bluuebunny/crossref_metadata_2025_split huggingface dataset:
The role of F-18 FDG PET/CT and breast MRI in the management of breast cancer
Authors: Iagaru A. , Masamed R. , Silberman H. , Keesara S. , Conti P. S. 
Published: March 2020

10778 Background: F-18 FDG PET/CT combines functional and morphologic information in a single study, thus becoming a powerful imaging tool for diagnosis, staging and establishing the response to therapy in various malignancies, including breast cancer (BC). Breast MRI (BMRI) is gaining a major role in the management of high risk BC patients (pts), demonstrating high sensitivity and specificity for detection of small lesions. It is not clear whether to request both studies prior to therapy or opt only for one. We were therefore prompted to review our experience with PET/CT and BMRI in BC. Methods: This is a retrospective study of 21 pts with BC, 30–76 years old (average: 52±13.5), who had BMRI and PET/CT from June 2002 to May 2005. 6 pts (group A) had BMRI and PET/CT in the preoperative period (3–78 days, average: 25) and 15 pts (group B) had BMRI and PET/CT as follow-up after surgery (4–175 days, average: 51.3). The interval between the PET/CT and BMRI ranged 2–188 days (average: 52.7). Specificities and sensitivities for BC and metastases detection using PET/CT and MRI were calculated using pathology (17 pts) or clinical follow-up (4 pts) as gold standard. Results: In group A, BMRI identified BC in 4 pts, while PET/CT did so in 5 pts. All were proven to be malignancy on pathology. In group B, BMRI detected recurrent BC in 8 pts, with 88.9% sensitivity (95% CI: 56.5–98) and 83.3% specificity (95% CI: 43.6–96.9). In the same patient population, PET/CT was 33.3% sensitive and 91.7% specific. As a whole body exam, PET/CT revealed metastases in 6 pts (100% sensitive and 90% specific). Overall, sensitivities and specificities for BC detection were 85.7% (95% CI: 60.1–95.9) and 85.7% (95% CI: 48.7–97.4) for breast MRI, and 75% (95% CI: 40.9–92.8) and 92.3% (95% CI: 66.7–98.6) for PET/CT. Conclusions: BMRI is more sensitive than PET/CT for detection of breast lesions. However, PET/CT detected distant metastases in 6 of the 21 pts (100% sensitive, 90% specific). Larger prospective studies, with the addition of dedicated breast PET and dual time imaging are needed to define the sequence of studies during initial work-up. Our study suggests that PET/CT and BMRI should be considered complimentary imaging tools in the pre- and perioperative work-up of pts diagnosed with BC and at high risk for metastatic disease. No significant financial relationships to disclose.
Combination procarbazine and temozolomide for temozolomide-resistant adult gliomas
Authors: Kavan P. , Huang F. , Roberge D. 
Published: March 2020

11503 Background: As Temozolomide has become incorporated in the first line treatment of glioblastoma multiforme as well as the salvage therapy of many low-grade gliomas, we are increasingly faced with Temozolomide failures. There is currently no standard second-line chemotherapy for Temozolomide-resistant tumors. In what is usually a palliative setting, toxicity and convenience are important considerations in the choice of a second-line regimen. Methods: We reviewed our experience with a combination oral regimen for Temozolomide failure. The regimen consisted of a 28-day cycle with Procarbazine given at 100–150mg/m2/d on days 1–5, and Temozolomide at 150mg/m2/d on days 1–5. This was initiated at the time of radiological and/or clinical progression while on Temozolomide, and continued until further progression or toxicity was documented. Results: 12 patients, median age 52 (range 38–68), were treated with concomitant Procarbazine and Temozolomide at our institution since November 2004. All patients had histologically confirmed gliomas (glioblastoma multiforme (10), grade II oligodendroglioma (1), grade II oligoastrocytoma (1)), and all had undergone prior maximal safe resection and external beam radiotherapy. All patients were receiving Temozolomide, either in the adjuvant setting (after concurrent chemo-radiotherapy in 6 of 12), or as salvage monotherapy for recurrence. No patient met the RECIST criteria for PR. Patients progressed after a median of 2 cycles (range: 1–10) but the 6-month actuarial progression-free survival was 40% (80% of patients with SD had glioblastoma multiforme). No Grade 3 or 4 toxicity was seen. No patient discontinued treatment because of toxicity. The Procarbazine dose was prophylactically reduced (75mg/m2/d) in one patient with poor hematological tolerance to prior chemotherapy. Conclusions: The combination of Procarbazine and Temozolomide given in a 28-day cycle is a well-tolerated oral second-line regimen for glioma patients failing Temozolomide. The activity of this regimen is modest but prolonged progression-free survival can be seen. [Table: see text]
Determination of human brain tumour therapy response using an ex vivo invasion assay provides a potential step toward individualized treatment
Authors: Costello P. C. , MacDonald D. , McDonald W. , Hammond R. , Sloby V. , Faubert B. , Megyesi J. 
Published: March 2020

11509 Background: Malignant brain tumours are the 6th leading cause of pre-mature death in Ontario with over 10,000 potential years of life lost each year. Improved treatment for malignant brain tumours is needed. Models assessing chemotherapy response employ clonal malignant human tumour cells while patient responses are heterogeneous. Tumour spreading is dependent on tissue invasion and in this study, a surgical sample of each patient’s tumour was used to assess invasion and growth while exposed to a panel of clinically relevant chemotherapies. Methods: Tissue specimens were placed into a nutrient-rich collagen gel that mimics the tumour environment in the body. Chemotherapy treatments were suspended in the matrix surrounding the tumour. Growth and invasion in the presence of chemotherapies was assessed for 5 days following surgical removal in this 3 dimensional matrix and compared to control conditions using student t- test. Results: 12 patient’s individual tumour response was assessed. 4 patients tumours did not respond to any chemotherapy tested. Table 1 shows the number of responders to each therapy tested. Conclusions: Individual response to chemotherapy is highly variable both clinically and in our ex vivo assessment of tissue fragments. Several patients (8/12 or 67%) tumour assessment displayed significant (p<.05) response to one or more therapies. Results from this data will continue to be compared to patient response, The overall predictive value of the data obtained using this ex vivo model will be determined by continuing to collect information time to recurrence and survival at 3, 6, 12 and 24 months) from 90 solid tumour patients per year. Pre-assessment each patient’s responsiveness to chemotherapies could lead to more individualized and therefore more effective treatment. [Table: see text] [Table: see text]
Determination of expression of platelet derived growth factor receptors (PDGFR) in astrocitic tumors
Authors: Barrios C. H. , Viola F. S. , Coutinho L. M. , Paglioli E. 
Published: March 2020

11518 Background: PDGF and its receptors (α and β) are frequently expressed together in gliomas raising the possibility that an autocrine/paracrine loop could contribute to the pathogenesis of these tumors. Studies with immunohistochemistry (IHC) and in situ hybridization have clarified that PDGF-α receptors (PDGF-R α) are preferentially expressed in tumor cells, whereas PDGF-β receptors (PDGF-R β) are preferentially expressed in proliferating endotelial cells within the tumor vasculature. Objective: Determine the expression of PDGF-R α and β in astrocitic tumors. Methods: Paraffin blocks samples from patients with a diagnosis of low-grade astrocitoma, anaplastic astrocitoma, and glioblastoma were obtained from the Neuro-Oncology Unit at Hospital São Lucas-PUCRS. These patients presented and were treated from 1996 through 2001. We collected a total of 130 cases: 57 Low-grade astrocitomas (LGA), 13 Anaplastic Astrocitomas (AA), and 60 Glioblastomas (GBM). All cases were studied with standard IHC techniques using antibodies for PDGFR α and β (Santa Cruz Biotechnology). Results: See table . Conclusion: The expression of PDGF-R α and β in low-grade tumors reflects the possible role these receptors may have in the evolution of these neoplasms. More importantly we documented that over 60% of high-grade gliomas (61% in AA; 65% in GBM) show expression of PDGF-R β predominantly in the endothelial cell compartment of the tumors. This is consistent with and reflects the extensive angiogenesis observed in these diseases. The level of expression we encountered identifies an attractive molecular target to explore. [Table: see text] No significant financial relationships to disclose.
Evaluation of the safety of C-1311 administered in a phase 1 dose-escalation trial as a 1-hour infusion once every 3 weeks in patients with advanced solid tumors
Authors: Thomas A. , Anthoney A. , Ahmed S. , Drouin M. , Major A. , Capizzi R. L. , Grieshaber C. , Loadman P. , Twelves C. 
Published: March 2020

12005 Background: C-1311 (Symadex) is the most active member of a new series of anti-cancer agents, the imidazoacridinones, specially designed compounds developed from research on the structure-activity relationships of existing cancer therapies. This clinical trial was designed to assess the safety profile of ascending doses of C-1311 and to determine the recommended dose when administered every 3 weeks (Q3W). Methods: Patients with advanced solid tumors refractory to conventional therapy were enrolled. The dose escalation scheme was divided into 2 phases with different schedules. Initially, C-1311 was given as a 1-hour daily infusion over 5 consecutive days. Following review of pre-clinical data, coupled with preliminary results of a parallel weekly study, a day 1 only schedule was explored. The maximum tolerated dose (MTD) is defined as the dose at which 2/3 or 2/6 pts experience a dose-limiting toxicity (DLT). The recommended dose (RD) is defined as the dose level below the MTD, confirmed by expansion of the RD cohort to 9 pts. Results: The first 5 patients were treated at doubling doses of 6, 12, 24, 48 and 96 mg/m2 on a schedule of 1-hour daily infusions over 5 consecutive days, repeated every 3 weeks; no DLTs were seen. The 6th pt received the same total dose as the 5th (480 mg/m2) but on day 1 only, following which a modified Fibonacci design with cohorts of 3 pts and 33% dose increments was utilized. Subsequently, pts received C-1311 at doses of 640 mg/m2 (3 pts), 850 mg/m2 (3 pts) and 1100 mg/m2 (5 pts); 2/5 pts treated at 1100 mg/m2 experienced an identical DLT (grade 4 neutropenia for ≥7 days with grade 4 thrombocytopenia), defining this as the MTD. The 850 mg/m2 cohort was expanded to confirm this as the RD. Neutropenia, thrombocytopenia, anemia and fatigue have been reported as drug-related grade 3 or 4 adverse events (AEs). Grade 1 or 2 AEs most commonly described as drug-related are fatigue, nausea, vomiting and diarrhea. Stable disease was observed in two patients with advanced malignancy. A pt had a stable disease over 8 cycles and one over 6 cycles. Plasma drug concentrations are linear and proportional to dose. Conclusions: A C-1311 dose of 850 mg/m2 administered once every 3 weeks offers a predictable and tolerable safety profile. [Table: see text]
Preclinical efficacy evaluation of ixabepilone (BMS-247550) in combination with cetuximab or capecitabine in human colon and lung carcinoma xenografts
Authors: Lee F. Y. , Camuso A. , Castenada S. , Flefleh C. , Ingio I. , Kan D. , McGlinchey K. , Menard K. , Rose W. 
Published: March 2020

12017 Background: Ixabepilone belongs to a class of structurally novel, microtubule-stabilizing agents that exert their antimitotic action by binding to tubulin with a binding mode that is distinct from the taxanes. Preclinical findings that ixabepilone has antitumor activity in a broad spectrum of tumor types, including taxane-resistant tumors, is borne out by Phase II clinical trials where ixabepilone has demonstrated activities in multiple tumor types including breast, renal, pancreatic, prostate and lymphoma. The aim of this series of studies was to further characterize the therapeutic potential of ixabepilone in combination with currently approved chemotherapy agents. Methods: Antitumor activity was evaluated in the GEO human colon and L2987 human lung carcinoma xenografts. Therapeutic synergism of the combination was defined as the attainment of efficacy that was significantly better than the best response of the individual single agents administered at their maximum-tolerated dose (MTD) or optimal dose (OD). Results: In the GEO tumors, single-agent ixabepilone produced 1.1 log cell kill (LCK) at its MTD. Cetuximab at its OD yielded 0.8 LCK. The combination of ixabepilone and cetuximab produced 1.7 LCK which was significantly superior to ixabepilone alone (P=0.0173) and cetuximab alone (P=0.0002). Similar synergistic efficacy was observed in the L2987 tumors. The combined efficacy of capecitabine plus ixabepilone was evaluated in the GEO tumors. In this tumor, single-agent ixabepilone was modestly active (LCK = 0.8) at its MTD. Single-agent capecitabine was not effective (LCK = 0.4) at its MTD. However, the combination of the two agents produced therapeutic synergism, yielding antitumor efficacy (1.9 LCK) that was superior to either of the agents alone at their MTDs (P=0.035 and 0.0004, respectively). Conclusions: Ixabepilone demonstrates robust synergistic antitumor efficacy when used in combination with cetuximab or capecitabine in human xenografts providing a biologic rationale for these combinations in the treatment of cancer. [Table: see text]
The efficacy of combination chemotherapy with cisplatin and gemcitabine in patients with advanced adrenal cortical carcinoma (ACC)
Authors: Menefee M. , Edgerly M. , Velarde M. , Herbert K. , Fojo A. T. 
Published: March 2020

12033 Background: ACC is a rare, but highly lethal disease for which more effective systemic therapies are needed. Prior studies have concluded that cisplatin and doxorubicin have single agent activity and that combinations of these and other agents, most notably etoposide, may have additive or synergistic effects. However, the majority of responses are neither complete nor durable. Anecdotal evidence of activity by gemcitabine in patients with ACC motivated the present analysis, designed to assess the efficacy of cisplatin and gemcitabine in combination in patients with metastatic ACC. Methods: 18 patients with metastatic disease were evaluated. Patient’s ages ranged from 19 to 63 years with a median age of 46 years. 5 patients were treated at initial presentation, while 13 were treated after disease progression on or following a previous chemotherapy regimen. Among the latter, the median number of prior regimens was 1, with a median of 4 prior drugs. Sites of metastases included lung (10/18), liver (12/18), retroperitoneum/adrenal bed (5/18) and bone (2/20). The starting dosages were 100 mg/m2 of cisplatin and 1250 mg/m2 of gemcitabine. A total of 56 cycles were administered to 18 patients, with a range of 2 to 12 cycles and a median of 3. Results: The toxicity of this regimen in this patient population was similar to that reported with this regimen in other tumor types. The partial response rate was 11% with an additional 16% of patients demonstrating cytoreduction that did not meet the criteria for a partial response. Conclusions: We conclude that the combination of cisplatin and gemcitabine has activity in ACC. While the superiority of this combination over single agent platinum is not established, the combination does not appear to be superior enough to warrant its routine use, especially in patients with more indolent disease, where single agent platinum can be followed by single agent gemcitabine. An attribute this combination has over other regimens used in patients with ACC, notably those incorporating doxorubicin and/or etoposide, is that it can be given at full doses without excessive toxicity to patients with hormone producing tumors in combination with ketoconazole. No significant financial relationships to disclose.
Gemcitabine and capecitabine synergism and biomodulation with dipridamole in a mouse tumor model
Authors: Demir G. , Klein H. O. , Yildirim S. , Esen I. , Altug T. 
Published: March 2020

12034 Background and Aim: Gemcitabine and capecitabine are antimetabolites that are effective in the pyrimidine pathway of the DNA synthesis. Capecitabine through a 3-step activation process is transformed to 5-FU in the tumor cell by thymidine phosphorilase. On the other hand, gemcitabine interacts with the enzymes thymidine kinase, tymidine phosphorilase ve ribonucloetide reductase. Our hypothesis is based on a possible synergistic blockade by concurrent administration of these two antimetabolites. Additionally, dipridamole is an inhibitor of the nucleoside transport; and that can prolong the accumulation of antimetabolites within the tumor cell. In this study, combinations of these drugs are tested on an animal model. Methods and Results: 80 male balb-c mice were inoculated dorsally with 0.1 cc Ehrlich ascites tumor, and 10 days later the animals were separated into 5 groups having a similar tumor load. The control group received no treatment, while in the gemcitabine arm the animals received 50 mg/d gemcitabine on day 1. In the capecitabine arm, the animals received 1mg/day capecitabine administered in drinking water on days 1–4. In the gemcitabine + capecitabine combination arm, the animals received both treatments. In the gemcitabine + capecitabine + dipridamole arm, in addition to both of the drugs, dipridamole was also given 2mg/day in drinking water on days 1–4. In the control group (n=16) median survival was 17 days, while it was 33 days in gemcitabine arm (n=11), 35 days in capecitabine arm (n=14), and 44 days in the gemcitabine + capecitabine combination arm (n=22) which was significantly higher (p<0.007). Dipridamole added to this combination (n=17) did not prolong survival any further. Conclusion: combination of gemcitabine with capecitabine suggests favorable results in an animal model. Testing of this combination in clinical trials seems to be justified. No significant financial relationships to disclose.
A phase I study of antisense Bcl-2 oligonucleotide (G3139) in combination with carboplatin (C) and paclitaxel (T) in patients with advanced solid tumors
Authors: Lalich M. , Wilding G. , Kolesar J. , McNeel D. G. , Schell K. , Leith C. , Chappell R. , Marnocha R. , Alberti D. , Liu G. 
Published: March 2020

13006 Background: G3139 is an 18-mer oligonucleotide that targets the mRNA of Bcl-2, a protein that inhibits apoptosis conferring treatment resistance, and is synergistic with taxanes in studies using Bcl-2 over-expressing xenografts. Here we conduct a study combining G3139 with C + T in order to define the recommended phase II dose, as well as evaluate the direct biologic effect of G3139 on tumor. Methods: Patients with advanced solid tumors were treated with a dose escalation of G3139 (3–7 mg/kg/day) by continuous infusion days 1–7, with C (AUC 5) and T (150 mg/m2) given on day 4, repeated in 3 week cycles. At the planned expanded cohort (G3139 7 mg/kg/day dose), 12 patients underwent paired tumor biopsies (baseline and day 4 pre-chemotherapy) for assessment of Bcl-2/Bax expression by RT-PCR and IHC, as well as intratumoral G3139 levels using ELISA. Likewise, peripheral blood mononuclear cells (PBLs) were assessed using flow cytometry and RT-PCR for changes in Bcl-2/Bax expression. Results: 34 patients have been treated: 11 melanoma, 7 bladder, 3 prostate, 2 esophageal, 3 non-small cell lung, and 1 head/neck, kidney, breast, pancreas, liver, gastrointestinal stromal, biliary, and unknown primary cancers. G3139/C/T appeared well tolerated at the doses administered with the main toxicities observed being attributed to the C + T chemotherapy (myelosuppression and thrombocytopenia). The maximal tolerated dose is yet to be achieved. Assessment of paired tumor biopsies on 12 patients show decreases in Bcl-2 transcription in laser capture microdissected tumor using RT-PCR, with concordance observed using IHC. Likewise, decrease in Bcl-2 gene expression in PBLs was seen. 2 confirmed PRs were observed, including a bladder patient with baseline Bcl-2 tumor expression 10-fold greater than any other patient assessed. Conclusions: G3139/C/T is well tolerated, with main toxicities attributable to the chemotherapy alone. Bcl-2 is suppressed in tumor and PBLs supporting that a biologically active dose of G3139 is being achieved. Currently, the C + T is being escalated to define a MTD. Complete clinical data, G3139 pharmacokinetics, and Bcl-2/Bax data will be presented in detail. No significant financial relationships to disclose.
A prospective pharmacogenetic study of thymidylate synthase (TS) polymorphisms in high risk stage II or stage III colon cancer patients treated with 5-fluorouracil (5-FU) and leucovorin (LV)
Authors: Mulder K. E. , Butts C. A. , Scarfe A. , Au H. , Koski S. , Fields A. , Hanson J. , Kuzma M. , Graham K. , Sawyer M. B. 
Published: March 2020

13018 Background: Retrospective studies suggest TS polymorphisms predict toxicity from TS inhibitors as well as therapeutic response. The TS promoter has a variable number of tandem repeats (VNTR) polymorphism containing putative E-box binding sites that bind upstream stimulatory factor (USF) -1 and -2. One E-box binding site exists in TSER*2 and 2 binding sites exist in TSER*3. A single nucleotide polymorphism (SNP) at position 12 (G→C) in TSER*3’s 2nd repeat abolishes binding of USF-1/2. Combined effects of VNTR and SNP means individuals may have 2, 3 or 4 enhancer regions. We hypothesized that decreased enhancer numbers predicts for patients at risk for grade ≥3 mucositis, diarrhea, neutropenia, and overall toxicity and performed a prospective pharmacogenetic study of TS polymorphisms in adjuvant colon cancer patients treated with 5-FU/LV. Methods: High risk Stage II or Stage III colon cancer patients treated with 5FU/LV (425 mg/m2/ 20 mg/m2) daily for 5 days every 4 weeks had blood drawn for genotyping prior to starting therapy. Patients were assessed for toxicity using NCI CTC 2.0 in cycle 1. Three year disease-free survival will also be assessed. Results: 103 patients were enrolled and genotyped with 95 evaluable for toxicity. Patient characteristics: median age 61yrs (36–79): M 52%/F 48%; Stage III 77%, Stage II 23%. Frequency of genotypes containing 2 enhancers (TSER*2/ TSER*2, TSER*2 / TSER*3C, TSER*3C/ TSER*3C), 3 enhancers (TSER*2/ TSER*3G, TSER*3C/ TSER*3G) and 4 enhancers (TSER*3G/ TSER*3G) was 0.64, 0.31, and 0.05 respectively. No significant difference was seen in overall toxicity, mucositis, diarrhea and neutropenia based on TS polymorphism genotypes. Frequency of recurrence in 2 enhancer patients was 13% versus 26% in 3/4 enhancer patients but this did not reach statistical significance (p = 0.16). Conclusions: This prospective study does not confirm previously published retrospective studies suggesting that TS VNTR and SNP predict toxicity from TS inhibitors in patients treated with 5-fluorouracil for colon cancer. There is a trend for prediction of recurrence which requires further follow-up. No significant financial relationships to disclose.