine carcinoma of the cervix: A meta-analysis.

INTRODUCTION: Neuroendocrine carcinoma of the cervix (NECC) is an aggressive disease with high rates of nodal disease spread even in seemingly cervix-confined disease. Many providers routinely prescribe postoperative radiation therapy in an effort to reduce recurrences despite a lack of supporting studies. The objective of this study was to determine recurrence and mortality in patients with early-stage NECC who had pelvic radiation after radical hysterectomy compared to those who did not receive radiation. METHODS: We performed a meta-analysis of 13 unique studies that reported recurrence and/or mortality for patients with early-stage NECC who underwent radical hysterectomy with or without adjuvant radiation therapy. RESULTS: In 5 studies that reported overall recurrence rates, 63 (52.5%) of 120 patients who received postoperative radiation recurred compared to 70 (37.8%) of 185 patients who did not (RR 1.21, 95% CI: 0.85-1.70, p = 0.29). In 5 studies that reported pelvic recurrence rates, there were 15 pelvic recurrences (12.5%) in the 120 patients who received postoperative radiation compared to 45 pelvic recurrences (24.3%) in the 185 patients who did not (RR 0.60, 95% CI: 0.34-1.08, p = 0.09). In 13 studies that reported mortality rate, there were 138 deaths (34.8%) in 396 patients who received postoperative radiation therapy compared to 223 (35.2%) in 632 patients who did not (RR 1.08, 95% CI: 0.75-1.56, p = 0.66). CONCLUSIONS: The addition of routine postoperative radiation therapy in all patients with early-stage NECC after radical hysterectomy may reduce pelvic recurrences but does not appear to decrease overall recurrence or death. However, there may still be a role for postoperative radiation therapy in patients with additional high-risk pathologic factors.

Cytogenetic discrepancy between uncultured amniocytes and cultured amniocytes in mosaic trisomy 15 at amniocentesis in a pregnancy with a favorable outcome.

OBJECTIVE: We present prenatal diagnosis of mosaic trisomy 15 in a pregnancy with a favorable outcome. CASE REPORT: A 33-year-old, primigravid woman underwent amniocentesis at 19 weeks of gestation because non-invasive prenatal testing (NIPT) revealed gene dosage increase at chromosome 15. Cytogenetic analysis revealed a karyotype of 47,XX,+15[10]/46,XX[13]. Using uncultured amniocytes, array comparative genomic hybridization (aCGH) revealed arr [GRCh37] (X) × 2, (15) × 3 [0.75], multiplex ligation-dependent probe amplification (MLPA) analysis showed rsa [GRCh36] 15q11q13 (21,362,818-27,196,819) × 3 [0.76] and methylation-specific (MS)-MLPA analysis showed a methylation index = 0.41 with paternal gene dosage increase at 15q11-q13. Repeat amniocentesis at 25 weeks of gestation revealed a karyotype of 47,XX,+15[6]/46,XX[14]. Using uncultured amniocytes, quantitative fluorescent polymerase chain reaction (QF-PCR) assays excluded uniparental disomy (UPD) 15 and determined a paternal origin of the extra chromosome 15, aCGH analysis showed 75%-80% mosaicism for trisomy 15, and interphase fluorescence in situ hybridization (FISH) showed 45.5% (46/101 cells) mosaicism for trisomy 15. Repeat amniocentesis at 28 weeks of gestation revealed a karyotype of 47,XX,+15[2]/46,XX[23]. Using uncultured amniocytes, aCGH showed 75-80% mosaicism for trisomy 15, and FISH showed 70.6% (72/102 cells) mosaicism for trisomy 15. Using cultured amniocytes, QF-PCR assays excluded UPD 15. Cordocentesis at 30 weeks of gestation revealed a karyotype of 47,XX,+15[2]/46,XX[138]. Using cord blood, aCGH revealed 9% gene dosage increase at chromosome 15, and MS-MLPA analysis excluded UPD 15. At 36 weeks of gestation, a 2060-g phenotypically normal baby was delivered. The cord blood had 46, XX (40/40 cells). The placenta had 47,XX,+15 (40/40 cells). QF-PCR analysis on placenta showed a paternal origin of trisomy 15. FISH analysis on buccal mucosal cells at age 20 days showed 20% (20/100 cells) mosaicism for trisomy 15. CONCLUSION: Cytogenetic discrepancy may occur between uncultured and cultured amniocytes in mosaic trisomy 15 at amniocentesis. Cultured amniocytes may present progressive decrease in the levels of mosaicism for trisomy 15 as the fetus grows. Mosaic trisomy 15 at amniocentesis without UPD 15 can be associated with a favorable outcome.

Essential roles of surgical and pathological evaluations in the management of foreign bodies or inflammatory granulomas mimicking cervical cancer recurrence: A report of two cases.

OBJECTIVE: Positron emission tomography-computed tomography (PET/CT) is an effective modality for evaluating cervical cancer recurrence. We present two cases of suspected recurrent cervical cancer on PET/CT that were pathologically proven to be granulomas. CASE REPORT: Case 1: A 54-year-old woman with FIGO (2009) stage IB1 cervical cancer underwent radical hysterectomy and adjuvant chemoradiotherapy. Case 2: A 44-year-old woman with FIGO (2009) stage IB2 cervical cancer underwent incidental simple hysterectomy with pelvic lymphadenopathy and adjuvant concurrent cisplatin-based chemoradiotherapy. Both patients had peritoneal or pelvic masses with increased 18F-fluorodeoxyglucose (18F-FDG) uptake on PET/CT after 3 years. These masses were finally pathologically proven to be foreign bodies or inflammatory granulomas with abscess, respectively. CONCLUSION: Foreign bodies or inflammatory granuloma could be one of the differential diagnoses of increased 18F-FDG uptake on PET/CT in patients with cervical cancer after treatment. Pathological evaluation should be considered in these patients to guide further treatment.

Association of Patient-Reported Outcomes and Nutrition with Body Composition in Women with Gynecologic Cancer Undergoing Post-Operative Pelvic Radiotherapy: An Observational Study.

Pelvic radiotherapy is associated with gastrointestinal toxicities and deterioration of nutritional status. This study aimed to investigate the association of patient-reported outcomes (PROs) and nutritional status with body composition changes in women who underwent hysterectomy and post-operative radiotherapy for gynecologic cancer. We analyzed data of 210 patients treated with post-operative pelvic radiotherapy for gynecologic cancer between 2013 and 2018. The PRO version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) was used for gastrointestinal toxicity assessment. The Patient-Generated Subjective Global Assessment (PG-SGA) was used for nutritional assessment. Skeletal muscle index was measured from computed tomography scans at the L3 vertebral level. A reduction in skeletal muscle index ≥ 5% was classified as muscle loss. Odds ratios were calculated through logistic regression models. The PG-SGA score increased from the beginning to the end of radiotherapy (1.4 vs. 3.7, p < 0.001). Patients with PRO-CTCAE scores ≥ 3 had significantly higher PG-SGA scores at the end of radiotherapy than those with PRO-CTCAE scores ≤ 2 (8.1 vs. 2.3, p < 0.001). On multivariable analysis, PRO-CTCAE scores ≥ 3 and PG-SGA scores ≥ 4 at the end of radiotherapy were independently associated with increased risk of muscle loss (odds ratio: 8.81, p < 0.001; odds ratio: 72.96, p < 0.001, respectively). PROs and PG-SGA may be considered as markers of muscle loss after post-operative pelvic radiotherapy for gynecologic cancer.

Case Report: Ectopic Adrenocortical Carcinoma in the Ovary.

Adrenocortical carcinoma (ACC) is a rare malignancy with an incidence of 0.7-2.0 cases/million habitants/year. ACCs are rare and usually endocrinologically functional. We present the case of a 59-year-old woman who experienced abdominal fullness for 6 months and increased abdominal circumference. A large pelvic tumor was observed. She underwent cytoreductive surgery and the pathological test results revealed local tumor necrosis and prominent lympho-vascular invasion. Neuroendocrine carcinoma was the first impression, but positivity for synaptophysin, alpha-inhibin, transcription factor enhancer 3 (TFE-3), calretinin (focal), and CD56 (focal) and high Ki-67-labeling proliferating index (>80%) confirmed the diagnosis of ectopic ACC. Ectopic primary aldosteronism could not be excluded. However, we did not perform saline infusion test or captopril test due to poor performance status. When pathological test reports reveal neuroendocrine features not typically found in the organ being examined, IHC staining should be performed to rule out ectopic ACC. Whether the ectopic ACC is functional or not requires complete survey.

Progressive Skeletal Muscle Loss After Surgery and Adjuvant Radiotherapy Impact Survival Outcomes in Patients With Early Stage Cervical Cancer.

The effect of skeletal muscle loss associated with surgery and adjuvant radiotherapy on survival outcomes in patients with early-stage cervical cancer remains unclear. We analyzed the data of 133 patients with early-stage cervical cancer who underwent surgery and adjuvant radiotherapy between 2013 and 2018 at two tertiary centers. Skeletal muscle changes were measured using computed tomography scans at baseline, at simulation for radiotherapy, and at 3 months post-treatment. A decrease of ≥5% in the skeletal muscle was defined as "muscle loss." The Patient-Reported Outcome version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) was used to assess gastrointestinal toxicity. The Patient-Generated Subjective Global Assessment (PG-SGA) was used for nutritional assessment. Predictors of overall survival were identified using the Cox regression models. The median follow-up period was 3.7 years. After treatment, 32 patients (24.1%) experienced muscle loss. The rate of muscle loss was higher in patients with PRO-CTCAE score ≥3 or PG-SGA score ≥4 at the end of radiotherapy than in patients with PRO-CTCAE score ≤2 or PG-SGA score 0-3 (75.0 vs. 10.5%, p < 0.001; 71.4 vs. 2.2%, p < 0.001). The 3-year overall survival was significantly lower in patients with muscle loss than in those with muscle preserved (65.6 vs. 93.9%, p < 0.001). Multivariate analysis showed that muscle loss was independently associated with poor overall survival (hazard ratio, 4.55; 95% confidence interval: 1.63-12.72; p < 0.001). Muscle loss after surgery and adjuvant radiotherapy was associated with poor overall survival in patients with early-stage cervical cancer. Muscle loss is associated with patient-reported gastrointestinal toxicity and deterioration in nutritional status.

Muscle loss during primary debulking surgery and chemotherapy predicts poor survival in advanced-stage ovarian cancer.

BACKGROUND: Sarcopenia is commonly observed in patients with advanced-stage epithelial ovarian cancer (EOC). However, the effect of body composition changes-during primary debulking surgery (PDS) and adjuvant platinum-based chemotherapy-on outcomes of patients with advanced-stage EOC is unknown. This study aimed to evaluate the association between body composition changes and outcomes of patients with stage III EOC treated with PDS and adjuvant platinum-based chemotherapy. METHODS: Pre-treatment and post-treatment computed tomography (CT) images of 139 patients with stage III EOC were analysed. All CT images were contrast-enhanced scans and were acquired according to a standardized protocol. The skeletal muscle index (SMI), skeletal muscle radiodensity (SMD), and total adipose tissue index were measured using CT images obtained at the L3 vertebral level. Predictors of overall survival were identified using Cox regression models. RESULTS: The median follow-up was 37.9 months. The median duration between pre-treatment and post-treatment CT was 182 days (interquartile range: 161-225 days). Patients experienced an average SMI loss of 1.8%/180 days (95% confidence interval: -3.1 to -0.4; P = 0.01) and SMD loss of 1.7%/180 days (95% confidence interval: -3.3 to -0.03; P = 0.046). SMI and SMD changes were weakly correlated with body mass index changes (Spearman ρ for SMI, 0.15, P = 0.07; ρ for SMD, 0.02, P = 0.82). The modified Glasgow prognostic score was associated with SMI loss (odds ratio: 2.42, 95% confidence interval: 1.03-5.69; P = 0.04). The median time to disease recurrence was significantly shorter in patients with SMI loss ≥5% after treatment than in those with SMI loss <5% or gain (5.4 vs. 11.2 months, P = 0.01). Pre-treatment SMI (1 cm2 /m2 decrease; hazard ratio: 1.08, 95% confidence interval: 1.03-1.11; P = 0.002) and SMI change (1%/180 days decrease; hazard ratio: 1.04, 95% confidence interval: 1.01-1.08; P = 0.002) were independently associated with poorer overall survival. SMD, body mass index, and total adipose tissue index at baseline and changes were not associated with overall survival. CONCLUSIONS: Skeletal muscle index decreased significantly during treatment and was independently associated with poor overall survival in patients with stage III EOC treated with PDS and adjuvant platinum-based chemotherapy. The modified Glasgow prognostic score might be a predictor of SMI loss during treatment.

Retrospective Analysis Of Comparative Outcomes In Recurrent Platinum-Sensitive Ovarian Cancer Treated With Pegylated Liposomal Doxorubicin (Lipo-Dox) And Carboplatin Versus Paclitaxel And Carboplatin.

PURPOSE: The aim of this study is to analyze the outcomes of platinum-sensitive (PS) recurrent ovarian cancer treated with pegylated liposomal doxorubicin and carboplatin (CD) versus paclitaxel and carboplatin (CP). Clinical features were examined to characterize the patient population that would benefit from CD. MATERIALS AND METHODS: This is a retrospective review of 122 cases at a tertiary hospital. Patients with PS recurrent ovarian cancer who received CD or CP were included. Progression-free survival (PFS) and overall survival (OS) were evaluated through the Kaplan-Meier method and log-rank test. Cox proportional hazards regression was used to examine PFS predictors. RESULTS: In total, 122 patients (75% with first recurrence and 25% with second recurrence) were included. The majority of the patients were diagnosed at an advanced stage and with the histology of serous carcinoma. Median PFS and OS were 14.8 and 55.5 months in the CD group and 13.5 and 56.8 months in the CP group. Subgroup analysis of patients revealed that the CD group had longer median PFS than the CP group among patients with PFI>12 months. Additionally, during the second recurrence, longer PFS was observed in the CD group than in the CP group (medians 22.3 and 13.5 months, respectively, p = 0.019). CONCLUSION: Comparable outcomes in recurrent platinum-sensitive ovarian cancer treated with CD versus CP were presented in this study. Longer PFS in CD group was observed among patients with PFI for more than 12 months or in second recurrence.

Replication of results from a cervical cancer genome-wide association study in Taiwanese women.

Genetic epidemiological studies show that genetic factors contribute significantly to cervical cancer carcinogenesis. Several genome-wide association studies (GWAS) have revealed novel genetic variants associated with cervical cancer susceptibility. We aim to replicate 4 GWAS-identified single nucleotide polymorphisms (SNPs), which were associated with invasive cervical cancer in Chinese women, in a Taiwanese population. The rs13117307 C/T, rs8067378 A/G, rs4282438 G/T, and rs9277952 A/G SNPs were genotyped in 507 women with cervical squamous cell carcinoma (CSCC) and 432 age/sex matched healthy controls by using TaqMan PCR Assay. Human papillomavirus (HPV) DNA test and typing were performed in CSCC patients. Only the rs4282438 SNP was found to be significantly associated (G allele, odds ratio [OR] = 0.67, P = 1.5 × 10-5). This protective association remained in HPV-16 positive CSCC subgroup (G allele, OR = 0.60, P = 1.2 × 10-5). In conclusion, our study confirms the association of rs4282438 SNP with CSCC in a Taiwanese population. However, larger sample sets of other ethnic groups are required to confirm these findings.

Correction: Optical imaging of ovarian cancer using a matrix metalloproteinase-3-sensitive near-infrared fluorescent probe.

[This corrects the article DOI: 10.1371/journal.pone.0192047.].

Optical imaging of ovarian cancer using a matrix metalloproteinase-3-sensitive near-infrared fluorescent probe.

Epithelial ovarian cancer (EOC) is the seventh most common cancer among women worldwide. The 5-year survival rate for women with EOC is only 30%-50%, which is largely due to the typically late diagnosis of this condition. EOC is difficult to detect in its early stage because of its asymptomatic nature. Recently, near-infrared fluorescent (NIRF) imaging has been developed as a potential tool for detecting EOC at the molecular level. In this study, a NIRF-sensitive probe was designed to detect matrix metalloproteinase (MMP) activity in ovarian cancer cells. A cyanine fluorochrome was conjugated to the amino terminus of a peptide substrate with enzymatic specificity for MMP-3. To analyze the novel MMP-3 probe, an in vivo EOC model was established by subcutaneously implanting SKOV3 cells, a serous-type EOC cell line, in mice. This novel MMP-3-sensitive probe specifically reacted with only the active MMP-3 enzyme, resulting in a significantly enhanced NIRF emission intensity. Histological analysis demonstrated that MMP-3 expression and activity were enhanced in the stromal cells surrounding the ovarian cancer cells. These studies establish a molecular imaging reporter for diagnosing early-stage EOC. Additional studies are required to confirm the early-stage activity of MMP-3 in EOC and its diagnostic and prognostic significance.

PI3K inhibitor enhances the cytotoxic response to etoposide and cisplatin in a newly established neuroendocrine cervical carcinoma cell line.

BACKGROUND: Neuroendocrine cervical carcinoma (NECC) is a rare and aggressive subtype of cervical cancer. To date, no NECC cell-based model is available, which hinders the development of new therapeutic strategies for NECC. In this study, we derived a new NECC cell line from an ex vivo biopsy and used it to explore novel drug combination approach for NECC. RESULTS: The stable HM-1 cell line displayed high expression levels of the neuroendocrine marker, synaptophysin. HM-1 cell transplantation could induce tumor growth in nude mice. As expected, the combination of etoposide and cisplatin synergistically inhibited HM-1 cell proliferation. Strikingly, when etoposide and cisplatin were combined with PI3K inhibitor BEZ235, the growth of HM-1 cells was significantly reduced. Taken together, the data implied the combination of etoposide and cisplatin with BEZ235 not only inhibited HM-1 cell proliferation but also increased cell apoptosis. MATERIALS AND METHODS: A NECC tissue sample from a 75-year-old female patient was processed to derive a primary cell line annotated as HM-1. The features of HM-1 were analyzed to establish its characteristic profile. Next, HM-1 was treated with PI3K inhibitors, BKM120 and/or BEZ235, in combination with two well-known genotoxic drugs, etoposide and/or cisplatin, to evaluate which combination could serve as a more effective treatment approach. Their inhibiting effects on HM-1 were evaluated by cell viability, apoptosis, and target kinase expression. CONCLUSIONS: The newly established NECC cell line HM-1 could serve as a cell-based model for NECC research. The synergistic drug combination of PI3K inhibitor with genotoxic drugs might become a potential new treatment strategy against NECC.

ITPR3 gene haplotype is associated with cervical squamous cell carcinoma risk in Taiwanese women.

Host immunogenetic background plays an important role in human papillomavirus (HPV) infection and cervical cancer development. Inositol 1,4,5-triphosphate receptor type 3 (ITPR3) is essential for both immune activation and cancer pathogenesis. We aim to investigate if ITPR3 genetic polymorphisms are associated with the risk of cervical cancer in Taiwanese women. ITPR3 rs3748079 A/G and rs2229634 C/T polymorphisms were genotyped in a hospital-based study of 462 women with cervical squamous cell carcinoma (CSCC) and 921 age-matched healthy control women. The presence and genotypes of HPV in CSCC was determined. No significant association of individual ITPR3 variants were found among controls, CSCC, and HPV-16 positive CSCC. However, we found a significant association of haplotype AT between CSCC and controls (OR = 2.28, 95% CI 1.31-3.97, P = 2.83 × 10-3) and the OR increased further in CSCC patients infected with HPV-16 (OR = 2.89, 95% CI 1.55-5.37, P = 4.54 × 10-4). The linkage disequilibrium analysis demonstrated that ITPR3 association with CSCC was independent of HLA-DRB1 alleles. In conclusion, these findings suggest that AT haplotype in the ITPR3 gene may serve as a potential marker for genetic susceptibility to CSCC.

Functional variant of the P2X7 receptor gene is associated with human papillomavirus-16 positive cervical squamous cell carcinoma.

Human papillomavirus (HPV) infection and the fate of HPV infected cervical epithelial cells are strictly associated with cervical cancer development. P2X7 receptor has been implicated in both the regulation of immune responses and apoptosis of cervical cancer cells. The study aims to investigate if polymorphisms in the P2RX7 gene are associated with the risk of cervical cancer in Taiwanese women. P2RX7 253 T/C, 835 G/A, and 1513 A/C loss-of-function polymorphisms were genotyped in a hospital-based study of 507 women with cervical squamous cell carcinoma (CSCC) and 1619 age-matched healthy control women. The presence and genotypes of HPV in CSCC was determined. The frequency of 253 C/C genotype was found to increase significantly in patients with HPV-16 positive CSCC compared with controls (odds ratio = 10.2, 95% confidence interval 1.39-87.8, Pc = 0.03). No significant associations were found for other 2 polymorphisms. Analysis of haplotypes also revealed no significant differences among women with CSCC, those with HPV-16 positive CSCC and controls. In conclusion, inheritance of the C/C genotype at position 253 in the P2RX7 gene may contribute to the risk of HPV-16 associated CSCC in Taiwanese women.

Prognostic factors and adjuvant therapy on survival in early-stage cervical adenocarcinoma/adenosquamous carcinoma after primary radical surgery: A Taiwanese Gynecologic Oncology Group (TGOG) study.

OBJECTIVE: We aimed to identify prognostic factors of early-stage cervical adenocarcinoma (AC) and adenosquamous carcinoma (ASC) treated with primary radical surgery, and to evaluate the impact of postoperative adjuvant therapy on outcome. METHODS: The clinical-pathological data of all patients (n = 1132) with stages I-II cervical AC/ASC treated with primary radical surgery at the member hospitals of the Taiwanese Gynecologic Oncology Group were retrospectively reviewed. RESULTS: In multivariate analysis, stage II, deep stromal invasion (DSI), lymphovascular space invasion (LVSI), positive pelvic lymph node (PLN), and parametrial involvement (PI) were significant factors for recurrence-free survival (RFS), while only DSI, PI, and positive PLN were independent factors for cancer-specific survival (CSS). Low- and high-risk groups were defined by prognostic scores derived from the four factors (DSI, LVSI, positive PLN, PI) selected by internal validation. Postoperative adjuvant therapy significantly improved outcome for PLN-positive patients (RFS, p = 0.014; CSS, p = 0.016), but not for PLN-negative high-risk group because of higher mean prognostic score (p = 0.028) of adjuvant+ than adjuvant- patients. CONCLUSIONS: PLN metastasis, PI, DSI, and LVSI were independent prognostic factors. Prospective studies of postoperative adjuvant therapy with prognostic score and nodal status stratification for cervical AC/ASC are necessary.

Possible surrogate marker for an effective dose-dense chemotherapy in treating ovarian cancer.

OBJECTIVE: To dissect the correlated hematologic markers that reflect the clinical outcome or treatment response in patients receiving dose-dense chemotherapy with a combination of platinum (cisplatin or carboplatin) and paclitaxel. MATERIALS AND METHODS: From 2009 to 2014, we enrolled 55 ovarian cancer patients (total 67 courses) including first-line, persistent, platinum-sensitive, or platinum-resistant disease in MacKay Memorial Hospital, Taipei, Taiwan. Weekly pretreatment complete blood counts and calculated ratios [platelet/neutrophil ratio, neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), neutrophil/monocyte ratio, platelet/monocyte ratio, lymphocyte/monocyte ratio] during dose-dense chemotherapy were collected. By grouping these hematologic biomarkers into three different response subgroups (responsive, stable, and nonresponsive) according to CA125 trend, the data were analyzed using one-way analysis of variance, and using post hoc-Tukey test for comparing each other. A p value < 0.05 was considered to be statistically significant. RESULTS: Absolute counts of lymphocytes and platelets, PLR, platelet/neutrophil ratio, platelet/monocyte ratio (all p < 0.001), and NLR (p=0.013) had statistically significant differences. Moreover, using box-and-whisker plot, absolute count of lymphocyte, PLR, and NLR showed most remarkable discrepancy in responsive, stable, and nonresponsive patients. Subgroup analysis for primary, platinum-sensitive, and platinum-resistant patients further revealed that PLR and NLR were significantly correlated to the outcome of dose-dense chemotherapy. CONCLUSION: Lower PLR or lower NLR had better treatment response for dose-dense chemotherapy and are possible markers for representing treatment response in dose-dense chemotherapy. For a clinician, this is useful for timing when to switch to another chemotherapy regimen.

Evodiamine from Evodia rutaecarpa induces apoptosis via activation of JNK and PERK in human ovarian cancer cells.

BACKGROUND: Evodiamine (EVO; 8,13,13b,14-tetrahydro-14-methylindolo[2'3'-3,4]pyrido[2,1-b]quinazolin-5-[7H]-one derived from the traditional herbal medicine Evodia rutaecarpa was reported to possess anticancer activity; however, the anticancer mechanism of EVO against the viability of human ovarian cancer cells is still unclear. PURPOSE: A number of studies showed that chemotherapeutic benefits may result from targeting the endoplasmic reticular (ER) stress signaling pathway. The objective of the study is to investigate the mechanism by which ER stress protein PERK plays in EVO-induced apoptosis of human ovarian cancer cells. METHODS: Cell death analysis was performed by MTT assay, DNA fragmentation assay, and Giemsa staining. DiOC6 staining was used for mitochondrial membrane potential measurement. Protein levels were analyzed by Western blotting. Pharmacological studies using MAPK inhibitors and PERK inhibitor GSK2606414 were involved. RESULTS: The viability of human ovarian cancer cells A2780, A2780CP, ES-2, and SKOV-3 was inhibited by EVO at various concentrations in accordance with increases in the percentage of apoptotic cells, DNA ladders, and cleavage of caspase 3 and poly(ADP ribose) polymerase (PARP) proteins. Decreased viability of cells was reversed by adding caspase inhibitors VAD and DEVD in SKOV-3 and A2780CP cells, and incubation of cells with JNK inhibitor SP600125 (SP) and JNKI, but not other MAPK and AKT inhibitors including PD98059, SB203580, significantly prevented the apoptosis elicited by EVO in human ovarian cancer cells. Furthermore, increased expression of phospho-eIF2α (peIF2α) and phospho-PERK (pPERK) proteins was detected in EVO-treated human ovarian cancer cells, and that was inhibited by adding JNK inhibitors SP600125 and JNKI. Application of a PERK inhibitor GSK2606414 showed a significant protection of human ovarian cancer cells A2780 and A2780CP from EVO-induced apoptosis. EVO disruption of mitochondrial membrane potential (MMP) was also inhibited by adding JNK or PERK inhibitors. The structure-activity relationship study indicated that the alkyl group at position 14 in EVO is important for apoptosis induction via activation of JNK and PERK in human ovarian cancer cells. CONCLUSION: Evidence supporting EVO induction of apoptosis via activation of JNK and PERK to disrupt MMP in human ovarian cancer cells is provided, and the alkyl at position 14 is a critical substitution for the apoptotic actions of EVO.

Nilotinib reduced the viability of human ovarian cancer cells via mitochondria-dependent apoptosis, independent of JNK activation.

Nilotinib (AMN) induces apoptosis in various cancer cells; however the effect of AMN on human ovarian cancer cells is still unclear. A reduction in cell viability associated with the occurrence of apoptotic characteristics was observed in human SKOV-3 ovarian cancer cells under AMN but not sorafenib (SORA) or imatinib (STI) stimulation. Activation of apoptotic pathway including increased caspase (Casp)-3 and poly(ADP-ribose) polymerase 1 (PARP1) protein cleavage by AMN was detected with disrupted mitochondrial membrane potential (MMP) accompanied by decreased Bcl-2 protein and increased cytosolic cytochrome (Cyt) c/cleaved Casp-9 protein expressions was found, and AMN-induced cell death was inhibited by peptidyl Casp inhibitors, VAD, DEVD and LEHD. Increased phosphorylated c-Jun N-terminal kinase (JNK) protein expression was detected in AMN- but not SORA- or STI-treated SKOV-3 cells, and the JNK inhibitors, SP600125 and JNKI, showed slight but significant enhancement of AMN-induced cell death in SKOV-3 cells. The intracellular peroxide level was elevated by AMN and H2O2, and N-acetylcysteine (NAC) prevented H2O2- but not AMN-induced peroxide production and apoptosis in SKOV-3 cells. AMN induction of apoptosis with increased intracellular peroxide production and JNK protein phosphorylation was also identified in human A2780 ovarian cancer cells, cisplatin-resistant A2780CP cells, and clear ES-2 cells. The evidence supporting AMN effectively reducing the viability of human ovarian cancer cells via mitochondrion-dependent apoptosis is provided.