bluuebunny/crossref_metadata_2025_split huggingface dataset:
CETUXICOL, a phase II trial randomizing standard treatment with or without cetuximab in primary cervical cancer treatment.
Authors: Scholl Suzy Marie Elisabeth , De la Rochefordiere Anne , Petrow Peter , Floquet Anne , Petit Thierry , Alran Severine , Berton-Rigaud Dominique , Campitelli Maura , Chiara-Bruneaud Claire , Fabbro Michel , Fourchotte Virginie , Guyon Frederic , Joly Florence , Kerr Christine , Maillard Sophie , Minsat Mathieu , Plancher Corine , Pop Marius , Sastre Xavier , Beuzeboc Philippe 
Published: March 2020

e15535 Background: Advanced stage cervical cancer (CC) remains a public health issue despite preventive vaccines and screening. EGFR is over-expressed in 50 to 85% of CC and activated in 20%, suggesting that EGFR blockage may be a promising treatment approach. Methods: A randomized phase 2 trial on 78 stage IB2–III patients from 11 French Cancer Centres evaluated the tolerance and early response to cetuximab, an anti EGFR antibody. 40 patients received cetuximab + standard RT and Cisplatinum based chemotherapy (arm A) and 38 patients received standard treatment (B). Primary endpoint is DFS at 2 years and presently not reached. MRI imaging revealed no difference in median (44 vs 40) tumour sizes between arms; there was no difference in age, menopausal status, PI and smoking habits. Parametrial involvement was clinically diagnosed in 19 and 20 cases respectively. Presence of lumbar or para-aortic lymph nodes was an exclusion criterion. Three patients withdrew consent in the cetuximab arm, one accepted standard treatment. Treatment schedules were incomplete in 13 (A) and 14 (B) patients for reasons of haematological or renal toxicity. Results: Surgical resection was feasible in 24 (65%) and 26 (70%) patients in arms A and B respectively.Tolerance was satisfactory in both arms, with significantly more acne form reactions in the cetuximab arm of grade 2 (n= 19) and 3 (n=4). More patients had diarrhea (n=8 vs 4: ns) associated with nausea and vomiting of grade 3 (n=4) and 4 (n=1) in the cetuximab arm (ns).Early results show a complete response at 6 weeks by MRI in 18% and 8% for arms A and B respectively. A central blinded review of the imaging and pathology slides is presently ongoing. Conclusions: The prediction of a response to EGFR targeted therapy in cervical cancer remains a matter of debate since no precise molecular studies are available. Consequently, no decisive results have been achieved in early trials of non selected patients with late stage disease (GOG 76-DD). Biopsy samples are available for the majority of our patients and analyses of EGFR expression, cellular sub-localization and main mutations in the PI3K pathway are ongoing. Molecular studies to allow hierarchical decision making are warranted in future studies.
Neoadjuvant chemotherapy without a fixed number of cycles in advanced ovarian cancer not candidates for optimal primary surgery.
Authors: Mendiola Cesar , Manneh Ray , Pascual Tomas , De Velasco Guillermo , Vega Estela , Manso Luis , Ghanem Ismael , Ciruelos Eva M. , Seoane J, , Cortes-Funes Hernan 
Published: March 2020

e15552 Background: Neoadjuvant chemotherapy (N-CT) is a valid alternative for patients with advanced ovarian cancer (AOC) getting similar survival rates to primary debulking surgery (PDS) followed by chemotherapy (CT), with less postoperatory complications (Vergote et al N Engl J Med 2010;363:943-53). Our objective was to evaluate the results of N-CT with a flexible number of cycles according to the clinical and biological evolution of the patients. Methods: 22 patients with stage IIIC-IV AOC, diagnosed by laparoscope or cytology (no primary laparotomy) were registered between January 2007 and September 2011 and treated with N-CT including paclitaxel 175 mg/m2 and carboplatin AUC 6-5 every 3 weeks. The number of cycles of N-CT was dictated by the clinical response, CT scan and CA125 that could allow an interval debulking surgery (IDS) with intent of optimal cytoreduction (R0). After IDS consolidation chemotherapy treatment was given to complete a total of at least 8 cycles. Results: Median age 63.7 years (40 – 80). Histologic types: serous 28%, adenocarcinoma not specified 66%, endometrioid 4.5%. FIGO stage IIIC 57%, IV 43%, Median CA125 at diagnosis: 1744 U (157 – 14483). Mean N-CT cycles 7.8 (4-23). 90.1 % of patients responded before IDS, 2 patients progressed before surgery. Mean CA125 after N-CT was 20.5 U (9-108). 54% of patients achieved complete resection of all macroscopic disease during IDS (R0). 5/22 (22.7%) obtained a pathological complete response (pCR) (no microscopic tumour in all specimens removed). Complications in the postoperatory occurred in 2 patients consisting in suture dehiscence. The range of total number of CT cycles were as follows: <6: 4.54%; 7-8: 31.8%; 9-10: 31.8%, >10: 31.8%. With a mean follow-up of 22.4 months (4 - 57.6), 50% patients live without recurrence. Median PFS has not been reached. Conclusions: N-CT according to clinical and biologic response and not to a fixed number of cycles is an useful tool for patients with stage IIIC-IV AOC not candidates for optimal /R0 PDS, getting a high proportion of patients with optimal /R0 IDS. The complications of IDS are also very limited. pCR as surrogate marker for long-term survival in other tumours, has to be evaluated in AOC.
Correlation of tumor-profiling results with drug selection in ovarian cancer patients.
Authors: Shawver Laura K. , Zajchowski Deborah A. 
Published: March 2020

e15555 Background: With the aim of informing therapy-selection decisions for ovarian cancer patients, we have profiled tumors from 190 ovarian cancer patients since 2008 for expression of 25 biomarkers associated with drug response. For 48 patients with mature follow-up data, we asked how frequently the drugs designated as likely to be of clinical benefit based on the tumor profile were administered. Methods: The tumor profiles and therapeutic choices of 48 patients that received a median of 2 (range 1-9) prior therapies for recurrent disease were extracted from our privacy-protected database. Protein levels of drug sensitivity (ER/PR, hormonal agents; TOPO1, topotecan/irinotecan (T-I); TOP2A, liposomal doxorubicin/etoposide (PLD-E); SPARC, nab-paclitaxel, N-P) and resistance (TS, pemetrexed/capecitabine (PC); RRM1, gemcitabine (G)) markers in each tumor were compared to expression in the ovarian cancer population to assign drugs likely to be associated with clinical benefit (values ≥ 25th percentile: sensitivity; ≤ 25th percentile: resistance). Results: A median of two drugs (range 1-5) were prioritized for each patient based on marker expression. 38 patients received one of the 6 drug classes evaluated by the profile. Of those 38, 22 (58%) received a therapy that correlated with the profile and 16 (42%) received drugs that were not prioritized by the profile. G and PLD were most frequently administered both before (68%) and after (48%) profiling but were supported by the tumor profile in only 40% (4/10: G) and 30% (3/10: PLD-E) of the cases. These frequencies are similar to the patient fraction (26-34%) in which those drugs were each prioritized by profiling, suggesting that the profile is not influencing therapy choice. In contrast, 11 of the 14 patients who received N-P, T-I, or hormonal agents had tumor profiles that prioritized those agents, a frequency of profile match to the treatment received that is higher than expected based on the patient fraction assigned to each therapy. Conclusions: These results require confirmation in a much larger study, but suggest that tumor profiling may guide clinical decision-making for some therapies, although frequently used drugs are often given regardless of the tumor profiling evidence.
Preliminary evidence of activity of pralatrexate in relapsed/refractory ovarian cancer.
Authors: Gabrail Nashat Y. , Smith Carrie L. 
Published: March 2020

e15557 Background: Pralatrexate, a novel antifolate, is approved in the US for the treatment of relapsed/refractory peripheral T-cell lymphoma at a dose of 30mg/m2 weekly for 6 weeks of a 7-week cycle. Previous studies in solid tumors have focused on a q2w schedule at 190mg/m2. As pralatrexate is 30-40% renally excreted, an ongoing renal impairment study is investigating the impact of mild, moderate and severe renal impairment on pralatrexate distribution in patients with hematological malignancies and solid tumors. As folate receptor alpha is frequently overexpressed in epithelial ovarian cancers, we hypothesized that ovarian cancer may be a target for pralatrexate treatment and therefore have included a number of ovarian cancer patients in this trial. Methods: Patients with solid tumors and hematological malignancies were enrolled in a phase I clinical trial. Patients are treated in cohorts depending on renal function normal, mild renal insufficiency, moderate renal insufficiency and severe non-dialysis dependent renal failure. This analysis is limited to 6 patients with refractory ovarian cancer. The dose of pralatrexate is 30mg/m2 weekly for 6 weeks of a 7-week cycle, with dose adjustment depending on toxicity. Results: The 6 patients, all with stage 4 refractory ovarian cancer had received 4 or more prior chemotherapy regimens and had refractory disease, defined as, nonresponsive to the last chemotherapy regimen or progression within 3 months of the last dose of chemotherapy. Of the 6 patients, 2 experienced objective responses lasting 9 months and 4 months respectively. Disease response was assessed by CA- 125 and RECIST criteria. Two patients experienced stable disease for 4 months and 5 months respectively. One patient had grade 5 mucositis after the second weekly dose and one patient had progressive disease after disease stabilization for 3 months. Conclusions: Pralatrexate given at a dose of 30mg/m2 to patients with refractory ovarian cancer has demonstrable activity that needs to be confirmed in well-designed efficacy trials. Importantly, this is the first demonstration of clinical activity in a solid tumor at the currently approved dose.
PDGFR and c-Kit as therapeutic targets and p53 and ki67 as prognostic markers for low-grade endometrial stromal sarcoma.
Authors: Park Jeong-Yeol , Kim Jong-Hyeok , Kim Kyu-Rae , Nam Joo-Hyun 
Published: March 2020

e15559 Background: To determine whether proteins targeted by currently available targeted agents are expressed in low-grade endometrial stromal sarcoma (LGESS) and to test these can be prognostic markers for LGESS. Methods: Of 48 patients with LGESS, 39 patients whose paraffin blocks of tumor in hysterectomy specimen were available were included. Using tissue microarrays, immunohistochemical expression of five therapeutic targets (EGFR, HER-2/neu, VEGFR, PDGFR and c-kit), and three proteins involved in cell proliferation (p16, p53, and ki67) were investigated. The association of these targets and markers with other clinopathologic factors and disease-free (DFS) and overall survival (OS) were analyzed. Results: EGFR and HER-2/neu were not expressed in 39 patients. VEGFR, PDGFR, c-kit, p16, p53, and ki67 was expressed in 10 (25.6%), 28 (71.8%), 32 (82.1%), 18 (46.2%), 4 (10.3%), and 21 (53.8%) patients, respectively. Expression of each marker was not significantly associated with other clinicopathologic factors. In multivariate analysis, p53 and ki67 were associated with significantly poorer DFS and OS. The 5-year DFS was 88%, 46% and 0% for p53(-)/ki67(-) group (n=18), p53(-)/ki67(+) group (n=17), and p53(+)/ki67(+) group (n=4), and the 5-year OS was 100%, 71%, and 0%, respectively. The time interval to recurrence was longer and more patients had distant recurrence in p53(+)/ki67(+) group. Conclusions: In patients with LGESS, c-kit and PDGFR were expressed in high portion of patients, suggesting imatinib mesylate may be a potential target agent. Both p53 and ki67 had strong prognostic implication, suggesting the combination of these proteins may be used as a prognostic marker.
Causes of discontinuation of intraperitoneal chemotherapy in patients with ovarian cancer.
Authors: Tamburelli Mercedes , Gatica Gabriela , Sena Susana , Castillo Javier Omar , Roca Fernanda , Bas Carlos Arturo , Gomez-Abuin Gonzalo 
Published: March 2020

e15570 Background: Intraperitoneal chemotherapy (IP) showed benefit in efficacy in patients with ovarian cancer but with high rates of complications and/or toxicity. We reviewed our experience and the identification of factors for discontinuing treatment. Methods: We conducted a retrospective review of electronic medical records of patients undergoing IP catheter placement at our medical center from May 2006 to December 2012; our institutional protocol for stages II/III ovarian carcinoma after optimal surgical resection is the following: 2 cycles of IV carboplatin/paclitaxel follow by 4 cycles of IP chemotherapy (paclitaxel 135 mg/m2 day 1 IV, cisplatin 75mg/m2 day 2 IP, paclitaxel 60mg/m2 day 8 IP). For statistical analysis, we used Fisher's exact test. Results: Thirty-seven patients underwent IP catheter placement. Median follow-up was 31.2 months. Eight patients did not receive IP chemotherapy: 3 patients for stage I, 2 patients stage IV, 1 patient synchronous breast cancer, one for unusual histology, and 1 patient for partial bowel obstruction. IP chemotherapy was administered to 29 patients. In total, 94 cycles IP chemotherapy were given with a median of 3 cycles per patient. IP chemotherapy was completed as planned in 24 patients (82.7%). The reason for treatment discontinuation: abdominal pain in 2 patients, extravasation in 1 patient, one patient due to peptic stricture, and other for esophageal ulcer. Grade 3-4 toxicity for IP chemotherapy was observed in 20% of patients. Median body mass index (BMI) was 24.3. IP chemotherapy was completed as planned in 94% of patients with BMI<25 and in 64% of patients with BMI> 25, p <0.05. Conclusions: This modified IP chemotherapy regimen is feasible with acceptable toxicity. Most patients completed the scheduled treatment with IP. BMI > 25 was identified as a possible risk factor for discontinuation of treatment.
Angiogenesis biomarker study of a phase II trial of pazopanib (P) in recurrent or persistent ovarian (EOC), peritoneal (PPC), or fallopian tube cancer (FTC): A Spanish Ovarian Cancer Group (GEICO) study.
Authors: Lopez-Guerrero Jose Antonio , Oaknin Ana , González-Martín Antonio , García Yolanda , Catot Silvia , Caballero Cristina , Garcia-Donas Jesus , Bover Isabel , Santaballa Ana , Guerra Alia Eva , Pardo Beatriz , Vidal Boixader Laura , Marquez Raul , Freixinos Víctor , Romero Ignacio , Ruiz-Sauri Amparo , Poveda Andres 
Published: March 2020

e15575 Background: Angiogenesis is essential to tumor growth, invasion, and metastasis in EOC. The aim of this study was to identify angiogenic biomarkers to predict response to P, a potent and selective multi-targeted receptor tyrosine kinase inhibitor of VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-a/β, and c-kit, in a clinical phase II trial. Methods: We analyzed a series of 20 out of 25 women enrolled in a GEICO Phase II trial that studied the Clinical Benefit Rate (CBR) of P in platinum-resistant EOC, PPC and FTC (results will be presented in an additional abstract). Formalin-fixed, paraffin-embedded tumors at diagnosis were evaluated for the microvessel density (MVD) by using CD31 immunostaining and the Image Pro-Plus 7.0 Image Analysis System (Media-Cybernetics). In addition, several angiogenic factors were evaluated by means of immunohistochemistry (IHC) on tissue arrays sections, and quantitative real-time PCR (qRT-PCR) using the Human Angiogenesis Arrays (Applied Biosystems). Serum samples were also collected at different moments of the treatment schedule and a panel of 14 citokines and growth factors were evaluated using the Luminex technology (Millipore). Results: Fifteen (75%) of the tumors were high grade serous EOC. Eight patients (40%) showed a CBR on treatment.MVD analysis, (number of vessels/mm2) was 2025 (835-3242) and 2410 (1449-3543) in patients with and without CBR respectively (p=0.278). IHC showed very low expression of angiogenesis-related factors including VEGF and VEGFRs, PDGF and PDGFRs, HIF and pAKT. Expression analysis by qRT-PCR and serum levels of cytokines and growth factors revealed no statistical differences between patients with and without CBR. Conclusions: No predictive biomarkers of CBR to P in platinum-resistant EOC could be identified in a population of patients with low expression level of angiogenic factors at diagnosis.
Demographics of uterine serous cancer (USC) patients: A single institutional experience.
Authors: de Leon Maria , Lu Lingeng , Hui Pei , Santin Alessandro , Rutherford Thomas J. , Arin-Silasi Dan , Azodi Masoud , Ratner Elena , Schwartz Peter E. 
Published: March 2020

e15581 Background: The common uterine cancer (UC) occurs in obese, diabetic (DM), hypertensive (HTN), postmenopausal women and are estrogen dependent. Small institutional series suggest USC occurs in older, thin women and is not associated with estrogen dependency. The objective of this study is to report demographic features of USC patients (pts) in a large single-institution experience and compared them with SEER data for UC (National Cancer Institute, SEER 2004-2008, uterine cancer. http://seer.cancer.gov/statistics/ ). Methods: Institutional records were reviewed from 1987 to 2009. Pts age, menopause status, race, disease stage, histology, past medical history (PMH) and additional demographics were collected. Results: 334 USC (pts) were identified. Their average age at diagnosis was 69.1 years (range 37-92). 282 (88.1%) were Caucasian and 32 (10%) were African Americans. The FIGO stage was IA 121 (36.2%), IB 36 (10.8%), II 27 (8.1%), IIIA 39 (11.7%), IIIB 2 (0.6%), IIIC1 32 (9.6%), IIIC2 9 (2.7%), IVA 28 (8.4%) and IVB 40 (12%). PMH revealed 177 of 221 (80%) had HTN and 69 of 221 (32%) had DM. 132 of 292 (45.3%) were obese; 95 (32.5%) had BMI between 30-39,31 (10.6%) had BMI between 40-49 and 6 (2.1%) had BMI >50. 89 of 315 (28.2%) smoked cigarettes, 48 of 250 (19.2%) used oral contraceptives for an average of 4 years (range 1-15) and 42/299 (14%) used HRT for an average of 4 years (range 1-20). 35 (17.3%) had a prior history of breast cancer, 5 (2.5%) colon cancer and 13 (6.4%) had other forms of cancer. Compared to published SEER data1 for all UC, more USC pts were diagnosed with advanced stage disease (II-IVB) 53% vs. 28%. USC patients were older at diagnosis (mean age of 69 vs. 61 years). Conclusions: Like UC, USC often presents in obese (45.3%), hypertensive (80%) diabetic (33%) women who have a prior history of breast cancer (17%). However, USC typically is found in older pts and at a more advanced stage.
Nucleophosmin expression in ovarian cancer.
Authors: Khabele Dineo , Wilson Andrew J , Liu Annie Y , Roland Joseph , Fletcher Sarah , Slaughter James , Crispens Marta A. , Gold Michael , Jones Howard , James Samuel , Fadare Oluwole 
Published: March 2020

e15582 Background: The nucleolar protein, nucleophosmin (NPM1) is implicated multiple cellular processes, including proliferation, duplication of centrosomes, ARF-HDM2-p53 signaling. NPM1 is associated with sites of double strand DNA breaks, with persistence of its expression indicative of impaired DNA repair. Data from the TCGA data have emphasized that genomic instability through impaired DNA repair processes is a characteristic feature of many ovarian cancers. Our aim was to determine the expression of NPM1 in ovarian cancers and to determine the relationship between NPM1 expression and clinical outcomes including overall survival (OS), progression-free survival (PFS) and chemotherapy response. Methods: Tissue microarrays were created from 209 patients treated for ovarian cancer at a single institution from 1994-2004. Expression levels of NPM1 were examined by immunohistochemical staining. Slides were scored using the an automated image capture and analysis system. Positive nuclear staining was used to stratify tumors into high (>50%) and low (<50%) groups, and the results were related to overall survival (OS) and progression-free survival (PFS) via Kaplan-Meier analysis. The relationship between ki67, a proliferation marker and pH2AX, a mark of double strand DNA breaks was measured with Spearman rank correlation coefficient analyses. Results: The majority of tumors, 140/209 (69%) were of serous histology, advanced stage 146/209 (70%) and high grade 158/209 (76%). There was >50% NPM1 expression in 83/209 (40%) and <50% in 126/209 (60%) of the cases. Expression of NPM1 was higher in high grade tumors, and its expression alone was a significant predictor of PFS (p=0.022) but not OS (p=0.053). When adjusting for other predictors, NPM1 expression was predictive of PFS (p=0.047), but not OS (p=0.054). No relationship between NPM1 expression and response to platinum chemotherapy was observed. However, NPM1 expression correlated with Ki67 (r=0.43, p<0.0001) and pH2AX (r=0.22, p=0.0014). Conclusions: NPM1 expression is a mark of poor prognosis in ovarian cancer. Whether these observations reflect increased proliferation and/or genomic instability in ovarian cancer cells will be the focus of future investigation.
Nutlin-3: A novel potential therapeutic in p53 wild-type ovarian carcinomas.
Authors: King Erin Rebecca , Mullany Lisa K , Richards JoAnne S , Gershenson David Marc , Wong Kwong-Kwok 
Published: March 2020

e15583 Background: Epithelial ovarian cancer (OC) is a molecularly and clinically heterogeneous disease, yet treatment is the same for all subtypes. Type I carcinomas, including low grade serous, mucinous, clear cell, and endometrioid OCs, are relatively chemoresistant. In contrast, Type II or high grade serous OCs are more aggressive yet responsive to chemotherapy. Molecularly, 96% of high grade serous OCs harbor p53 mutations, whereas Type I carcinomas are more frequently p53 wild-type. Nutlin-3 is a novel therapeutic which inhibits MDM2, activates wild-type p53, and induces apoptosis. We therefore sought to validate nutlin-3 as a therapeutic compound for p53 wild-type OCs. Methods: Two low grade serous, 2 clear cell, 2 endometrioid, 3 mucinous, and 4 high grade serous OC cell lines were treated with varying concentrations of nutlin-3, and proliferation assays were performed. A p53-null cell line was used as a negative control. The cells were then treated with nutlin-3 at their IC50s, and qRT-PCR and Western blot (WB) quantified MDM2, p53, and p21 expression at 24, 48, and 72 hours after treatment. The cell lines were sequenced for p53 mutations in exons 5-8. Results: Responses to nutlin-3 were variable and dependent on p53 mutation status. Low grade and clear cell lines were most sensitive to nutlin-3, endometrioid type were intermediately sensitive, and mucinous were resistant. Two of the four high grade cell lines were sensitive to nutlin-3, both of which were p53 wild-type. Endometrioid and low grade serous cell lines possessing heterozygous p53 mutations were still more sensitive than the p53-null cell line. On qRT-PCR and WB, levels of p53 were decreased after nutlin-3 treatment and were absent in the p53-null cell line. MDM2 and p21 were initially upregulated in sensitive cell lines, but returned to near-baseline levels after 72 hours. In the more resistant cell lines, p21 induction was reduced or absent. Conclusions: Nutlin-3 is a novel potential therapeutic agent for p53 wild-type ovarian carcinoma, and is dependent on an intact p53 pathway with p21 upregulation. Even OC cell lines with heterozygous p53 mutation responded modestly to nutlin-3 treatment. Further investigation of nutlin-3 treatment in ovarian cancer is warranted.