bluuebunny/crossref_metadata_2025 huggingface dataset:
A new prostate cancer biopsy reporting system with prognostic potential.
Authors: Shah Paras Hemant , Olsson Carl A. , Paulucci David J , Elmasri Matthew , Vira Manish Arvind , Yaskiv Oksana , Kapoor Deepak A.
Published: September 2018

e16572

Background: Presently, prostate biopsy (PBx) results typically report the highest Gleason Grade Group in the PBx as the single metric used to gauge the clinical aggressiveness of tumor and dictate treatment. However, using that single parameter alone limits the clinician by lack of consideration of the entire PBx. Intuitively we presumed that a PBx showing multiple cores of cancer would represent more aggressive disease. Herein, we propose the Weighted Gleason Grade Group (WGGG), a novel scoring system that synthesizes histopathologic data and cancer volume into a single numeric value representing the entire PBx, allowing the urologist to more accurately predict adverse pathologic outcomes of radical prostatectomy (RP). Methods: We studied 246 men who underwent RP after standard multi-core PBx. The highest Gleason score of each PBx was converted to its final GGG. The WGGG was calculated by summing the Gleason score of each positive core and normalized for a 12 core total. RP pathology was studied to determine adverse pathological outcomes, specifically, extraprostatic extension (EPE), positive surgical margins (PSM), seminal vesical invasion (SVI), pathological up-grading and any adverse feature. We then studied the ability of conventional GGG versus WGGG to have ‘predicted’ the risk of these adverse features comparing their respective receiver operating characteristic (ROC) areas under the curve (AUC) for each, as well as any adverse feature. Results: The AUC for the WGGG vs. GGG was significantly higher for predicting EPE (AUC 0.782 vs. 0.697, respectively; z = -3.29; p = .0009), PSM (AUC 0.644 vs. 0.563, respectively; z = -3.00; p = .0027), SVI (AUC 0.829 vs. 0.713, respectively; z = -3.05; p = .0023) and pathologic up-grading (AUC 0.584 vs. 0.349, respectively; z = -3.13; p = .002). Finally, the AUC for any adverse feature was 0.637 for WGGG versus 0.556 for GGG; z = -3.29; p = .001. Conclusions: The WGGG, by providing a metric reflecting the entirety of the PBx, is more informative than conventional single GGG alone in ‘predicting’ adverse pathologic outcomes on radical prostatectomy specimens. We are now studying if % cancer/ PBx core will improve WGGG performance.
Hypofractionated radiation therapy in low-risk prostate cancer: Outcome, toxicity, and sexual function.
Authors: Marinelli Luca , Reverberi Chiara , Osti Mattia Falchetto , De Sanctis Vitaliana , Giuliani Manuela , Tronnolone Lidia , Valeriani Maurizio
Published: September 2018

e16575

Background: To evaluate efficacy, toxicity of image-guided hypofractionated radiotherapy (HFRT) in patients with low-risk prostate cancer. Methods: Eighty-five low-risk prostate cancer patients (Gleason score ≤6, clinical stage T1/T2a-b N0 M0, and PSA ≤10 ng/mL) were treated with HFRT from March 2007 to November 2015. All patients were staged with multi-parametric contrast-enhanced MRI. Clinical target volume (CTV) encompassed prostate with proximal seminal vescicles. Margin from CTV to PTV was 5 mm in all directions. Patients received a total dose of 60 Gy in 20 fractions with 3D-CRT. Daily cone beam CT (IGRT) was executed. RTOG/EORTC morbidity Scoring Scale was used for evaluate toxicities. Results: Median follow-up was 54 months (range 11-116 months). The actuarial 8-years Overall Survival was 97.1%. Eight-years Cancer Specific Survival was 100%, 8-years Biochemical Relapse Free Survival was 98.8%, no patients presented clinical local recurrence. Median of PSA at diagnosis was 3.27 ng/mL (range 1.69-9.98 ng/mL) and at the last follow-up was 0.39 ng/mL (range 0.01-2.26 ng/mL). Acute grade 1-2 gastrointestinal (GI) toxicity occurred in 13 patients (15.3%), grade 1-2 genitourinary (GU) toxicity in 33 cases (38.8%). Grade 3 GU toxicity occurred in 2 patients (2.4%). Grade 1-2 GI and GU late toxicities were observed in 4 (4.7 %) and 25 (29.4 %) patients, respectively. Sexual functionality was qualitatively evaluated, scoring 0 for absence, 1 for presence of erection but insufficient for intercourse, 2 for a sufficient one. Before RT, 4.7 % had score 0, 47.1% had score 1 and 48.2% had score 2. After RT, 34.1% of patients presented score 0, 51.8% score 1 and 14.1% score 2 (Chi-square p = 0,004). After treatment, patients with < 70 years presented score 0 in 4.7% of patients, score 1 in 20% and score 2 in 8.2%. Those with > 70 years, 29.4% presented score 0, 31.8% score 1 and 5.9% score 2 (Chi square p = 0.011). Conclusions: Long-term results of our study demonstrated that HFRT in low-risk prostate cancer is efficacy and well tolerated. HFRT significantly worsened sexual function, even if patients with age < 70 years had a higher probability to maintain any form of sexual function after therapy.
Effects of ALK1Fc treatment on prostate cancer cells interacting with bone and bone cells in bone metastasis models.
Authors: Kruithof-de Julio Marianna , Astrologo Letizia , Zoni Eugenio , Karkampouna Sofia , Gray Peter C , Klima Irena , Grosjean Joel , Goumans Marie Jose , Hawinkels Lukas J.A.C. , Van der Pluijm Gabri , ten Dijke Peter , Spahn Martin , Thalmann George N.
Published: September 2018

e16576

Background: Prostate cancer is the second most common cancer in men worldwide. Lethality is normally associated with the consequences of metastasis rather than the primary tumor. In particular, bone is the most frequent site of metastasis and once prostate tumor cells are engrafted in the skeleton, curative therapy is no longer possible. Bone morphogenetic proteins (BMPs) play a critical role in bone physiology and pathology. However, little is known about the role of BMP9 and its signaling receptors, ALK1 and ALK2, in prostate cancer and bone metastasis. In this context, we investigate the impact of BMP9 on primary prostate cancer and derived bone metastasis. Methods: The human ALK1 extracellular domain (ECD) binds BMP9 and BMP10 with high affinity. In order to study the effect of BMP9 in vitro and in vivo we use a soluble chimeric protein, consisting of ALK1 ECD fused to human Fc (ALK1Fc), for preventing the activation of endogenous signaling. ALK1Fc sequesters BMP9 and BMP10, preserving the activation of ALK1 through other ligands. Results: We show that ALK1Fc reduces BMP9-mediated signaling and decreases proliferation of highly metastatic and tumor initiating human prostate cancer cells in vitro. In line with these observations, we demonstrate that ALK1Fc reduces tumor growth in vivo in an orthotopic transplantation model. The propensity of the primary prostate cancer to metastasize to the bone is also investigated. In particular, we report how the ALK1Fc influences the prostate cancer cells in vitro and in vivo when these are probed in different bone settings (co-culture with bone cells and intraosseous transplantation in mice). Conclusions: Our study provides the first demonstration that ALK1Fc inhibits prostate cancer cells growth identifying BMP9 as a putative therapeutic target and ALK1Fc as a potential therapy. All together, these findings justify the ongoing clinical development of drugs blocking ALK1 and ALK2 receptor activity.
Evaluation of PRUNE2 and PCA3 expression as metastasis predictors in Gleason 7 prostate cancer.
Authors: Lauer Richard C. , Barry Marc , Wu Jin , Lee Ji-Hyun , McCance Dennis J. , Du Ruofei , Rao Arpit , Dobroff Andrey S. , Dias-Neto Emmanuel , Chen Isan , Pasqualini Renata , Arap Wadih
Published: September 2018

e16583

Background: There is an urgent need to differentiate from truly localized prostate cancer and micrometastatic disease. PCA3 is an FDA-approved biomarker for prostate cancer; however, it is not a predictor of metastasis behavior. We have recently identified PRUNE2 as an unrecognized tumor suppressor gene. Here we examined if the ratio of PRUNE2 and its corresponding dominant-negative oncogene PCA3 might serve as a better predictor of the metastatic potential of prostate cancer, compared to PCA3alone. Methods: We studied 105 prostate cancer patients who underwent a radical prostatectomy at UNM Hospital from 2001 to 2009. At the time of prostatectomy, these patients had a Gleason score of 7 and organ-confined disease. They had at least 5-year follow-up for disease recurrence, and 19 patients developed recurrent disease. PCA3 and PRUNE2 gene expression was quantified by qRT-PCR and normalized to housekeeping control genes. Each experiment was carried out in triplicates. The Wilcoxon rank sum test was used to evaluate whether or not the difference in gene expression of PRUNE2 or PCA3 or the gene expression ratio ( PRUNE2/ PCA3), between patients with and without recurrence, was significant. The association between the time to recurrence and expression levels of each single gene or ratio were also analyzed by the Kaplan-Meier method along with log-rank test and the COX PH modeling. Results: There was no significant difference in expression levels of PRUNE2, PCA3, or the ratio PRUNE2/ PCA3, between patients who developed recurrent disease relative to those who did not. Conclusions: PRUNE2 and PCA3 expression levels, as well as PRUNE2/ PCA3 ratio, did not predict the metastatic potential of Gleason 7 prostate cancer in our retrospective patient cohort. We postulated that the deregulation of the molecular axis of PRUNE2 and PCA3 might occur early in the development of prostate cancer. We are currently examining this mechanistic hypothesis in other studies. [Table: see text]
Biologic target volume delineation and the application of three-dimensional ultrasound image system in hypofractional radiotherapy for prostate cancer.
Authors: Wang Jie , Ma Jiabao , Lang Jin Yi
Published: September 2018

e16585

Background: To investigate the value of magnetic resonance spectroscopy (MRS) and positron emission computed tomography (PET-CT) in biological target volume(BTV) delineation of prostate cancer using hypofractional intensity modulated radiotherapy (HF-IMRT) with simultaneously integrated boost(SIB), and the preliminary efficacy and adverse effects of 3D ultrasound (3DUS) guided imaging in the treatment of prostate cancer using HF-IMRT and SIB. Methods: Between August 2015 and May 2016, 13 patients diagnosed with mid-high risk prostate cancer were retrospectively enrolled. All the eligible patients had underwent MRI MRS and PET-CT(18F-FDG or 11C-CHO) examination before radiotherapy. 5 patients had explicit BTV by examinations mentioned above. Radiation oncologists fused 3DUS and CT images and delineated tumor target volume referring to MRS and PET-CT. The target volumes were named as GTVMRI BTVMRS BTVPET-CT respectively and the volume were recorded. 3DUS guided HF-IMRT were applied during the radiotherapy. Results: The volumes of GTVMRI BTVMRS BTVPET-CT among the 5 patients were different. The mean volume of GTVMRI BTVMRS and BTVPET-CT were 3.52±1.69cm3, 6.64±2.27cm3 and 5.47±2.60cm3,respectively. Significant difference was only observed between GTVMRI and BTVMRS( P = 0.046). Compared to GTVMRI, the average increasing volumes of BTVMRS and BTVPET-CT were 89.07% and 55.52%. The prescription dose and biological effective dose(BED) of BTVMRS were 70.09-73.45Gy and 129.06-135.54Gy. The prescription dose and BED of the whole prostate were 66.02-69.40Gy and 113.32-124.82Gy. The dose of bladder and rectum were within safe control. The prostate specific antigen (PSA) were significantly decreased after radiotherapy. No local recurrence or distant metastasis was observed. Conclusions: MRS and PET-CT can be applied to delineation of the BTV of prostate cancer. With the help of multi-modal image guidance, dose painting for prostate cancer is feasible. 3DUS guided HF-IMRT with SIB is an alternative for radiation oncologists based on BTVMRS. With shortened time and less cost, this technique is safe and non-radioactive compared to CBCT guidance.
Utility of 11C choline PET CT and MRI in relapsed prostate cancer (PC).
Authors: Tarter Thomas H , Esparaz Benjamin , Lieber David , Zorn Adam , Locke Jon , Muscato Mark , Rashid Thomas , Whisnant Mindy , Wade James Lloyd
Published: September 2018

e16586

Background: Choline intracellular transport is upregulated in PC, and it is phosphorylated by choline kinase and becomes trapped within PC cells. 11 C Choline has t½ life of 20.4 minutes and emits positrons detectable by PET. Retrospective studies of 11 C choline PET CT in (PC) have been reported. In this original prospective study, we calculated the performance of 11C choline with whole body PET CT and pelvic PET MRI in patients (pts) with biochemical PC relapse. Methods: From November 2014- June 2016, 101 pts with biochemical PC relapse underwent 11C choline PET CT and pelvic PET MRI. Scans were read in blinded fashion. Tissue was obtained from area of 11 C Choline positivity and correlated with scan results. Results: Sixty-two pts (61%) were included in the analysis. 49 pts were excluded due to non-compliance with protocol. 11C choline PET CT and pelvic MRI showed a sensitivity of 92.5%, specificity of 45.5%, positive predictive value of 75.5%, and negative predictive value of 76.9%. Of 37 pts with positive 11C choline PET scans and confirmation of PC, 12 (32%) had positive 11C choline PET scans and negative CT and MRI scans; 7 (18%) had positive C11 choline and CT scans and negative MRI scans; 12 (32%) had positive 11C choline and MRI scans and negative CT scans, and 9 (24%) had positive 11C choline, CT and MRI scans. Mean PSA level in this group of 37 pts was 9.86 ng/mL (range 0.4 – 107.9 ng/mL), and 7 (19%) of the pts had PSA levels < 2 ng/mL. Conclusions: 11C choline PET improves detection of relapsed PC over CT and MRI scans. 11C choline PET pelvic MRI improves detection over 11C choline PET CT.
A prospective study on neoadjuvant chemoradiotherapy plus nimotuzumab followed by surgery for patients with advanced cervical cancer.
Authors: Lu Heming , Yu Jinming , Wu Yuying , Liu Xu , Jiang Hailan , Peng Luxing , Deng Shan , Qin Jian , Cheng Jinjian , Pang Qiang , Gu Junzhao , Lu Zhiping , Liang Ping , Zhao Renfeng , Chen Changyi , Hu Xiaoxia
Published: September 2018

e17000

Background: This study was to investigate the efficacy and safety of neoadjuvant chemoradiotherapy plus nimotuzumab followed by surgery for advanced cervical cancer. Methods: The inclusion criteria of this study were as follows: age: 18-75 years old; ECOG 0-1; FIGO stages IB2-IIIB; not eligible for surgery. IMRT with a total dose of 50-54 Gy was delivered to the tumor and the whole uterus, and 45-48.6 Gy to the high-risk regions. Weekly cisplatin or nedaplatin was administered concurrently with IMRT. Weekly nimotuzumab was given for 6 cycles. Patients were then assessed for clinical tumor response and operability. For those who were candidates for surgery, radical hysterectomy and pelvic lymph node dissection were performed 5-6 weeks after the completion of neoadjuvant therapy. Results: Twenty-eight patients were enrolled. Stage distributions were as follows: IB2, 3 pts; IIA, 5 pts; IIB, 16 pts; IIIA, 2 pts; IIIB, 2 pts. Twenty six (92.8%) patients completed ≥ 5 cycles of chemotherapy, and all completed ≥5 cycles of nimotuzumab. Complete clinical response and partial response were found in 8 patients (28.5%) and 20 patients (71.5%), respectively. Four patients were not eligible for surgery and 2 candidates refused surgery. They were not included in this analysis. Radical surgery was performed for the remaining 22 patients. Among them, 8 (36.4%) had complete pathology response, 9 (40.9%) presented with persistent atypical cells or cervical intraepithelial neoplasia, and 5 (22.7%) presented with macroscopic and/or microscopic residual disease. Median follow-up was 22 months (range, 5-39 months). The 2-year locoregional control rate, progression-free survival rate, distant metastasis-free survival rate, and overall survival rate were 95.0%, 85.2%, 84.0%, and 90.0%, respectively. Acute toxicity profiles were mainly manifested as marrow suppression, nausea, diarrhea, and loss of appetite. They were mild in general and easily manageable. Chronic toxicities were mainly limited to grade 1. No severe late toxicities were observed Conclusions: This treatment approach is highly effective and safe in advanced cervical cancer. Further studies are warranted to confirm the findings. Clinical trial information: NCT01938105.
Analysis of short-term efficacy and pathological outcome of paclitaxel plus platinum as neoadjuvant chemotherapy in the treatment of locally advanced cervical cancer.
Authors: He Yue , Wu Yu-Mei , Zhao Qun , Geng Yu-Ning , Yang Shu-Li , Finas Dominique , Yin Cheng-Hong
Published: September 2018

e17002

Background:The purpose of this study is to observe the short-term efficacy and pathological outcomes of paclitaxel combined with platinum (TP) as neoadjuvant chemotherapy (NACT) regimen in patients with locally advanced cervical cancer (LACC). Methods: This is a prospective study involving 61 women with histologically confirmed LACC referred for NACT at Beijing Obstetrics and Gynecology Hospital between April 2013 and January 2015. Results: The short-term efficacy of NACT was evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST). The short-term efficacy of NACT was 91.8% (complete remission and partial remission). The cervical invasion ≤1/2 was 82.4% in the complete remission (CR) group, 46.2% in the partial remission(PR) group and 20% in the stable disease (SD) group. The difference between groups was statistically significant (p=0.012). The slides of all surgical specimens were reviewed and classified according to Tumor Regression Grade (TRG). The good response was defined by good short-term efficacy (RECIST) and the difference between the groups was statistically significant (p=0.042). The short-term efficacy of NACT in artery intervention (AI) group (70-80%) was better than that in intravenous (IV) group (20%-30%) and the difference was statistically significant (p=0.011). The patients with tumor diameter ≤5cm and multiple cycles of chemotherapy have good short-term efficacy of NACT in LACC. All patients were followed up to the last day of 2015 with the median follow-up time of 21.5 months for NACT. For the 61 patients referred for NACT in LACC, two patients had relapsed and 1 patient died from the disease. Conclusions: The study showed that the Paclitaxel plus platinum as NACT for LACC treatment had a significant local effects. It could reduce tumor myometrial invasion and regress tumor. The short-term efficacy of the treatment in the AI group was more effective than in the IV group, two cycles of NACT of AI treatment to LACC patients would obtain an optimal short-term efficacy. Clinical trial information: NCT02471027.
Surgical outcomes of single port lapraroscopic radical hysterectomy in cervical cancer.
Authors: Yoo Ji Geun , Lee Yoon Kyung Elena , Lee Keun Ho
Published: September 2018

e17003

Background: We aim to see the postoperative outcomes of single port laparoscopic radical hysterectomy in cervical cancer. Methods: Twenty five cervical cancer patients (FIGO stage 9 IA, 13 IB, and 3 IIA) were treated by single port laparoscopic radical hysterectomy in single center. Results: Six patients were performed by type A hysterectomy, 6 by type B, and 13 by type C radical hysterectomy. Median operation time was 91, 197, and 275 minutes, respectively. Median number of pelvic nodes retrieved was 20. There was no postoperative complication except a colon serosa injury in type C radical hysterectomy and which repaired by single port approach. Ten out of 25 patients got an adjuvant radiation therapy and there were 3 recurrences (1 in type A, 2 in type C). Median disease free survival was 9.5 months in type A, 14 months in type C. Conclusions: Single port radical hysterectomy is safe and comparable to conventional laparoscopic hysterectomy in cervical cancer
Expression profile associated with CD274 (PD-L1) expression in cervical cancer.
Authors: Roman Bassaure Edgar , Berumen Campos Jaime , Medina Ingrid Yasbeth
Published: September 2018

e17005

Background: In Mexico, cervical cancer (CaCU) is the second leading cause of death in women. New treatment strategies are now emerging specifically the pathway of PD-1. We evaluated the frequency of PD-L1 expression at mRNA level and analyzed the expression profiles associated with different levels of CD274 expression. Methods: We analyzed the mRNA of 17 controls and 59 cervical cancer tumors by an expression microarray that allows the analysis of 22,607 human genes. Tumors were classified based on the mRNA expression of CD274. The deregulated genes in each group of tumors were compared against the control group using a T-test and Fold Change value. Functional analysis was using the DAVID tool. Correlation gene analysis was performed using the Pearson test. Results: The 59 cervical cancer tumors were classified in 3 groups: CD274-, CD274 low expression and CD274 high expression. The 71.2% of the tumors of CaCU have CD274 expression, 20 tumors with low expression and 22 tumors with high expression. 786 altered genes in the CD274- group, 1759 in the group of low expression and 2465 in the group of high expression were found. We found 19 altered biological processes in the CD274- group, being the most significant, cell cycle, DNA replication and DNA repair. In the tumors CD274 low were found 20 biological processes altered and were similar to those identified in the CD274- tumors. In the group CD274 high, 28 altered biological processes were found, interestingly 5 biological processes associated with innate immune response and antigenic processing. We found 24 genes correlated with the CD274 expression related to the immune response. Conclusions: The frequency of CD274 expression in cervical cancer is similar to that found in other tumors, it would be interesting explore the correlation between mRNA and protein. The number of altered genes is higher in the group of high expression of CD274. In the CD274 high group genes associated with processes related to the immune response are altered. The genes that correlate with the expression of CD274 are mostly associated with the immune system, these results suggest that overexpression of CD274 is accompanied by other immune processes.
The role of parents awareness to decision on HPV vaccination in Kazakhstan.
Authors: Kaidarova Dilyara , Nasrytdinova Nadejda , Kairbayev Murat
Published: September 2018

e17008

Background: Despite the proven effectiveness of HPV vaccination against cancer and precancerous lesions the acceptance rates are not perfect. The goal of the study was to look how parents awareness about HPV affected decision to vaccinate their daughters. Methods: The interview was held in schools where first HPV vaccination trial program started. The survey included questions about social and economic status, HPV and HPV vaccine awareness, the source of information on HPV and decision about vaccination. The number of surveyed parents was 357. Correlation statistics and chi-square test have been used with SPSS 19 (IBM corp.). Results: 34.7±2.52% though that HPV vaccine can protect from other STI. There was significant dependability from the country region (p=0.001) and type of urban area (p=0.017). 136 respondents out of 357 agreed to vaccinate their daughters (38.1%±2.6%). The decision to vaccinate depends from age (p=0.006), sex (p= ≤0.001) and family history of cancer (р=0.001). As the main source of information about HPV vaccine parents highlighted gynaecologists (54.0±3.02%), and paediatricians (22.8±2.54%). Most belief that vaccine protects from cancer 65.4±2.46%, whereas 16.8±1.98% trust their medical caregivers. The answers of parents depends from country region (р≤0.001), urban area (р≤0.001), sex (р=0.004), education (р=0.001), religion (р≤0.001) and family history (р≤0.001). Conclusions: The acceptance rate of HPV vaccine in trial is very low, most have doubts regarding the importance of vaccinations. There is a significant room for improvement, HPV and HPV vaccination awareness programs are needed to increase the acceptance rate of the vaccine in Kazakhstan.
Apatinib as a salvage treatment in gynecologic cancer patients failed from two or more lines of prior chemotherapy.
Authors: Xie Congying , Su Meng , Jin Xiance
Published: September 2018

e17009

Background: The aim of this study was to evaluate the efficacy and safety of apatinib, an oral VEGFR2 inhibitor, in the treatment of advanced cervical and ovarian cancer patients who failed from two or more lines of chemotherapy. Methods: The advanced cervical and ovarian cancer patients, who experienced two or more lines of chemotherapy and treated with apatinib from April 2015 to January 2017, were retrospectively reviewed. All eligible patients received continuous apatinib treatment until disease progression, death, or intolerable toxicity. Survival and toxicities outcome were evaluated by Kaplan-Meier method and according to NCI-CTC4.0. Results: Twenty-six patients were eligible (cervical cancer:12 and ovarian cancer:14). After dose adjustment, 14 patients (53.8%) received 500 mg daily of apatinib, 8 patients received 250mg, 3 received 425mg and 1 received 675mg daily. The median progression-free survival (PFS) of cervical cancer and ovarian cancer were 8 months (95%CI:3.83-12.17) and 4 months (95%CI:1.57-6.44), respectively. Objective response rates in cervical cancer and ovarian cancer were 50% and 50%, respectively. Disease control rates were 100% for cervical cancer and 71.4% for ovarian cancer. Complete response was not observed in either cervical cancer or ovarian cancer. A 52-year old patient with recurrent ovarian cancer, experienced two lines of chemotherapy failure, was orally administered with apatinib at a dose of 250mg daily from November 2015, got partial response (PR) after one month, PFS have not yet reach. A 43-year old female patient with advanced cervical cancer, experienced three lines of chemotherapy failure, was orally administered with apatinib at a dose of 250mg daily from September 2015, got PR with a PFS of 14 months. The toxicities associated with apatinib treatment was generally acceptable with 8 patients developed grade 3/4 toxicity. The most common adverse events in this study were hypertension(n = 17), hand-foot syndrome(n = 24), and mouth mucositis(n = 20). Conclusions: Apatinib monotherapy showed promising efficiency with tolerable toxicity for advanced/recurrent cervical and ovarian cancer patients who failed from two or more lines of chemotherapy.
Impact of cervical cancer care volume on clinical outcomes of laparoscopic radical hysterectomy: A systematic review and meta-analysis.
Authors: Lee Banghyun , KIM Kidong
Published: September 2018

e17013

Background: This study investigated the impact of hospital and physicain cervical cancer case volume on clinical outcomes of laparoscopic radical hysterectomy (LRH) to clarify the hypothesis that clinical outcome of cervical cancer may depend on experience of hospital and physician performing radical hysterectomy (RH). Methods: In January 2017 the PubMed search identified 556 articles. A combination of the following key words was used in the search: (cervical cancer and laparoscopy and RH) and (cervical cancer and LRH). When filtered for studies presenting operative outcomes and/or perioperative complications of LRH 59 studies including 4,367 patients met the selection criteria: high volume hospitals (HVH) (≥15 cases/year; 13 studies, 2227 patients) and low volume hospitals (LVH) (<15 cases/year; 46 studies, 2140 patients); high volume physicians (HVP) (≥10 cases/year; 7 studies, 1167 patients) and low volume physicians (LVP) (<10 cases/year; 35 studies, 1258 patients). Linear regression analysis which is weighted by the number of patients per year in each study was performed to evaluate differences between the groups using Stata/SE 14. Results: Analyses according to hospital volume showed following outcomes in HVH compared with LVH: tendency of lower operative time and blood loss; the higher number of lymph nodes (LN) retrieved; older age; and lower frequency of stage IA. Moreover, hospital stay, intra- and post-operative complications, adjuvant therapy, 5-year overall survival, disease free survival and recurrence rate, stage IB1, IB2, and IIA, LN metastasis, and lymphovascular space, parametrial and surgical margin invasion were not different between the groups. Analyses according to physician volume showed following outcomes in HVP compared with LVP: the higher number of LN retrieved; longer hospital stay; higher 5-year recurrence rate; and lower frequency of stage IA and surgical margin invasion. Moreover, other factors were not different between the groups. Conclusions: Higher hospital and physician volumes are associated with better operative outcomes. However, those might not be favorable prognostic factors for cervical cancer.
Changes in ovarian hormonal status in cervical cancer patients under the influence of combined HPV/chlamydia trachomatis infection.
Authors: Bandovkina Valeria , Frantsiyants Elena Mikhaylovna , Guskova Nailya , Moiseenko Tatiana , Vovkochina Marina , Cheryarina Natalia D. , Pogorelova Yulia A. , Agarkova Elena I. , Vereskunova Marina I. , Guskova Ekaterina , Avanesova Kristina , Tselishcheva Irina V. , Abakumova Svetlana V. , Golomeeva Nadezhda , Zakharchenko Viktoria , Belgova Svetlana V. , Nozdricheva Anastasia , Gornostaeva Ekaterina
Published: September 2018

e17019

Background: The purpose of the study was to analyze hormonal disorders in tissues of histologically unchanged ovaries of patients with cervical cancer infected with HPV/Chlamydia trachomatis. Methods: We studied levels of estrone (E1), estradiol (E2), free estriol (E3), free (fT) and total (T) testosterone, progesterone (P4), steroid-binding globulin (SBG) and prolactin (PRL) by the ELISA in intact ovaries of 25 patients aged 53.4±3.2 years with cervical cancer T1b-2aN0M0. HPV presence was determined by Е7 protein expression, Chlamydia trachomatis (Ch. tr.) – by IgG and IgА to Ch. tr. and antigen/DNA by ELISA and Real-time PCR. Tissues of intact ovaries obtained during hysterectomy from 22 non-infected women of similar age with endometrial cancer T1N0M0 were used as the control. Results: The data demonstrated a sharp decrease in E2 level by 9.3 times and increase in E1 by 2.3 times in intact ovaries of cervical cancer patients infected with HPV and Ch. tr., compared with the values in controls. Changes were noted in the balance between some estrogen fractions: E1 percentage increased by 5 times, E3 – by 2.4 times and E2 percentage decreased by 4 times. Androgenic status in intact ovaries in cervical cancer was characterized with increased levels of T (by 5.1 times) and fT (by 1.6 times). We noted an increase in SBG concentration by more than 3 times in response to the release of androgens registered in ovarian tissue, as well as significant (by 4.4 times) increase in PRL and decrease in P4 by 1.5 times compared with non-infected tissues. Estrogens to P4 ratio in co-infected patients reduced by 1.6 times, while the PRL to P4 ratio increased by 6.4 times, mainly due to disorders in hormone-producing ovarian function. Conclusions: The development of malignant process in the cervix in a combined HPV and Chlamydia trachomatis infection is accompanied by disorders of the endocrine status in tissues of intact ovaries and shows the undeniable role of consequences of HPV/Chlamydia trachomatis coinfection in this process.
Influence of chlamydia infection on DNA damage in patients with cervical cancer.
Authors: Guskova Nailya , Goroshinskaya Irina A. , Kit Oleg Ivanovich , Surikova Ekaterina Igorevna , Tarnopolskaya Olga Vladimirovna , Guskova Ekaterina , Golomeeva Nadezhda , Abakumova Svetlana V. , Tselishcheva Irina V. , Avanesova Kristina , Nozdricheva Anastasia , Zakharchenko Viktoria , Belgova Svetlana V.
Published: September 2018

e17020

Background: The role of Chlamydia trachomatis (Ch. tr.) in development of cervical neoplasia is widely discussed. However, molecular mechanisms of Ch. tr. contribution to carcinogenesis are poorly studied. The purpose of the study was to analyze degrees of DNA damage in blood leucocytes in patients with cervical cancer with Ch. tr. infection and in non-infected patients and healthy women. Methods: DNA damage was assessed by the comet assay, the alkaline single-cell gel electrophoresis (20 min, 300 mA, 20 V, 2 V/cm, 4°C) allowing detection of DNA base modifications leading to alkali-labile sites. The preparations were stained with ethidium bromide solution and microscoped (Axio Imager M2, Zeiss) at the excitation wavelength 520 nm and emission wavelength 640 nm. 200 cells were analyzed in each preparation. Percentage of DNAs in the comet tail (T%DNA) was used as an indicator of DNA damage. DNA damage was assessed in 14 patients with cervical cancer and in 13 healthy women. The data were analyzed using Exsel and Statistika 6.0 programs and Mann-Whitney U test and Student's t-test. Results: Mean T%DNA in 8 cervical cancer patients non-infected with Ch. tr. was 4.35±0.63, being significantly (р=0.012580) higher (by 53.7%) than in women without oncopathology (2.83±0.20). The value in infected patients was 10.44±0.11 which was significantly higher than in non-infected patients (by 2.4 times, р=0.000056) and in healthy women (by 3.7 times, р=0.000000). Thus, presence of Ch. tr. was associated with more than 2 times increase in DNA damage in cervical cancer patients. The results are consistent with previously reported data of cell culture studies according to which chlamydia causes histone modification and DNA double strand breaks [Chumduri C. et al., 2013]. Conclusions: The results confirm the role of chlamydia infection in DNA damage in blood cells in cervical cancer patients which promotes malignant development in organs of the female reproductive system.
Bevacizumab eligibility in patients with metastatic cervical cancer: A retrospective review.
Authors: Skelton William Paul , Markham Merry Jennifer
Published: September 2018

e17021

Background: Bevacizumab (BEV) is approved for use in combination with chemotherapy for metastatic/recurrent cervical cancer (CC) based on the GOG 240 trial, which showed increased survival and response rates (RR). However, because of its contraindications, use of BEV is not always feasible or safe. The purpose of this study was to identify the percentage of metastatic/recurrent CC patients at our institution who would have been eligible to receive BEV according to eligibility criteria from GOG 240. Methods: A retrospective study was conducted to identify metastatic CC patients treated at UFHealth between 2006-2016. Chart review was performed to determine their kidney, liver, and bone marrow function, ECOG performance status (PS), presence of an active bleeding condition or nonhealing wound, or inadequately treated venous thromboembolism. Data analysis was performed to determine if the patient would have been eligible to receive BEV based on eligibility criteria from GOG 240. Results: We identified 62 patients with metastatic CC treated at UFHealth between 2006-2016: 1 patient was excluded due to insufficient data. 55 patients (90.2%) would have been ineligible to receive BEV based on the GOG 240 exclusion criteria, and 6 patients (9.8%) would have been eligible. The most common reason for exclusion from BEV use was active bleeding (45 of 61 pts: 73.8%); 42 of the 45 with bleeding (93.3%) had vaginal bleeding. 18 of 61 (29.5%) would be excluded due to poor PS, 17 of 61 (27.9%) due to poor renal function, and 13 of 61 (21.3%) due to an inadequately anticoagulated thromboembolism. Conclusions: Despite the improved survival and higher RR associated with BEV use in combination with chemotherapy, only 9.8% of metastatic CC patients treated at UFHealth over a ten year period would have been eligible to receive BEV. Most patients would have been excluded due to active bleeding, most commonly vaginal bleeding. Though clinical trial data supports the use of BEV with chemo, many patients are simply not eligible due to complications from their disease. Identifying novel therapies for metastatic/recurrent CC patients with improved safety profiles that would allow for their use in this challenging population is critical.
Phase II study of adjuvant chemotherapy with paclitaxel and nedaplatin for FIGO stage IB-IIA uterine cervical cancer with lymph node metastasis following radical hysterectomy: A Kansai Clinical Oncology Group study (KCOG-G1101).
Authors: Takekuma Munetaka , Kasamatsu Yuka , Nishio Shin , Omi Hideo , Tabata Tsutomu , Takei Yuji , Nasu Kaei , Takahashi Yoshiyuki , Toyoda Shinji , Ichikawa Yoshikazu , Arakawa Atsushi , Ito Fuminori , Tsubamoto Hiroshi , Mori Taisuke , Ito Kimihiko
Published: September 2018

e17024

Background: A multicenter phase II trial was conducted to assess the efficacy and toxicity of paclitaxel and nedaplatin as the initial postoperative adjuvant chemotherapy for high-risk uterine cervical cancer. Methods: The patients with FIGO stages IB1-IIA2 squamous cell carcinoma of the uterine cervix were enrolled. Histologic confirmation of lymph node metastasis was mandatory. Intravenous paclitaxel 175 mg/m(2) over 3hours and nedaplatin 80 mg/m(2) over 1 hour were administered on day 1 of a every 28 day cycle, of which there were 5 cycles after radical hysterectomy. Results: 62 patients were enrolled into the study protocol from November 2011 to July 2015. The median age of patients was 48.5 years (range; 28-64). Median tumor diameter was 37 mm (0-34). 10 patients (16.1%) had parametrial invasion, 44 (71.0%) had deep stromal invasion, and 53 (85.5%) had lymph-vascular invasion. 30 patients (48.4%) had one metastatic lymph node, 11 (17.7%) had two, 3 (4.8%) had three, 5 (8.1%) had four and 13 (21.0%) had five or more. With a median follow-up of 36.9 months (range: 17.2-61.5), the 2-year progression-free survival rate and pelvic disease progression-free rate were 78.9% (95% CI, 68.5% to 89.3%) and 85.0% (95% CI, 75.8% to 94.3%), respectively. The 2-year overall survival rate was 93.3% (95% CI, 86.8% to 99.8%). Adverse events were almost acceptable. Grade 3-4 adverse events (NCI-CTC ver4.0) that occurred in 5% or more patients were neutropenia (60.7%) and infection (6.6%). The proportion of patients who completed 5 cycles of treatment was 90.3%. Conclusions: Adjuvant chemotherapy with paclitaxel and nedaplatin for patients with high-risk cervical cancer after radical hysterectomy was demonstrated to be an effective and feasible treatment. Phase III trial should compare this with concurrent chemoradiotherapy. Clinical trial information: 000005605.
Components of tissue fibrinolytic system as markers for processes in tumors of female reproductive organs.
Authors: Vereskunova Marina I. , Frantsiyants Elena Mikhaylovna , Kozlova Larisa , Bandovkina Valeria , Cheryarina Natalia D. , Chugunova Natalya , Saforian Natalya S. , Kit Oleg I. , Ezhova Maria
Published: September 2018

e17032

Background: Components of tissue fibrinolytic system are now considered as important agents providing progressive tumor growth. The purpose of the study was to analyze fibrinolytic system components in uterine and breast tumors. Methods: We studied tumor samples in breast cancer (BC, n=24), nodular type of fibrocystic breast disease (FBD, n-15) and uterine myoma (UM, n=14) and in synchronous BC and UM (n=12). Intact breast tissues (IBT, n=16) and intact myometrium (IM, n=14) were used as the control. Activity of plasmin (P), total content and activity of uPA-Ag and uPA-act, tPA-Ag and tPA-act were determined by ELISA; plasminogen (PG) concentration was measured by spectrophotometry (ACTICHROME PLG, USA). Results: uPA-Ag in solitary BC was 6.5 times higher and uPA-act – 4.5 times higher than in IBT. Concentration of tPA-Ag in 75% of BC patients exceeded the value in IBT by 2.1 times, and tPA-act in 87.5% – by 1.5 times. tPA-Ag and tPA-act in FBD tissues were similar to IBT values, while uPA-Ag and uPA-act were increased by 2.2 times each. uPA-Ag in BC in BC+UM exceeded the norm by 10.6 times, uPA-act – by 5.5 times; tPA-Ag in 75% of samples was 3.8 times higher than in IBT, and tPA-act – 2.7 times higher. uPA-Ag and uPA-act levels in UM in BC+UM were similar to IM values, while tPA-Ag and tPA-act exceeded the norm by 1.8 and 1.5 times, respectively. Both uPA and tPA levels and activity in solitary UM did not differ significantly from IM. Conclusions: The results show an active conversion of plasminogen into plasmin in both solitary and synchronous BC and in synchronous UM. Components of tissue fibrinolytic system can be considered as reliable markers for processes in solitary and synchronous tumors of female reproductive organs.
Sonic hedgehog inhibitors: Potential targeted therapy for squamous cell carcinoma of the vulva.
Authors: Yap Jason , Ganesan Raji , Fox Richard , Dawson Christopher , Kehoe Sean
Published: September 2018

e17035

Background: Vulval squamous cell carcinoma (VSCC) is predominantly a disease of the elderly; with three-quarters of cases occurring in those aged over 60 years. Currently, chemotherapy is only used as an adjunct to surgery in advanced disease or for palliation. Unfortunately, the treatment response of VSCC to chemotherapies is variable, and toxicity remains a major problem, rendering it unsuitable for most patients. Dysregulation of the Hedgehog (HH) pathway has been described in many cancers, and HH inhibitors are being employed for the treatment of many cancers displaying aberrant pathway activation. To this end, we set out to evaluate 1) whether the HH pathway is dysregulated in VSCC and 2) the therapeutic utility of using HH inhibitors in the treatment of VSCC. Methods: Immunohistochemical staining of HH pathway components was performed on formalin-fixed paraffin-embedded sections of a well-characterized cohort of 201 patients with primary VSCC. Expression of HH pathway proteins was then correlated with clinico-pathological data, disease recurrence and survival. A panel of VSCC-derived cell lines was examined for HH pathway activity using an HH-GLI luciferase reporter assay. The effects of HH inhibitors on the growth and viability of VSCC cell lines, alone and in combination with cisplatin, was examined by BrdU label incorporation and XTT viability assays. Results: The HH signaling pathway was found to be over-expressed in approximately 80% of VSCC cases. Moreover, patients whose tumours displayed Sonic HH (SHH) ligand overexpression were more likely to develop a local recurrence within 3 years. Two HH inhibitors, Itraconazole and LDE225, not only inhibited the growth of VSCC cell lines in a dose-dependent manner, but also sensitized cells to the genotoxic affects of Cisplatin. Conclusions: We have shown for the first time that HH pathway is overexpressed in VSCC and that SHH overexpression may serve as a useful biomarker to predict local disease recurrence. In addition, results from our laboratory studies have shown that HH inhibitors may be used as a neo-adjuvant therapy to augment the actions of chemotherapeutic agents in this disease.
Lipid peroxidation in tissues of ovarian tumors after neoadjuvant chemotherapy.
Authors: Kravtsova Oksana E. , Nerodo Galina Andreevna , Nikitina Vera P. , Verenikina Ekaterina V. , Nikitin Ivan , Pustovalova Alla V.
Published: September 2018

e17036

Background: The purpose of the study was to analyze neoadjuvant chemotherapy (NACT) effect on parameters of monoaminergic, free radical and hydrolytic systems in tissues of malignant ovarian tumors. Methods: Activity of parameters of monoaminergic, free radical and hydrolytic systems was determined in ovarian tissue of 92 patients with ovarian cancer. Tissues of tumorous and contralateral (non-tumorous) ovaries were studied, and results were compared to the data in 30 patients with uterine fibroids and other benign tumors. Results: Tumorous ovaries showed the decrease in vitamins E and A by 2.6 and 4.1 times, respectively, compared to the norm. The levels in contralateral ovaries were 5 and 2.8 times lower than the norm, respectively. SOD in tumor tissue exceeded the norm by 46%. Content of copper-zinc-SOD amounted to 15.7% of the total activity in healthy ovaries, while in tumorous ones – 8.2%. Diene conjugates in tumors were increased by 42% compared to the healthy ovaries. Contralateral ovaries showed 2.1 times increase in SOD activity compared to the norm; catalase activity was decreased by 35% which was similar to the value in tumor tissue. Diene conjugates in contralateral ovaries were increased by 38% compared to the healthy ovaries and did not differ from the value in tumor. MDA level was decreased by 4.1 times and did not differ from the value in tumor. Tumorous ovaries after NACT showed an increase in vitamins A and E by 1.8 and 3.2 times, respectively, compared to the levels before treatment; copper-zinc-SOD activity increased by 40.3%. Lipid peroxidation changed as well: diene conjugates level increased by 24.7% and MDA decreased by 47.7% compared to the values before treatment. Levels of the main antioxidant enzymes – SOD and catalase – in contralateral ovaries after NACT were similar to the normal ones; diene conjugates were close to the norm, vitamin E decreased by 40%, vitamin A – by 30%, MDA content did not change. Conclusions: Morphologically healthy tissue of the contralateral ovary in the organism affected by malignant tumor demonstrates signs of imbalance in antioxidant factors similar to those in the tumorous ovary. NACT results in normalization of metabolism indices in both tumorous and contralateral ovaries.
Anti-LeY monoclonal antibody (mAb) hu3S193 as consolidation therapy for patients (pts) with relapsing platinum sensitive ovarian cancer (OC) after achieving a second complete response (2CR).
Authors: Smaletz Oren , Ismael Gustavo , Estevez-Diz Maria Del Pilar , Nascimento Ivana Lucia Oliveira , Wiermann Ana Luiza Gomes de Morais , Cunha Geraldo Felicio , Azevedo Sergio J , Alves Venâncio A , Moro Ana M , Yeda Fernanda Perez , dos Santos Mariana Lopes , Majumder Indrani , Hoffman Eric W.
Published: September 2018

e17039

Background: Lewis-Y (LeY) antigen is a blood group related antigen expressed in 75% of OC. hu3S193 is a humanized anti-LeY IgG1 mAb with strong complement and antibody dependent cytotoxicity with clinical benefit shown in a phase II study in pts with platinum-resistant OC and small tumor burden. Improving progression free survival (PFS) in pts who achieve a 2CR is an unmet need. Methods: This phase II study accrued pts with relapsed OC, LeY expression by IHC, and a KPS ≥ 70% who had achieved a 2CR after 5-8 cycles of platinum doublet chemotherapy (chemoRx). Patients received intravenous infusions of hu3S193, 30mg/m2every 2 weeks starting ≤ 8 weeks after the last dose of chemoRx and continuing for 12 doses (24 weeks) or until disease progression or unacceptable toxicity. Primary endpoint was PFS with a sample size calculated to detect a 50% increase in PFS, compared to a historical value of 10.8 months. Secondary objectives were safety and pharmacokinetics (PK). Results: 29 pts were enrolled. Median age: 55 yrs (range 29-67); Median KPS: 90% (range 80-100); LeY expression by IHC (N): strong (20), weak (9); stage at initial diagnosis: I/II (2), III/IV (27); median CA-125 prior to 2CR chemoRx: 104 (range 9-514); chemoRx agents to achieve 2CR: paclitaxel/platin (21), liposomal doxo/carboplatin (8); median cycles of prior chemoRx to achieve a 2CR:6; median doses of hu3S193 delivered: 10 (range 10-12). Evaluable pts: 28 (1 pt did not have 2CR); median PFS: 11.8 months (95% CI: 10.6-13.9) while 3 pts achieved PFS of 25+ months. Grade 4 toxicities observed: none. Most frequent toxicities (any grade/grade 3): Nausea (16/2), Vomiting (15/3), Hypersensitivity (9/0). PK data will be presented. Conclusions: Despite the good tolerance and the longer PFS compared to historical control, this trial did not show a significant improvement with hu3S193 as a consolidative strategy in patients with 2CR in platinum-sensitive OC. Tumor molecular analysis of patients with long PFS may provide insight for future studies. Clinical trial information: NCT01137071.