bluuebunny/crossref_metadata_2025 huggingface dataset:
Defining the mechanisms by which leptin stimulates proliferation of ovarian cancer cells
Authors: Olawaiye A. B. , Sakamoto H. , Serikawa T. , Friel A. , Kiyama R. , Inoue A. , Drapkin R. , Foster R. , Gonzalez R. R. , Rueda B. R.
Published: March 2020

15017

Background: Ovarian cancer (OvCa) ranks fourth as the cause of death related to cancer in women in the U.S. The vast majority (>90%) of OvCa originates from the ovarian surface epithelium. There is sufficient evidence to suggest that hormones, especially estrogen, may be involved in the etiopathogenesis of epithelial OvCa. Recent studies indicate that leptin participates either directly or indirectly to promote carcinogenesis in both breast and endometrial cancers. Furthermore it has been proposed that leptin may elicit its action via an estrogen related pathway. Leptin can stimulate proliferation of some OvCa cell lines and has been implicated as a potential biomarker for OvCa. However the mechanism(s) by which leptin contributes to the growth of OvCa has yet to be defined. We hypothesize that leptin’s effect will be mediated in part by estrogen receptor (ER) pathways. Methods: Three epithelial OvCa cell lines (IGROV1, OVCAR5 and TOV21G) and one benign human ovarian surface epithelial cell line (HOSE) were evaluated. Enzyme linked immunosorbent assay (ELISA) and Western blotting were used to assess leptin and leptin receptor (ObR), respectively. Leptin (0.06 nM–6.25 nM) induced effects on cell proliferation were assessed in the presence or absence of an aromatase enzyme inhibitor (Anastrozole) or the ER antagonist (ICI182780). Further, we explored leptin-induced effects on ERα promoter activity as evidenced by change in fluorescence via a dual luciferase promoter reporter. All experiments were conducted in triplicate. All data were subjected to ANOVA followed by Tukey’s post hoc test (p < 0.05). Results: All ovarian cell lines expressed ObR; whereas, no measurable amounts of leptin were detected in conditioned media. Leptin stimulated cell proliferation in both the benign and malignant lines. Leptin-induced cell proliferation was inhibited by Anastrozole and ICI182780. Furthermore, leptin stimulated luciferase activity of the ERα promoter/reporter. Conclusions: Leptin promotes proliferation of benign and malignant ovarian epithelial cells and appears to be mediated, at least in part, via aromatase and ER which may have therapeutic implications. This work was supported by the Vincent Memorial Hospital, SG Komen Foundation and the Advanced Medical Research Foundation.

No significant financial relationships to disclose.
Concurrent chemoradiotherapy using high-dose-rate intracavitary brachytherapy with a modified dose schedule: Retrospective analysis of a single institutional experience
Authors: Toita T. , Tamaki W. , Maehama T. , Ogawa K. , Nagai Y. , Iraha S. , Kakinohana Y. , Moromizato H. , Kanazawa K. , Murayama S.
Published: March 2020

15019

Background: The purpose of this study was to assess the effectiveness of concurrent chemoradiotherapy (CCRT) using high-dose-rate intracavitary brachytherapy (HDR-ICBT) with a dose schedule modified from the American Brachytherapy Society (ABS) recommendation. Methods: 68 consecutive patients (IB2: 3, IIA: 2, IIB: 32, and IIIB: 31) with cervical squamous cell carcinoma consecutively treated with CCRT using HDR-ICBT were retrospectively analyzed. Patients with para-aortic lymphadenopathy (greater than 10mm in minimum diameter assessed by CT) were excluded. The median tumor size (assessed by MRI) was 60mm (range: 40–86mm). Cisplatin (20 mg/m2/day) was concurrently administered with radiotherapy (RT) for 5 days at 21-day intervals for a median of 2 courses (range: 1–5). The planned RT schedule consisted of pelvic external beam RT (EBRT) with 40Gy/20 fractions followed by HDR-ICBT with 18Gy/3 fractions and pelvic EBRT with 10Gy/5 fractions using a midline block (MB). The cumulative biologically effective dose (BED) at point A of this schedule was 77Gy10. 60 patients (88%) were treated with this schedule. In the remaining 8 patients, pelvic EBRT was delivered without MB (up to 50Gy), and/or additional HDR-ICBT (up to 24Gy) was given. The actual BED for all 68 patients thus ranged from 77 to 89 Gy10. Median follow-up of the surviving 54 patients was 46 months (range: 8–91 months). Late complications were graded by the RTOG/EORTC criteria. Results: The actuarial overall survival rate, disease-free survival rate, and pelvic control rate at 4 years were 78% (95% CI, 68–90%), 74% (95% CI, 63–85%), and 90% (95% CI, 83–97%), respectively. Only one patient suffered a grade 3 complication (enterocolitis). The actuarial late complication (Grade 1or higher) rates at 4 years were 12% (95% CI, 3–20%) for proctitis, 2% (95% CI, 0–5%) for cystitis, and 21% (95% CI, 10–33%) for enterocolitis. Conclusions: This retrospective analysis suggests that CCRT using HDR-ICBT with a modified dose schedule was able to achieve favorable pelvic disease control without severe late complications for patients with cervical cancer.

No significant financial relationships to disclose.
Clinical outcome of atypical uterine smooth muscle tumors
Authors: Pothuri B. , Kehoe S. M. , Wright T. , Herzog T.
Published: March 2020

15028

Background: Smooth muscle tumors of uncertain malignant potential (STUMP) and atypical leiomyomas have increased mitotic activity, cellular atypia and necrosis but the degree is less than that used to define uterine leiomyosarcomas. Our objective is to evaluate the clinical outcome of patients with uterine masses histologically defined as smooth muscle tumors of uncertain malignant potential or atypical leiomyomas. Methods: A thorough search of our institution’s pathology database from 1990 to 2005 was performed. A retrospective chart review was performed to obtain initial and subsequent treatments, documented recurrences and clinical outcomes. Pathology reports and slides were reviewed and the presence of atypia, necrosis and number of mitosis was recorded. Statistical analysis was performed by Student’s T-test. Results: Eighteen patients with a histologic diagnosis of atypical leiomyoma were identified with 14 STUMP, 2 bizarre leiomyomas, 1 myxoid and 1 mitotically active leiomyoma. The mean age of these patients was 41.8 years (range: 25–77) and was significantly younger than those with leiomyosarcoma (mean age was 54 years, p < 0.001). The histologic characteristics of the tumors included the presence of atypia at 50%, necrosis at 82% and mitoses at 94%. The rate of necrosis and number of mitosis was significantly less in the atypical group as compared to the leiomyosarcoma group (p values < 0.05). However the rate of cellular atypia was not statistically different between the two groups. The median follow-up period was 25 months, range 1–138 months. One of the eighteen patients developed a pelvic and pulmonary recurrence at which time a low grade leiomyosarcoma was diagnosed. The recurrence occurred 32 months after the initial diagnosis of a mitotically active leiomyoma. Sixteen patients demonstrated no recurrence or metastatic disease at the time of follow-up. Conclusions: Atypical leiomyomas appear to be diagnosed in younger women which leads to challenging treatment issues involving fertility preservation. While these tumors generally behave in a benign fashion, they have histologic characteristics that may allow for progression or recurrence. Close follow-up is warranted for patients who are diagnosed with atypical leiomyomas and smooth muscle tumors of uncertain malignant potential.

No significant financial relationships to disclose.
Ovarian cancer treatment patterns and outcomes in the United States: A National Program of Cancer Registries (NPCR) study
Authors: Stewart S. L. , Wike J. M. , Cress R. , O’Malley C. , Neloms S. , Kahn A. R. , Schymura M. J.
Published: March 2020

15031

Background: Ovarian cancer (ovca) is the fifth leading cause of cancer death among women in the United States. In 2001, the NPCR program (administered by the Centers for Disease Control and Prevention) initiated a multi-year study to determine the first course of treatment for ovca patients in order to assess whether the ovca standard of care (as defined by the NIH Physician Data Query) was met. Methods: Population-based cancer registries in Maryland, New York, and Northern California were funded to collect patient, tumor, provider, and treatment data on patients diagnosed in these areas between 1997 and 2000. Information was collected through a retrospective medical record abstraction; all ovca records in Northern California and Maryland were included in the study, a simple random sample of ovca medical records in New York was included. Data on over 3000 patients from Northern California and New York were obtained (about 1500 patients each); data on about 1000 patients from Maryland was obtained. Patient vital status was followed through 2002. Results: Most patients were non-Hispanic white and between the ages of 50 and 79. About 30% of the tumors were papillary serous cystadenocarcinomas and almost 40% were poorly differentiated; about 66% of tumors were distant stage at diagnosis. The percentage of distant stage diagnoses increased with increasing age through age 79. Over half of patients were treated by gynecologic oncologists; obstetrician/gynecologists treated a little over 10% of patients. Overall, over 80% of patients underwent cancer directed surgery; about 50% were treated with carboplatin and about 55% were treated with paclitaxel. Patients ages 70 and older received cancer-directed surgery less often than younger patients. Overall, about 50% of patients were alive at the end of the follow-up period, with the percentage alive within age categories decreasing with increasing age. Conclusions: Age remains a negative factor in ovca presentation, treatment, and survival. Continued assessment of ovca patterns of care will enhance ovca knowledge and may aid clinicians in determining appropriate treatments for their ovca patients.

No significant financial relationships to disclose.
Phase II study of nab-paclitaxel plus carboplatin in patients with recurrent platinum-sensitive ovarian or primary peritoneal cancer
Authors: Benigno B. B. , Hines J. F.
Published: March 2020

15033

Background: This open-label, non-randomized study was designed to determine the efficacy and safety of nab-paclitaxel (a 130-nm albumin-bound particle form of paclitaxel) plus carboplatin in patients with metastatic ovarian or primary peritoneal carcinoma following platinum-based chemotherapy. Methods: Eligible patients had to have either measurable disease (based on RECIST criteria) or pretreatment CA-125 levels ≥2 times the upper limit of normal in the absence of measurable disease. Patients also had to have good performance status, adequate hepatic/renal function, peripheral neuropathy ≤ grade 1, and life expectancy ≥6 months. Patients may have received prior chemotherapy for ovarian cancer, including taxane-containing regimens, provided the treatment was completed at least 6 months before enrollment. nab-Paclitaxel 100 mg/m2 was administered IV over 30 minutes on days 1, 8, and 15 every 28 days. Carboplatin AUC6 was administered IV over 1−2 hours on day 1 every 28 days. Treatment continued for 6 cycles (or longer in the absence of unacceptable toxicity). Planned sample size was 43 patients (39 evaluable). Efficacy was determined by changes in tumor size for patients with measurable disease or changes in CA-125 levels for those with non-measurable disease. Results: To date, 10 patients have been enrolled, 2 of whom completed 2 treatment cycles; both patients had a 50% reduction in their disease (partial response). One patient had grade 4 neutropenia; grade 3 hematologic events were neutropenia (2 patients), thrombocytopenia (3), and anemia (1). Severe headache and severe nausea were reported for 2 patients each; all 4 events required medication. Conclusions: Preliminary results suggest that nab-paclitaxel 100 mg/m2 plus carboplatin AUC6 will have antitumor activity in patients with recurrent platinum-sensitive ovarian or primary peritoneal cancer and that treatment appears to be well tolerated. Updated response and toxicity data from this study will be presented.

No significant financial relationships to disclose.
The significance of the ratio of metastatic to examined lymph nodes in endometrioid uterine cancer
Authors: Teng N. N. , Cheung M. K. , Husain A. , Osann K. , Berek J. S. , Kapp D. S. , Chan J. K.
Published: March 2020

15043

Background: To determine the impact benign to positive lymph node ratio (LNR) on the disease-specific survival of women with advanced endometrioid corpus cancer. Methods: Demographic and clinico-pathologic information were obtained from the Surveillance, Epidemiology and End Results Program from 1988–2001 and analyzed using Kaplan-Meier methods and Cox proportional hazards regression. Results: Of the 1,222 women diagnosed with stage IIIC-IV endometrioid uterine cancer with nodal disease, the median age was 64 (range: 28–93). 1,025 (83.9%) were White, 75 (6.1%) Black, 91 (7.5%) were Asian and 31 (2.5%) were Other. All patients underwent surgical staging including a lymph node assessment and were found to have nodal metastases. 639 (52.3%) had stage IIIC, 24 (2.0%) IVA, and 559 (45.7%) IVB disease. Furthermore, 123 (10.1%), 466 (38.1%), and 581 (47.6%) women had grade 1, 2, and 3 disease, respectively. Grade information was unavailable for 51 (4.2%) patients. The benign to positive lymph node ratios (LNR) were divided in four subgroups: ≤5%, >5% to ≤10%, >10% to ≤20%, and >20% to determine impact of LNR on disease-specific survival. Increasing LNR (≤5%, >5% to ≤10%, >10% to ≤20%, and >20%) was associated with a decrease in disease-specific survival at 83.8%, 73.2%, 62.4%, and 50.8%, respectively (p < 0.0001). More specifically, LNR was an important factor only in patients with 11–20 and >20 lymph nodes removed but not for those with less than 10 nodes resected. Women with higher (LNR) received significantly more adjuvant radiotherapy at 72.0%, 69.7%, 61.1%, and 52.6%, respectively. On multivariate analysis, age, stage, grade, and lymph node ratio were significant independent prognostic factors for survival. Adjuvant radiation was not an important independent prognostic factor in multivariate analysis. Conclusion: The ratio of metastatic to examined lymph nodes in endometrioid uterine cancer is an important prognostic factor. Clinical trials on adjuvant therapy should be designed with consideration of this significant prognosticator.

No significant financial relationships to disclose.
A preclinical study of cellular immunotherapy redirected by bispecific antibodies in uterine cell lines and primary cancer cells
Authors: Hamilton C. A. , Zhang M. M. , Chan J. K. , Cheung M. K. , Thorne S. H. , Baker J. , Contag C. H. , Negrin R. S.
Published: March 2020

15044

Background: Cytokine induced killer cells (CIKs) are ex-vivo activated and expanded CD8+ natural killer T cells that have been shown to have cytotoxic activity against cancers in randomized clinical trials. We determined the cytotoxic activity of CIK cells against endometrioid and serous papillary (UPSC) uterine cancer cell lines and evaluated the ability of Trastuzumab and Her2xCD3 bispecific antibodies to enhance CIK-mediated cytotoxicity in Her2/neu expressing uterine cancer cells. Methods: The cytotoxicity of CIKs was quantified by 4-hour 51Cr release assays against uterine cell lines HEC-1A (endometrioid) and SPEC-2 (UPSC). Bispecific antibodies against Her2/neu (BSAbHer2) were designed using chemical conjugation methods. Results: Using FACS analysis, we found that the population of CD3+ CD8+ T cells increased from 24% to 56% over 21 days, while the CD3+ CD56+ T cells increased from 7% to 14%. Immunofluorescence microscopy revealed that both cell lines overexpressed Her2/neu. Cytotoxicity assays were performed at effector to target (E:T) ratios of 10:1, 20:1, 40:1 and 100:1 with increasing E:T ratio correlating directly with mean percent specific lysis. At the 100:1 E:T ratio, the mean percent lysis of CIKs against HEC-1A and SPEC-2 cells was 38.8% (±0.21) and 35% (±3.4), respectively. Trastuzumab did not affect the cytotoxic activity of CIKs. However, BSAbHer2 redirection significantly enhanced the cytotoxicity of CIKs against HEC-1A and SPEC-2 cells with a mean percent lysis of 66.3% (±1.0) and 50% (±2.7), respectively. Anti-NKG2D antibodies significantly reduced CIK activity by 49% and 47% in HEC-1A and SPEC-2 cells, respectively. The effects of CIK on advanced uterine cancers were demonstrated using our in vivo bioluminescence imaging system. Conclusion: CIK cells have cytotoxic activity both endometriod and UPSC cell lines. Redirection by BSAbHer2 significantly increased CIK-cell mediated cytotoxicity against Her2/neu expressing cell lines. The mechanism of CIK cytotoxicity appears to be partly mediated by the NKG2D receptor.

No significant financial relationships to disclose.
Use of complementary and alternative medicine and spiritual practices among women with ovarian carcinoma in the southeastern United States
Authors: Spannuth W. A. , Estes J. M. , Powell L. , Straughn. J. M. , Partridge E. E. , Parham G. P.
Published: March 2020

15048

Background: The use of complementary and alternative medicine (CAM) among women with gynecologic malignancies has been described in a number of studies from the Midwestern and Western United States. There is limited data on the use of CAM in women with gynecologic malignancies in the Southeastern United States. Therefore, we sought to evaluate the use of CAM and spiritual practices among women with ovarian carcinoma in the Southeastern United States. Methods: Women with the diagnosis of ovarian carcinoma undergoing chemotherapy were recruited from the gynecologic oncology clinic. Patients underwent a face-to-face interview by a research assistant regarding their use of CAM as well as their spiritual practices. Results: 39 women participated in the interview. 26 patients (67%) had used CAM since being diagnosed with cancer. CAM use was not affected by age, annual income, or number of treatments. The majority of women who used CAM had a college education or higher (69%). The most frequently used CAM therapies included mind-body techniques (44%), herbal therapy (38%), and dietary supplements (28%). The most common mind-body technique was music therapy (28%) followed by meditation (21%). The most common dietary supplement used was fish oil, and the most common herbal therapy was green tea (77%). 28% of patients had used an alternative health care provider, most commonly a chiropractor (13%). The most common reason for using CAM was relief of side-effects from treatment (28%). All patients reported some use of spiritual practices. 95% of patients pray with 90% having asked others to pray for their health. 82% had spoken to a religious figure and 26% had a religious sacrament performed for their health. 87% of patients would like their physician to pray with them. Conclusion: Patients with ovarian cancer in the Southeastern United States frequently use CAM including mind-body techniques, herbal therapy, and dietary supplements. The majority of patients believe that spirituality is an important aspect of their cancer therapy. Physicians should be aware of the number of patients who incorporate CAM and spirituality into their standard therapy.

No significant financial relationships to disclose.
Feasibility study comparing docetaxel-cisplatin versus docetaxel-carboplatin as first-line chemotherapy for ovarian cancer
Authors: Kigawa J. , Shimada M. , Minagawa Y. , Kanamori Y. , Itamochi H. , Kitada F. , Okada M. , Terakawa N.
Published: March 2020

15055

Background: The carboplatin-paclitaxel combination therapy is a gold standard regimen for patients with ovarian cancer. However, combination chemotherapy continues to produce significant neurotoxicity, a serious adverse effect. We conducted the present study to determine the feasibility of docetaxel-cisplatin combination therapy compared with docetaxel-carboplatin combination therapy as first-line chemotherapy for patients with ovarian cancer. Methods: Fifty patients with International Federation of Gynecology and Obstetrics stage Ic-IV ovarian cancer who underwent primary surgery were randomly assigned to receive treatment with docetaxel-cisplatin (n = 23) or docetaxel-carboplatin (n = 27). Docetaxel 70 mg/m2 and cisplatin 60 mg/m2 or carboplatin to an area under the curve = of 5 were administered consecutively on Day 1 of a 3-week cycle, for 3 cycles in patients with stage Ic-II cancer and for over 5 cycles in patients with stage III-IV cancer. Patients were evaluated for treatment-related toxicity in each cycle using the National Cancer Institute Common Toxicity Criteria version 2.0. Results: Five patients (2 in the docetaxel-cisplatin arm and 3 in the docetaxel-carboplatin arm) discontinued the treatment at the end of the second course of chemotherapy because of apparent disease progression; however, no patients came off the protocol therapy because of treatment-related toxicity. Overall, 103 cycles of docetaxel-cisplatin treatment and 130 cycles of docetaxel-carboplatin treatment were delivered. The major toxicity was neutropenia in both regimens. The total incidence of grades 3 and 4 neutropenia was 83% (19/23) in the docetaxel-cisplatin arm and 96% (26/27) in the docetaxel-carboplatin arm. The incidence of grade 4 neutropenia was significantly lower in the docetaxel-cisplatin arm [39% (9/23) vs. 74% (20/27)]. Conclusions: Docetaxel-cisplatin combination therapy may be feasible as first-line chemotherapy for patients with ovarian cancer.

No significant financial relationships to disclose.
Feasibility of ovarian preservation in patients with early stage endometrial carcinoma: A retrospective study
Authors: Lee T. , Jung J. , Kim J. , Kim J. , Park N. , Song Y. , Kang S. , Lee H.
Published: March 2020

15064

Background: The treatment of endometrial cancer involves surgical removal of the ovary; this elimination induces an abrupt menopause and may deteriorate the qualities of life. Therefore, ovarian preservation may be a consideration for premenopausal women. Our main objectives are to examine the occurrence of ovarian metastasis or synchronous malignancy and to evaluate the feasibility of ovarian preservation in patients with early stage endometrial carcinoma. Methods: We reviewed the medical records of 259 patients undergoing surgical treatment for endometrial cancer at a single institute from 1992 to 2004. Results: Among the 224 patients with endometrial adenocarcinoma who had undergone ovarian removal, cancer in ovarian tissue was detected in 21 cases (9.4%, 14 ovarian metastasis, 7 synchronous cancer). Synchronous ovarian cancer showed abnormal gross finding in all 7 cases. Thirteen cases of ovarian metastasis were high grade lesion in preoperative evaluation, or showed intraoperative peritoneal seeding or abnormal gross lesion around adnexa. In 35 patients, grossly normal ovary was saved selectively in compliance with patients’ need (19 bilateral, 16 unilateral). Thirty-one of 35 (89%) were under 45 years and mostly showed early stage (Ia, 24; Ib, 7; Ic, 1; IIa, 1; IIb, 2). Pre-operative MRI was available in 30 cases, and none of them showed findings suggesting tumor extension outside of uterus. In 2 cases of IIb, postoperative radiation therapy was done. There was no recurrence or death in all cases of ovarian preservation except one in which a patient died of sepsis caused by postoperative bowel perforation (median duration of follow-up, 76 mon.; range 3∼121). Conclusions: Ovarian preservation can be cautiously performed, preceded by a thorough preoperative and intraoperative assessment of the adnexa in young women with endometrial carcinoma. The patients who desire ovarian preservation should be counseled regarding the rate of ovarian metastasis or synchronous malignancy.

No significant financial relationships to disclose.
Analysis of paired glioma tissues from initial diagnosis and recurrence in patients enrolled on NCCTG clinical trials: De-differentiation and association with survival
Authors: Jaeckle K. A. , Decker P. A. , Ballman K. V. , Flynn P. J. , Giannini C. , Scheithauer B. W. , Jenkins R. B. , Buckner J. C.
Published: March 2020

1521

Background: Gliomas are known to progress from low to high grade at relapse, but the frequency is not well understood. It is unclear whether survival of these pts differ as a function of histologic subtype, and as measured from initial diagnosis and from relapse; yet such pts are frequently combined in clinical trials. Methods: Central review of paired glioma tissues obtained at initial diagnosis (DX) and recurrence was performed in 208 pts enrolled in prospective NCCTG trials (recurrence ≤ 90 d excluded). Kaplan-Meier, log rank, ANOVA, and chi-square tests were utilized. Results: Relapse from low (1–2) to high grade (3–4) occurred in 18/42 (43%) oligodendrogliomas (oligo), 28/41 (68%) oligoastrocytomas (OA), and 14/20 (70%) astrocytomas (astro); p=0.031. There were differences in median OS (in yrs; 95% CI) from initial DX: oligo-7.5 (5.0, 12.6); OA-4.5 (3.8, 5.6); and astro-3.3(1.8, 5.1), p=0.002; and OS from high grade recurrence: oligo-2.1 (0.9,3.0); OA-1.0 (0.8,1.3); and astro-0.7 (1.8, 5.1); p=0.02. Median OS from initial DX (yrs, 95% CI) also differed between primary (initial DX) GBM-1.7 (1.5–2.2); secondary (at recurrence) GBM-3.7 (2.8, 4.2) and non-GBM (initial+recurrence)- 5.5, (4.9–7.0) respectively, p < 0.001. Mean time to recurrence (TTR), (yrs ± S.D.) also differed: 1.1±1.1; 2.9±1.8; and 4.0±2.9, respectively, p < 0.001; as did median OS from recurrence (yrs, 95% CI) [0.7 (0.5, 1.1); 0.6, (0.5, 1.0); and 1.6 (1.1, 2.1), respectively], p <0.001. OS differed between primary vs. secondary GBM from time of initial DX (p=0.041) and also from recurrence (p=0.017). Conclusions: Low grade astro and OA progressed to grade 3–4 more frequently than did pure oligo; these groups had significant differences in OS from initial diagnosis and from recurrence. There were significant differences in OS between pts with primary and secondary GBM from initial diagnosis and recurrence. These data have important implications in design of clinical trials.

[Table: see text]

No significant financial relationships to disclose.
Phase II study of POLY-ICLC in recurrent anaplastic glioma–A North American Brain Tumor Consortium study
Authors: Chang S. M. , Lamborn K. , Wen P. , Deangelis L. , Fink K. , Lieberman F. , Yung A. , Robins I. , Cloughesy T. , Junck L. , Prados M.
Published: March 2020

1550

Background: The goals of this study were to determine the 6-month progression free survival (PFS) for patients with recurrent anaplastic glioma (AG) treated with the immune-modulatory agent POLY-ICLC, and to evaluate toxicity. Low dose Poly-ICLC has a direct immune enhancing action which includes an increased antibody response to antigen and activation of NK-cells, T-cells, macrophages and cytokines. Previously documented side effects include transient flu-like symptoms, which responds to acetaminophen and pain related to the intramuscular administration. Methods: Eligibility included age >18 years, recurrent AG, no more than 2 prior relapses, normal laboratory parameters and informed consent. Poly-ICLC was administered at 20mcg/kg 3x/week by intramuscular injection in 4 week cycles continuously. Dose reductions were allowed for toxicities. Patients were assessed for tumor response every 2 months. Treatment continued until tumor progression, unacceptable toxicity or patient withdrawal. The study had a 2 stage design with the initial assessment of 6 month PFS for the first 22 patients with possible expansion to a total of 46 patients, if more than 7 patients of the 22 had a 6 month PFS. Results: As of 12/05, 46 patients were treated (49% males). Median age was 42 years (range 21–70 years) and median KPS was 90. The agent was well tolerated and the toxicity profile was as previously reported. The response rate and 6 month PFS of the 22 patients in the first stage of the study was 9% and 23% respectively. Based on these findings the cohort was expanded to 46 patients. Of the 15 patients in the second cohort with at least 1 post treatment response assessment available, there is 1PR and 7 SD (47%). Conclusions: 6 month PFS for the entire cohort continues to be assessed but preliminary results suggest antitumor activity of this agent in recurrent anaplastic glioma.

No significant financial relationships to disclose.
Pattern of local failure after primary 2-dimensional radiotherapy (2DRT) in non-metastatic nasopharyngeal carcinoma patients: Predominance of within-field failure and hints on dose escalation effect
Authors: Kam M. K. , Leung S. F. , Kwan W. H. , Chau R. M. , Cheung K. Y. , Yu K. H. , Chiu S. K. , Chan A. T.
Published: March 2020

15506

Background: To investigate the pattern of local failure and explore any dose-response effect in locally recurred NPC patients treated by 2DRT. Methods: Based on a retrospective review on 2DRT-planned, non-metastatic NPC patients treated between 1996–99, 50 patients had local recurrence (LR). Computer tomography (CT) images at primary treatment and at LR were co-registered for each patient. The pre-treatment gross tumor volumes (GTV) and LR volumes were mapped, and 3-dimensional (3D)dosimetric reconstruction were performed. 20 patients were excluded due to insufficient data. All patients (n = 30) were treated with 2DRT (median dose 66 Gy), and 15 received additional external boost (median dose 20 Gy). The 66 Gy isodose level (IL) was taken as prescription reference. Patterns of LR were classified according to the table below. Comparisons of mean dose (D mean) between LR volume and non-recurrent GTV (GTV-LR) were performed using Wilcoxon signed ranks test. Results: The proportion of within-field (IF) failure, marginal failure, and outside-field failure for the entire cohort were 83.3% (25/30), 13.3% (4/30), and 3.3% (1/30), respectively. Elements of sub-optimal target coverage and radiographic miss were identified in 13.3% (4/30) and 16.6% (5/30) of patients, respectively. The D mean within the non-recurrent GTV was statistically higher than that in the LR volume (73.3 Gy v.s. 69.9 Gy, p = 0.037). Conclusions: Improvement in target localization or dose distribution alone can only avoid less than 20% of local failure that is attributable to radiographic miss or sub-optimal target coverage. Within-field failure was the predominant mode of local recurrence. The dose-response effect observed in this study is hypothesis-generating and forms the background for future randomized trials to verify the dose-escalation benefit using modern radiotherapy technique with high conformal capacity.

[Table: see text]

No significant financial relationships to disclose.
Methotrexate (MTX), procarbazine and CCNU for primary central nervous system lymphoma (PCNSL) in patients younger than 60: Can radiotherapy (RT) be deferred?
Authors: Omuro A. M. , Taillandier L. , Chinot O. , Carnin C. , Barrie M. , Soussain C. , Leblond V. , Hoang-Xuan K.
Published: March 2020

1551

Background: Deferring RT following MTX based chemotherapy has been an acceptable initial approach for elderly PCNSL pts because of a high risk of neurotoxicity (NT). However, given the lower NT risk, such an approach is more controversial in younger pts . In this study we report outcomes of an innovative MTX-based regimen for PCNSL pts younger than 60 and seek to investigate whether withholding RT is an acceptable option in selected pts. Methods: We reviewed records of all patients <60y with confirmed PCNSL seen in 3 institutions from 1994 to 2003. Through prior agreement among institutions, pts were offered a standardized treatment consisting of an induction chemotherapy with MTX (3g/m2- days 1, 10, and 20), CCNU (40 mg/m2- day 1), procarbazine (60 mg/m2- days 1–7), methylprednisolone (120 mg/m2- days 1–20) and IT MTX (15mg), cytarabine (40 mg) and methylprednisolone (40mg)- days 1, 5, 10 and 15. Pts with a complete response (CR) proceeded to a maintenance chemotherapy consisting of 5 monthly cycles with same doses of MTX- day 1, CCNU- day 1, procarbazine- days 1–7, and same IT chemotherapy on day 1; those patients received no further treatment. Pts with less than a CR to induction were treated on an individual basis, and typically received consolidation with RT or high-dose chemotherapy (HDC) with stem cell rescue. Results: Among the 64 identified pts, median age was 47 (19–60), median KPS was 70 (20–100), and 41 (64%) were men. For the entire population, median progression-free survival (PFS) was 13m and median overall survival (OS) has not been reached (median follow-up: 54m). 90% of patients responded to induction treatment (CR: 52%; PR: 38%). Consolidation or salvage treatment with RT has been given to a total of 27 pts, and HDC to 23. For the 26 pts who completed maintenance chemotherapy and received no further treatment, median PFS was 36m. Grades 3/4 hematotoxicity developed in 18 pts, nephrotoxicity in 2 pts, and NT in 6 patients (none in the chemotherapy-only treated patients). Two toxic deaths occurred. Conclusions: Deferring RT in chemosensitive patients seems to compromise PFS but not OS, with minimal NT. HDC and RT are effective salvage treatments. Further studies on the role of RT versus HDC in younger patients are warranted.

No significant financial relationships to disclose.
Phase II study of gemcitabine concurrent with radiation in locally advanced squamous cell carcinoma of head and neck: Trial of the Cancer Research Group Pakistan
Authors: Javed A. A. , Shaharyar A. , Shah I. H. , Shah M. A. , Ansari T. N. , Faheem M. , Mehmood H. , Khan M. S. , Afridi M. A. , Rasool S.
Published: March 2020

15520

Background: The optimum radiosensitizing dose and schedule of gemcitabine for squamous cell carcinoma of head and neck are not known. The objectives of this study were to evaluate the efficacy and toxicity of weekly gemcitabine as a radiosensitizer concurrent with radical radiotherapy in locally advanced head and neck cancer. Method: Thirty-nine patients with stage III or IV B inoperable carcinoma of head and neck were enrolled. Eligible patients had histopathologically confirmed squamous cell carcinoma with age between 18–70 years. Patients had a KPS >70 with an adequate marrow, hepatic and renal function. No prior chemotherapy or radiotherapy was allowed. Patients with nasopharyngeal, glottic or sub-glottic cancer were excluded. Gemcitabine 150 mg/m2 or a total dose not exceeding 200 mg was given on day 1,8,15,22,29, and 36 during radiation treatment. Gemcitabine was infused in 200 ml of normal saline in 2 hours and radiation was delivered two hours after the completion of gemcitabine infusion. Conventional fractionation was used to deliver a total dose of 66 Gy. CTC version 2.0 of NCI and RTOG/EORTC Late Radiation Morbidity Scoring Scheme were used for evaluation of toxicity and RECIST was used for response evaluation. Results: Only 35 patients were considered evaluable for response. Complete response was seen in 8 (22.9%) (95% CI; 10.4–40.1%), partial response in 25 (71.4%), with an overall response rate of 94.3% (95% CI; 80.8–99.3%). All the thirty-nine patients were evaluable for toxicity. Grade 3 and 4 mucositis was seen in 28 (71.8%) and 2 (5.1%) patients respectively. Grade 3 pharyngeal toxicity was seen in 6 (15.4%). One patient developed pharyngo-cutaneous fistula. Despite vigorous symptomatic and supportive care acute toxicities led to treatment interruption in 16 (41%) of patients. Conclusion: Weekly gemcitabine at a dose of 150mg/m2 concurrent with radiation therapy gives a high overall response rate and a high rate of acute toxicity.

No significant financial relationships to disclose.
Phase II study of hydroxyurea and gemcitabine in recurrent or persistent squamous cell cancer of the head and neck
Authors: Shibata S. , Lim D. , Yen Y. , Koczywas M. , Morgan R. , Leong L. , Somlo G. , Margolin K. , Ruel C. , Doroshow J.
Published: March 2020

15524

Background: Preclinical studies demonstrate increased activity when hydroxyurea (HU) is given prior to gemcitabine (G). Clinical feasibility was demonstrated in a phase I trial (Yen, et. al. Cancer Chemother Pharmacol. 2002 ). We performed a phase II trial treating patients (pts) with squamous cell head and neck cancers (SCCHN). Methods: Pts had metastatic or incurable locally recurrent SCCHN. Prior chemotherapy was allowed, but not required. Serum creatinine ≤2.0 mg/dl, bilirubin <3.0 gm/dl, AST/ALT <5× ULN and KPS ≥60% were required. HU 500 mg orally every 6 hours for 4 doses was given on day 1 of a 21-day cycle. On day 2, 6 hours after HU, G 750 mg/m2 was given over 30 minutes. This sequence was repeated on day 8 and 9. After 8 pts, G was given at 500 mg/m2. G-CSF was given on day 10 and until the WBC count was >10k/μl. The primary endpoint was response rate (RR), with an early stopping rule for <3 objective responders among the first 18 pts. Results: 22 pts (17 M) were accrued, 16 with prior chemotherapy and 19 with prior radiation. The first 8 pts received G 750 mg/m2. Two pts died of neutropenic fever (NF) during course 1. Subsequently 14 pts received G 500 mg/m2. 18 pts were evaluable for response, with 1 still in follow-up. Partial response was seen in 1 pt, stable disease in 9, and progressive disease in 8. The overall median survival of the 22 pts was 6 months and the median progression free survival (PFS) was 2 months. The primary toxicity was hematologic. Grade 4 neutropenia was seen in 7/22 pts during the 1st cycle (5 at G 750 mg/m2) with 5 cases of NF. Grade 4 thrombocytopenia occurred in 1 pt at G 750 mg/m2. Conclusions: The RR and PFS of treated pts treated were not promising and further accrual is not planned. Analysis of biopsy materials is planned to see if responsive pts can be selected. (Supported by NCI Grant CA33572).

No significant financial relationships to disclose.
Treatment outcome in patients undergoing surgery for carcinoma larynx and hypopharynx: A follow-up study
Authors: Varghese B. T. , Sebastian P.
Published: March 2020

15545

Background: In the Regional Cancer Centre (RCC) Trivandrum, India, carcinoma of the larynx account for approximately 5% of all new registries and carcinoma of the hypopharynx for another 3%. It is estimated that the division of surgical oncology RCC has performed about 200 laryngectomies since it’s beginning (1989). Currently i.e. after the year 2000,about 30–40 laryngectomies are estimated to be performed a year thus forming about 3–4% of overall major head and neck surgeries performed which is around 1000 cases per year. 80% of these surgeries are salvage procedures for failed radical radiation/chemoradiation. Aim: (1) To evaluate the role of surgery in disease free and overall survival. (2) To evaluate the prognostic significance of factors that generally affect the surgical outcome in laryngectomies. (3) To evaluate the morbidity associated with salvage surgeries and laryngectomies involving complex reconstructions. (4) To follow up all the patients and evaluate quality of life. (5) To evolve a protocol for selecting cases for primary and salvage laryngectomy. (6) To evolve a protocol for reconstructing the pharynx after laryngectomies. Methods: All patients who have undergone laryngectomy at the Division of Surgical Oncology RCC from June 1995 to Dec 2005 are included in the study which retrospectively records the age and sex distribution initial TNM staging and staging of recurrence/ residual disease at the time of surgical salvage, the indications and types of laryngectomy, and reconstructive options used and analyze the therapeutic outcome, disease free survival (DFS), overall survival (OS), voice preservation, post operative voice rehabilitation and quality of life. Major outcome measures Complications and factors contributing to it, DFS, OS, Voice Preservation, Postoperative rehabilitation and Quality of life. Results and Conclusions: An update of the results as on 31/12/05 the final conclusions and recommendations will be presented.( The study is currently on going with the Institutional Review Board (IRB) and the local Ethical committee (EC) clearance already obtained.and final document is expected to to be prepared by March 2006).

No significant financial relationships to disclose.
Esthesioneuroblastoma (ENB): A case report
Authors: Troncoso E. , Bonicatto S. , Mainella A. , Barbero A. , Lavezzaro M. , Zapata G.
Published: March 2020

15546

Background: ENB is a rare embrionary tumor derived from neuroblasts of the olfactory sensory system. Polypoid mass with epistaxis or nasal obstruction are the most common clinical manifestations of this tumor. It’s invasive and it frequently causes regional and distant metastasis. ENB requires a multimodality therapy. The objective of this study is to describe the form of presentation, diagnosis, treatment and evolution of this tumor on a female patient (pt), as a casuistic contribution. Methods and Case Report: A 61 year old woman with a four month history of epistaxis, nasal pain and anosmia. CT shows nasal mass invading the entire nasal cavity and upper maxillary. Pt underwent nasal resection and reconstruction with frontal flaps. Anatomopathology: ENB invading the bone. Cromogranin (+), sinaptofisin (+), CK (−), NSE (−). Three months later: lesion on the right wing nasal and a mass in the soft palate. MRI: mass on the floor of the nasal fossa that involve the left maxillary sinus and the bone palate. Kadish stage C. We treated her with three cycles of chemotherapy using cisplatin 30 mg/sqM d 1–3 iv and etoposide 100 mg/sqM d 1–3 iv. After that, remission was observed in the wing nasal lesion but the the soft palate mass shows progression. MRI: mass in nasal fossa that destroys the left maxillary sinus and causes lysis of the upper maxillary and orbital floor. Pt was treated with radiotherapy (6000 cGy) showing complete remission of the nasal lession and partial response on the soft palate, verified by physical examination and RMI. Four months after the end of radiotherapy, she continues under control and maintains the response to therapy without evidence of progression. Conclusion: ENB is an unfrequent tumor without any standard treatment. In our case, the combination of surgery, CH and RT has been effective for local control of the disease with good tolerance and acceptable quality of life.

No significant financial relationships to disclose.
Curative interstitial brachytherapy for early stage carcinoma of lip—A case report
Authors: Jha A. K. , Prasiko G. , Mod H. , Chaurasia P. P. , Shrivastava R.
Published: March 2020

15547

Background: Brachytherapy is potentially useful in the treatment of carcinoma lip. Small cancers of the lip (less than 2 cm) are treated equally well with surgery or radiation therapy with excellent cosmetic and functional results seen in radiation therapy. Methods: We treated an 18-year old male diagnosed as stage 1 carcinoma lip with curative interstitial brachytherapy. Under anaesthesia, three catheters were inserted at 0.5 cm separation through the lesion. Patient was simulated, planned, treated in VARISOURCE (Varian, USA). He received dose of 3 Gy per fraction, two fractions per day at a minimum interval of 6 hours between the two fractions for 6 days. He therefore received a total dose of 36 Gy with High Dose Rate (HDR) Brachytherapy. During treatment, he received hyperalimentaion via naso-gastric tube with intravenous antibiotic prophylaxis. Results: Upper lip swelling occurred in first 12 hours of treatment and remained for 6 days that subsided subsequently. Catheters were removed on 6th day of treatment. Scar formation occurred over the lesion in 1 month’s follow up. In next one month’s follow up, there was no clinical evidence of disease. Cosmetic result was satisfactory. At two months follow, the patient is clinically disease free and has no complaints. Conclusions: Interstiatial brachytherapy is a excellent method for treating early stage carcinoma lips with excellent cosmetic outcome. This kind of treatment is now available in my country at our institution.

No significant financial relationships to disclose.
A phase I study of temozolomide (TMZ) and the farnesyltransferase inhibitor (FTI), lonafarnib (Sarazar, SCH66336) in recurrent glioblastoma
Authors: Gilbert M. R. , Gaupp P. , Liu V. , Conrad C. , Colman H. , Groves M. , Puduvalli V. , Levin V. , Hsu S. , Horowitz J. , Yung W.
Published: March 2020

1556

Background: Farnesylation is essential for the post-translational modification of several proteins that play a role in cell proliferation and growth. FTIs demonstrate antiproliferative effects in a variety of tumor cell lines and xenograft models and enhanced efficacy by combining lonafarnib with TMZ compared with TMZ alone. Clinical studies show that dose-intense TMZ may have better efficacy then conventional dosing (Wick, Neurology 2004). Objective: Determine the maximum tolerated dose of lonafarnib when combined with a dose-intensified schedule of TMZ. Eligibility criteria: Histologically proven GBM; evidence of relaspe or progression; up to 2 prior chemotherapy regimens, prior TMZ permitted; KPS ≥ 60. No enzyme-inducing anticonvulsants. Methods: TMZ was given at 150 mg/m2 days 1–7 and 15–21; lonafarnib escalated by cohort: 100 mg BID, 150 mg BID, 200 mg BID on days 8–14 and 22–28 of a 28-day cycle. Response: Toxicity measured after cycle 1 using NCI CTCAE v3. Patient (pt)accrual used a 3 + 3 design. Response was evaluated q2 cycles. Standard response criteria (MacDonald) were used. Results: 15 patients were accrued. Median age 47 yrs; median KPS 90. M:F ratio was 11:4. No DLTs in any dose cohort, a pt (cohort 1) died day 29 of unrelated cardiac disease. 4 pts demonstrated partial response, all with prior TMZ failure, 3 pts showed prolonged stable disease. 6-month PFS rate estimated at 33%, median PFS 14 weeks. Treatment was well tolerated: 1 episode each of grade 3 diarrhea, esophagitis, fatigue and hypokalemia; 3 episodes of grade 3/4 leukopenia, 2 episodes of grade 3/4 neutropenia, and 2 episodes of grade 4 thrombocytopenia. Seven pts had grade 3/4 lymphopenia, some with persistant lymphopenia from prior TMZ. 1 pt had grade 4 pneumonitis of uncertain etiology. Conclusions: The alternating week schedule of TMZ/lonafarnib was well tolerated. Preliminary results suggest anti-tumor activity even in pts who had failed prior TMZ. It is not certain whether this activity is due to the dose-intensified TMZ or the treatment combination. Studies are planned to evaluate potential predictors of response (i.e MGMT gene promoter methylation) and expand the trial to obtain pharmacokinetic and additional efficacy data.

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