bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase II, pharmacokinetic (PK), and pharmacodynamic (PD) study of weekly docetaxel (DOC) in patients with platinum-resistant ovarian cancer
Authors: Odunsi K. , Ghamande S. , Macfee M. , Yin Chieh Yu A. , Lele S. B. , Rodabaugh K. J. , Thomas B. , Zamboni W. C. 
Published: August 2020

e16531 Background: DOC at 30 mg/m2 q wk for 3 wks q 4 wks was modestly active and minimized toxicity in patients (pts) with platinum resistant epithelial ovarian cancer compared to historical data of DOC at 75 to100 mg/m2 q 21 days (Berkenblit, Gynecologic Oncology 2004). However, the optimal schedule of weekly DOC in pts with ovarian cancer has not been determined. Our study assessed the activity and safety of weekly DOC at 36 mg/m2 q wk for 6 wks q 8 wks in platinum and paclitaxel resistant ovarian cancer. PK and PD studies of DOC were performed on wks 1 and 6. Methods: Pts (n = 25) with platinum and paclitaxel resistant ovarian cancer with up to 3 previous treatments were eligible. DOC was administered at 36 mg/m2 IV over 30 min q wk for 6 wks repeated q 8 wks until complete response or disease progression. Plasma samples were obtained from 0 to 24 h after administration of DOC on wks 1 and 6 of cycle 1. DOC plasma conc were determined by liquid chromatography mass spectrometry (LC-MS). Non-compartmental analysis of area under the plasma conc versus time curves (AUC) was calculated by WonNonLin. Results: Of the 25 pts, 6 pts (24%) had a partial response (PR) and 4 pts (16%) had stable disease using GCIG criteria or NCI RECIST criteria. Median duration of response in these 10 pts (40%) was 16.5 wks. Median survival was 32.5 wks with 4 out of 10 pts alive with disease. Hematological toxicity was mild with 20% grade 3 anemia and 20% grade 3/4 neutropenia. Mean ± SD DOC AUC on wks 1 and 6 were 2,520 ± 1,017 and 2,808 ± 1,247 ng/mL·h, respectively. Mean ± SD ratio of DOC AUC on wk 6 to wk 1 for each pt was 1.11 ± 1.23. Conclusions: DOC at 36 mg/m2 q wk for 6 wks q 8 wks was active and well tolerated, and offered meaningful palliation in pts with platinum and paclitaxel ovarian cancer. Significant reduction in hematological toxicity over standard DOC schedule was observed. There is high inter-patient and low intra-patient variability in the PK of DOC from wk 1 to wk 6. No significant financial relationships to disclose.
Epigenetic alteration of BRCA1 in human ovarian tumors
Authors: Takehara K. , Miyamoto K. , Kawakami Y. , Kumagai M. , Samura O. , Egawa M. , Nakamura H. , Mizunoe T. , Taniyama K. , Saji F. 
Published: August 2020

e16532 Background: The breast cancer susceptibility gene 1 (BRCA1) is mutated in half of hereditary breast cancers, and in about 80% of hereditary breast and ovarian cancers. Also, BRCA1 expression is decreased in sporadic breast cancers by other mechanisms, such as epigenetic alteration, suggesting its important role in sporadic breast cancers. The epigenetic alteration of BRCA1 and its contribution in sporadic ovarian tumors are not fully understood. Methods: We evaluated the DNA methylation status of the BRCA1 5’ CpG island by methylation-specific PCR in 12 human ovarian cancer cell lines and 39 primary epithelial ovarian tumor specimens. Cases included the following: malignant (n = 16), borderline (n = 8), and benign (n = 16) tumors. The correlation between these results and clinicopathological features was examined. Results: BRCA1 was hypermethylated in one of 12 (8%) ovarian cancer cell lines and 15 of 39 (38%) primary ovarian tumors. Relative to clinicopathological features, BRCA1 methylation was detected in 39% of malignant and borderline tumors and in 38% of benign tumors, suggesting the importance of BRCA1 pathway in both types of tumors. Some adjacent nontumorous tissues also showed aberrant methylation. Conclusions: BRCA1 was found to be frequently hypermethylated both in benign and malignant ovarian tumors. Our results suggest that epigenetic alteration of BRCA1 might play a role in the development of benign and malignant sporadic ovarian tumors. No significant financial relationships to disclose.
Carboplatin, ifosfamide, and mesna (CIM) for the treatment of gynecological carcinosarcoma
Authors: Walji N. , Zachariah A. , Yap C. , Hussain S. A. , Poole C. J. , El-Modir A. , Ganesan R. , Fernando I. N. 
Published: August 2020

e16539 Background: A GOG trial comparing cisplatin/ifosfamide/mesna chemotherapy versus whole abdominal irradiation for FIGO stages I-IV carcinosarcoma (CS) showed an estimated median survival (MS) of 50 months for chemotherapy but high toxicity. This study investigates the efficacy and tolerability of a novel regimen using carboplatin AUC 5, ifosfamide 3 g/m2 and mesna 1 g/m2 (CIM) in both the adjuvant and metastatic setting. Methods: Retrospective analysis of women with CS treated from May 1997-May 2007 with CIM (group 1) versus other chemotherapy regimens (group 2). Toxicity was graded according to the Common Toxicity Criteria and MS estimated using the Kaplan-Meier method. Results: Of 51 eligible women (median age 71 years) 35 (69%) had stage 3 or 4 disease. 35/51 (69%) received chemotherapy; 2 with stage 1c disease received pelvic radiotherapy (pRT) alone whilst the remaining 14 were unfit for any treatment. Median follow-up for the treated patients is 45 months. 11/35 patients (31%) received CIM as first-line chemotherapy. Other regimens included: carboplatin (n = 14); carboplatin/paclitaxel (n = 3); carboplatin/epirubicin (n = 3); carboplatin/doxorubicin (n = 2); doxorubicin/ifosfamide (n = 1); cisplatin/ifosfamide (n = 1). 20/35 (57%) received adjuvant chemotherapy (AC) of which 8 received CIM; 11/20 patients also received adjuvant pRT. MS in the CIM AC group is 54.7 months compared to 37.4 months for other regimens. 3/8 patients (37.5%) in the CIM arm developed recurrent disease compared to 9/12 (75%) for other regimens. 4/16 patients received CIM as first- or second-line palliative chemotherapy. All patients responded of whom 2 achieved clinical and radiological complete response (CR). One woman subsequently relapsed and achieved a second CR with CIM. MS for all chemotherapy-treated patients is 54.7 months (group 1) versus 20.6 months (group 2) (p = 0.07). No patients in group 1 experienced any grade 3/4 toxicity and all patients completed the prescribed treatment. There were 2 unexpected treatment-related deaths in group 2, one of whom received carboplatin/paclitaxel and the other carboplatin/epirubicin. Conclusions: CIM appears to be efficacious and well tolerated in the treatment of CS and merits further investigation in clinical trials. No significant financial relationships to disclose.
Treatment of pseudomyxoma peritonei by intraoperative and intraperitoneal chemotherapy
Authors: Friedrich M. , Poleska W. , Baltzer J. , Salehin D. 
Published: August 2020

e16540 Background: Pseudomyxoma peritonei occurs mostly in conjunction with the type of intestinal mucinous borderline tumour and is characterized by building up a lot of mucus pour of cells. The most common tumor is the pseudomyxoma peritoneii with mucinous borderline tumours of the ovaries or with mucinous tumours of the appendix, normally without showing a rupture of the ovarian tumour pre- or intraoperatively. The diagnosis of pseudomyxoma peritonei is mainly difficult and guidelines for the treatment are unknown. Methods: In the period from 1991 to 2008, 52 patients with pseudomyxoma peritonei were treated by tumour debulking and intraoperative and intraperitoneal chemotherapy with Mitoxantron (40 mg in 300 ml of NaCl over 72 hours). During the tumour debulking a CUSA system was used. Results: The median follow-up was 8.2 years. There were the following histologies: mucinous cystadenoma of the ovary n = 29, mucinous cystadenoma of the appendix n = 10, mucinous cystadenocarcinoma n = 13. Reccurrences were seen in 4 patients. These patients were treated for reccurrences by the same way as mention above. All these patients were now without any recurrences. The other 48 patients are still alive with recurrences. Conclusions: The instillation of mitoxantron intraperitoneally and intraoperatively is an effective and safe therapy without any side effects after maximal tumour debulking of pseudomyxoma peritoneii. No significant financial relationships to disclose.
Do patients with recurrent ovarian cancer benefit from relative tumor reduction? Results from a prospective study
Authors: Gil B. , Oskay-Oezcelik G. , Richter R. , Neumann U. , Neuhaus P. , Lichtenegger W. , Sehouli J. 
Published: August 2020

e16541 Background: Primary cytoreduction is the cornerstone in the management of epithelial ovarian cancer (OC). However, the roles of salvage surgery and of tumor reduction are still discussed controversially. The present study was conducted to assess the impact of secondary tumor reduction surgery on progression-free survival and on overall survival. Methods: Between September 2000 and April 2006, 177 consecutive patients (pts) with a first relapse of OC underwent secondary tumor reduction surgery at our department. The achieved tumor reduction was categorized as 1/5 (20% tumor debulked), 2/5 (40%), 3/5 (60%), 4/5 (80%), or 5/5 (macroscopic tumor-free) and the maximal tumor diameter was also denoted (tumor free, < 1cm, ≥ 1cm). Results: The median age was 56 years (95% CI: 23–83), median follow-up was 10.8 months (95% CI: 1–65). In 79 pts (44.6%) complete macroscopic tumor resection was achieved (median overall survival (OAS) 60.6 months, 21.3–99.8 and median progression-free survival (PFS) 14.9 months, 11.7–18, p < 0.001). In 56 pts (31.6%) 4/5 of the tumor was removed (OAS 15.6 months, 10.3–20.8 and PFS 9 months, 7.2–10.7, p < 0.001), in 13 (7.3%) 3/5 (OAS 21.7 months, no interval and PFS 12 months, 0.0–24.5, p < 0.001) and in 7 (4%) each 2/5 tumor reduction (OAS was 14.2 months, 4.1–24.2 and PFS 11 months, 5.9–16, p < 0.001) and if 1/5 tumor reduction was achieved OAS was 11.1 months, 2–20.1 and PFS 7 months, 2.5–11.4, p < 0.001. Fifteen pts (8.5%) had a bulky unresected disease (OAS 4.7 months, 1.0–8.3 and PFS of 3.7 months, 0–7.6, p < 0.001). From these 98 (55.4%) pts without complete macroscopic tumor resection, 46 were left with <1cm tumor diameter (OAS 17.2 months, 13–21.4 and PFS 9 months, 7.4–10.6 p < 0.001) and 52 with ≥1cm tumor diameter (OAS 8.7 months, 4.2–13.2 and PFS 7 months, 5.8–8.2 p < 0.001). All in all, the median postoperative survival for pts with tumor residuals and any tumor reduction (4/5, 3/5, 2/5. and 1/5 tumor reduction) were better when compared to pts with no tumor reduction (24.8 months vs. 4.7, p < 0.001). Conclusions: Our data demonstrate a significant benefit for salvage surgery if a macroscopic complete tumor resection can be achieved. We could not see any effect of relative tumor reduction on PFS or OAS. No significant financial relationships to disclose.
Efficacy and safety of gefitinib and potential prognostic value of soluble EGFR, EGFR mutations, and tumor markers in a Gynecologic Oncology Group phase II trial of persistent or recurrent endometrial cancer
Authors: Leslie K. K. , Sill M. W. , Darcy K. M. , Baron A. T. , Wilken J. A. , Godwin A. K. , Cook L. , Schilder R. J. , Schilder J. M. , Maihle N. J. 
Published: August 2020

e16542 Background: A phase II trial was performed to evaluate the efficacy and safety of gefitinib and to explore epidermal growth factor receptor (EGFR, sEGFR), estrogen receptor (ER) and progesterone receptor (PRA, PRB) expression in persistent/recurrent endometrial cancer (EC). Methods: Women with histologically-confirmed, measurable, persistent/recurrent EC following one or two prior regimens were eligible and treated with 500 mg oral gefitinib daily until progression or severe toxicity. A 2-stage group sequential design was used to evaluate the regimen with PFS at 6 months as the primary endpoint. The trial had a 10% type I error rate with 90% power. sEGFR was quantified in serum and categorized at the median (1960 fmol/ml). Mutations in exons 18–21 of EGFR and IHC-expression of EGFR, pEGFR, ER, PRA, PRB, pERK, or Ki67 were examined in tumors. Results: Of the 29 enrolled, 26 were evaluable for efficacy and toxicity. Four had PFS ≥6 months, 1 had a complete response, 7 had stable disease, 16 had progressive disease and 2 were indeterminate. High pre-cycle 1 sEGFR level was favorably associated with OS (hazard ratio = 0.33, 95% confidence interval = 0.13–0.84). A mutation in exon 18 of EGFR (E709K) was observed but was not associated with clinical outcome. None of the tumor markers was associated with response, PFS, or OS. Among some of the notable correlations observed in primary tumor expression were ER with PRA (r = 0.504), EGFR with pERK (r = 0.802), and pEGFR with pERK (r = 0.728). Changes in expression were notable for pEGFR (increasing) and pERK (increasing) in primary versus pre-treatment persistent/recurrent tumor. Conclusions: The regimen was tolerable but lacked sufficient efficacy to warrant further evaluation in this setting, however, the association between serum sEGFR and OS, correlations between tumor markers, and changes in expression of pEGFR and pERK are interesting and should be validated in future investigations. This study was supported by NIH grant R01CA099908 and NCI grants CA27469, CA11479 and CA37517. No significant financial relationships to disclose.
Adjuvant hysterectomy following unsuccessful intracavitary brachytherapy in cervical carcinoma
Authors: Chue A. L. , Walji N. , Rogers L. J. , Hussain S. A. , Chan K. K. , Singh K. , Fernando I. N. 
Published: August 2020

e16543 Background: In cervical carcinoma unsuccessful intracavitary brachytherapy (ICBT) treatment results in sub-optimal chemoradiation (CRT) thus increasing risk of recurrence. Optimal management following unsuccessful ICBT remains undefined. Methods: Retrospective analysis of all women with cervical carcinoma treated from January 2000-July 2007 where ICBT insertion was unsuccessful following initial pelvic external beam radiotherapy (EBRT). Data collected and analysed included histology, stage of disease, response to initial CRT, cause for unsuccessful ICBT insertion and subsequent treatment received, morbidity, and recurrence and survival rates. Results: ICBT insertion was unsuccessful in 18 out of 207 (8.7%) women. Causes of failure included: unable to dilate cervix (3); uterine perforation (2); vesicovaginal fistula (2); patient refusal (3); other problems, e.g., pyometrium (4); consultant choice- no obvious reason (4). 13/18 women (72%) received further pelvic EBRT alone. The remaining 5 women (28%) underwent adjuvant hysterectomy, all within 21 days of completing EBRT. 12/18 women (66%) remain alive and recurrence-free at a median follow-up of 6 years. 6/13 women (46%) in the EBRT alone group have died of disease recurrence of which only 1 patient did not develop pelvic relapse. 3/6 patients had potentially resectable disease at examination under anaesthesia (EUA) prior to attempted ICBT insertion with subsequent MRI scanning demonstrating an apparent near complete initial radiological response. Another patient with initial FIGO stage 2A cervical carcinoma absconded from treatment and potentially had resectable disease following initial CRT. The remaining 2 patients had unresectable disease at EUA. All 5 women in the adjuvant hysterectomy group remain alive and recurrence-free with no patient developing any significant late toxicity such as bowel stenosis or fistula. Conclusions: Adjuvant hysterectomy following unsuccessful ICBT does not appear to increase late toxicity and reduces risk of pelvic recurrence. This may be considered as a treatment option for any woman having sub-optimal CRT where the residual tumour remains operable after initial EBRT. No significant financial relationships to disclose.
Significance of changes in serum CA125 level on overall survival in ovarian cancer
Authors: Williams S. , Gupta D. , Dahlk S. , Dzike K. E. , Lambert G. M. , Lammersfeld C. A. 
Published: August 2020

e16546 Background: The role of baseline serum CA125 as a prognostic indicator in ovarian cancer is well documented. However, little is known about the impact of change in CA125 on survival after 3 months of therapy. We conducted survival analysis to answer the question “what is the prognostic impact of change in serum CA125 after 3 months of therapy in ovarian cancer?” Methods: A case series of 170 ovarian cancer patients treated at Cancer Treatment Centers of America between Jan 01 and May 06. Based on CA125 levels at baseline and 3 months, patients were classified into 4 groups: 1) Normal (0–35U/ml) at baseline and three months; 2) High (>35U/ml) at baseline, normal at three months; 3) Normal at baseline, high at 3 months; 4) High at baseline and three months. Kaplan Meier method was used to calculate survival across the 4 categories, which was defined as the time interval between date of patient visit at 3 months from first visit and date of death from any cause or date of last contact. Results: Of 170 patients, 36 were newly diagnosed while 134 had received prior treatment. 25 had stage I disease at diagnosis, 15 stage II, 106 stage III and 14 stage IV. The median age at presentation was 54.2 years (range 23.1 - 82.5 years). At baseline, 31 patients had normal (0–35U/ml) serum CA125 levels while 138 had high (>35U/ml) levels. At 3 months, 59 had normal while 111 had high levels. In this cohort, patients with a reduced CA125 at 3 months (stratum 2) had a significantly better survival than those with increased CA125 at 3 months (stratum 3). Patients with normal values of CA125 at both baseline and 3 months (stratum 1) had the best overall survival. Conclusions: These data show that reduction in CA125 after 3 months of therapy is associated with better overall survival in ovarian cancer. Patients without a significant decline in CA125 after 3 months of therapy have a particularly poor prognosis. [Table: see text] No significant financial relationships to disclose.
Prognostic significance of immunohistochemical markers in endometrial cancer treated with chemotherapy
Authors: Lord S. R. , Vasudev N. , Knight S. , Speirs V. , Hall G. 
Published: August 2020

e16551 Background: The proportion of patients receiving chemotherapy for endometrial cancer is increasing both in the adjuvant and advanced setting. The literature describes many prognostic immunohistochemical factors in early stage endometrial cancer, the majority of whom will not receive chemotherapy. The aim of this study was to describe the biomarker expression for endometrial tumours treated with chemotherapy and to assess what constitutes a favourable and unfavourable profile for this patient group. Methods: For a subset of patients with either endometrioid, serous or a mixed mullerian morphology treated with chemotherapy at our centre between 1996 and 2008 an immunohistochemical profile of 14 biomarkers was studied (ERα, Erβ1, Erβ2, PR, PRB, P53, Rb, E-cad, MDM2, MIB-1, E2F1, p16, p13, and p21). A univariate analysis using cox regression of potential prognostic factors was then carried out. Results: In total 199 patients received chemotherapy for endometrial cancer over the 12 year period studied. Two year survival from commencement of chemotherapy for patients receiving adjuvant treatment was 45.2% and palliative treatment 28.1%. The commonest histological subtypes were endometrioid adenocarcinoma (40%), serous carcinoma (24.1%) and mixed mullerian tumours (14.6%). For the subset of 35 patients 38.2% of patients had positive immunohistochemical staining for ERα, 53% for PR, 73.5% for p16, and 94% for E2F1. Good prognosis was predicted by the strength of staining for E2F1 (HR 0.757, CI 0.216/0.902, p = 0.025) and poor prognosis by p16 (HR 1.470, CI 1.040/2.077, p = 0.029). Conclusions: Positive staining for ERα and PR was of similar frequency to previous studies of early stage endometrial cancer and did not significantly influence prognosis. Good prognosis correlated with E2F1 expression and poor prognosis with p16. A greater proportion of patients had serous morphology compared to published series of early stage endometrial cancer. Further study of prognostic factors in larger numbers of patients and built into prospective randomised trials may allow the creation of a prognostic model and guide the development of future clinical trials of targeted therapy. No significant financial relationships to disclose.
Targeting the extrinsic apoptotic pathway in endometrial carcinoma cell lines and tumor cell explants
Authors: Matias-guiu X. , Dolcet X. , Llobet D. , Poveda A. , Pallares J. , Eritia N. , Yeramian A. , Sorolla A. , Ortega E. , Llombart-Cussac A. 
Published: August 2020

e16555 Background: Endometrial carcinoma (EC) frequently shows deregulation of the extrinsic apoptotic pathway. One of the critical regulators of apoptosis resistance in EC is FLIP, under the control of NFkB and a cellular complex composed of CK2, KSR1, and BRAF. Methods: Four different EC cell lines, which are known to exhibit resistance to TRAIL/FAS-induced apoptosis (Ishikawa, KLE, HEC1A, and RL-95) were exposed to various pharmacologic substances that target proteins involved in the regulation of the extrinsic apoptotic pathway and receptor tyrosine kinases including bortezomib, sorafenib, sunitinib, DRB, apigenin, MG-132, epoxomicin, and ALLN. Moreover, EC cell lines were subjected to down-regulation of several of these genes (FLIP, CK2, KSR1, and BRAF) by shRNA. Cell viability and apoptotic morphology was determined. Results were validated in tumor cell explants. Results: Bortezomib induced cell death on EC cells and primary explants to a 70% extent. However, 100% of treated explants and cell lines activated NF-kB instead of blocking its transcriptional potential. Combination of sunitinib plus bortezomib induced 75% fold reduction in NFkB activity and induced a 5% of synergistic increse of apoptotic cell death in Ishikawa cells. Treatment of the four cell lines with TRAIL failed to induce cell death. However, FLIP knock-down sensitized the cells to TRAIL-induced apoptosis (80%). Moreover, down-regulation of CK2, KSR1, and BRAF by pharmacological inhibition, or shRNA, reduced FLIP cellular levels, and induced TRAIL-dependent apoptosis in 70%-100% of EC cell lines tested. Sorafenib induced a dose-dependent cell death in all four cell lines, to a 70%-100% extent at 48 hours. Conclusions: In vitro pharmacologic targeting of the apoptotic pathway effectively induces cell death in EC cell lines. These findings justify clinical trials with these agents in EC. [Table: see text]