bluuebunny/crossref_metadata_2025 huggingface dataset:
Dalteparin low molecular weight heparin (LMWH) in ovarian cancer: A phase II randomized study
Authors: Elit L. , Lee A. , Julian J. , Hoskins P. , Julian D. , Parpia S. , Levine M.
Published: August 2020

e16529

Background: Up to 17% of women with ovarian cancer (OC) develop venous thromboembolism (VTE). LMWH reduces the risk of VTE and may have antineoplastic effects because tissue factor on OC cells stimulates tumor growth. A multicentre, open-label phase II randomized trial was undertaken to identify a potentially efficacious and safe dose of dalteparin to investigate its antineoplastic potential in OC. Methods: Women with newly diagnosed epithelial OC were randomized to receive taxane and platinum chemotherapy (CT) and one of 3 doses of dalteparin (50 IU/kg, 100 IU/kg, or 150 IU/kg) subcu daily during the first 3 cycles of CT. With each cycle of CT, patients had a CA125 and were assessed for bleeding or VTE. A response was defined as a ≥50% reduction in CA125 from baseline sustained for at least 28 days (according to GCIG criteria). To select the best LMWH group with a ≥ 80% response rate (RR) {vs. 60% with CT alone} with 90% probability, 39 patients per group were needed. Patients were followed until the end of CT. Results: 77 women were randomized and 72 of them completed follow-up. Compliance with injections was > 80%. There were no major bleeding events and 3 patients in the highest dose group had minor bleeding. There were no VTEs while on or within 7 days of finishing LMWH. There were 2 deaths attributed to the underlying OC. A 50% drop in CA125 by the start of cycle 4 was seen in 87% of the 50 IU/kg group, 92% of the100 IU/kg group, and 84% of the 150 IU/kg group, respectively. The corresponding RRs by the end of cycle 6 were 91%, 92% and 92%. Conclusions: Use of dalteparin is safe and well tolerated in women who are receiving CT for newly diagnosed OC. This therapy was effective in preventing VTE. A dose response effect on CA125 levels was not identified.

[Table: see text]
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]
Survival impact of neoadjuvant treatment in cervical cancer stage IIB
Authors: Oliveira H. F. , Peria F. M. , Andrade J. M. , Marana H. R. , Santos A. C. , Mendonça L. M. , Elias J.
Published: August 2020

e16559

Background: A few previous studies demonstrated that neoadjuvant chemotherapy, followed by preoperative radiotherapy in diagnosed IIB cervical cancer patients, had similar therapeutic results as the standard protocol with concurrent chemoradiotherapy, considering complete response; overall survival; disease free survival and toxicity; requiring its evaluation as an alternative approach. Methods: One hundred sixteen women with IIB stage cervical cancer stages were submitted to a platinum combined based neoadjuvant chemotherapy followed by chemoradiotherapy with cisplatin. Those who had a good response, allowing a surgical approach, underwent the Wertheim-Meigs procedure. Those that could not be submitted to surgery remained in clinical follow-up. Results: The age of the patients were 22 to 75 years old (48.7±11.4 years). The average follow-up was about 48 months (1–120). The good response to the neoadjuvant treatment was found in 76 patients (65.5%), and surgery was possible in 86 (74%). The pathological complete response was found in 39 (33%), and the partial response in 40%. The global recurrence was diagnosed in 37 (32%) patients. In the operated group (n = 86), the overall-five years survival was 76%, and in the non-operated group (n = 30) was 17,5%. The five years-global survival was 79,2% in “good response” (GR) patients, and 27.4% in that with “no-good response” (NGR) to combined neoadjuvant treatment ( p < 0.01). The free-relapse survival was 79.4% in GR, and 32.5% in NGR group (p < 0.01). Conclusions: Amongst the studied prognostic factors, the most important one for interval of relapse and survival (global and free-relapse) was a good response to the neoadjuvant treatment, and that this treatment had an acceptable toxicity and could be considered in other trials as an option to standard treatment.

No significant financial relationships to disclose.
Behavior of borderline ovarian tumours (BOTs): Single institution experience
Authors: Oaknin A. M. , Romeo M. , Pons F. , Perez X. , Barretina P. , Vidal A. , Martí L. , Barahona M. , Germá J. , Ponce J.
Published: August 2020

e16560

Background: To provide useful material for discussion, we report an analysis of a retrospective accrued, single-institution population with BOTs. Methods: 99 consecutive patients treated between April 1989 and July 2008, were reviewed for clinical characteristics, histology, surgical types, recurrence, and prognosis. Results: Median age was 46 years (19–77). 90% of patients were diagnosed by vaginal ultrasound as complex adnexal mass. CA-125 and CA19.9 was elevated in 60% and 30% of patients respectively. Primary treatment was surgery: laparotomy and laparoscopy (LT/LC) approach in 78% and 22% of patients, respectively. 33 patients (34%) underwent comprehensive staging operation; fertility-sparing surgery was performed in 18 patients (18%), and an incomplete staging in 47 patients (48%). The pathology results were: clear cell BOTs 1 case (1%); serous 42 cases (42.4%); mucinous in 56 women (56.6%) (46 intestinal/10 mullerian). 2 out of 56 mucinous BOTs were associated with pseudomixoma peritonei. Cyst-rupture was found in 22.5% and 38.9% of patients with LT/LC approach. 91women (93.8%) had stage I; 2 (2%) had stage II; and 6 (4.2%) had stage III disease. We identified 6 patients (7.8%) with noninvasive implants involving abdominal peritoneum (1), pelvic peritoneum (1), omentum (2) and both pelvic peritoneum and omentum (2). With a median follow-up of 3.6 years (0–18.4), we observed 5 recurrences (2 in contralateral ovary, 1 ipsilateral, 1 invasive peritoneal implant, and 1 para-aortic node). All were stage I disease at diagnosis. 2 out of 5 had incomplete staging, 3 had conservative surgery.3 cases were serous type. Histology recurrences were: 2 borderline, 2 invasive ovarian cancer, and 1 unknown. All patients underwent secondary cytoreduction achieving an optimal debulking in 4. Only one patient received chemotherapy. Two women died of intercurrent disease and 1 woman died of disease. The 5-year overall survival rate for entire cohort was 98.5% (95.6%-100%; CI95%). Conclusions: Our results confirm published data. Overall BOTs have an excellent prognosis. Proper staging is the cornerstone of treatment. Laparoscopy approach is associated with higher cyst rupture. Recurrences are more frequent after incomplete or conservative surgery.

No significant financial relationships to disclose.
Outcome analysis of stage II and III cervical carcinoma: Importance of optimal radiation therapy
Authors: Diaz J. J. , Thomas Mr B. , Hernandez E.
Published: August 2020

e16562

Background: The objective of our study was to conduct an outcome analysis of patients with stage II and III cervical cancer (CC) treated in our institution. We sought to asses the effectiveness and toxicity of carboplatin concomitant with pelvic irradiation and the importance of compliance with treatment. Methods: A retrospective chart review was conducted of all patients with stage II and III CC treated at Temple University Hospital from January 2001 to December 2006. Results: Forty-eight patients with stage II and III CC without radiographic evidence of extra-pelvic disease (IIA = 11, IIB = 15, IIIA = 4, IIIB = 18) were treated during the period under study. Four (8%) patients had adenocarcinoma and 44 (92%) had squamous cell carcinoma. Median age at diagnosis was 48.5 (range, 24–83) years. Median follow-up was 23 (range, 1–74) months. Nonsurgical therapy consisting of radiation (RT) with or without chemotherapy (CT) was offered to all patients. Nine patients (19%) received no CT, whereas 36 (75%) received weekly carboplatin (90 mg/m2) and 3 (6%) received weekly cisplatin (40 mg/m2). Median numbers of CT cycles was 5 (range, 1–7). Optimal dose of RT was defined as a minimal cervical dose exceeding 7000 cGy, point A dose of 8000–9000 cGy and treatment duration not exceeding 56 days. Only 21 (44%) patients received optimal RT. Only 2 patients treated with carboplatin had grade 3 or 4 toxicity. The 5-year progression free survival (PFS) and overall survival (OS) was 41% and 56%, respectively. The pelvic failure (PF) and distal failure (DF) were 38% and 26%, respectively. There were only 4 PF (19%) and 4 DF (19%) in the 21 patients who received optimal RT. The estimate of probability of 5-year pelvic failure rate in patients who received optimal therapy and patients who received suboptimal therapy was 23% vs. 48% (p = 0.2) . On subset analysis patients who received optimal RT had a better 5-year OS (72% versus 45%, p = 0.09). The most important predictor of optimal radiation was compliance with treatment plan. Conclusions: Optimal RT is crucial for successful treatment of advanced CC. Chemo-sensitization with carboplatin is effective and well tolerated.

No significant financial relationships to disclose.
Effects of ascites on perioperative and postoperative outcome in epithelial ovarian cancer
Authors: Novetsky A. P. , Pua T. L. , Curtin J. P.
Published: August 2020

e16567

Background: A third of epithelial ovarian cancer (EOC) patients (pts) present with ascites at the time of diagnosis. Though not universally accepted, ascites has been reported to be a poor prognostic factor. Our purpose is to study the effects of ascites on the peri and postoperative outcome in EOC patients undergoing cytoreductive surgery. Methods: 172 EOC pts were retrospectively evaluated to determine the prognostic significance of ascites. Pts were divided into two groups based on the presence of ascites defined in pre-operative CT scans as A, none/small, versus B, moderate/ large. Influence of ascites on peri- and post-operative characteristics such as estimated blood loss (EBL), rates of optimal cytoreduction, intensive care unit (ICU) admission, minor complications (infection, ileus/bowel obstruction, transfusion, wound separation, DVT/PE), major complications (death or readmission within 30 days) and length of hospital stay (LOS) were analyzed using Chi Square, multivariate linear and cox regression, where appropriate. Results: There was no significant difference in EBL between the two groups (p = 0.27). Pts in A were more likely to be optimally cytoreduced compared to B (96% vs 61%, p < 0.001). After controlling for stage, women in B were more likely to be admitted to the ICU, (OR 3.03 (95% CI: 1.05–8.71). The rates of major complication was higher for B (3% vs 10%) though this did not reach statistical significance (p = 0.06). Overall minor complications were greater for B than in A (64% vs 26%, p < 0.0001). After controlling for stage, LOS was 2.9 days longer in B (p = 0.02). 21 women received at least 3 cycles of neoadjuvant chemotherapy prior to cytoreduction. EBL, LOS and major complications were no different than those undergoing primary cytoreduction then adjuvant chemotherapy. Conclusions: Optimal management of EOC pts with ascites is uncertain. Pts with ascites are more likely to be suboptimally cytoreduced, have increased rates of complications and consume more healthcare resources (ICU admission and longer LOS). Though our numbers are small, patients who received neoadjuvant chemotherapy do not have any difference in peri-post operative characteristics, but were all optimally cytoreduced.

No significant financial relationships to disclose.
The Ep-CAM: A potential candidate for diagnosis in ovarian cancer
Authors: Sawasaki T. , Katsube Y.
Published: August 2020

e16571

Background: The purpose of this study was to examine the expression of splice variants of the Ep-CAM gene in normal ovarian epithelial tissue and ovarian carcinoma and further to associate the expression of Ep-CAM with clinicopathologic characteristics if such an association exists. Methods: Ep-CAM expression was examined by semiquantitative PCR in 122 ovarian tumors (92 adenocarcinomas, 10 low malignant potential (LMP) tumors, and 10 adenomas) and 10 normal ovaries. Results: In carcinomas as well as LMP tumors and adenomas, Ep-CAM mRNA expression was significantly elevated compared to that in normal ovary samples. Ep-CAM mRNA expression level in carcinomas was significantly elevated compared to that in adenomas and Ep-CAM mRNA expression level in advanced clinical stage diseases was significantly higher than that in early stage diseases in ovarian carcinomas. With regard to histological type, Ep-CAM mRNA expression level in mucinous adenocarcinomas was significantly higher than those in the other tissue subtypes. Conclusions: These features imply that Ep-CAM expression may play an important role in ovarian cancer development and progression, and this may be useful as a diagnostic marker.

No significant financial relationships to disclose.
Hormonal treatment of metastatic endometrial stromal sarcoma
Authors: Terada K. Y. , Davis J. , Kitayama J. , Shimizu D.
Published: August 2020

e16576

Background: Endometrial stromal sarcomas (ESS) traditionally have been classified as low grade or high grade based on mitotic activity and histologic appearance. High-grade tumors are currently referred to as undifferentiated uterine sarcomas and are not included in this series. ESS are known to have high expression of estrogen and progesterone receptors. This is a retrospective study of patients with metastatic ESS treated with hormonal therapy. Methods: Following approval by the institutional review board all patients diagnosed with ESS from 1987–2007 were identified. Clinical and demographic information were abstracted from the charts and all histologic materials were re-reviewed. Estrogen and progesterone receptor testing was performed utilizing mouse monoclonal antibodies and the Cell Analysis Systems 200 Image analyzer. Survival was calculated using the Kaplan-Meier method and comparisons utilized the log rank test. Results: Thirteen patients with ESS were identified during this period. Seven had disease confined to the uterus. Six had extrauterine disease; 5 patients presented with metastases and 1 patient presented with a pelvic recurrence 20 years following a hysterectomy. All underwent surgical resection except for 1 patient that declined surgery. All 6 patients with metastases had tumors that tested positive for estrogen and progesterone receptors; all were treated with megestrol acetate initially for a period of 1–4 years. Two patients were then changed to maintenance with medroxyprogesterone acetate. Three patients with persistent disease were changed to aromatase inhibitors; 1 to letrozole and 2 to anastrazole. One of these patients has had a complete response and 2 have had stable disease. One patient has been lost to follow-up. Follow-up for the 6 patients was 2–22 years; no known patients died of their disease. Actuarial 2- and 5-year survivals were 80% and 65%, respectively. There was no significant difference in survival between patients with metastases and without metastases. Conclusions: ESS tumors are relatively uncommon and there is an absence of studies to guide treatment of patients with metastases. This experience indicates that these tumors respond well to hormonal manipulation. Treatment with progestins or aromatase inhibitors may result in remission or stable disease.

No significant financial relationships to disclose.
Inhibition of human head and neck squamous cell cancer growth by modulation of heat shock proteins and induction of the mitochondrial apoptotic pathway with withaferin A
Authors: Cohen M. S. , Timmermann B. N. , O'Donnell G. , Samadi A. K.
Published: August 2020

e17003

Background: Epithelial cancers, particularly lung cancer and head and neck squamous cell carcinoma (HNSCC), continue to pose formidable challenges in clinical practice. Novel chemotherapeutic agents have been developed, but even those have limited long-term benefits in the treatment of these tumors, illustrating the need to continue to improve systemic therapy for affected patients. The objective of the present study was to investigate the effect of withaferin A (WA), a plant-derived small molecule, on cancer cell growth, heat shock protein expression and induction of apoptosis in human HNSCCs. Methods: MDA1986 and JMAR HNSCC cells were used in all experiments. The effect of WA on cell viability was determined by MTS assay. Apoptosis and mitochondrial membrane potential changes were assessed by annexin V/propidium iodide and JC-1 staining respectively using standard flow cytometry methods. Effect of WA on modulation of heat shock proteins was determined by Western blot analysis. Results: Withaferin A reduces cell viability in both MDA1986 and JMAR cells with IC50 levels of 265 ± 5 nM by MTS assay, which is 5 fold higher than its reported activity in breast cancer cells. WA completely down-regulates HSP90beta, GRP94, and TRAP-1 expression at 250 nM concentration in HNSCC cells at 24 hours treatment. In addition, WA markedly increased HSP70 levels and mildly increased HSP27 levels in a dose-dependent manner at 24 hours treatment. Flow cytometry with Annexin V/PI staining shows that 5 μM WA treatment for 24 hours induced apoptosis in 63% of MDA1986 and 60% of JMAR cells. WA at 5 μM also reduced mitochondrial membrane potential by JC-1 staining with flow cytometry to less than 10% of controls in both JMAR and MDA1986 cells at 24 hours treatment. Conclusions: Withaferin A is a potent novel inhibitor of HSP90 in human HNSCCs. In addition to HSP modulation, its anticancer mechanistic effects involve apoptotic cell death through the mitochondrial pathway. This molecule shows promise for further in vivo studies to establish preclinical proof of concept as a novel anticancer therapy in this disease.

No significant financial relationships to disclose.
Survival for nasopharyngeal cancer with distant metastatic disease at presentation
Authors: Dandona M. A. , Morgensztern D. , Auethavekiat V. , Adkins D. , Thorstad W. , Nussenbaum B. , Zhang Q. , Kuperman D. I.
Published: August 2020

e17004

Background: Nasopharyngeal carcinoma (NPC) is a unique form of head and neck cancer, with distinct epidemiology and sensitivity to chemotherapy (CT) and radiation (RT). Long-term survival has been reported for selected patients with metastatic disease. However, given its rarity in the Western Hemisphere, data is limited to case series. We used the Surveillance Epidemiology and End Results (SEER) database to determine factors that correlated with prolonged survival in patients with metastatic NPC at presentation. Methods: The SEER database was searched for patients with NPC who have distant metastatic disease at presentation, defined as extent of disease (EOD10) code 85, aged 20 or older, diagnosed between 1988 and 2003. Survival probability was estimated by Kaplan-Meier method and covariate effects were examined using log-rank tests. Parameters evaluated include age, gender, race, tumor grade, and use of RT. Results: Among the 2,610 patients with NPC in SEER, 177 (6.7%) were identified with distant metastatic disease at presentation. Five patients were excluded from subsequent analysis because RT data was not available. RT was administered to 114 patients (66.3%). Median survival was 9 months (95%CI: 7–13 months) and 5-year overall survival (OS) of 20% (95%CI: 14–26%). Outcomes were significantly improved for patients treated with RT compared to those not receiving it, with the 5-year OS rates of 28% versus 3% (p < 0.0001) respectively. Other factors associated with improved survival included non-white race (p = 0.01) and younger age (p < 0.0001). Conclusions: Although SEER lacks information on performance status, site of metastases, and CT use, our data shows that selected patients with metastatic NPC may achieve prolonged survival, particularly if RT is used. It is unclear whether RT is a determinant of better OS or an epiphenomenon.

No significant financial relationships to disclose.
A phase II study of single agent OSI-7904L in patients with metastatic or recurrent squamous cell carcinoma of the head and neck (SCCHN)
Authors: Hough B. , Posner M. , Chung C. , Hainsworth J. , Horan J. , Chick J. , Gibson M. K.
Published: August 2020

e17005

Background: Given the limited efficacy and relative toxicity of chemotherapy for metastatic or recurrent squamous cell carcinoma of the head and neck, further research is needed to both increase the efficacy and decrease the toxicity of treatment. OSI-7904L is a novel liposomal formulation of a non-competitive thymidylate synthase inhibitor. In a phase I study, 12 mg/m2 dosing given every 21 days was both feasible and well tolerated. Methods: This multi-center, two-stage, phase II trial was designed to assess the efficacy and toxicity of OSI-7904L in patients with advanced, refractory SCCHN. A total of 41 patients were to be enrolled by completion of stage II. Enrollment was limited to patients with histologically proven squamous histology, locally recurrent and/or metastatic disease, with no more than one prior chemotherapy regimen. Patients were required to have a performance status of ≤ 2, predicted life expectancy of at least three months and adequate hematopoietic, hepatic and renal function. Efficacy was assessed according to RECIST guidelines, and toxicity was evaluated per CTC AE 3.0. Results: Ten patients enrolled in stage 1. Median age was 60 (range 42–66). Nine were evaluable for response assessment with one withdrawn after one cycle due to a grade 4 papular rash. There were no objective responses while 4 of the 10 patients had stable disease during their first restaging. Median time to progression was 2.5 months for the 9 evaluable patients. Besides the one grade 4 dermatologic reaction, other toxicities were grade 3 fatigue and dehydration, and grade 2 anorexia. Assuming an expected 20% response rate required to initiate enrollment in stage II, the probability of the tenth patient being a responder was less than 3%, thus the study was closed due to lack of response in this population. Conclusions: OSI-7904L was well tolerated similar to the phase I data, but did not demonstrate efficacy in metastatic or recurrent HNSCC patients. Further study of this drug as a single-agent with the current dosing regimen is not recommended.

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Effect of human papillomavirus (HPV) 16 E6 and E7 gene silencing on epidermal growth factor receptor (EGFR) phosphorylation status in HPV16+oropharyngeal cancer cell lines
Authors: Rampias T. , Sasaki C. , Psyrri A.
Published: August 2020

e17006

Background: Aberrant activation of EGFR intrinsic tyrosine phosphotransferase activity correlates with poor prognosis in several cancers. In this study, we sought to determine the effect of HPV16 E6 and E7 gene silencing on the status of EGFR phosphorylation in HPV16+ oropharyngeal cancer cell lines. Methods: Short hairpin RNAs targeting HPV type 16 E6 and E7 genes were delivered by retrovirus infection to HPV16+ oropharyngeal cancer cell lines 147T and 090. E6/E7 repression was assessed by quantitative reverse transcription polymerase chain reaction and western blotting for p53 and Rb protein levels 48 hours after retrovirus infection. Phospho-EGFR (Tyr1068), (Tyr845), (Tyr992), (Tyr1045) and total EGFR protein levels before and after silencing were then analyzed by western blotting in 147T and 090 oropharyngeal cancer cell lines. Results: Quantitative RT-PCR analysis showed reduction in E6/E7 mRNA levels up to 85% the level in uninfected or control shRNA infected cell lines. Protein expression revealed substantial downregulation of phospho-EGFR (Tyr992) protein levels, 48 h after the retrovirus infection of 090 and 147T cell lines. A slight reduction of phospho-EGFR (Tyr845) was also observed in both HPV16+ cell lines after silencing. No phosphorylation was detected at sites Y1068 and Y1045 of EGFR. Conclusions: We provide evidence that E6 and E7 are involved in tyrosine phosphorylation of epidermal growth factor receptor at sites Y992 and Y845. Phospho-tyrosine 992 is a direct binding site for the PLCγ SH2 domain and phosphorylation in this site is associated with activation of PLCγ-mediated downstream signaling. Phosphorylation of Tyr845 in the kinase domain is implicated in stabilizing the activation loop maintaining the enzyme in an active state. Since enhanced EGFR activation appears to be a direct consequence of E6/E7 expression, targeting E6/E7 may be effective EGFR blockade in HPV16+oropharyngeal cancers.

No significant financial relationships to disclose.