bluuebunny/crossref_metadata_2025 huggingface dataset:
Primary hormonal therapy for patients with localized or locally advanced prostate cancer
Authors: Shklar Z. , Rubinov R. , Steiner M. , Rabkin A. , Leviov M. , Keren S. , Sinatzky K.
Published: March 2020

14630

Background: During 1998–2000, 68 patients with localized or locally advanced prostate carcinoma who were not suitable for radical therapy received primary hormonal therapy as the only treatment modality. The group consisted 15.8% of all prostate cancer patients referred to our center during the three years period. Methods: Their median age was 76.7 years (65–89). 42.4% had T1c disease, 30.3% T2a, 15.2% stage T2b and 12.1% T3. 78.4% had Gleason score 4–6, 10.8% Gleason 7 and 10.8% Gleason 8–10 prostate cancer. Median serum PSA level before starting therapy was 15.8 ng/ml (3.4–289). 76% received LHRH agonists monotherapy while 24% had complete androgen blockade. Patients were followed using repeated serum PSA level during 39–95 months (median 79.5). Results: 32/68 patients (47%) experienced PSA recurrence during the study period. Median time to PSA failure was 38.9 months (13–77). No clinical difference was observed between recurrent and non recurrent patients as regarding stage of disease or type of hormonal therapy. In relapsing patients high Gleason score (7–10) was more common (32.3% vs 11.6%) and median initial serum PSA value was higher (22.4 vs 14.5 ng/ml) than in the non recurrent group. During the study period, only 4/68 patients (5.9%) developed clinical disease, 10/68 patients (14.7%) died of unrelated causes and no patient died of prostate cancer. Conclusions: We conclude that primary hormonal therapy is a safe option for prostate cancer patients not suitable for more radical procedures. As expected, high Gleason score and higher initial serum PSA value are predictive for earlier relapse.

No significant financial relationships to disclose.
Post-operative conformal radiotherapy on prostate cancer after radical prostatectomy. Results and dose constraint on bladder volume
Authors: Nakamura R. A. , Monti C. R. , Ferrigno R. , Trevisan F. A. , Castilho L. N. , Reinato J. A.
Published: March 2020

14647

Background: To report on the results of post-operative conformal radiotherapy (3DCRT) on patients submitted to radical prostatectomy with high risk of biochemical failure or with biochemical failure. Methods: From July 1998 to December 2001, 40 patients with high risk of biochemical failure (T3 stage or positive margins) or with biochemical failure (PSA ≥ 0.2 ng/ml) after radical prostatectomy were submitted to 3DCRT on a single institution and were analyzed retrospectively. The median age was 65 years (52–74). The median pre-3DCRT PSA was 1.3 ng/ml (0–8.98). Twenty eight patients were submitted to pelvic 3DCRT. The median radiation dose on prostate region was 77 Gy (68.4–81). Biochemical failure was considered after 3 consecutive PSA increasing or the beginning of androgen suppression therapy for any reason after 3DCRT. Results: The median follow-up was 56.1 months (19.7–84.6). The 5-year actuarial biochemical progression-free survival was 84.5%. Six (15%) patients had biochemical failure and 4 (10%) distant metastases. The 5-year actuarial biochemical progression-free survival was 94.9% with pre-3DCRT PSA ≤1.5 ng/ml and 69.9% when >1.5 ng/ml (p = 0.0215). Two patients had rectal bleeding grade 2. Nine patients had urinary toxicity grade 2–3. The 5-year actuarial free from urinary toxicity grade 2–3 was 72.9%. Age >65 years and radiation dose >65 Gy on 30% of bladder volume resulted on more late urinary toxicity grade 2–3 (p = 0.0410 and p = 0.0177, respectively). Conclusions: 3DCRT was effective for biochemical control on patients with high risk of biochemical failure or with biochemical failure after radical prostatectomy. Patients with pre-3DCRT PSA ≤1.5 ng/ml have more biochemical control. It was suggested to restrict radiation dose ≤65 Gy on 30% of bladder volume to minimize late grade 2–3 urinary toxicity. More cautious on patients >65 years submitted to post-operative irradiation are required.

No significant financial relationships to disclose.
Molecular profiles of prostate cancer versus today’s diagnostic tools
Authors: Vuaroqueaux V. , Diener P. , Eppenberger-Castori S. , Labuhn M. , Horica C. , Németh T. , Sulmoni M. , Fürstenberger G. , Eppenberger U. , Morant R.
Published: March 2020

14659

Background: Tumor size, nodal status, the Gleason grading system and serum PSA values are today’s available prognostic tools of localized prostate cancer and the only help for adjuvant therapy. Based on the results of a feasibility study we continued the evaluation of the recently developed prognostic molecular signature. Methods: Of 60 CaP patients, who underwent primary prostatectomy in 2003 to 2005, fresh frozen samples of the tumor were asserved. The RNA extracted from cryocuts was tested. The quantitative RNA expression levels of 90 relevant genes involved in the different tumor hallmarks were simultaneously assessed. Results: Unsupervised agglomerative clustering of the obtained molecular profiles revealed different signatures. Correlations between these groups and the known TNM staging as well as Gleason scores were strongly present. Of interest was that all recurrences observed within this short period of time were found in a single cluster expressing higher levels of proliferation markers. Conclusions: The molecular profile of primary prostate cancer by quantitative RT-PCR is a powerful tool describing the biology of an individual tumor. Gene expression profiling can be precisely quantified and seems to be better reproducible than pathological judgments of the Gleason scores. Moreover, the gene panel is partially based on drug target genes and therefore of predictive value. Finally the method could be applied also in core biopsies.

[Table: see text]
Recurrent epithelial ovarian cancer (EOC): What determines the outcome?
Authors: Kumanthem P. , Kumar L. , Janga D. , Hariprasad R. , Patnaik R. , Gupta A. , Kumar S. , Singh R.
Published: March 2020

15003

Background: Recurrent EOC is a common clinical problem and treatment is not curative. We retrospectively analyzed the data on 354 patients with recurrent EOC to determine the impact of various prognostic factors on outcome. Methods: Between August, 1989 and June, 2005, 354 patients (median age 49 years, range, 28 to 80 years) were diagnosed as recurrent EOC. 259 patients received chemotherapy alone, 44 were treated with combination of secondary debulking surgery and chemotherapy or radiotherapy. Remaining 51 (14.4%) patients had no treatment. Main types of salvage chemotherapy included- cisplatin + cyclophosphamide (CP, n = 53), CP + adriamycin (CAP, n = 68), paclitaxel + carboplatin/cisplatin (TP, n = 78). 10 factors were analyzed for survival. Results: 56.5% of patients responded to chemotherapy; complete (CR)-34.2% and partial response (PR) in 22.3% of patients. 124 (35%) patients had no response or progressive disease. 10 (2.8%) died of chemo-toxicity and in remaining 20 status was not known. Median overall survival for patients who received treatment is 19 months vs 3 months for 51 patients who did not receive treatment, p < .001. Predictors of survival were - response to salvage chemotherapy (20 vs 8 months, p < .001), treatment-free interval (>6 months vs ≤ 6 months, 23 vs 9 months p < .001), site of relapse (single vs multiple, 22 vs 16 months, p < .001), Chemotherapy regimen (CP vs CAP vs Paclitaxel + carboplatin) p < .003 on univariate analysis. Age (≤50 years vs >50 years, p = 0.02), initial stage (I vs II vs III vs IV, p = 0.079), histology (serous vs others, p = 0.849), site of relapse (vault vs others, p = 0.156) were not significant predictors. On multivariate logistic regression analysis- response to salvage chemotherapy (HR 0.21, 95% CI 0.15–0.30), treatment-free interval (HR 0.36, 95% CI, 0.20–0.64), and site of relapse (vault vs others, HR 1.22, 95% CI 0.78–1.94) attained significance among 10 factors analyzed. Conclusions: Present study confirms that all patients with recurrent EOC should receive treatment. Response to salvage chemotherapy, a longer treatment-free interval (>6 months) and single site of metastasis are predictors of significantly superior outcome.

No significant financial relationships to disclose.
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.
RTOG 0131: Phase II trial of pre-irradiation and concurrent temozolomide in patients with newly diagnosed anaplastic oligodendrogliomas and mixed anaplastic oligodendrogliomas: Relationship between 1p/19q status and progression-free survival
Authors: Vogelbaum M. A. , Berkey B. , Peereboom D. , Giannini C. , Jenkins R. , Suh J. , Brown P. , Blumenthal D. , Biggs C. , Mehta M.
Published: March 2020

1517

Background: In a previous report, we showed in patients with newly diagnosed anaplastic oligodendrogliomas (AOs) and mixed anaplastic oligoastrocytomas (MAOs) that temozolomide (TMZ) can be given concurrently with radiation therapy (RT) with acceptable toxicity. We have now evaluated the efficacy of this regimen and correlated durability of response with tumor 1p/19q genotype. Methods: A phase II study was performed to evaluate the use of pre-RT TMZ followed by concurrent RT and TMZ in patients with newly diagnosed AO or MAO. The primary endpoint was to determine the pre-RT TMZ six-month progression rate, and secondary endpoints included progression-free survival and overall survival. Results: 40 eligible patients were entered into the trial. Thirty-two patients completed 6 months of pre-RT TMZ and concurrent RT and TMZ. Of the remaining eight patients, 4 withdrew due to toxicity and 4 other patients withdrew from study without evidence of toxicity or pre-RT progression. 1p/19q data are available in 37 cases; 23 tumors had loss of heterozygosity (LOH) of both 1p and 19q (double-deleted) while 14 tumors had LOH of either 1p or 19q (n = 3), or no LOH (n = 11). To date, 11 patients have experienced tumor progression; 1p/19q data are available for 10 of these cases (2 are double-deleted (2/23 = 9%), 8 have at least one intact chromosome (8/14 = 57%). Kaplan-Meier analysis demonstrates that progression free survival is significantly better for the double-deleted group (median time to progression not reached) than for the intact group (median time to progression = 15.2 months, p = 0.001). Overall survival is 98% (39/40) with a median follow-up of 17.5 months (2.8 - 31.1 months). Conclusions: LOH of both 1p and 19q is strongly correlated with a durable response of AO and MAO to a combined regimen of chemotherapy and radiation therapy. Tumors that are intact at 1p and/or 19q progress early despite an aggressive therapeutic regimen. These results suggest that future clinical trials should be prospectively stratified by tumor 1p/19q genotype.

[Table: see text]
NCCTG 96–94–53: Clinical variables associated with overall survival (OS), progression-free survival (PFS), 6 month progression-free survival (PFS6), immediate progression (ImmProg), and response in patients enrolled in recurrent glioma clinical trials
Authors: Buckner J. C. , Ballman K. , Schaefer P. , Furth A. F. , Giannini C. , Scheithauer B. W. , Galanis E. , Jaeckle K. A.
Published: March 2020

1520

Background: Multiple variables may impact endpoints utilized to assess efficacy of investigational therapies for pts with recurrent gliomas. Understanding the nature of these variables should aid interpretation of results. Methods: 583 pts were enrolled to 15 consecutive recurrent glioma clinical trials conducted between 1980 and 2004. Identical patient, tumor, treatment and time variables were identified for each trial. Central neuropathology review was completed and pts were grouped by WHO diagnoses. Pts alive and progression-free at 6 months after start of treatment were a PFS6 ‘success’. Pts whose outcome was progression at first evaluation were classified as “Immediate Progression (ImmProg)”. Response was defined as regression, partial regression, or complete regression in the absence of worsening neurologic symptoms or increased corticosteroid dose. Univariable and multivariable Classification and Regression Trees (CART) models were used to identify factors associated with OS, PFS, PFS6, ImmProg, and Response. Results: Variables associated with outcomes for each endpoint assessed by CART models are shown in Table below. Conclusions: In clinical trials of recurrent glioma, age, PS, duration of disease, primary and recurrent histologic diagnosis, and primary and recurrent extent of resection are associated with outcomes. These variables should be validated in additional datasets for potential inclusion in reports of future clinical trials.

[Table: see text]

No significant financial relationships to disclose.
Concurrent weekly cisplatin and radiation therapy for nasopharyngeal carcinoma
Authors: Beldjillali Y. , Benhadji K. A. , Yekrou D. , Dali Youcef F. , Djellali L. , Yamouni M.
Published: March 2020

15507

Background: Platimum based chemotherapy and radiotherapy combinations are the corner stone of management of nasopharyngeal carcinoma. Concomitant chemoradiotherapy may increase activity of the treatment but also increase toxicity. The purpose of the present study was to evaluate both aspects in patients (pts) with nasopharyngeal carcinoma (NPC). Methods: Previously untreated patients with NPC and ECOG performance status 0–2, were enrolled in this study. Cisplatin was administered weekly, starting on day 1 as an intravenous infusion at 40 mg/m2 together with radiation therapy: 1.8–2.0 Gy per fraction, 5 fractions a week. The total dose delivered to the nasopharynx was 65 to 70 Gy and 45 Gy to lymph nodes with a boost of 15 Gy the node-bearing areas. Treatments were administered during 6 weeks. Results: 86 pts were enrolled in this study, 56 male and 30 female, with a median age of 41 years (range 16–69). 26 pts had stage IVb, 24 pts stage IVa, 17 pts stage III, 18 pts stage II and one pt stage I disease. 62 pts had undifferentiated, 22 poorly differentiated and 2 differentiated NPC. The complete response rate was 86% for all patients and the overall response rate was 93%, 7% of cases remained stable. After 494 cycles, grade 3 & 4 toxicity (NCI) were: neutropenia (1%), anemia (1%), nausea and vomiting (14%), dysphagia (12%). 4 pts had cutaneous induration/fibrosis. All pts presented hyposialosis. The disease free survival and overall survival at one year were 78% and 83% respectively. Conclusion: Concomitant chemotherapy and radiotherapy in pts with NPC result in a high complete response rate with an acceptable safety profile. Further follow-up is necessary to assess the curative potential of this combined modality.

[Table: see text]
Induction chemotherapy followed by alternating chemo-radiotherapy in advanced undifferentiated nasopharyngeal carcinoma (UNPC)
Authors: Ponzanelli A. , Vigo V. , Bacigalupo A. , Marcenaro M. , Benasso M.
Published: March 2020

15508

Background: Concomitant chemo-radiotherapy is the standard treatment for advanced UNPC. Induction chemotherapy may improve the results further by enhancing both locoregional and distant control. Methods: Fifty patients with previously untreated, locoregionally advanced UNPC were initially treated with 3 courses of epidoxorubicin, 90 mg/mq, day 1 and cisplatin, 40 mg/mq, days 1 and 2, every 3 weeks. After a radiological and clinical response assessment patients underwent 3 courses of cisplatin, 20 mg/mq/day, days 1–4 and fluorouracil, 200 mg/mq/day, days 1–4, i.v. bolus, (weeks 1,4,7) alternated to 3 splits of radiation (week 2–3, 5–6, 8–9-10), with a standard fractionation, up to 70 Gy. Histology was WHO type 1 in 1 pt (2%), WHO type 2 in 10 pt (20%), WHO type 3 in 39 pts (78%). All patients had stage IV disease (UICC 1992). Results: All the patients are evaluable for toxicity and response. All but one received 3 cycles of induction chemotherapy. Toxicities from induction chemoyherapy were: 2% grade 3 or 4 mucositis, 22% grade 3 or 4 nausea/vomiting, 6% grade 3 or 4 haematological toxicity and one episode of febrile neutropenia. At the end of induction phase 12% of CRs, 84% of PRs and 4% of SD were recorded. All patients but two had the planned number of chemotherapy courses in the alternating phase and all but one received the planned radiation dose. Toxicities from alternating chemo-radiotherapy were: 28% grade 3 or 4 mucositis, 8% grade 3 or 4 nausea/vomiting, 24% grade 3 or 4 haematological toxicity with no episodes of febrile neutropenia. At the final response evaluation 86% of CRs and 14% of PRs were observed. At a median follow up of 39 months, 14% of patients had locoregional failure, 20% had distant failure and 2% both. The 4-year actuarial progression free survival and overall survival rates were 71% and 81%. Conclusions: Treatment of locoregionally advanced UNPC with induction chemotherapy followed by alternating chemo-radiotherapy is feasible and patients’ compliance is optimal. 4-year outcomes seems better than those reported with concomitant chemo-radiotherapy alone.

No significant financial relationships to disclose.
Phase II study of gefitinib in metastatic or locoregionally recurrent nasopharyngeal carcinoma (NPC)
Authors: Chan A. T. , Ma B. , Hui E. P. , King A. , Kam M. , Kwan W. H. , Mok T. , Leung S. F.
Published: March 2020

15509

Background: Our preclinical work has shown that epidermal growth factor receptor (EGFR) is expressed in ∼ 80% of undifferentiated NPC & gefitinib is a small molecule inhibitor against EGFR with anti-proliferative activity in NPC in vitro. Methods: We report the preliminary result of a phase II study of gefitinib in patients (pts) who progressed after 1–2 lines of chemotherapy (at least 1 line had to contain platinum) for metastatic or locoregionally recurrent NPC. Fourteen Chinese pts were accrued, of whom the median age was 48 years (range 34–64 years), 12 were males, 9 had metastatic & 5 had locoregionally recurrent NPC. All received gefitinib at 500mg/day orally, every 28 days with radiological assessment performed every 2 cycles for a maximum of 8 cycles. Ten pts had 1 line & 5 pts had 2 lines of prior chemotherapy. Results: The median number of administered cycles was 2 (range 1–8). Of the 14 pts evaluable for toxicity, the most commonly reported were acneiform rash (86%, grade 1–2, n = 10; grade 3, n = 4), dry skin (86%, grade 1–2), diarrhea (71%, grade 1–2), fatigue (64%, grade 1–2), anorexia (64%, grade 1–2) & nausea (20%, grade 2). Other grade 3–4 toxicities included fever (n = 2, skin cellulitis, infective pneumonia), hyponatremia (n = 2), near-syncope (n = 2), anemia (n = 1). Dose reduction to 250mg/day was required in 4 pts who encountered grade 3 skin rash. Of the 11 pts evaluable for response, 2 had stable disease (SD) for ≥ 6 months (m) (mean 6.8 m) 9 progressed and no partial responders. Five pts have died mostly of progressive disease & there were no treatment-related deaths. Conclusions: Gefitinib is well tolerated in pts with advanced NPC with some pts experiencing disease stabilization for over 6 months & study accrual is ongoing.

No significant financial relationships to disclose.
Modulation of integrin α5 in head and neck cancer cells by epidermal growth factor and its contribution to the malignant phenotype
Authors: Kertsman J. , Cohen E. , Abdellatif M. , Wieder R.
Published: March 2020

15512

Background: The primary therapy for head and neck cancer consists of combination treatment with radiation and chemotherapy. While this combined modality approach is often curative, a significant fraction of patients have residual viable tumor cells after treatment that can result in progressive disease or relapse. We hypothesize that a significant contribution of cell survival results from interaction of cancer cells with the tumor microenvironment that includes soluble ligands of growth factor receptors and structural ligands of cell surface adhesion molecules. One of the growth factors with reported tumor survival effects is epidermal growth factor (EGF). We investigated the contribution of EGF to the relationship of 1483 head and neck cancer cells with their microenvironment. Methods: We treated 1483 head and neck cancer cells with variable concentrations of EGF from 0.1 to 20 nM and carried out western blots and flow cytometry to determine the expression of relevant integrins. Effects of interventions were evaluated by soft agar colony assays, proliferation and survival in tissue culture and adhesion to culture plates coated with integrin ligands. Results: Western blots demonstrated an EGF-induced increase in the expression of intgerin α5 but no change in the expression of integrins α2 or β1. The presence of dissolved fibronectin, a ligand of integrin α5β1, but not of collagen I, a ligand of integrin α2β1, provided a survival advantage to colonies in soft agar in EGF-treated cells. Experiments are determining whether this survival advantage translates to a shift in the dose-response curve to paclitaxel and ionizing radiation, on activation of caspases 3 and 8 and cleavage of poly (ADP- ribose) polymerase (PARP). These data are being correlated with EGF-induced modulation of adhesion to fibronectin, collagen and control plates. We have constructed adenoviral vectors expressing short hairpin RNA (shRNA) sequences to integrins α5 and α2 to confirm the role of integrin α5 expression in the EGF-induced modulation of survival. Conclusions: These data support a potential contribution to survival of head and neck cancer cells by modulation of integrins by EGF through interaction with their ligands in the microenvironment.

No significant financial relationships to disclose.
Chemotherapy alternating gemcitabine and cisplatin concomitant with radiotherapy in locally advanced (LA) squamous cell carcinoma of the head and neck (SCCHN)
Authors: Tellez Bernal E. , Aguilar J. L. , Cruz J. , Granados M. , Maldonado F. , Moran A. , Martinez J. , Cabrera G. , Martinez-Said H. , Frias-Mendivil M. , Herrera A.
Published: March 2020

15514

Background: In the Pignon’s meta-analysis, the OS benefit was 8% with chemoradiation in LA SCCHN. Unfortunately it is still unclear what scheme is the best, cisplatin (CDDP) being the most widely used drug. Other drugs such as gemcitabine (GMZ) has promising results, although toxicity has been severe but tolerable. We have published an initial study using GMZ and radiotherapy (ann oncol. 2004;15:301). In the present study we wished to determine if a scheme in which GMZ is alternated with CDDP and concomitant radiotherapy reduced toxicity yet maintains our previously described therapeutic effectiveness. This is a preliminary report with a short follow-up period. Methods: Inclusion criteria: patients with SCCHN (EC: III, IVa and IVb ) or with recurring disease, and no sytemic metastases or patients rejection of surgery between 03/2003 and 09/2004. Chemotherapy scheme consisted of GMZ at 100 mg/m2 once a w, ws 1, 3, 5, 7 and CDDP at 50 mg/m2 once a w, ws 2, 4, y 6. Radiotherapy consisted of 2 Gy/day, for a total of 70 Gy during the 7 ws. Toxicity evaluation focused on mucositis, xerostomia, dysphagia y leukopenia. Results: 28 patients were treated. 7 (25%)/ stage III, 11 (39.3%) IVa, 10 (35.7%) IVb. The tumor sites distribution was as follows: 9 patients with oropharynx and larynx disease (32.1%), 6 patients with oral cavity disease (21.4%), 3 patients with paranasal sinus disease (10.7%), and 1 hypopharinx (3.5%). A CCR was observed in 21 patients (75%), a partial response was observed in 5 patients (17%). Organ preservation was achieved in 68% of the patients. Toxicity: mucositis Grade 3–4 was in 42% of patients, leucopenia grade III in 29%, dysphagia in 19% and xerostomia in 10%. 40%of the patients stopped treatment for one or two weeks due to toxicity without affecting the doses of both treatments. Conclusions: The scheme with alternating GMZ and CDDP concomitant with radiotherapy is safe and effective. We observed a lower incidence in mucositis and few systemic toxic effects. Our findings support further studies in which alternating chemotherapeutic schemes are utilized given that tumor response is increased without an increment in toxicity.

No significant financial relationships to disclose.