bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic value and optimal cut off of neutrophil/lymphocyte ratio (NLR) in patients with metastatic renal cell cancer (mRCC).
Authors: Jankilevich Gustavo , Salazar Matias , Nacuzzi Gabriela , Chirino Daniel , Gennari Luciana
Published: September 2018

e16059

Background: Several biomarkers were tested in mRCC but only outcome scores showed prognostic significance. Neutrophil-to-lymphocyte ratio (NLR) has shown prognostic significance for OS in a number of cancer types but value and cutoff in mRCC is unknown. Methods: The aim of this study was to evaluate NLR as prognostic factor and find a cutoff in mRCC pts. The medical records of 103 pts with mRCC were reviewed. Analysis included adjusting for baseline disease and patient characteristics and investigating potential interaction effects between NLR status and significant BL predictors of outcome. Overal Survivall (OS) was estimated by the Kaplan-Meier method.Univariate and multivariate analysis was performed by Cox regression. Results: Total pts reviewed were 103, MSKCC risk groups (37% Good, 47% Intermediate,16% Poor).Median follow up were 50 months and median OS 29 months. Nephrectomy was performed in 81% of cases.Ninety six percent received treatment (tki – mTor inhibitors). The optimal cutoff was 4, pts with NLR ≤4 vs ≥4 have higher OS 32m vs 10m HR 3,38 (IC95%: 2,60- 4,50 p:0,0001) univariate and HR: 4,32 (IC 95%: 3,35-5,4 p:0,003) in the multivariate analysis. Conclusions: Our series show MSKCC score and RLN were prognostic factors in univariable and multivariable analisys. NRL ≥ 4 identify a group of patients with poor overall survival. The NLR provides independent prognostic information for patients with mRCC and could be useful in academic and community setting. [Table: see text]
MicroRNAs (miRNAs) as predictors of extreme response to tyrosine kinase inhibitors in renal cell cancer (RCC).
Authors: Garrigos Carmen , Molina-Pinelo Sonia , Espinosa Marta , Lerma Antonio , Ávila Rainiero , Medina Rafael , Salinas Ana , Melendez Ricardo , Garcia-Donas Jesus , Rodriguez-Antona Cristina , Duran Ignacio
Published: September 2018

e16076

Background: A number of different drugs are approved for the 1stline treatment of mRCC and provide a median PFS of ≈ 11 months. Yet, a small subset of pts will present an unusually either short or prolong response [extreme responders]. MiRNAs are small fragments of RNA that modulate gene expression controlling cell development and differentiation. Promising results about their value as predictors of drug response have been published in lung and colorectal cancer [Molina-Pinelo]. This study aims to define miRNA profiles in RCC and determine whether they can predict “extreme responses”. Methods: The expression of 754 miRNAs was analyzed with TaqMan Low Density Array Human MicroRNA Panel (TLDA) (ThermoFisher). QPCR was carried out in the System of Gene Expression and Genotyping Arrays module ViiA7. We defined long-term response pts (LR) (PFS˃11 months, n = 7) and primary refractory pts (PR) (progression as best response, n = 8). MiRNAs differentially expressed were independently analyzed by individual qPCR assays in the study cohort and in an external validation cohort of pts (n = 35). Statistical analysis was performed with SPSSv20. Results: Four miRNAs were significantly associated with patient response and differentially expressed in PR vs LR (up-regulated in PR: miR-425-5p, down-regulated in PR: miR-139-3p, let-7d and let-7e). Let-7d and let-7e were validated internally (p < 0.05) and all of them showed the same tendency but without statistically significance in the external validation cohort. Fourteen miRNAs had differential expression in tumor vs healthy tissue and seven were validated in the study cohort (tumor up-regulated: miR-146b, miR-21, miR-155, miR-122; tumor down-regulated: miR-135a, miR-200c and miR-187). When externally validated four (miR-135a, miR-200c, miR-187 and miR-21) (p < 0.05) were confirmed. Conclusions: MiRNAs could represent a valid predictive biomarker in the development of RCC and its treatment. These results have been validated in an independent cohort. MiRNAs regulation in PR vs LR patients need to continue being validated in a more extensive cohort of pts.
Temsirolimus-induced interstitial lung disease as an on-target effect in patients with metastatic renal cell carcinoma.
Authors: Eto Masatoshi , Motoshima Takanobu , Sugiyama Yutaka , Fujimoto Kiyohide , Ohyama Chikara , Mita Koji , Masumori Naoya , Kamoto Toshiyuki , Matsumoto Koichiro
Published: September 2018

e16086

Background: An inhibitor for mammalian target of rapamycin (mTORi), temsirolimus, has been used for metastatic renal cell carcinoma (mRCC) pts with poor risk. mTOR is known to regulate proliferation of lymphocytes, which has been rationale of applying mTORi for preventing graft rejection in transplantation. However, nobody knows the immune status of mRCC pts treated with temsirolimus. In addition, accumulation of clinical practices of temsirolimus has revealed a variety of AEs including interstitial lung disease (ILD). The underlying mechanisms of ILD by mTORi remain uncertain. Moreover, the clinical impact of ILD on the clinical response to mTORi remains unknown. So, we have conducted a prospective clinical trial investigating immune parameters in mRCC pts treated with temsirolimus. This project was denominated in Japanese m-TOR Immune Modulation trial (J-TORIM) (UMIN000009662). Methods: J-TORIM was a prospective observational study recruited pts at 25 hospitals in Japan with a targeted sample size of 30. The primary objective was to evaluate whether administration of temsilorimus has consistent effects on immune parameters collected from the peripheral blood before and 3-to-5 weeks after the beginning of temsirolimus therapy. The secondary objectives were to evaluate the associations of immune parameters or ILD with ORR, PFS, and OS, and the associations of immune parameters with ILD. Immune parameters include PBMC culture with con A or lipopolysaccharide (LPS), PBMC flow cytometry with anti- CD4, CD8, CD3, PD-1, PD-L1, CD25, Foxp3 mAbs. Results: Twenty-eight patients were enrolled in the study. ORR of temsirolimus was 10.7% (1 CR and 2 PR). The most commonly reported treatment-related AEs were ILD (28.5%) and stomatitis (28.5%). There were no significant changes after temsirolimus therapy for any immunological parameters. Interestingly, a significant correlation between ILD development and ORR was observed (p < 0.01). In addition, a significant increase of regulatory T cells was also observed after the recovery of ILD (p < 0.05). Conclusions: This is the first prospective study demonstrating that ILD development can be predictive for response to temsirolimus in mRCC pts. Clinical trial information: 000009662.
Association of prostate specific-antigen doubling time (PSADT) with metastasis-free survival (MFS) and overall survival (OS) in non-metastatic castration-resistant prostate cancer (nmCRPC).
Authors: Lin Jennifer H , Macomson Brian , Tunceli Ozgur , Pericone Chris , Behl Ajay S. , Deshmukh Siddhant , Shore Neal D.
Published: September 2018

e16525

Background: For optimal nmCRPC management, it is important to assess the rate of disease progression and its predictors. MFS and OS endpoints are likely to be important determinants in evaluating the relative impact of treatments in nmCRPC patients. This study assessed the association of PSADT with MFS and OS in real world practice. Methods: A retrospective cohort study of men ≥18 years old was conducted using the Optum electronic health record (EHR) database (2007-2016). nmCRPC was defined as a prostate cancer diagnosis, no ICD-9/10 code or therapy indicating metastatic disease, a testosterone (T) level < 50 ng/dL (castrate level) and 2 rising PSAs (relative rise ≥25%; absolute rise ≥2 ng/mL above nadir) ≥1 week apart. Baseline PSADT, calculated from the PSA nadir until 2nd rise of PSA, was grouped into < 6, 6-18 or > 18 months. A Cox proportional hazard model was used to assess the association of baseline PSADT with MFS and OS, comparing PSADT < 6 and 6-18 months against PSADT > 18 months. Multivariable analysis was adjusted for age, race, comorbidity index score, T levels, therapy and bone scans before nmCRPC. A linear trend was tested by taking PSADT as a continuous variable (median value in each group) in the model. Results: A total of 901 patients were identified. Mean nmCRPC onset age was 76 years and mean follow-up time was 2 years. The median PSADT was 7 months, ranging from 0.5 to 267 months. During follow-up, 477 patients developed metastasis and 384 died. MFS was 89%, 60%, and 47% at year 1, 3 and 5, respectively. Men with PSADT < 6 and 6-18 months had ≥50% increased risk of shorter MFS than men with PSADT > 18 months; hazard ratios (HR) were 1.87 (95% confidence interval [CI]: 1.39-2.54) and 1.50 (95%CI: 1.11-2.04), respectively. OS was 87%, 64% and 57% at year 1, 3 and 5, respectively. Shorter PSADT was associated with shorter OS (p for trend < 0.001). Men with a PSADT < 6 months had a 2-fold increased risk for decreased OS (HR = 2.04, 95% CI: 1.44-2.90). Conclusions: Patients with nmCPRC with shorter PSADT had significantly shorter MFS and OS compared to those with longer PSADT. Baseline PSADT may serve as a predictor for nmCRPC progression.
Differences in the expression of PTP-1B phosphatase in prostate cancer (PC) patients with and without adverse pathologic features (APF).
Authors: Bourlon Maria Teresa , Pineda Mauricio Mora , Urbina Ramírez Shaddai , Leon Rodriguez Eucario , Atisha-Fregoso Yemil , De Anda Gonzalez Jazmin
Published: September 2018

e16543

Background: Localized PC is a heterogeneous disease. Currently, clinical markers are insufficient to predict the presence of APF before prostatectomy. PTP-1B phosphatase is implicated in insulin/leptin receptor activity and in cancer cells migration and invasion. PTP-1B could be a predictor marker of APF in PC. The aim was to compare the expression of PTP-1B in PC patients with vs without APF. The secondary aim was to evaluate PTP-1B as an independent predictive factor. Methods: Radical prostatectomy samples of patients with localized PC performed in a single center were identified (1990-2015). Pathologic features were re-evaluated by an expert pathologist. APF was defined as: seminal vesicle invasion or extra-capsular invasion or positive surgical margins. Tissue microarrays (TMA) immunohistochemistry for PTP-1B was done and evaluated in a 0-9 score. Statistics: Mann Whitney U-test was used to compare variables, and Spearman´s rho for correlation. To evaluate the association of PTP-1B score with the outcome of APF, a logistic regression analysis with two models was performed. The first, included biologically associated variables (metformin use, T2DM), and the second, stablished risk factors (PSA, Gleason score (GS)). Results: We identified 352 PC cases. In 190 a TMA was done, and 73 were optimal for PTP-1B expression evaluation and were included for analysis. Patient´s mean age was 62 ± 7 yo. Twenty nine (40%) without APF, and 44 (60%) with APF. Median PTP-1B score was 5 [3-8] in patients without APF vs 8 [5-9] in patients with APF (p = 0.026). PTP-1B score correlated with GS (r = 0.24, p = 0.042) and PSA (r = 0.24, p = 0.046). PTP-1B was a risk factor for the presence of APF even adjusted for the presence of metformin use and T2DM (OR 1.21; 95% CI 1.01-1.45; p = 0.037). However, PTP-1B score was not an independent risk factor for APF when PSA and GS were included (OR 1.68; 95% CI 0.97-1.41; p = 0.11). The addition of PTP-1B score to the prediction model for APF, which includes GS and PSA, only provided a slight increase in accuracy (AUC 0.73; 95% CI 0.61-0.84 vs AUC 0.71; 95% CI 0.59-0.82). Conclusions: Patients with PC and APF have an increased expression of PTP-1B.
A combination of computer extracted measurements of prostate capsule shape and tumor texture on MRI to predict biochemical recurrence post treatment.
Authors: Shiradkar Rakesh , Ghose Soumya , Purysko Andrei , Madabhushi Anant
Published: September 2018

e16554

Background: Prostate cancer (PCa) biochemical recurrence (BCR) occurs in a significant proportion of men after treatment and is associated with increased mortality. Identifying PCa patients at risk of BCR following definitive therapy may help identify patients who might benefit from adjuvant therapy. Multi-parametric MRI (mpMRI) is being increasingly used in pre-treatment staging and risk stratification of PCa. In this work, we sought to explore whether a combination of computer extracted features relating to prostate capsule shape and tumor texture from pre-treatment mpMRI is predictive of BCR post treatment. Methods: This single center and retrospective study included 80 men with PCa who underwent pre-treatment 3T mpMRI and were followed for > 3 years post treatment. These men were grouped into a training set D1 (N = 50, 25 each of BCR+ and BCR-) and an independent validation set D2 (N = 30, 10 BCR+ and 20 BCR-). The prostate capsule and cancer region of interest (ROI) were annotated on mpMRI by a single experienced radiologist. Shape features (curvature and orientation) were extracted from a surface of interest where statistically significant differences were observed between BCR+ and BCR- patients in the training set. Radiomic features for capturing tumor textural patterns (including 1st and 2nd order statistics, Gabor and Haralick) were extracted from within the radiologist annotated cancer ROIs. Features from D1 were used to train random forest classifiers, one each with shape (Cs) and radiomic (CR) features. A fused Bayesian classifier (CR+S) was created by integrating decisions from both Cs and CR. Results: The classifiers Cs, CR and CR+S were evaluated on independent validation set D2, resulting in area under the curve (AUCs) of 0.71, 0.81 and 0.84 respectively. Cs added value in patients who had extra prostatic spread of PCa, but suffered from mpMRI intensity artefacts that affected performance of CR. Conclusions: Integrating prostate capsule shape and tumor radiomic features from pre-treatment mpMRI enabled prediction of PCa BCR after treatment. Multi-site validation is needed to establish the robustness of the approach.
Inherited germline mutations in men with prostate cancer.
Authors: Reid Robert , DiGiovanni Marcie , Bernhisel Ryan , Brown Krystal , Saam Jennifer , Lancaster Johnathan
Published: September 2018

e16564

Background: Recent studies have demonstrated a high prevalence of pathogenic variants (PVs) in genes that confer hereditary cancer risk among men with metastatic prostate cancer (PC); however, PC does not currently receive attention as an indication for genetic testing. We assessed the clinical features of men with PC who received clinical testing as well as the distribution of PVs identified. Methods: A commercial laboratory database was queried to identify men with PC who underwent testing with a multi-gene hereditary cancer panel from September 2013–September 2016. Clinical information was obtained from provider-completed test request forms. Individuals with PC only were evaluated separately from those who had ≥1 additional malignancy. Personal/family history was evaluated relative to the 2013 NCCN guidelines for hereditary breast and ovarian cancer (HBOC) testing. Results: Overall, 700 men with a personal history of PC were identified: 384 (54.9%) with only PC and 316 (45.1%) with PC and ≥1 additional malignancy. The most common additional malignancies were colorectal (115) and breast cancer (105). The median age of diagnosis in men with only PC was 57.5, which is younger than tested men who had an additional malignancy (62) and the SEER data (2009-2013) for all men with PC (66). HBOC testing criteria were met by 75.9% of men, including 44 (6.3%) who met based only on a personal/family history of PC and 202 (28.9%) who met in part due to a personal/family history of PC. PVs were identified in 14.0% of all men: 11.5% of men with PC only and 17.1% of men with PC and a second malignancy (see Table). Conclusions: PC patients selected for genetic testing here were younger than men diagnosed with PC from the general population (SEER), and almost half had a diagnosis of an additional malignancy. They also have a high positive mutation rate across a broad spectrum of genes. [Table: see text]
Clinical variables associated with overall survival in metastatic castration resistant prostate cancer (mCRPC) patients treated with sipuleucel-T immunotherapy.
Authors: Wei Xiao , Perry Jaselle , Chang Emily , Zhang Li , Hiatt Robert A. , Fong Lawrence
Published: September 2018

e16565

Background: Sipuleucel-T (Sip-T) is a cellular-based cancer immunotherapy for men with asymptomatic or minimally symptomatic mCRPC. Its approval was based on overall survival (OS) benefit in randomized placebo-controlled phase 3 trials. However, treatment was associated with PSA decline in only a small minority of pts. Understanding clinical factors predictive of OS may help to guide treatment decisions, including pt selection and timing of Sip-T relative to other therapies. Methods: This is a retrospective chart review of mCRPC pts treated with Sip-T at UCSF between April 2010 and April 2016. All pts completed 3 Sip-T infusions. Patients with localized prostate cancer treated with neoadjuvant Sip-T (NCT00715104) and pts with mCRPC treated with an ongoing phase 2 Sip-T/Ipilimumab trial (NCT01804465) were excluded. Kaplan-Meier method was used to estimate OS. The predictive value of candidate variables – including age, ECOG performance status (PS), Gleason score, metastatic volume, baseline PSA, baseline PSADT, prior abiraterone or enzalutamide, and prior chemotherapy – was assessed using univariate and multivariate Cox proportional hazard model. Results: Of 43 patients evaluated to date, 74.4% had ECOG PS 0, 88.4% had bone +/- nodal metastasis, 81.4% had low metastatic volume, 9.3% had prior abiraterone, 2.3% had prior enzalutamide, and 9.3% had prior chemotherapy. The median age was 69 years (range 53-85), median baseline PSA was 8.3 ng/mL (range 0.05-227.9) and median PSA doubling time (PSADT) was 3.9 mo (range 1.4-15.1). At a median follow-up of 21.4 mo, the median OS was 34.1 mo (95% CI 25.7-41.4). Univariate analysis showed that ECOG PS (HR 6.66, p < 0.001) and PSA (log-transformed) (HR 3.36, p = 0.002) were significantly associated with OS. There was a trend towards worse OS with faster baseline PSADT (log-transformed) (HR 0.16, p = 0.11) and prior chemotherapy (HR = 4.13, p = 0.11). By multivariate analysis, ECOG PS, baseline PSA and baseline PSADT were statistically significant (p < 0.05). Conclusions: In this ongoing retrospective cohort, ECOG PS, baseline PSA and baseline PSADT were associated with OS in mCRPC patients treated with Sip-T.
Retrospective correlational study between dyslipidemia and prostate cancer characteristics.
Authors: Sackey Korkor , Schwartzman Larisa , Shapero Stephen P. , Lewis Steven A. , Bruno Debora S.
Published: September 2018

e16569

Background: Numerous studies have suggested metabolic syndrome’s association with advanced prostate cancer and patient outcomes but the data has not been conclusive. The goal of our research project was to analyze the relationship between lipid profiles and prostate cancer characteristics that predict outcomes in our patient population. Methods: A retrospective study was conducted on patients with a new diagnosis of prostate cancer seen at MetroHealth Medical Center (MHMC) between the years of 2009-2014. 427 electronic medical records of patients with stages I-III prostate cancer were reviewed. Dependent variables were pathological TNM stage, Gleason score (GS) and Prostate-Specific Antigen (PSA) level at time of diagnosis. Independent variables included components of the lipid profile (highest triglycerides, highest and lowest HDLs), body mass index, hypertension, diabetes and use of lipid lowering agents. Patients who did not have lipid panels available were excluded from final evaluation. Results: A total of 363 patients met inclusion criteria. The median age was 63, with African Americans accounting for 56% of all cases. The average BMI was 28.6 consistent with overweight and at time of prostate cancer diagnosis, 23% of patients had diabetes and 69% had hypertension. 68% of patients had stage I disease at time of diagnosis and no correlations were noted between TNM stage, GS or PSA at diagnosis with any of the components of the lipid profile, hypertension, hemoglobin A1c or use of lipid lowering medication. African Americans were noted to have higher PSA at diagnosis than other races (p < 0.0001). Conclusions: Of patients with stage I-III prostate cancer diagnosed between 2009-2014 at MHMC, 85% were screened for dyslipidemia. Preliminary analysis of our data did not establish a correlation between dyslipidemia and prostate cancer characteristics. However, by limiting our study to only patients with lipid profiles, a subset of patients and their characteristics were not analyzed. This could explain the results noted in our study. Further studies are needed in our population to investigate which factors affect prostate cancer characteristics so better screening and interventions can be developed.
The association of polymorphism in gonadotropin releasing hormone with serum testosterone level during androgen-deprivation therapy and prognosis in metastatic prostate cancer.
Authors: Shiota Masaki , Fujimoto Naohiro , Takeuchi Ario , Kashiwagi Eiji , Dejima Takashi , Inokuchi Junichi , Tatsugami Katsunori , Yokomizo Akira , Uchiumi Takeshi , Eto Masatoshi
Published: September 2018

e16570

Background: Serum testosterone suppression during androgen-deprivation therapy (ADT) have been reported to affect ADT efficacy. However, the factor affecting hormonal variations during ADT was less explored. Therefore, in this study, we investigated the missense polymorphisms in gonadotropin releasing hormone (GNRH) and hormonal variations during ADT as well as the prognosis among men treated with primary ADT for metastatic prostate cancer. Methods: This study included 80 Japanese patients with metastatic prostate cancer, whose serum testosterone levels during ADT were available. The association of the GNRH1 gene polymorphism (rs6185, S20W) and the GNRH2 gene polymorphism (rs6051545, A16V) with clinicopathological parameters including serum testosterone levels during ADT as well as the prognosis including progression-free survival and overall survival was examined. Results: The CT allele and the CT/TT alleles in the GNRH2 gene (rs6051545) were associated with higher serum testosterone levels during ADT compared with the CC allele. Consequently, the CT alleles was associated with higher progression risk after adjustment with age and serum testosterone levels during ADT [hazard ratio (95% confidence interval), 1.73 (1.00-3.00), P = 0.049]. Conclusions: Taken together, these findings suggested that genetic variation in rs6051545 ( GNRH2) may result in the inadequate suppression of on serum testosterone during ADT, which may lead to detrimental effect of ADT on prognosis among men with metastatic prostate cancer.
Active surveillance and watchful waiting for localized prostate cancer in elderly patients >70 years in a community-based setting: Results from the HAROW study.
Authors: Herden Jan , Schnell Dietrich , Heidenreich Axel , Weissbach Lothar
Published: September 2018

e16577

Background: Since more than half of patients with prostate cancer (PCa) are older than 70 years, this age group remains underrepresented in clinical trials. Possible non-invasive treatment options for these patients include Active Surveillance (AS) and Watchful Waiting (WW). In this prospective, non-interventional, health services research study, the use of different treatment options for localized PCa are observed under everyday conditions. The subgroups of patients ≥ 70 years, receiving AS- or WW are presented in terms of inclusion criteria, follow-up examinations and changes in treatment strategy. Methods: The study was conducted from July 2008 to July 2013 at 259 study centers in Germany, mainly office based urologists. The mean follow-up was 27.6 months. Clinical data (tumor category, digital rectal examination, PSA level, Gleason score, Charlson Comorbidity Index = CCI) and information about therapy and disease progression were collected at the time of study inclusion and subsequently at six-month intervals. According to the non-interventional study design, only recommendations were made for enrollment, course and discontinuation of AS and WW. The final therapeutic decision rested with treating physicians. Results: Overall, 2957 patients were enrolled, of whom 1165 were ≥ 70 years. 210 patients received AS and 87 patients received WW. AS patients were younger (73.9 vs. 76.8 years, p ≤ 0.001). The rate of low, intermediate and high risk tumors was 81.6%, 14.6% and 3.9% in the AS- and 39.1%, 43.5% and 17.4% in the WW-group (p ≤ 0.001). No differences were seen in the average number of PSA testing during the course of follow-up (AS = 3.97 vs WW = 3.79, p = 0.95). 37.6% of the AS patients and 12.4% of the WW patients received at least one follow-up biopsy. Conclusions: The results of HAROW indicate a clear distinction between AS and WW in terms of inclusion criteria. Interestingly, no clear distinction was seen in terms of follow-up examinations, since both groups were monitored frequently with PSA tests and even re-biopsies were performed in WW patients, neither of which is usually provided in WW programs.
Which is better? Carboplatin versus cisplatin for locally advanced cervical cancer: Peruvian experience.
Authors: Valdivieso Natalia , Paitan Amaro Victor , Rabanal Carretero Connie , Poma Nieto Nathaly , Flores Claudio J. , Vasquez Chavez Jule Franve , Alvarez Arredondo Manuel , Heredia Zelaya Adelaida , Mas Luis
Published: September 2018

e17004

Background: Cervical cancer occurs mostly in developing countries, being locally advanced cancer the majority. The standard treatment is chemo-radiation with platinum salts. Carboplatin is commonly used because of its synergy with radiation reported in other malignancies and its safe toxicity profile, besides it is not clear use of it. We want to evaluate the equivalence of cisplatin versus carboplatin concurrent to radiotherapy in terms of response rates and toxicity profile. Methods: Retrospective observational analysis in women older than 18 years old, with diagnosis of locally advanced cervical cancer (stages Ib2 – IVA) at the “Instituto Nacional de Enfermedades Neoplasicas”, Lima – Peru, between 2014 and 2015. We determined two arms; cisplatin 40 mg/m2 per week for 5 weeks and Carboplatin 2AUC per week for 5 weeks. Both groups were given concurrent to radiotherapy. Results: 247 patients were evaluated, 119 received carboplatin and 128 cisplatin. Both groups have similar characteristics; median age was 50 years, the most frequent hystologic type was squamous cell carcinoma in 90.7%, and TNM stage IIB 59.5%, IIIB 27.5% and IV-A 2.8%. The complete response (CR) rate in cisplatin group was of 88.3% and carboplatin group 73.9% (p = 0.004). The toxicity profile was similar in both groups, except to renal toxicity (Cisplatin: 0% vs. Carboplatin: 5%, p = 0.010) and diarrhea (Cisplatin:26.6% vs. Carboplatin: 16.0%, p = 0.043). In patients with CR, the recurrence rate does not present a significant difference according to treatment schedule (Cisplatin: 15.9% vs. Carboplatin: 13.6%, p = 0.651). Overall survival (OS) and disease free survival (DFS) are on going. Conclusions: Our study found that cisplatin had better response rates than carboplatin with similar toxicity profile. This intervention to be remains to be clarified with following-up.
Changes in cervical cancer course under the influence of HPV/chlamydia trachomatis co-infection.
Authors: Guskova Nailya , Frantsiyants Elena Mikhaylovna , Bandovkina Valeria , Moiseenko Tatiana , Vovkochina Marina , Cheryarina Natalia D. , Pogorelova Yulia A. , Guskova Ekaterina , Vereskunova Marina I. , Avanesova Kristina , Tselishcheva Irina V. , Golomeeva Nadezhda , Abakumova Svetlana V. , Zakharchenko Viktoria , Belgova Svetlana V. , Nozdricheva Anastasia , Gornostaeva Ekaterina
Published: September 2018

e17018

Background: The purpose of the study was to analyze the effect of HPV/Chlamydia trachomatis co-infection on the hormonal status of tumor and visually unchanged cervical tissues in cervical cancer patients. Methods: We studied levels of estrone (E1), estradiol (E2), free estriol (E3), free (fT) and total (T) testosterone, progesterone (P4) and prolactin (PRL) by the ELISA in tumors and visually unchanged cervical tissues of 49 patients with cervical cancer T1b-2aN0M0 with endophytic (25 patients) and exophytic (24 patients) patterns of tumor growth. 13 patients with endophytic tumors and 12 patients with exophytic ones were infected with HPV and Сhlamydia trachomatis (Ch.tr.). HPV infection was determined by Е7 protein expression, Ch.tr. – by IgG and IgА and antigen/DNA in ELISA and PCR. Intact cervical tissues obtained during hysterectomy from 22 non-infected women with endometrial cancer were used as the control. Results: Tumor tissues of the cervix without infection demonstrated increased levels of all sex steroids: estrogens by 3 times, androgens by 3.1 times and progestins by 1.8 times. Co-infected tissues were characterized by the sex-steroid imbalance. We observed reduced coefficients of estrogens to T and fT by 1.6 and 6 times, respectively, compared to intact tissues (most significant in a tumor with endophytic growth pattern) and an increase in the estrogens to P4 ratio by 1.5 times – only in endophytic growth pattern. Androgenic status in co-infected tumor tissues increased by 1.7 in endophytic and by 3.1 times in exophytic growth pattern. PRL level was increased only in co-infected tumors (by 2.5 times). Unchanged co-infected tissues, unlike non-infected samples, showed E2 increase by 2.6 times in exophytic and by 1.5 times in endophytic growth pattern, T increase by 1.6 times only in endophytic tumors and P4 decrease by 1.5 times and PRL increase by 1.8 times regardless the tumor growth pattern. Conclusions: Hormonal profile of both tumor and unchanged cervical tissues was dependent on HPV/Ch. tr. co-infection and tumor growth patterns. The changes could result from HPV and Ch. tr. interaction triggering malignant processes.
Investigation of the clinicopathological features of vulva cancer: A retrospective survey of the JGOG Net Work study.
Authors: Nishio Shin , Shibata Takeo , Yamaguchi Satoshi , Kanao Hiroyuki , Kojima Atsumi , Takekuma Munetaka , Tozawa Akiko , Tokunaga Hideki , Miyagi Etsuko , Kato Hisamori , Kurihara Kazuko , Yanase Toru , Mikami Mikio , Sugiyama Toru
Published: September 2018

e17029

Background: Vulvar cancer is a rare malignancy in women. During the past 30 years, large surveys of vulva cancer have not been performed in Japan. We therefore conducted a multicenter study to clarify the clinicopathological features of vulva cancer in Japan. Methods: In this multicenter retrospective cohort study, the clinical data of patients with vulva cancer were surveyed. The medical records of patients with vulvar cancer patients treated between 2001 and 2010 were retrospectively reviewed after obtaining approval from the Institutional Review Board of each institution. Survival analysis was performed using Kaplan-Meier curves. The effects of the clinical factors on overall survival were investigated using a Cox regression model. Results: A total of 1082 patients treated in 108 centers were studied. The median age was 72 years (range, 20 to 96). The disease stage was stage I in 415 patients (38.3%), stage II in 249 (23%), stage III in 255 (23.6%), and stage IV in 163 (15.1%) (FIGO 2009). The diagnosis was squamous cell carcinoma in 779 patients (72%), Paget’s disease in 158 (14.6%), adenocarcinoma in 63 (5.8%), and others in 82 (7.6%). Positive lymph nodes were found in 237 patients (21.9%). The median tumor diameter was 35 mm (range, 1 to 180). The 5-year overall survival was 86% in stage I, 74.7% in stage II, 48.2% in stage III, and 39.3% in stage IV (P < 0.001), and that according to histology was 63.9% in squamous cell carcinoma, 57.1% in adenocarcinoma, 79.7% in Paget’s disease, and 85.4% in others. The hazard ratio was 0.51 in patients with a histology of Paget’s disease or others (vs. squamous cell carcinoma or adenocarcinoma; P = 0.001; 95% CI, 0.35-0.75), 2.14 in patients with a the number of positive lymph nodes 2 or more (vs. 0 or 1; P < 0.001; 95% CI, 1.50-3.05), 2.10 in patients with a tumor diameter of ≥35mm (vs. < 35mm; P = 0.001; 95% CI, 1.36-3.25). Conclusions: Treatment outcomes in Japanese patients with vulvar cancer were similar to those reported previously. However, squamous-cell carcinoma, adenocarcinoma, positive lymph nodes, and bulky tumors were associated with poor outcomes. Multidisciplinary treatment might be required in patients with these characteristics. Clinical trial information: UMIN000017080.
Interaction of α2-macroglobulin with kallikrein and plasmin in ascitic fluid in ovarian cancer.
Authors: Moiseenko Tatiana , Frantsiyants Elena Mikhaylovna , Kozlova Larisa , Tkalya Lyudmila Dmitriyevna , Adamyan Meri Viktorovich , Kravtsova Oksana E. , Chalabova Tatiyana Georgievna , Kit Oleg I.
Published: September 2018

e17030

Background: The kallikrein (KLKs) family is considered to be a regulator of many systems of limited proteolysis but can also be involved into pathology. Plasmin (P) regulates functions and density of the extracellular matrix, angiogenesis, maturation of gametes, sanation of cavities, tissues and body fluids, development of inflammation and malignant tumors. α2-Macroglobulin (α2M) is a molecular component of the body's endogenous protection. Ascitic fluid (AF) in various diseases of the ovaries is the biological environment valuable for the study of the affected organism containing protein about 20-50 g/L. KLKs, their proenzymes (pro-KLKs), Р, plasminogen (PG) and α2М in AF are poorly studied. Our purpose was to analyze the proteinase-inhibitory balance in AF of patients with ovarian cystadenocarcinoma (CAC) and tuberculosis of the uterine appendages (TA) to reveal its role in the development of the diseases and targets for the therapy. Methods: KLKs, pro-KLKs, Р, PG and α2М in AF in CAC of one ovary (n=26, T3-4N0M0) were compared with the levels in AF of TA patients before treatment (n=11). All women were menopausal, aged 56.5±2.6 years. KLKs, pro-KLKs, Р, PG and α2М were determined before treatment using the U-2900 UV Solutions double-beam spectrophotometer (USA), the result was calculated per 1 mg of protein (by Lowry). The protein content in AF was comparable to the blood plasma one, so we took the values in the plasma of healthy donors as the norm (N). The data were processed using the Statistica 10 program. Results: The exudate is believed to occur mainly from inflammation-damaged vessels. High protein content in AF in CAC and TA allowed us to consider AF as the exudates. The pro-KLKs/KLKs ratio reflecting the rates of KLKs formation in AF was decreased in TA and CAC by 4.6 and 6.7 times compared to N. The РG/Р ratio in AF in CAC was decreased by 3.8 times; in TA it was similar to N with increased PG and P. The KLKs/α2М ratio in TA and CAC exceeded N by 4.6 and 2.7 times. The Р/α2М ratio in TA and CAC was 6.5 and 4.5 times higher than N. Conclusions: Activity of KLKs and P in AF in CAC and TA was higher than in the blood plasma of healthy donors. Activity of α2М in AF in CAC and TA was not sufficient to control KLKs and P.
Potential role of MAD1 1673G>A and ERCC1 8092C>A polymorphisms in the resistance to chemotherapy in advanced ovarian cancer: A pilot study.
Authors: Hernandez Cruz Irwin Alejandro , Prada Diddier , Díaz-Chávez José , Barquet-Munoz Salim , Cantu De Leon David Francisco , Herrera Luis Alonso
Published: September 2018

e17045

Background: Ovarian cancer (OC) is the most lethal gynecological cancer and 70% of cases are in advanced stages at diagnosis. The standard treatment for those stages is optimal cytoreduction plus chemotherapy based on carboplatin-paclitaxel. Nevertheless, 60%-70% of patients will progress after diagnosis, becoming resistant in some point of the disease. There are no biomarkers to predict response to chemotherapy in OC. Some polymorphisms, including MAD1 1673G > A and ERCC1 8092C > A have shown potential to predict chemoresistance in other tumors. Thus, we explored the role of these polymorphisms in the resistance to chemotherapy in advanced OC. Methods: We genotypified 89 OC patients samples, and also determined the mRNA expression for both genes by RT-PCR. We compared distributions using chi-squared test and determined differences in overall survival and free-relapse survival using Kaplan-Meier curves and log-rank test. Results: Most of cases were IIIC stage (35.48%), papillary histological subtype (32.26%), highly differentiated (67.74%), and 35.48% tumors with recurrence. Distribution for MAD1 genotype was 35.48% for wild-type (WT), 32.26% for heterozygous (HT), and 32.26% for homozygous polymorphic condition (Poly). For ERCC1, we found a distribution of 25.81% for WT, 51.61% for HT, and 22.58% for Poly. When comparing distributions, we found statistically significant differences between sensitive vs. resistant tumors ( p= 0.02), with lack of the WT condition for ERCC1 in sensitive tumors. When analyzing haplotypes in regard to platinum-sensitivity, we also found statistical differences in the distribution of haplotypes ( p = 0.02). No association between genotypes and expression was observed. Remarkably, we found a lower free-relapse survival in the presence of at least one WT allele for the MAD1 polymorphism (p = 0.021, log-rank test). Conclusions: In this pilot study, we have found that ERCC1 8092C > A polymorphism, as well as haplotypes for these two genes, could be associated with chemoresistance. MAD1 1673G > A polymorphism could play also a role in recurrence in advanced OC.
Tumoral genetic variations of the homologous recombination (HR) reparation system in brain metastases in women with epithelial ovarian cancer (EOC).
Authors: Fontanilles Maxime , Castera Laurent , Gouardon Nicolas , Jeanne Corinne , Vaur Dominique , Brachet pierre-Emmanuel , Joly Florence
Published: September 2018

e17048

Background: Brain metastases (BM) EOC are rare and late events. We explored tumoral genetic variations of HR system. We identify genomic alterations with NGS in both primary tumor and BM EOC Methods: Seven patients suffering from histologically proven EOC and BM, which underwent neurosurgery, were included in the study. Seven matched samples (primary tumor and BM) were analyzed by high throughput sequencing after enrichment by capture of the whole exome. After bioinformatics procedures (BWA, HaplotypeCaller, Varscan2, Outlyzer) the analysis was restricted firstly to a in silico panel of 69 genes involved in HR system. Results: Mean age was 56 years (47 to 71). Five had serous and 2 endometrioid carcinomas. All the patients had an initial FIGO stage ≥IIIA, were platine-sensitive. Median time from diagnosis of EOC to BM was 29 months (24 to 76). BM occurred after first line treatment in 5 cases and after at least 2 relapses in the 2 other cases. Median Overall survival (OS) from diagnosis of BM was 17 months (1 to 45). Five primary tumor showed a variation of at least one HR gene: pathogenic variants inactivating in BRCA2 (n = 2), CDK12 (n = 1) and probably pathogenic missenses in BRIP1 (n = 1) and TOPB1 (n = 1). These 5 variations have been also found in the BM tissues. Among the 2 patients without variations in the primary tumor, 2 probably pathogenic missenses were detected in the BM tumor (1 FANCD2 and 1 FANCM). Time to BM relapse and OS were longer among these 2 last patients compared to the remaining 5 patients (median 68 vs 29 months and 90 vs 56 months, respectively). Conclusions: Patients with BM presented HR somatic mutations and are susceptible to have high response to Parp inhibitors.
Inhibition of Wnt signaling as therapeutic option in platinum-resistant ovarian cancer.
Authors: Trillsch Fabian , Preinfalk Valentina , Rahmeh Martina , Vogel Marianne , Czogalla Bastian , Burges Alexander , Jeschke Udo , Mahner Sven
Published: September 2018

e17050

Background: New therapeutic approaches for platinum-resistant ovarian cancer patients are urgently needed. In this context, Wnt signaling appears to be a promising target so that inhibition of this pathway in platinum-resistant cell lines was aim of the present study. Methods: The ovarian cancer cell line A2780 and its platinum-resistant clone A2780cis were treated with different concentrations of Wnt singaling inhibitors SB216761, XAV939, and triptolides. Metabolic activity and cell viability was estimated by MTT cell proliferation assays. Immunohistochemistry for ß-Catenin visualized activity of the Wnt pathway. Results: MTT proliferation tests revealed an impaired proliferation following treatment with all three agents. While triptolides already led to significantly reduced metabolic activity after 48h, this effect was seen for SB216761 and XAV939 not before 72h. Immunohistochemistry for ß-Catenin confirmed inhibition of Wnt signaling. Following XAV939 treatment of A2780cis, ß-Catenin signals shifted from the nucleus towards the cell membrane. Conclusions: Re-sensitizing platinum-resistant ovarian cancer cells for platinum-based chemotherapy by inhibition of Wnt signaling seems to be mechanism visualized by the translocation of ß-Catenin from the nucleus towards the cell membrane. In this context, a dose-dependent response was noted for XAV939. Inhibition of Wnt Signaling appears to be a prospective therapeutic approach for platinum-resistant ovarian cancer patients.
Clinical characterization of long term survivors (LTS) in ovarian cancer (OC): Results of a propensity score matched (PSM) analysis of the international prospective tumor bank for ovarian cancer (TOC Network).
Authors: Braicu Elena Ioana , Woopen Hannah , Glajzer Joanna , Hunsicker Oliver , Woelber Linn , Feldheiser Aarne , van Nieuwenhuysen Els , Mueller Michael D , Concin Nicole , Achimas Patrick , Ruscito Ilary , Mahner Sven , Benedetti Panici Pierluigi , Gasparri Maria Luisa , Papadia Andrea , Birrer Michael J. , Vergote Ignace , Darb-Esfahani Silvia , Sehouli Jalid
Published: September 2018

e17063

Background: OC has the highest mortality rate amongst gynecological malignancies. Nevertheless a small fraction of OC patients will survive longer than 8 years. Aim of our study was to analyze differences in the clinical appearance and management of LTS versus “classical” OC patients. Methods: OC patients living longer than 8 years were identified within the TOC Network between 1998 and 2008, representing the LTS subgroup. PSM analysis was used to select comparable groups of LTS and OC patients who died within first 5 years (control group - CG). PSM was conducted using nearest neighbor caliper matching without replacement to match LTS and CG for age, FIGO and residual tumor mass. All calculations were performed with the R project for Statistical Computing (R-packages used: “MatchIt”). Results: A total of 347 OC patients with different histological subtypes were included in the current analysis, i.e. 173 LTS and 174 in the CG. After PSM 114 patients remained in each group. Patients had similar age, FIGO stage and residual mass (p = 0.99, p = 0.35 and p = 0.88, respectively). Tumor spread in middle and upper abdomen (p = 0.002 and 0.013, respectively) was higher and diaphragm, mesentery and peritoneum (p = 0.009, 0.037 and 0.002, respectively) were significantly more often involved in CG than in the LTS. When only considering the HGSOC patients, 95 patients remained in each group. All patients received surgery and platinum based chemotherapy. The PSM analysis showed significant higher involvement of upper abdomen (p = 0.028), higher peritoneal spread (p = 0.002), higher ascites volume (p = 0.0007) and higher bowel resection rates (p = 0.002) in the CG compared to LTS. Neoadjuvant chemotherapy rate was similar in the LTS and CG (p = 0.5). Conclusions: Based on this PSM analysis, HGSOC-LTS seem to have mainly similar clinical pattern as the control group, however with lower rates of ascites and involvement of upper abdomen. Molecular characterization including analysis of clonal diversity might help elucidate mechanisms of tumor spread and good prognosis.
Performance of preoperative plasma HE4 and CA-125 levels in predicting ovarian cancer mortality in women with epithelial ovarian cancer (EOC).
Authors: Bairati Isabelle , Gregoire Jean , Plante Marie , Douville Pierre
Published: September 2018

e17076

Background: Additional prognostic biomarkers are needed to better manage women with EOC, especially dichotomized indicators for decision making. The objective of this external validation study was to assess the performance of preoperative plasma HE4 and CA-125 levels in predicting mortality by EOC. Methods: Eligible EOC women were newly diagnosed cases treated by upfront debulking surgery in a gynecology oncology center (CHU de Québec, L’Hôtel-Dieu, Canada) in 1988-2006 (cohort 1, n=136) and in 2007-2013 (cohort 2, n=177). All FIGO stages were included. Preoperative plasma HE4 and CA-125 levels were measured by Elecsys® automated immunoassay (Roche Diagnostics). Dates and causes of death were obtained by record linkage with the Quebec mortality files. In cohort 1, time-dependent receiver operating characteristic (ROC) curves were performed and optimal thresholds for HE4 and CA-125 were generated using the Youden index J. In cohort 2, crude and standardized Cox proportional models were done to validate the usefulness of these biomarkers according to their optimal thresholds. Standardized models included standard prognostic factors. The Likelihood Ratio (LR) tests were done to compare the standardized models with and without each biomarker. Results: In cohorts 1 and 2, medians of follow-up were respectively 5.3 and 3.2 years. Five-year disease free survival rates were 53% in cohort 1 and 54% in cohort 2. In cohort 1, the AUC for HE4 and CA-125 were respectively 64.2 (95% CI: 54.7-73.6) and 63.1 (95%CI: 53.6-72.6). The optimal thresholds were 277 pmol/L for HE4 and 282 U/ml for CA-125. In cohort 2, higher levels of plasma HE4 (≥277 pmol/L) were significantly associated with death by EOC (adjusted hazard ratio (aHR): 1.80; 95% CI: 1.03-3.15; p-value for LR test: 0.03), while higher levels of CA-125 (≥282 U/ml) were not associated with death by EOC (aHR: 1.50; 95% CI: 0.88-2.55; p-value for LR-test: 0.12). In serous EOC, the associations with mortality were respectively 2.46 (95% CI: 1.26-4.80) for HE4 and 1.56 (0.87-2.80) for CA-125. Conclusions: Preoperative plasma HE4 is a promising prognostic biomarker in women with EOC and performs better than CA-125 to predict mortality.