bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prelinical evaluation of selective inhibitors of nuclear export (SINE) CRM1 (XPO1) inhibitors in prostate cancer (PrCa).
Authors: Shacham Sharon , Gravina Giovanni Luca , Ricevuto Enrico , Mancini Andrea , Chin Lynda , Shechter Sharon , Sandanayaka Vincent , McCauley Dilara , Kauffman Michael , Draetta Giulio Francesco , Festiccia Claudio 
Published: March 2020

e15200 Background: CRM1 (XPO1) is the sole exportin mediating transport of multiple tumor suppressor proteins (TSP) including p53, pRB, FOXO, APC and NPM1 out of the nucleus, abrograting their function. Many tumor types show overexpression of CRM1, thus extinguishing TSP function. CRM1 inhibition forces nuclear accumulation of TSPs inducing apoptosis in cancer cells. Methods: MSKCC PrCa gene database was used for mRNA analyses. Inhibition of CRM1 mediated NE was determined by IHC. MTT assays were used to determine cytotoxicity across divergent PrCa lines: LAPC-4 (p53wt, AR+, low Akt/mTOR); LnCaP (p53wt, AR+, high Akt/mTOR); LnCaP-C81 and LnCaP-C4-2B (p53wt, AR+, androgen independent, high Akt/mTOR); 22rv1 (p53wt, AR+, androgen independent, low Akt/mTOR); PC3 (p53-del, AR–, high Akt/mTOR), DU145 (p53mut, AR–, low Akt/mTOR). BPH1 and prostatic epithelial line EPN were used as non-neoplastic controls. 22rv1 xenografts were initiated in the flanks of SCID mice and treatment begun when tumors reached ~150mm3. Results: Analyses of nuclear pore complex (NPC)-related mRNA levels shows coordinate regulation of transcripts and allow PrCa to be segregated into high and low NPC expression. Low NPC expressing tumors tended to have reduced AR expression; APC, NPM1, and RB1 mRNA levels were also low (p<10e-12) and p16INK4A levels were elevated. As NE is dysregulated in PrCa, we assessed the effects of SINE, irreversible CRM1 inhibitors, across PrCa cell lines. SINE block CRM1 mediated nuclear export of TSPs with IC50 values <100 nM in all tested cell lines. SINE are selectively cytotoxic for neoplastic (EC50 10-1000nM) versus non-neoplastic lines (EC 50 >5-20µM). SINE cytotoxic effects are independent all tested genetic alterations. In the aggressive, androgen independent 22rv1 xenograft, oral SINE KPT-251 showed dose-dependent inhibition of tumor growth and synergy with cisplatin. Conclusions: These data show that PrCa shows coordinate NPC regulation, and that selective blockade of CRM1 dependent NE represents a completely novel, neoplasia-selective and well-tolerated target for use as single agent or in combination with chemotherapy for PrCa.
Retrospective mathematical analysis of serial prostate specific antigen (PSA) measurements for patients with M0 prostate cancer treated with intermittent androgen suppression (IAS).
Authors: Higano Celestia S. , Hirata Yoshito , Akakura Koichiro , Bruchovsky Nicholas , Aihara Kazuyuki 
Published: March 2020

e15201 Background: Recently a phase III trial demonstrated that IAS was non-inferior to continuous AS in men with M0 disease after primary or salvage radiation and quality of life was better in the intermittent arm (Crook ASCO 2011). In that trial, men were treated with 8 months of AS followed by a variable time off AS driven by the absolute PSA value. The Hirata mathematical model describes the dynamics of prostate cancer treated with IAS (Hirata et al, J of Theoretical Biol 2010). In the model, there are three classes of cancer cells: a class of androgen dependent (AD) cells and two classes of androgen independent (AI:X1 and AI:X2) cells. During AS, AD cells will change to the two AI classes, and during the off treatment period, AI:X1 cells will revert to AD cells whereas AI:X2 cells cannot revert to either AD or AI:X1 cells. Methods: After IRB approval, we applied the Hirata model using serial monthly PSAs from men with M0 disease treated with IAS from Japan, Canada, and the United States. The proportions of men from each country who fell into the 3 categories of patients previously defined by the Hirata model were compared. Results: Serial PSAs from 26 men from Japan, 72 from Canada, and 79 from US were put into the model. The 3 categories of patients from the model include: (i) those with disease that will remain androgen sensitive and will respond to IAS without development of castration resistance (CRPC) (ii) those who will benefit from IAS but will develop CRPC sooner than those in group (i), (iii) those for whom continuous AS is superior to IAS. The datasets from each country show a similar distribution among the categories, and overall there were 42%, 51%, and 7% falling into groups i, ii, and iii respectively. Conclusions: This retrospective analysis shows that men with M0 disease treated with IAS fall into the 3 categories predicted by the Hirata model in similar proportions, regardless of country of origin. The ability to apply this model to the individual patient in the clinic is currently under development. The model may ultimately be able to optimize both the on and off treatment durations of IAS and to predict those patients who will most benefit from this approach.
NF-κB p65 as a prognostic tool in prostate cancer: An immunohistochemical study from biopsy samples.
Authors: Labouba Ingrid , Gannon Philippe O. , Forest Valerie , Le Page Cécile , Storoz Cristina , Lessard Laurent , Mes-Masson Anne-Marie , Saad Fred 
Published: March 2020

e15202 Background: Our previous immunohistochemical studies of NF-κB p65 in prostate cancer (PCa) highlight its clinical potential as a prognostic marker in different cohorts of Canadian and European men. However these studies are essentially based on tissue microarrays (TMAs) built from samples obtained from radical prostatectomy specimens where other prognostic parameters, such as pathologic stage, Gleason score, and margin status are also available. However, limited prognostic parameters are available to clinicians at the time of diagnosis. The current study aims to assess whether the immunohistochemical staining of p65 could offer prognostic information at the time of diagnosis and help risk stratify patients. Methods: Prostatebiopsies were obtained from a cohort of 328 prostate cancer patients who were further treated by radical prostatectomy. NF-κB p65 was stained by immunochemistry on biopsy samples containing malignant tissue. The nuclear frequency was quantified as a percentage of positive p65 nuclear cells. Results: Our first statistical analyses revealed that the nuclear frequency of NF-κB p65 on biopsy samples was correlated with clinical paramaters as final Gleason score and BCR. Patients with Gleason score post-prostatectomy of 7 or more had a higher NF-κB p65 nuclear frequency in biopsy samples (p<0.05, Student test). NF-κB p65 nuclear frequency was also higher in patients developing a BCR and bone metastasis (p<0.05, Student test). Conclusions: These preliminary results show an association between NF-κB p65 nuclear distribution in biopsy samples and PCa aggressivity. We showed that NF-κB p65 immunohistochemical staining on biopsies was predictive of BCR. NFkB p65 may be prognostic marker at the time of diagnosis and could eventually be useful in clinical decision making.
Targeting mTOR and VEGF in CRPC: Preliminary results of a phase I/II trial of temsirolimus (T) and bevacizumab (B) in docetaxel-refractory metastatic CRPC.
Authors: Garcia Jorge A. , Elson Paul , Cooney Matthew M. , Tyler Allison Janine , Dreicer Robert 
Published: March 2020

e15208 Background: Despite the availability of novel agents in the docetaxel-refractory setting, their activity is often short lived as all pts eventually progress. Activation of the PI3K/AKT/mTOR/VEGF/CXCR6 pathway regulates proliferation, differentiation, and malignant transformation in PCa progression. mTOR inhibition inhibits CXCL16, IL8/VEGF levels and other CXCR6 targets including CD44 and matrix metalloproteinase 3. Combination strategies capable of blocking the CXCR6/VEGF/AKT/mTOR signaling pathway could become a more effective therapeutic strategy for CRPC. Methods: Eligible docetaxel-refractory CRPC pts had serologic or objective PD after 1 or 2 prior chemotherapies. Pts with CNS metastases or active spinal cord compression were excluded. A staged-cohort design to study primarily safety of the combination was undertaken. Once the MTD was established a two-stage phase 2 trial was implemented. An underlying ORR >20% was deemed sufficient to warrant further study, whereas an ORR rate <5% would not. Starting doses of T and B were 15mg wk and 5mg/kg e/2 wk. Exploratory endpoints included CTCs, VEGF levels and Th1 cytokine production. Results: To date 22 of a total planned 28 pts are enrolled, median age was 64 and half of the pts were ECOG 1. Most pts had bone disease and the median PSA was 205 ng/mL. Pts have received a median of 4 cycles of treatment (range: 1-12). All pts have discontinued therapy; 48% PD, 38% AEs and 5% consent withdrawal. PSA reductions were observed in 30% of pts. No RECIST defined PR was seen. The most common AEs included anorexia (67%), mucositis (53%), fatigue (57%) and myelosuppression in over 60% of pts. CTC analysis and VEGF/TOR and cytokine levels are currently underway. Conclusions: The combination of T and B demonstrated significant toxicity in a heavily pretreated CRPC pt population. Minimal antitumor activity was observed. Exploratory studies and their correlation with clinical outcome are underway.
The incidence of vascular, genitourinary, and intestinal tract injuries in gynecologic oncology: An extensive, single institutional experience.
Authors: Rettenmaier Christopher , Rettenmaier Nicholas , Abaid Lisa , Mendivil Alberto , Brown John V. , Micha John P. , Lopez Katrina , Wojciechowski Tomasz , Goldstein Bram 
Published: March 2020

e15500 Background: Iatrogenic vascular, genitourinary, and intestinal tract injuries are an unfortunate consequence in gynecologic surgery because the uterus and ovaries are adjacent to critical pelvic structures. The incidence of these complications in general gynecology reportedly varies from 0.3-8.0%; conversely, in gynecologic oncology, the rate is presumably higher although the outcomes are not well documented. Methods: We reviewed the charts of gynecologic oncology patients treated at a single medical institution from January 2003 to February 2011. The following study variables were noted for evaluation: patient characteristics (age, body mass index (BMI)), medical history, cancer origin (e.g., ovarian, uterine), disease pathology, previous pelvic surgery, injury type (genitourinary, vascular or intestinal tract) and injury diagnosis (intra- or post-operative). Descriptive analyses were initially employed, followed by further evaluation of the clinicopathologic parameters via logistic regression, ANOVA and Cox proportional-hazard ratios. Results: In the current, retrospective investigation, 810 gynecologic cancer patients were identified; from this group, there were 25 (3.1%) intestinal tract, 10 (1.2%) genitourinary and 20 (2.5%) vascular injuries encountered. The logistic regression model classified correctly 84% of the injuries. Moreover, a Cox proportional hazard model revealed that cancer origin (p=0.023), previous pelvic surgery (p=.003), BMI (p=0.002) and disease stage (p < 0.01) were surrogate markers for operative injury occurrence. Conclusions: The incidence of vascular, genitourinary and intestinal tract injuries in this large group of gynecologic oncology patients was quite reasonable. Fortunately, when these conditions arise, gynecologic oncologists have extensive surgical experience and are well prepared to address them. Additional study of the clinicopathologic factors that may predispose these cancer patients to a surgical complication is necessary.
Recurrence patterns in patients with stage IIIC1 versus IIIC2 endometrial adenocarcinoma.
Authors: Bevan Catherine , Nagel Christa Irene , Boren Todd Patrtick , Miller David Scott , Kehoe Siobhan Marie , Richardson Debra L. , Lea Jayanthi 
Published: March 2020

e15501 Background: To identify differences in recurrence patterns between stage IIIC1 and IIIC2 endometrial adenocarcinomas. Methods: A retrospective review was performed with IRB approval of all patients treated for stage IIIC1 and IIIC2 endometrial adenocarcinoma at our institution from 1989-2011. Patients were required to have comprehensive surgical staging including total abdominal hysterectomy, bilateral salpingo-ophorectomy, pelvic and paraaortic lymph node dissection. Descriptive statistics were performed using Microsoft Excel 2011 and Fischer’s exact test, Kaplan-Meier analyses were used to compare disease free (DFS) and overall survival (OS). Results: Eighty-seven patients with stage IIIC endometrial adenocarcinoma were identified, of which 69 were evaluable. The mean age was 59 years and the mean follow up was 32 months. There were 31 patients with stage IIIC1 and 38 patients with stage IIIC2 disease. There was no statistical difference in histology between the two groups: 47 endometrioid, 11 papillary serous, and 11 with other types of adenocarcinoma. Patients with stage IIIC1 disease were more likely to receive pelvic radiation (p=0.0004) and patients with IIIC2 disease were more likely to receive chemotherapy (p=0.014). Median DFS was 28.9 months (range 0-112) and 15.0 months (range 0-166) (p=0.017) and median OS was 31.9 months (range 0-134) and 18.0 months (range 0-166) (p=0.061) for the IIIC1 and IIIC2 groups respectively. Seven of 31 (23%) patients with stage IIIC1 disease recurred: 1 (14%) at the vaginal cuff and 6 (86%) distant. The patient who recurred locally was initially treated with chemotherapy alone. Of the 6 patients with distant recurrences only 1 received chemotherapy. Twelve of the 38 (32%) patients with stage IIIC2 experienced a recurrence: 6 (50%) vaginal/pelvic and 6 (50%) distant. There was a difference between the rates of local versus distant recurrence in patients with IIIC1 and IIIC2 endometrial cancer. Conclusions: IIIC1 patients were less likely to receive systemic chemotherapy and more likely to recur distantly. Our findings suggest a role for adjuvant chemotherapy and radiation in the frontline treatment of both IIIC1 and IIIC2 endometrial cancer.
Hormone receptor expression and risk of recurrence in patients with high-risk endometrial carcinoma treated with chemotherapy.
Authors: Barrett Olivia Claire , Burnett Omer L. , Conner Michael G. , Li Yufeng , Estes Jacob Michael , De Los Santos Jennifer F. 
Published: March 2020

e15502 Background: Poor long-term survival in high-risk endometrial cancer patients attests to a need for new therapeutic strategies. The prevalence of estrogen (ER) and progesterone receptors (PR) among high-risk endometrial carcinomas has not been systematically studied and is a target to which individualized therapies may be tailored. Methods: 41 women with high grade, stage III/IV and/or aggressive histology endometrial cancer who received post-hysterectomy chemotherapy were identified. Patient, tumor and treatment characteristics were recorded. Immunohistochemical staining of ER and PR was scored on a 0-4 scale incorporating intensity and extent of expression. Receptor-positivity was defined as a score of >= 2. Univariate and multivariate logistic regression analysesand the Cox proportional hazards model were performed to examine hormone receptor expression and recurrence risk. Results: Median age at surgery was 59 years (range 34-79). Median follow up time was 39 months (range 1-82). Recurrence occurred in 21 women (51%) with median time to first recurrence of 19 months (range 1-71). 22 cancers (54%) were ER+ and 21 (51%) PR+. Median ER and PR expression was 2 and 2, respectively (range 0-4). While ER and PR were not independent factors for recurrence, on multivariate logistic regression analysis ER and PR as continuous values showed recurrence associated with greater ER expression (p = 0.0836) and lesser PR expression (p = 0.0986). Cox proportional hazards model supported the association between increasing ER and decreasing PR with shorter recurrence free survival (p=0.0034, p = 0.0021). An increase in ER score of 1 corresponded to a hazard ratio (HR) of 2.647 (95% CI 1.38-5.08); an increase in PR score of 1 corresponded to a HR of 0.362 (0.19-0.693). Conclusions: More than 50% of high-risk endometrial cancers in this small retrospective cohort receiving cytotoxic chemotherapy expressed positive hormone receptors. Multivariate analyses of hormone receptors suggest increased recurrence with discordant expression of ER and PR. Further investigation is warranted to verify whether differential hormone receptor expression predicts poorer response to cytotoxic systemic therapy.
Prediction of major surgical complications by comprehensive geriatric assessment in elderly patients with gynecologic cancers: A prospective cohort study.
Authors: Kim Jae Weon , Suh Dong-Hoon , Kim Jae Hoon 
Published: March 2020

e15503 Background: To evaluate the ability of a preoperative comprehensive geriatric assessment (CGA) to predict the risk of postoperative complications in elderly patients who underwent primary surgery for gynecologic cancers. Methods: Fifty-six consecutive patients (24 ovarian, 15 cervical, 6 endometrial, 5 uterine sarcoma, 4 vulvar, and 2 metastatic cancers) older than 70 years scheduled to take surgery electively for gynecologic cancer were preoperatively assessed by CGA. Every category of CGA was evaluated for in-hospital postoperative complications and mortality within 30 days of surgery. Major complication included any complication of 2 or higher grade according to Memorial Sloan-Kettering Surgical Complication Criteria 12/99. Results: Mean age was 73.5±3.5 years (range 70-85). Overall postoperative complication rate was 28.6% (16/56) with 7 (12.5%) and 6 (10.7%) being major and multiple complications, respectively. Mean hospital stay was 18.7±13.6 days (range 3-81), during which in-hospital mortality was 2 (3.6%). There was no postoperative complication that occurred after discharge within 30 days of surgery. Dependent instrumental activity of daily living (IADL) was associated with high incidence of postoperative complication, especially for multiple complications. However, poor performance status (PS) was associated only with major and multiple complications. Multivariate regression analysis revealed that only poor PS was associated with postoperative in-hospital mortality (p=0.006). Conclusions: IADL and PS were useful to predict postoperative complication, in particular, major and multiple complications, in elderly patients with gynecologic cancers. Major and multiple postoperative complications can be prevented by identifying the elderly patients with gynecologic cancers who showed dependent IADL and poor PS in CGA.
Evaluation of the overall survival rates in locally advanced cervix cancer patients treated with radiotherapy alone and chemoradiation: A Brazilian experience.
Authors: Campos Conceicao Souza , Salvajoli Joao Victor , Novaes Paulo Eduardo , da Silva Marcelo Gurgel 
Published: March 2020

e15509 Background: Locally advanced cervical cancer is a major worldwide health problem. The treatment might include radiotherapy and few trials evaluate the timing of pelvic external irradiation (RT) and high dose rate brachytherapy (HDR) in local control and survival rates of these patients as well as the addition of chemotherapy. The objective were to evaluate the overall survival rates in locally advanced cervix cancer patients and determine the clinical and treatment prognostic factors for local control and overall survival rates. Methods: A retrospective cohort study was carried out with 261 patients stage IIIB, 164 patients received 54 Gy RT to the pelvis and 30 Gy HDR without chemotherapy and 97 patients received 54 Gy RT to the pelvis and 30 Gy HDR with weekly cisplatin 40mg/m2 IV (CDDP) from August 1998 to June 2004 in Hospital Haroldo Juacaba, a Brazilian northeastern hospital. The mean follow-up time was 50 months (2-185 months) and the Kaplan-Meier method was used to calculate survival curves. The Cox regression was used to evaluate multivariate analysis and p values =<0.05 was considered significant. Results: Local control and 5-year survival rates were 39.6% and 38.4% for exclusively radiation and 50.5% and 47.4% for chemoradiation (p = 0.19 and p = 0.36, respectively). The mean treatment time was 61 days. Both local control and overall survival rates were affected by age, parametrial involvement and the timing of brachytherapy (p<0.05). The overall treatment time did not influence survival or local control rates (p>0.05). But less than six cycles of chemotherapy improved local control rates better than six or more cycles (55.1% versus 44.9% p = 0.02). Conclusions: The study is a nonsuperiority one where the addition of weekly chemotherapy with six cycles of CDDP 40mg/m2 during the irradiation did not improve overall survival rates. Further prospective studies would be useful to evaluate the benefit of adding weekly chemotherapy to the standard radiotherapy treatment as well as the financial impact of the adoption of this international guideline in patients with advanced lesions from developing countries.
Proteomics of the ascitic fluid for the differentiation of advanced ovarian cancer.
Authors: Hariprasad Gururao , Hariprasad Roopa , Kumar Lalit , Kaushik Amit , Srinivasan Alagiri 
Published: March 2020

e15510 Background: Ovarian cancers are classified as primary, if it arises in the ovary and secondary or metastatic, if the origin is from other parts of the body. The clinical manifestations of these cancers in the advanced stage are very similar making it difficult to distinguish clinically, hiostopathologically and radiologicaly. The therapeutics and management of the primary and secondary malignancies are completely different. While, the advanced primary malignancies are treated by cytoreduction followed by chemotherapy, the metastatic tumors are treated mainly with palliative chemotherapy. The prognosis is better for primary than secondary ovarian cancer making their diagnosis very crucial for patient care. Methods: 1D and 2D-gel based proteomic approaches were used to study the differentially expressed proteins in the ascitic fluid of patients (10 primary and 4 secondary) with advanced ovarian cancer. The relative ratios of the protein expression were estimated by densitometric analysis. The bands/spots with more than three fold difference were subjected to in-gel trypsin digestion and identified by mass spectrometric analysis. The differential expression of one of the proteins was further validated by western blot experiments and ELISA. Results: Programmed Cell Death 1-Ligand 2 and apolipoprotein A1 were seen to be up regulated in the advanced primary ovarian cancer while apolipoprotein A4, and chain L, humanized version of the anti-human fas antibody Hfe7a were seen to be up regulated in the metastatic variant. Validation for the expression of apolipoprotein A1 shows that a 61.8ng/ml cut off is ideal to differentiate the primary and secondary advanced ovarian cancers. The assay has 100% sensitivity, 75% specificity, positive predictive value of 90.9%, negative predictive value of 100%, accuracy of 92.85% and a pre-test odds positive of 2.5. Conclusions: Proteomics of ascitic fluid is useful for the differentiation of advanced ovarian cancers. There are proteins which are differentially expressed in the ascitic fluid of patients with primary and secondary ovarian cancer. Apolipoprotein A1 is a potential biomarker that can be used to differentiate the closely mimicking clinical scenarios of advanced ovarian cancer.