bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase II study of low-dose prolonged infusional gemcitabine combined with oral treosulfan in patients with platinum- and taxane-resistant ovarian cancer or other Mullerian tract carcinomas
Authors: Kurbacher C. M. , Kurbacher J. A. , Cramer E. , Reinhold U. , Nagel W. J. , Reichelt R. , Cree I. A. 
Published: March 2020

15004 The prognosis of patients (pts) with epthelial ovarian cancer (EOC) and other Mullerian tract carcinomas such as papillary-serous peritoneal carcinoma (PSPC), fallopian tube cancer (FTC), and uterine papillary-serous carcinoma (UPSC) resistant to both platinum and taxanes is particularly poor. Recently, we have reported preliminary results of modified GeT - gemcitabine (dFdC) and treosulfan (TREO) (Kurbacher et al, Proc ASCO 2005). Now, mature results of this phase II trial are available. A total of 35 patients (pts) were included (EOC, 29; FTC, 4; PSPC, 1; UPSC, 1). Patients had failed a median of 2 prior chemotherapies (1, n = 10; 2, n = 11; 3, n = 7; 4, n = 3; 5, n = 3; 7, n = 1) including platinum and paclitaxel in all, anthracyclines in 16, dFdC in either 6, and topotecan in 5 pts. GeT was administered at a q2w schedule with dFdC at 450 mg/m2 (3 h infusion), day 1, and oral TREO at 1,000 mg/m2/d, day 1–4. A total of 192 cycles were given with a median of 6 (range: 2–10). All pts had measurable or evaluable disease according to RECIST and Rustin criteria, repectively. All treatments were evaluable for both toxicity and response. Myelosuppression was frequent but exceeded NCI-CTC grade 2 in only 17/192 cycles (9%). G 3–4 neutropenia was observed during 5/192 cycles (3%), G 3–4 thrombocytopenia did not occur. Interval prolongation due to febrile urinary tract infection or subileus was necessary in two pts. In another patient, treatment was terminated due to non-fatal pulmonary embolism. Other toxicities did not exceed NCI-CTC grade 2 nor did any other patient require hospitalization due to therapy-related complications. A total of 11 CR, 7 PR, 9 SD, and 8 PD were recorded accounting for an objective response rate of 51% with 27 pts (77%) benefiting from GeT. The median progression-free survival was 27 weeks. Until now, 15 pts are still alive, the median overall survival is 76.5 weeks. Regarding the intensive pre-treatment of the pts, the modified GeT treatment was easy to tolerate and produced a promising clinical efficacy in EOC and other Mullerian tract carcinomas resistant to both platinum and taxanes. Large-scaled clinical trials are now warrented to confirm these encouraging results. No significant financial relationships to disclose.
Evaluation of antibodies induced by an HPV vaccine to cross-neutralize pseudovirions of vaccine-related HPV types
Authors: Bryan J. T. , Smith J. F. , Ruiz W. , Brownlow M. K. , Brown M. J. , Esser M. T. 
Published: March 2020

15008 Background: Human papillomavirus (HPV) is the causative agent of cervical cancer. The HPV types 6, 11, 16 and 18 quadrivalent L1 virus-like particle (VLP) vaccine has been shown to be highly efficacious in preventing HPV vaccine type-related disease. The HPV A7 species contains types 18, 45 and 59. The A9 species include types 16, 31, 33, 35, 52 and 58. The potential of the vaccine induced antibodies to cross-neutralize infection of pseudovirions (PsV) of HPV types within the A9 and A7 species was evaluated. Methods: Sera from quadrivalent, monovalent HPV 16, or monovalent HPV 18 vaccinees were evaluated. Sera were tested in a multiplexed competitive Luminex Immunoassay (cLIA) against vaccine types to demonstrate HPV type-specific seroconversion. A9 and A7 VLP type cross-reactive binding ability was assessed by a total IgG LIA. HPV L1 and L2 PsV containing secreted alkaline-phosphatase (SEAP) sequences were constructed using native HPV sequences for 16 and 31 and with mammalian codon-optimized sequences for 18 and 45. Demonstrated expression of SEAP was used as an indirect measure of PsV infection of 293TT cells. Results: All subjects seroconverted to high titers against the vaccine HPV types. Cross-reactive antibodies were generated. Quadrivalent vaccinee sera bound to HPV 31, 45, 52 and 58 VLPs. These total IgG titers were 1.5–2 logs lower than the titers to the vaccine types. PsV types 18 and 45 were neutralized using the 18 monovalent and the quadrivalent sera. At month 7, the PsV 18 neutralization titer was ∼1–1.5 logs less than that required for PsV 45 cross-neutralization. Neutralization studies using PsV of the A9 species are in progress. Conclusions: High titers of anti-HPV antibodies are elicited by vaccination with HPV VLP vaccines. These antibodies can prevent in vitro PsV infection of vaccine-HPV types. Cross-reactive, cross-neutralizing antibodies are generated, however at reduced titers compared to the vaccine-specific types. Antibody titers required for cross-protection against non-vaccine types are not known. [Table: see text]
Phase II study on the combination carboplatin-celecoxib in heavily pre-treated recurrent ovarian carcinoma patients
Authors: Legge F. , Salutari V. , Paglia A. , Testa A. , Lorusso D. , Colangelo M. , Kaye S. , Scambia G. , Ferrandina G. 
Published: March 2020

15009 Background: Cyclooxygenase-2 (COX-2) has been shown to be involved in several steps of ovarian onset and progression and its overepression is associated with a poor chance of response to chemotherapy and poor prognosis in ovarian cancer. Celecoxib, an orally active selective COX-2 inhibitor, has been tested for its ability to potentiate the activity of carboplatin in treatment of heavily pretreated recurrent ovarian cancer patients. Methods: A phase II study was planned, considering the regimen active if at least 12 responses were observed among the 43 enrolled patients. Celecoxib (400 mg/die), and carboplatin (5 AUC) q28 were administered, until progression or unacceptable toxicity. Response was assessed by RECIST and also by Rustin criteria. Results: 34 pts (median age: 60 yrs, range 28–74) and an ECOG performance status (0/1/2) of (21/12/1), were enrolled. 58.8% of patients were platinum resistant (progressing during or < 6 months from primary treatment). Median number of previous chemotherapy regimens was 3 (range 2–6). Currently 27 patients are evaluable for response. The overall response rate (CR and PR) was 25.9% (2 CR, 5 PR) with stabilization of disease in 8 patients (29.6%). Four responses occurred in platinum sensitive and 3 in platinum resistant group Median time to response was 11 weeks (range 9–19) and median duration of response was 23 weeks (range 12–39). According to Rustin criteria 10 patients out of 25 (40%) were considered responsive to treatment (return of CA125 levels to normal level or >50% reduction). Overall, 143 cycles were administered with a median value of 3 cycles (range = 1–10). Moderate/severe toxicities were as follows: G3 anemia occurred in 2.3% cycles, G3 neutropenia in 4.6% cycles, G3 thrombocytopenia in 1.5% cycles, G3/4 gastrointestinal toxicity occurred in 4.6% cycles. Cutaneous diffuse erithema was observed in 2 patients, in both cases recovered with a short period of antihistaminic treatment; 2 cases of hypertension were documented, G2 hypersensitivity reactions during carboplatin infusion were observed in 4 cases. Conclusions: Celecoxib combined with carboplatin is well tolerated and has promising activity as salvage treatment in heavily pretreated recurrent ovarian cancer patients. No significant financial relationships to disclose.
A phase II trial of weekly one hour paclitaxel as second-line therapy for endometrial and cervical cancer
Authors: Homesley H. D. , Vaccarello L. , Lowendowski G. , Elbendary A. A. 
Published: March 2020

15013 Background: The antitumor activity of other regimens of paclitaxel (from Bristol-Myers Squibb Oncology, Bristol-Myers Squibb Company, Princeton, NJ, U. S. A.) has been identified in both cervical and endometrial cancer. A less toxic and better tolerated regimen for paclitaxel is a one hour infusion every 7 days. The primary aim of this study was to assess the activity of weekly paclitaxel in patients with recurrent or refractory endometrial cancer or squamous cell cancer of the cervix who had failed one prior chemotherapy regimen and had measurable disease. The nature and degree of toxicity of paclitaxel administered in this schedule in this group of patients was assessed. Methods: Eligible patients had initial histologic diagnosis. All patients presented with persistent or recurrent measurable disease with no more than one prior chemotherapeutic regimen and a GOG Performance Status of 2 or better. At entry hematologic and all other labs were within normal limits. Patients received paclitaxel 80 mg/m2 over one hour every 7 days. One cycle consisted of four weeks and patients had to receive at least two cycles of therapy to be evaluable for response unless progression occurred during the first eight weeks of the trial. Response by measurable disease change and survival were the endpoints of the trial. Results: Forty-three patients were registered. Evaluable for response were 15/16 patients with endometrial cancer and 20/29 patients with advanced cervical cancer. For the endometrial cancer patients 4 of 15 responded. Two of four responders had complete responses with durations of response of 16 to 23 weeks. Stable disease was present in 33%. There were two responders (one a complete response) in the 20 evaluable patients with cervical cancer while 35% had stable disease. Adverse effects were minimal and easily managed with dose adjustments as needed. Conclusions: In this trial, weekly paclitaxel as second line therapy had a response rate of 27% (4/15) in endometrial carcinoma but only 10% in advanced cervical cancer (2/20). Although confirmatory larger trials are needed, weekly paclitaxel appears promising for advanced endometrial carcinoma but not for squamous cell carcinoma of the cervix. [Table: see text]
Cambridge Translational Cancer Research Ovarian Study 01 (CTCR-OV01): Expression profiling of advanced epithelial ovarian cancer (EOC) to predict chemotherapy response. A randomised phase II trial design with prospective translational endpoints
Authors: Earl H. M. , Ahmed A. , Vallier A. , Hatcher H. , Parkinson C. A. , Iddawela M. , Latimer J. , Crawford R. , Brenton J. D. 
Published: March 2020

15018 Methods: CTCR-OV01 is a randomised phase II neoadjuvant study in stage III-IV epithelial ovarian cancer (EOC). Patients (pts) were consented for diagnostic and fresh tissue research biopsies, and after diagnosis was confirmed, were randomised (1:1) to: Arm A: Carboplatin AUC 7 every 3 weeks (C) × 3 cycles (cy); then interval debulking surgery (IDS); then C AUC 6 with paclitaxel 175 mg/m2 q 3w (CT) × 3 cy; and finally paclitaxel 175 mg/m2 q 3w (T) × 3 cy. Arm B: T × 3 cy; IDS; CT × 3 cy; C × 3 cy. At IDS further fresh tissue samples were collected. Clinical Endpoints: (i) Partial response rate after three cycles of chemotherapy based on CA125 (CA125 RR) and CT scan (CT RR). (ii) Median progression-free survival (PFS). Translational endpoints: Candidate genes and molecular profiles as predictive markers of response/resistance to C and T. Results: Jan ‘02-Dec ‘04, 48 pts were randomised in a single centre study. 4 patients were excluded from analysis (3pts severe toxicity; 1pt incorrect histopathology), leaving 44 patients (21pts A/23 pts B). Median age 60 yr (range 36–75 yrs); 42/44 serous papillary histology; stage III/IV = 77%/23%; grade I/II/III = 2%/34%/64%. All prognostic factors were well balanced between treatment arms. Median follow-up is 22 months (IQR 17–33.5). CA125 RR to pre-operative chemotherapy was A/B = 65%/60% (p = 1). CT RR was A/B = 47%/35% (p = 0.15). CA125 RR, was significantly associated with improvement in progression-free survival (PFS) compared to non-responders (17.3 v 12.4 months; log rank test p = 0.027). Optimal debulking surgery was possible in A/B = 53%/63%. Median PFS was 14 months (m) (A/B = 13 m/14 m (p = 0.53)). Supervised analysis of Affymetrix expression data showed significant enrichment for differential extracellular gene expression in paclitaxel resistant patients. Conclusions: Prospective controlled randomized trials using neoadjuvant treatment are ideally suited for translational research in EOC and provide unique sample sets molecular analysis. No significant financial relationships to disclose.
Pattern of care study for treatment of ovarian cancer patients among Japanese gynecologists. A Japanese Gynecologic Oncology Group (JGOG) study
Authors: Fujiwara K. , Sugiyama T. , Aotani E. , Kigawa J. , Kuzuya K. , Saji F. , Ochiai K. , Noda K. 
Published: March 2020

15029 Background: The Japanese Society of Gynecologic Oncology started a training program for the subspecialty of board certified gynecologic oncologists in 2005. This study aimed to assess the attitude of Japanese gynecologists for the treatment of ovarian cancer in pre-gynecologic oncologist era. Methods: The JGOG distributed a survey to 217 member institutions in January 2005. The principal investigator (PI) of each institution answered 33 questionnaires regarding diagnostic, surgical and chemotherapy issues. The survey was returned from 156 institutions (71.9%). Results: Hospital settings were general (44%), academic (44%), Cancer Center (8%), or private (4%). Only two of PIs were medical oncologists and rests of them were gynecologists. As the staging procedure in early ovarian cancer, 67% institutions do systemic pelvic lymphadenectomy (LNX) but 22% do only sampling. For the paraaortic nodes, 36% do systemic LNX and 10% do sampling below renal vein, and 14% do LNX and 12% do sampling below inferior mesenteric artery. However, intraabdominal explorations such as multiple peritoneal biopsies have been done only less than 30% except for omentectomy (90%). With regard to the surgery for advanced ovarian cancer, 57% institutions do not do any intestinal resection and anastomosis during the primary surgery. Among them 7% of institutions prefer neoadjuvant chemotherapy (no debulking at all) for advanced ovarian cancer. However, 84% of the institutions do interval debulking and 57% of them are quite aggressive for the procedure. These results demonstrate the high expectation that chemotherapy may reduce the aggressiveness of surgery for advanced ovarian cancer. In terms of chemotherapy for the high-risk early and advanced ovarian cancer, taxane plus platinum is the most used regimen (93–95%). However, 45% of institutions prefer different regimen for clear cell carcinoma. CPT-11 is the most used (88.6%). Intraperitoneal chemotherapy has been performed in 28.2% of institutions. 37.2% of institutions do consolidation chemotherapy. Conclusions: This is an important base-line information to assess the pattern of care for ovarian cancer patients in the era before gynecologic oncologist subspecialty is applicable in Japan. No significant financial relationships to disclose.
Aromatase inhibitor therapy for estrogen receptor positive ovarian cancer
Authors: Tchekmedyian N. S. , Liem A. K. , Quan E. T. , Burtzo D. M. , Ucar K. 
Published: March 2020

15038 Background: Aromatase inhibitors (AI) are effective therapy for estrogen receptor positive breast cancer. We retrospectively reviewed our experience with AI therapy of 14 advanced ovarian cancer patients. Methods: Between March 2001 and January 2006, 14 women with ages ranging from 40 to 80 years received letrozole 2.5 mg orally once a day for periods of 2 to 36 months. All 14 patients had received prior chemotherapy and had recurrent disease. Eleven had received a mean of 2.8 (range 1–7) different chemotherapy regimens for advanced recurrent disease. Six of the 14 patients had received tamoxifen for periods of 1 to 12 months. Thirteen patients had advanced recurrent invasive epithelial ovarian cancer. One patient had advanced progressive ovarian tumor of borderline malignant potential with pleural involvement refractory to chemotherapy. Estrogen receptor status was positive in 13 patients and unknown in 1. CA-125 levels and clinical evaluations were available for all patients. Results: The mean baseline CA-125 level (U/mL) prior to letrozole therapy was 262, and ranged from 4.1 to 2723. The mean lowest CA-125 level after letrozole was started was 143, and ranged from 1.3 to 1158. Five of the 14 patients had CA-125 declines of ≥50% while on letrozole. Seven of the 14 patients remain on therapy at 2+ to 20+ months. Ten of the 14 patients had sustained clinical improvements or stability and no evidence of disease progression while on AI therapy for a mean period of 12 months with a range of 2 to 36 months. AI therapy was well tolerated. Conclusion: This limited and anecdotal experience suggests that AI therapy may be effective in advanced estrogen receptor positive ovarian cancer, including patients refractory to chemotherapy. AI therapy should be studied further in advanced ovarian cancer and in the adjuvant setting. No significant financial relationships to disclose.
Reduced connexin 43 mRNA levels in human ovarian carcinoma
Authors: Sidell N. , Horowitz I. R. 
Published: March 2020

15071 Background: Cancer cells have been shown to exhibit many defects in gap junctions, which contribute to the loss of growth control and tissue homeostasis. In ovarian tissues, it is known that gap junction communication is predominantly mediated by connexin 43 (cx43) proteins. Recent studies have demonstrated that while human ovarian surface epithelial cells exhibit extensive expression of cx43, this protein is nearly absent in the vast majority of ovarian cancers. Differences in cx43 expression between normal and malignant ovarian tissue at the mRNA level has heretofore not been reported. Methods: In the present study, specimens of normal ovaries and serous adenocarcinomas were obtained at the time of laparotomy and flash frozen in liquid nitrogen. Results: Evaluation of cx43 mRNA levels by semiquantitative RT-PCR indicated significantly reduced expression in tissues obtained from ovarian adenocarcinomas compared to that from normal ovaries; the average relative levels of cx43 mRNA in tumors were less than 30% of that found in normal tissue. In one case in which tumor and adjacent normal tissue was obtained from the same patient, cx43 mRNA expression was reduced in the former to less than 10% of that found in the normal section. This data represents, to our knowledge, the first demonstration showing reduced cx43 mRNA in ovarian carcinoma. Conclusion: These findings suggest that the defect in cx43 expression in this tumor type is at the level of transcription and support the contention that its downregulation is involved in neoplastic transformation of ovarian epithelial cells. (This study was supported in part by the Vesa W. and William J. Hardman, Jr. Charitable Foundation Inc.) No significant financial relationships to disclose.
Tumor necrosis factor-α-induced protein 3 down-regulates nuclear factor-κB-mediated drug resistance in vitro and is a favorable clinical prognostic factor in human glioblastomas
Authors: Bredel M. , Bredel C. , Juric D. , Duran G. E. , Yu R. X. , Harsh G. R. , Vogel H. , Recht L. D. , Scheck A. C. , Sikic B. I. 
Published: March 2020

1508 Background: Resistance to chemotherapy is major impediment to the successful treatment of human glioblastomas. Methods: We used an integrated resistance model and genomics tools to globally explore molecular factors and cellular pathways mediating resistance to O6-alkylating agents in glioblastoma cells. Results: We identified a transcriptomic signature of 286 genes that predicts a common in vitro and in vivo resistance phenotype to these agents. This signature was significantly enriched for genes with functions in organismal survival (27.5%) and cell death (49.0%), both with P < 0.00001. Modularity was a predominant organizational principle of the signature, with functions being carried out by groups of interacting molecules in overlapping networks. A highly significant network was built around nuclear factor-κB (NF-κB), which included the persistent alterations of various NF-κB pathway elements. Tumor necrosis factor-α-induced protein 3 (TNFAIP3) was identified as a new endogenous regulatory component of a putative cytoplasmic signaling cascade that mediates NF-κB activation in response to DNA damage caused by O6-alkylating agents. Expression of the corresponding zinc finger protein A20 closely mirrored the expression of the TNFAIP3 transcript, and was inversely related to NF-κB activation status in the resistant cells. A prediction model based on the resistance signature enabled the subclassification of an independent, validation cohort of 31 glioblastomas into two outcome groups (P = .037). TNFAIP3 expression was a favorable factor in patient prognosis (P = .028), and was part of an optimized four-gene predictor (TNFAIP3, CD44 antigen, syndecan 1, and F-box protein 32) significantly associated with patient survival (P = .022). Conclusions: Our results offer strong evidence for TNFAIP3 as a key regulator of the cytoplasmic signaling to activate NF-κB en route to O6-alkylating agent resistance in glioblastoma cells. This gene may be an attractive target for therapeutic modulation of glioblastomas. No significant financial relationships to disclose.
Alternative schedules of adjuvant temozolomide in glioblastoma multiforme: A 6-year experience
Authors: Buttolo L. , Giunta F. , Ferrari V. D. , Grisanti S. , Marini G. , Mortini P. 
Published: March 2020

1511 Background: Temozolomide (TMZ) is an oral alkylating agent with proven efficacy in the therapy of glioblastoma multiforme (GBM). The activity of TMZ is drug-exposure dependent, however dosages are primarily limited by myelotoxicity. In the attempt to increase survival while limiting toxicity, we treated GBM patients (pts) with one of 3 alternative adjuvant TMZ schedules, including a low-dose daily regimen. Methods: We assessedthe overall survival and the development of grade 3–4 myelotoxicity in pts with GBM who were treated in our centre (November 1998-October 2005), following surgery, with one of the following TMZ schedules: standard schedule (SS: 200–300 mg/m2 × 5 days, every 28 days); extended schedule (ES: 150 mg/m2 × 7 days every 15 days); daily schedule (DS: 75 mg/m2 daily). Pts were treated until death or tumour progression. The analysis of survival was based on the Kaplan-Meier (KM) and the Cox models. Adverse events were graded according to NCICTC 3.0. Results: We evaluated 117 pts (73 m, 44 f, avg. age 57 yrs, 53% received radiotherapy, RT) with histologically diagnosed gliomas (GBM=92.3%) treated with TMZ SS (tot pts=48, RT pts=22, no. cycles: 1÷33, avg 6) or ES (tot pts=35; RT pts=19, no. cycles: 1÷43, avg 16) or DS (tot pts=34; RT pts=21, days of treatment: 25÷671, avg 212). The overall survival significantly differed among the 3 schedules (KM), with DS providing the best outcome (p=0.0357, log-rank). Median survival time was markedly increased in DS pts (DS=29.47 months; ES=15.73 months; SS=11.90 months) as well as the survival rate at 2 yrs after diagnosis (DS=51%; ES=30%; SS=21%). DS, but not ES, significantly reduced the mortality hazard ratio (HR) compared to SS (Cox: HR=0.494; IC95% 0.253–0.966, p=0.039). Grade 3–4 myelotoxicity (leukopenia, LP; neutropenia, NP; thrombocytopenia,TP) occurred less frequently with DS (NP=2.9%; TP=2.9%; any=5.9%) than with ES (LP=11.4%; NP=14.3%; TP=17.1%; any=28.6%) and SS (LP=14.6%; NP=8.3%; TP=20.8%; any=22.9%). Conclusions: In our experience with adjuvant TMZ in GBM, a continuous daily dose of 75 mg/m2 was on the whole more advantageous than a standard monthly or a biweekly regimen, as it resulted in the highest overall survival with the lowest hematologic toxicity. No significant financial relationships to disclose.