bluuebunny/crossref_metadata_2025 huggingface dataset:
Open-configuration magnetic resonance (MR) guided microwave thermocoagulation treatment for breast tumors: Preliminary report of hepatic metastases and resected breast tumors
Authors: Abe H. , Shimizu T. , Naka S. , Shiomi H. , Demura K. , Murakami K. , Kurumi Y. , Morikawa S. , Tani T.
Published: March 2020

11095

Background: Minimally invasive therapies such as radiofrequency ablation, focused ultrasound surgery, and cryotherapy for early stage primary breast cancers may be appropriate in carefully selected patients. In this study, open-configuration magnetic resonance (MR)-guided microwave thermocoagulation treatment was used for breast tumors, and the efficacy of this treatment was assessed. Methods: We used MR-guided microwave thermocoagulation treatment on eight patients with metastatic liver tumors from breast cancer. A 0.5 T open-configuration MR system and a microwave coagulator were used. Near-real-time MR images and real-time temperature images were collected and displayed on the monitor. Secondly, it was examined whether the description of breast tumors was possible with open- configuration MR device, and simulated a tumor puncture while imaging a real-time MR image. The resected breast tumor was punctured while confirming the tumor with open-configuration MR system, and microwave thermocoagulation was enforced. Tumor tissue viability after microwave thermocoagulation was assessed by hematoxylin and eosin and NADH vital staining. Results: The visibility of the tumor by MR imaging was not disturbed throughout the procedure. In 8 patients, 11 hepatic metastases were treated by MR-guided microwave thermocoagulation treatment successfully without any major adverse event. Five of the 8 patients are alive with new metastatic foci with a mean observation period of 25.9 months (range 1 - 43 months). It was able to be confirmed that viability of the tumor had disappeared by the microwave thermocoagulation in resected breast tumors. Conclusions: This technique is feasible and safe to treatment of breast tumor with real-time observation. Open-configuration MR-guided microwave thermocoagulation therapy appears to be a feasible method with advantages to add to the growing list for nonsurgical ablation therapy of early stage primary breast cancer and should be investigated in further comparative studies.

No significant financial relationships to disclose.
Efficacy of primary systemic chemotherapy regimen containing anthracyclines with/without taxanes in comparison to CMF in women with early breast cancer
Authors: Gschwantler-Kaulich D. , Fink-Retter A. , Bachrich T. , Ledesma M. , Ruecklinger E. , Kubista E. , Singer C. F.
Published: March 2020

11098

Background: Neoadjuvant chemotherapy is the treatment of choice for locally-advanced breast cancer and leads to down staging and improved BCT rates. While its efficacy is well established, considerably less is known about the most effective regimen. Methods: We have performed a retrospective analysis of 132 breast cancer patients who had undergone neoadjuvant chemotherapy at our institution. Patients had either received a) anthracyclines (“A”, n=35), b) anthracyclines and taxanes (“AT”, n=55), or c) neither of the two compounds (“NoA/T”, n=42). Clinical response, pathological response and survival were evaluated in each arm. Results: While all three regimen resulted in significant tumor regression, AT was most effective with a mean tumor shrinkage of 39% (ultrasound) and 41% (mammography) (Kruskal-Wallis, p=0.004, and p=0.027). Breast conservation was achieved in 75% by AT, in 49% by A, and in 19% by NoA/T (Kruskal-Wallis, p<0.001). The treatment groups did not differ in respect to pCR (χ2-test, p=0.068), although higher cumulative anthracycline doses were predictive of pCR in multivariate analyses (p=0.022). While the mammographic and not the ultrasound-determined tumor diameter determined whether a woman underwent BCT, only an ultrasound-determined size reduction was predictive for DFS and OS (log rank, p=0.0093, and p=0.044, respectively). Other parameters that affected BCT rates were age (p= 0.003), year of diagnosis (p=<0.001), presence of multifocal disease (p= 0.032) and the cumulative anthracycline dose (p= <0.001). Conclusions: While the combination of anthracyclines and taxanes is most effective in achieving clinical remission and BCT, the cumulative anthracycline dose appears most important for achieving pCR.

No significant financial relationships to disclose.
A phase II study of doxorubicin plus paclitaxel followed by weekly paclitaxel as neoadjuvant chemotherapy for breast cancer (SBCCSG-07)
Authors: Inoue K. , Takei H. , Kurozumi M. , Futsuhara K. , Kai T. , Kuroda T. , Ueda S. , Miyake H. , Hakamada Y. , Suemasu K. , Tabei T.
Published: March 2020

11103

Background: The primary aim of this study was to estimate the rate of clinical and pathologic response to preoperative doxorubicin and paclitaxel followed by weekly paclitaxel in stage II /III breast cancer. Secondary objective included the determination of time to progression, over all survival, the rate of breast conservation surgery, feasibility and safty. Saitama breast cancer clinical study group-07 study (SBCCSG-07; CTR:UMIN000000504) Methods: Patients were treated with 50 mg/m2 of doxorubicin intravenously and 150 mg/m2 of paclitaxel both administered intravenously on day 1 every 21 days for 4 courses followed by 80 mg/m2 of paclitaxel administered intravenously on day 1 every week for 12 courses(AP-wP). The rate of pathological, clinical response and breast conserving surgery and adverse events (CTCAE ver.3.0) were analyzed in stage II /III breast cancer. Results: From December 2005 to August 2006, 40 planned patients have been enrolled. One patient canceled chemotherapy for interstitial pneumonia. 16 patients have finished their treatment, received surgery and are evaluable for response. Clinical response rate was 81.2% (50.0%CR; 31.2%PR). Stable disease and progressive disease occurred in 2 (12.5%) patients and 1 (6.3%) patient. Four patients (25%) had pathological complete response. Conclusions: Preliminary results indicate that the AP-wP regimen feasible and very active as induction chemotherapy of operable breast cancer. Updated data including evaluation of biological markers will be presented at the meeting.

No significant financial relationships to disclose.
Oral treatment of metastatic breast cancer (MBC) with capecitabine (X): What influences the decision-making process?
Authors: Gornas M. , Szczylik C.
Published: March 2020

1111

Background: MBC may be considered a chronic disease. Many treatments require frequent clinic visits or hospitalization. Oral X is active, well tolerated, and offers several opportunities per cycle for dose adjustment. This observational study assessed patient (pt) preferences determining treatment choice. Methods: Female MBC pts eligible for X answered a questionnaire about influences on their preference for oral therapy: desire to continue their job, possibility of staying at home during treatment, more convenient way of taking medication, medical contraindications for i.v. treatment, and/or contraindication for combination therapy. Data on medical history (stage, treatment, metastatic sites) were also collected. Results: 218 questionnaires were analyzed. Median age at diagnosis was 52 years (range 27–77). Prior therapy included neoadjuvant chemotherapy (CT; 32%), surgery (93%, including 5% breast-conserving), adjuvant CT (62%), adjuvant endocrine therapy (ET; =52%), and ET for MBC (48%). X was given 1st-line for MBC in 38 pts (17%), 2nd-line in 85 (39%), and =3rd-line in 95 (44%). The most common reason for choosing oral X was more convenient form of drug delivery (154/218; 71%). 147 pts (67%) gave >1 reason for choosing oral therapy. In pts with only one reason (n=71), the most common were possibility of staying at home during treatment (30/71; 42%) and more convenient form of drug (15/71; 21%). Pts receiving 2nd-line X preferred to receive drugs in a more friendly way (62/85; 73%) and stay at home during therapy (63/85; 74%). Corresponding values in pts receiving =3rd-line X were 68/95 (72%) and 53/95 (56%), respectively. Conclusions: MBC causes many psychologic and social problems. Pts prefer to receive drugs in a more friendly way at home. Therefore exploration and introduction of new, effective oral drugs into MBC treatment is vital.

No significant financial relationships to disclose.
Renal safety of intravenous ibandronate 6mg infused over 15 or 60 minutes in patients with breast cancer and bone metastases: A randomized, open-label study
Authors: von Moos R. , Thürlimann B. , Caspar C. B. , Inauen R. , Greil R. , Schütz F. , Flores L. , Bergstrom B. , Schmieding K. , Pecherstorfer M.
Published: March 2020

1114

Background: Clinical data show that a single 15-minute intravenous infusion of ibandronate (IA) 6mg is associated with no significant changes in renal functioning. The aim of this study was evaluation of renal safety of repeated 15-minute intravenous infusions of IA 6mg in women with breast cancer and bone metastases. Methods: Patients (n=127) were randomized to receive treatment with intravenous ibandronate as a 15-minute infusion (n=101) or as a 60-minute infusion (n=26) every 3–4 weeks. Patients were stratified according to previous treatment and the presence or absence of visceral metastases. All patients had serum creatinine within normal limits and calculated creatinine clearance =50mL/min as assessed prior to each infusion throughout the trial. The primary endpoint was the percentage of patients with an increase in serum creatinine from baseline of =44.2μmol/L (0.5mg/dL) at any point in the study. Results: Three percent of patients in the 15 minute infusion (3/101) met the primary endpoint with either hydronephrosis due to tumor, severe diarrhea or pre-existing diabetes with urinary tract infection. No patients in the 60-minute infusion arm (0/26) had an increase in serum creatinine that met the primary endpoint. No clinically relevant changes were seen in serum creatinine, calculated or measured creatinine clearance, or levels of N-acetyl-β-D- glucosaminidase, a1-microglobulin or microalbumin in either arm. There were no marked changes in mean bone pain or analgesic requirement scores. A slight increase in mean WHO performance status score was seen in both arms. Most adverse events were mild or moderate. No clinically-relevant mean changes were observed in vital signs, hematology, blood chemistry including renal function or urinalysis parameters. Renal impairment was related to IA in the 3 patients with increased serum creatinine. Conclusions: IA 6mg administered as a 15- minute intravenous infusion every 3–4 weeks had a renal safety profile consistent with that of the 60-minute infusion, suggesting that a 15-minute infusion of ibandronate 6mg is well-tolerated in patients with breast cancer and bone metastases.

No significant financial relationships to disclose.
Metronomic chemotherapy with capecitabine and oral cyclophosphamide in combination with bevacizumab in metastatic breast cancer (mbc): Evidence of activity of an antiangiogenic treatment
Authors: Rocca A. , Dellapasqua S. , Pietri E. , Dettori M. , D’Alessandro C. , Ghisini R. , Colombo A. , Goldhirsch A. , Colleoni M.
Published: March 2020

11501

Background: Metronomic chemotherapy has shown efficacy in patients (pts) with MBC. Laboratory and clinical studies suggest that the combination with a specific antiangiogenic drug may be particularly effective. Methods: We evaluated the activity and biological effects of low dose continuous oral Capecitabine (500 mg PO TID) and Cyclophosphamide (50 mg PO QD) plus Bevacizumab (10 mg/Kg Q 2 weeks) in a two stage phase II trial in MBC pts, who received =3 lines of chemotherapy for advanced disease. Planned sample size is 46 pts. Results: To date, 26 patients have been enrolled on the study and 23 are evaluable. Pts characteristics: 1/2/=3 sites of metastatic disease 6/9/11 pts; dominant sites of disease soft tissues/bone/viscera 1/11/22; previous treatment for MBC: endocrine/chemo/trastuzumab 13/21/1 pts (=2 lines 25). Results: there were 1 CRs (4.3%), 10 PRs (43.5%), 6 SD (26.1%), and 6 PD (26.1%), for an overall response rate of 48% (exact 95% CI 27–69%). Median progression free survival was 6 months (+). Grade 3 side effects: 6 hypertension , 1 leucopenia , 2 neutropenia , 2 transaminitis (both with liver metastases). No patient was withdrawn from the study due to side effects, and hypertension was manageable with adequate therapy. Data on median circulating endothelial cells (CECs) will be available. Conclusions: Metronomic chemotherapy with capecitabine and cyclophosphamide in combination with bevacizumab has clinical activity and low toxicity in advanced breast cancer.

No significant financial relationships to disclose.
Impact of cyclooxygenase-2 expression on the survival of glioblastoma multiforme
Authors: Choi Y. , Kim D. , Lee H. , Hur W. , Kim K. , Song Y. , Choi S.
Published: March 2020

12505

Background: Expression of cyclooxygenase-2 (COX-2) protein in glioma patients increased proportionally to the pathologic grade. The extent of COX-2 expression is reported to have an inverse relation to survival rate in glioblastoma multiforme (GBM) patients, but the degree of COX-2 expression in the GBM specimens is variable from study to study. In order to evaluate the degree of COX-2 expression and its effect on survival in GBM patients, we conducted this study. Methods: Between 1997 and 2006, thirty consecutive patients of GBM who were treated with surgery and postoperative radiotherapy (range : 44 ∼ 65.1 Gy, median : 61.2 Gy) were included after exclusion of 3 patients who discontinued radiotherapy before 40 Gy due to mentality deterioration. Expression of COX-2 protein on surgical specimen was examined by immunohistochemistry. Survival analysis and verification were performed in respect to sex, age, resection extent, radiotherapy dose, and degree of COX-2 expression with Kaplan-Meier method and log rank test. Results: The median length of follow up was 13.25 months (6 ∼ 83 months). COX-2 was stained in all patients and COX-2 positives over 75% of tumor cells were found in 24 patients: positive in less than 25% of tumor cells, N = 3 (10.0%); 25 to 50%, 1 (3.3%); 50 to 75%, 2 (6.7%); 75 to 100%, 24 (80.0%). Median survival and 2-year survival rate were 13.5 months and 17.5%, respectively. The survival rate was influenced significantly by the degree of resection (tumor removal by 50% or more) and radiotherapy dose (60 Gy or greater) (p < 0.05). Median survivals of patients with COX- 2 positive in either more than 75% of tumor cells or at most 75% of tumor cells were 13.0 and 15.5 months, respectively (p>0.05), and the 2- year survivals of them were 13.3 and 33.3%, respectively (p>0.05). Conclusions: Eighty percent of the GBM patients were COX-2 positive in more than 75% of their tumor cells. The degree of COX-2 expression in the GBM patients had not a significant impact on survival, but the high positive rate of COX-2 in GBM could be a potential selective target for treatment.

No significant financial relationships to disclose.
A retrospective safety and efficacy analysis of combination therapy using Gliadel wafers plus external beam radiation therapy with concurrent temozolomide in newly diagnosed glioblastoma multiforme patients
Authors: Pan E. , Mitchell S. B. , Tsai J. S.
Published: March 2020

12510

Background: Safety and efficacy of malignant glioma treatment with carmustine-containing biodegradable implants (Gliadel® Wafers) followed by conventional radiotherapy (RT) and treatment with RT and concomitant temozolomide have both been well established. Multimodal therapy combining Gliadel® Wafers, RT, and temozolomide has recently demonstrated significant improvements in clinical outcomes of newly-diagnosed glioblastoma multiforme (GBM) patients. However, Gliadel® Wafer implantation in newly-diagnosed GBM patients is limited by the suspected risk of toxicities associated with multimodal therapy. Thus, the safety of multimodal therapy with Gliadel® Wafers, RT, and temozolomide needs to be determined. Methods: We conducted a retrospective analysis of medical records of 21 Florida Hospital Neuro- Oncology Center patients who were newly diagnosed with GBM from January 2003 to December 2005 and initially received multimodal therapy. All systemic and local toxicities were graded according to CTC AE v.3.0. Results were compared to historical data. Results: Our study population did not differ significantly from prior study populations with regard to patient demographics. 4 of 21 (19%) patients had grade 3 toxicities, which may have been related to multimodal therapy. None of the 21 patients had grade 4 toxicities. Median time to progression from initial surgery was 12.8 months (range 2–24 months). Median overall survival was 17 months (95% CI of 15–25 months). Conclusion: The addition of Gliadel® Wafers to concurrent RT and temozolomide did not result in a notable increase in grade 3 and 4 toxicities but did produce clinical outcomes comparable with those found in prior studies. The small sample size does not allow for definitive conclusions regarding efficacy. However, the addition of Gliadel® Wafers to concurrent RT and temozolomide appears to be safe in newly-diagnosed GBM patients.

[Table: see text]

No significant financial relationships to disclose.
Radiotherapy alone versus radiotherapy plus concomitant and post-radiotherapy temozolomide in newly diagnosed anaplastic astrocytoma
Authors: Elghazaly H. A. , Abdelkhalek S. A.
Published: March 2020

12523

Background: Malignant gliomas (glioblastoma multiforme and anaplastic astrocytoma) occur more frequently than other types of primary central nervous system tumors, having a combined incidence of 5–8/100,000 population. Even with aggressive treatment using surgery, radiation, and chemotherapy, median reported survival is less than 1 year. Temozolomide, a new drug, has shown promise in treating malignant gliomas. in this study we evaluate the value of adding temozolomide concomitantly with radiotherapy and for 6 cycles after in newly diagnosed anaplastic astrocytoma over radiotherapy alone. Methods: patients with newly diagnosed , histologically confirmed anaplastic astrocytoma were randomly assigned to receive, group A radiation therapy alone ( localized irradiation 60 Gy, fractionated 2 Gy / fraction, 5 fractions / week for 6 weeks) orgroup B radiation therapy alone ( localized irradiation 60 Gy, fractionated 2 Gy / fraction, 5 fractions / week for 6 weeks) plus temozolomide 200 mg per square meter daily for 5 days orally from the 1st day of radiotherapy to be repeated every 28 days for a total of 8 cycles ( 2 during radiotherapy and 6 after). The primary end point were overall survival and safety. Results: A total of 70 patients were randomized , with 35 in each treatment group. Median age was 41 years in group A and 43 years in group B. Surgical resection was complete in 5 % patients,partial resection in 88 % and stereotactic biopsy in 7% patients. In the temozolomide group median survival was 16.7 months and it was only 11.3 months in the radiotherapy alone group. Temozolomide was also associated with a high response rate 62%(CR 8.5% and PR 54.2 %) versus 37% in radiotherapy alone group with minimal additinal toxicity in the temozolomide arm. Conclusions: This randomized phase II trial suggest that temozolomid is effective and add statistically significant survival benefit over radiotherapy alone in newly diagnosed anaplastic astrocytoma with minimal toxicity.

No significant financial relationships to disclose.
Reirradiation for inoperable in-field recurrences of malignant gliomas
Authors: Schäfer U.
Published: March 2020

12527

Background: To evaluate the effect of sequential radiochemotherapy in preirradiated malignant gliomas in a phase II study. Methods: Sixteen patients (median age 61 years) were treated according to a standardized treatment protocol consisting of sequential radiochemotherapy. The chemotherapy (temozolomide) was carried out over a duration of 5 consequential days (Mon-Fri) with a dose of 200 mg/m2/d. Chemotherapy courses were repeated in 4 week intervals (day 1, 29, 57, etc.) until clinical progression. Radiotherapy with 30 Gy over 3 weeks (5 x 2 Gy/week) was interposed between the first two chemotherapy courses (days 8–26). Results: 14/16 patients had no acute side effects. One patient suffered from acute thrombocytopenia (6000x106/l) and leukocytopenia (0,6x106/l), a further patient developed mental degradation (treatment stopped at 24 Gy). All patients have died due to disease progression. Median event-free survival (Kaplan/Meier method) amounts to 6 months. 7/16 patients survived longer than 10 months and one patient longer than 2 years. Late treatment sequelae have not been observed so far. Conclusions: The reported radiochemotherapy protocol is feasible for these otherwise difficult to treat patients without a remarkable increase in toxicity. In individual cases it can lead to stable disease over a period of 10 months and more.

No significant financial relationships to disclose.
Venous thromboembolism in patients with brain tumors
Authors: Dhami M. S. , Goss D. , Dhami R.
Published: March 2020

12528

Venous Thromboembolism (VTE) is common in patients undergoing treatment for brain tumors. American College of Chest Physicians (ACCP) 2004 consensus conference recommends routine use of intermittent pneumatic compression devices (IPC), unfractionated heparin (UH) or low molecular weight heparin (LMWH) for VTE prophylaxis in these patients. There, however, continues to be a reluctance on using pharmacologic VTE prophylaxis in these patients. The goal of our study was to determine the incidence of VTE in patients with brain tumors treated at a community hospital and the frequency of use of thromboprophylaxis in these patients. Both electronic and paper charts of all patients treated for brain tumors between 1997 and 2003 were reviewed. Follow up data was obtained by contacting physicians caring for these patients. Forty two patients were identified (Anaplastic astrocytoma 10; Glioblastoma multiforme 16; Meningioma 15; oligodendroglioma 1). Twelve patients were treated with various adjuvant chemotherapy regimens. Only 16 patients (38%) received any form of VTE prophylaxis. UH (12) or LMWH (2) were used with or without IPCs or graduated compression stockings. There were eight episodes of symptomatic VTE among 42 patients (19%). These include 6 episodes of deep vein thrombosis (DVT) and two cases of superficial vein thrombosis. Three patients with DVT also had symptomatic pulmonary embolus (PE). All episodes VTE were seen in patients with malignant gliomas yielding a 29% incidence of VTE in patients with malignant gliomas. None of the 15 patients with meningioma had symptomatic VTE. All but one episode of VTE were associated with administration of systemic chemotherapy. Half of these episodes occured more than six weeks after surgical debulking. We conclude that incidence of VTE with malignant brain tumors is high (29%) and the administration of chemotherpy increases this risk. There continues to be underutilization of VTE prophylaxis in these patients at very high risk of VTE. Efforts should be directed at improving the understanding of type and duration of appropiate VTE prophylaxis in patients with brain tumors.

No significant financial relationships to disclose.
Predictive chemotherapy according to O6-methylguanine-DNA methyltransferase protein expression for treatment of malignant gliomas
Authors: Chen Z. , Zhang J. , Wu Q.
Published: March 2020

12530

Background: To evaluate the response to predictable chemotherapy according to O6-methylguanine-DNA methyltransferase (MGMT) expression pattern and toxicity in patients with malignant gliomas. Methods: Twenty-eight patients with histologically confirmed malignant gliomas were enrolled in this study. The glioma tissues were examined for MGMT protein expression by immunohistochemistry. The chemotherapeutic regimen wasn’t consisted of nitrosourea or temozolomide in patients with MGMT positive expression, while no limitation using nitrosourea or temozolomide in patients with MGMT negative expression. The patients who received 2 or more than 2 cycles of chemotherapy were evaluated for response to therapy according WHO standard, and toxicity according National Cancer Institute (NCI) standard. Results: Twenty-four patients were used one regimen while 4 patients received two regimens chemotherapy, and thus overall 32 cases were evaluated for response to chemotherapy. The complete response (CR) was observed in 5 cases (16%),partial response (PR) in 6 cases (19%), stable disease (SD) was seen in 12 cases (38%), and 9 cases (28%) developed progressive disease (PD). Objective response rate (CR + PR) was 35%, and response plus stable disease rate (CR+PR+SD) was 73%. Hematological toxicity was the principal limiting side-effect observed in this study. Seven patients (25%, 7/28) experienced grade 3 or 4 leucopenia and one (4%,1/28) grade 4 thrombocytopenia who received platelet transfusion. No hemorrhagic event due to thrombocytopenia occurred. Non- hematological toxicity mainly was nausea/vomiting and alopecia. Grade 3 nausea/vomiting occurred in 7% of patients (2/28) and grade 3 alopecia in 7% of patients (2/28). Conclusions: The predictive chemotherapy according to MGMT protein expression in patients with malignant gliomas could improve overall response rate with acceptable side-effect, as compared with conventional chemotherapeutic regimen, and thus worth for further investigation.

No significant financial relationships to disclose.
Monitoring effects of imatinib (Ima) plus gemcitabine (Ge) chemotherapy (CT) on functional status of tumors (T) using dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) and magnetic resonance spectroscopy (MRS)
Authors: Wolf W. , Presant C. A. , Waluch V. , Kim H.
Published: March 2020

13001

Background: The ability to monitor the effect of all interventions on the functional status of tumors is critical in allowing clinicians to optimize/individualize chemotherapy to a given patient (pt). This is especially true when such pts are treated with a combination of targeting agents and cytotoxic anticancer drugs. The present study tested the combination of Ima and Gem to determine T pharmacokinetics (PK) and pharmacodynamics (PD) using DCE-MRI and 19F-MRS. Methods: Pts with measurable and MRI-imagible refractory solid T possibly responsive to Ge were randomized to receive either: one course of Ima with PK/PD, followed by one course of Ge with PK/PD, followed by the combination ImaGe; or one course of Ge with PK/PD followed by one course of Ima with PK/PD, followed by ImaGe. Ge was given at 900 mg/m2 IV over 30 min. for PK/PD and at 10 mg/m2/min. for continued therapy. Ima was given at 400 mg daily for 5 d. with Ge given on day 3. Doses were adjusted for toxicity. T vascularity (V) was measured by the use of DCE-MRI (AACR 95:490,2004). The initial contrast accumulation rate (ICAR) and the delayed contrast accumulation rate (DCAR) were calculated as the slope of the influx and efflux curves. Ge T PK was measured by serial 19F-MRS for ∼ 1hr post Ge administration. Results: 4 pts are evaluable at present: 2 Ca pancreas, 1 Ca breast and 1 Ca ovary. Ge PK are still in analysis. DCE-MRI data indicated an increase in T ICAR 1 week after Ima of 18% and 180% in 2 pts, and a decrease of -14% and -21% in 2 pt. By 2 wk post Ima, ICAR had further decreased to -75% in the latter pt. T size evaluation by RECIST showed progression of Ca in the 2 pt with increased ICAR, and a PR and stable disease in the 2 pt with a decrease in ICAR. Additional correlations with DCAR and Ge T PK will be shown. Conclusions: Ima and Ge CT is associated with a heterogeneous response in DCE-MRI. Ima has an antiangiogenic effect in some pts. This effect may be correlated with T response to Ima plus Ge. Measuring PK and PD using DCE-MRI and MRS may be useful in understanding individual responses to Ima drug combinations.

No significant financial relationships to disclose.
Semi-physiological pharmacokinetic-pharmacodynamic (PK/PD) models for troxacitabine-induced neutropenia and thrombocytopenia
Authors: Ng C. M. , Muralidhar B. , Takimoto C. H. , Lin C. , Patnaik A.
Published: March 2020

13002

Background: Neutropenia and thrombocytopenia are the dose-limiting toxicities of troxacitabine in Phase 1 studies. The present study’s aim was to develop a novel semi-physiological PK/PD model that can simultaneously describe the time course of the absolute neutrophil and platelet count changes in cancer patients receiving troxacitabine. Methods: The mixed-effect modeling was performed using the Monte-Carlo Parametric Expectation Maximization algorithm implemented in SADAPT program. The analysis was based on PK/PD data from 31 subjects who received troxacitabine/cisplatin combination every 28 days at five different dose levels (4.8/50, 4.8/75, 6.4/50, 6.4/75, 8.0/75 mg/m2). The PD model consisted of 1) a troxicatabine-sensitive uncommitted progenitor cell compartment, which differentiates into committed neutrophil and platelet progenitor cells that are also sensitive to the troxacitabine, and 2) transit compartments for neutrophils and platelets that represent maturation stages in bone marrow. To capture the rebound phenomena and maintain the hemostasis, the model included a feedback mechanism for both neutrophils and platelets. The troxacitabine concentrationtion-time profiles affected the proliferation of sensitive progenitor cells through an inhibitory sigmoidal Emax model. A three-compartment linear pharmacokinetic model was developed to describe the troxaicibatine concentration-time profile. Results: The PD model described the time-course of troxacitabine- induced neutrophil and platelet cytopenias and accounted for the large observed inter-patient variability. The model predicted that neutrophil progenitor cells were more sensitive to troxacitabine therapy compared to platelet progenitor cells. Furthermore, the model suggested that the troxacitabine-induced neutropenia and thrombocytopenia are reversible and non-cumulative events. Conclusions: This novel model can describe both the intensity and duration of troxacitabine-induced thrombocytopenia and neutropenia rather than simply considering the nadir values. It may be valuable for selecting treatment regimens that minimize troxacitabine’s dose-limiting hematological toxicities.

No significant financial relationships to disclose.
Influence of single agent gemcitabine (GEM) schedule on the pattern of response and toxicity in patients with advanced pancreas, lung and breast carcinoma: A systematic review
Authors: Barrajon E. , Lopez A. , Esquerdo G.
Published: March 2020

13009

Background: Dose dense chemotherapy has been advocated as a way to improve results in patients with cancer. Increasing dose (and the area under the curve of concentration-time, AUC) may increase response and toxicity, limiting clinical benefit. For phase-specific agents such as GEM, different schedules with the same dose and AUC may produce different patterns of efficacy and toxicity. Partial comparisons between schedules in clinical trials are not able to design optimal schedules. A systematic analysis of all different schedules of GEM, integrating clinical, pharmacodynamic and pharmacokinetic data in a mathematical model may provide an optimum. Methods: Clinical trials of single agent GEM in advanced pancreas, lung and breast carcinoma have been searched in PubMed, references of published clinical trials, and presentations in cancer meetings. Prognostic factors (age, sex, sex, performance status, previous chemotherapy, stage), schedule details (dose, time and frequency of infusions), response rate and toxicity (hematological, mucosal, skin and diarrhea) were analyzed in a multivariate model. In vitro data (concentration and time of exposure) and pharmacokinetic/pharmacodynamic data were included in the model, estimating the AUC above a concentration threshold (AUCt) obtained for every clinical schedule. Results: Ninety five clinical trials including 7917 patients with cancer of the pancreas (39 trials), lung (45 trials) or breast cancer (11 trials) were pooled. GEM was administered at doses of 90–2800 mg/m2 (median 1000 mg/m2) infused in 0.5–24 hours (median 0.5 h). Except for 1 schedule, treatment was repeated for 1–7 consecutive weeks (median 3) followed by a 2 week rest period. Response rate was 2.7–33.3% (median 8%) for pancreas, 0–38.5% (median 18.5%) for lung and 0–37.1% (median 20%) for breast cancer. Epithelial toxicity was inferior to hematological toxicity (grade 3/4: 0% vs 11% for leucopenia). A mathematical model was applied to 24 different schedules. Conclusions: GEM schedules in literature show great homogeneity, most of them 1000 mg/m2 for 3 consecutive weeks followed by a 2 week rest period. The model allows simulations to optimize concentration over 12 nM.

No significant financial relationships to disclose.
Combined treatment with immunotherapy and chemotherapy using endoscopic ultrasonography guided injection for locally advanced pancreatic carcinoma
Authors: Nonogaki K. , Hirooka Y. , Itoh A. , Kawashima H. , Ohmiya N. , Niwa Y. , Goto H. , Yamamoto K. , Takamatsu J. , Yokokawa K.
Published: March 2020

13503

Background: Dendritic cells (DCs) play a pivotal role in T cell-mediated immunity. Usually, mature DCs were cultured using resected tumor tissue, but for inoperable cases, this method is impractical. The injection of immature DCs into the tumor after appropriate chemotherapy is reasonable, if DCs come to maturity capturing the specific cancer antigen . The aim of this study is to assess the toxicity and efficacy of combined treatment with immunotherapy and chemotherapy for locally advanced pancreatic carcinoma. Methods: Five patients with pathologically confirmed pancreatic ductal carcinoma using EUS-FNA were enrolled, median age 56 years (range, 46–70 years). All cases without distant metastasis were diagnosed as surgically unresectable . Patients underwent leukapheresis, immature DCs were prepared from peripheral blood by a culture with granulocyte macrophage colony-stimulating factor and interleukin 4. Lymphokine-activated killer (LAK) were also prepared from peripheral blood. Immature DCs were injected biweekly in the mass by endoscopic ultrasound-guided fine needle injection (EUS-FNI), LAK were administered intravenously. Patients received the treatment of gemcitabine 1000 mg / m2 by intravenous injection 3 days before the immunotherapy. One course with 6 times combined therapy was continued until the judgment of progressive diseases (PD) was given. The toxicity and efficacy of this treatment were assessed. We also assessed whether tumor associated antigen (TAA)-specific IFN-?producing cells increase after treatment. Results: Hematological toxicity occurred in one case, leucopenia of grade 2. No severe toxicities of grade 3 to 4 occurred. One had a partial response (PR), stable disease (SD) was observed in 2 patients for more than 6 months (long-term SD). PR patient could undergo curative operation after this therapy. The number of TAA-specific IFN-?producing cells in PR patient increased 12-fold higher than that seen before treatments. Conclusions: These results support the safety and efficacy of combined treatment with immunotherapy and chemotherapy for locally advanced pancreatic ductal carcinoma. This treatment may be a useful for the treatment of pancreatic ductal carcinoma.

No significant financial relationships to disclose.
A phase I/II study of an antitumor vaccination using α (1,3) galactosyltransferase expressing allogeneic tumor cells in pancreatic cancer
Authors: Oyama Y. , Talamonti M. , Mulcahy M. , Gonda E. , Burt R. K. , Vahanian N. N. , Bell R. , Tennant L. , Ramsey W. J. , Adrian T. , Link C.
Published: March 2020

13512

Background: Prognosis of pancreatic cancer remains poor despite surgical resection. In a phase I trial, we examined the safety and feasibility of antitumor vaccination in Pts with surgically resected pancreatic cancer with two irradiated genetically altered human pancreatic cancer cell lines engineered to express xenotransplantation antigens by retroviral transfer of the murine a(1,3) galactosyltrasferase gene {HyperAcute Pancreatic Cancer Vaccine (HAPa)}. Methods: Pts had undergone complete surgical resection for stage IA to IIB pancreatic adenocarcinoma, ECOG PS≤2, no immunosuppressive drug use and an adequate organ function were eligible. Various adjuvant treatments were allowed prior to the start of HAPa according to the institutional preferences (5FU/radiation, cisplatin/gemicitabine followed by 5FU/radiation, 5FU/radiation followed by gemicitabine or gemicitabine/capecitabine/bevasizumab/radiation). Six Pts were scheduled to receive 12 every two week-intradermal injections (initial priming dose followed by 11 boost doses). The first cohort (Pts 1–3) was to receive at lower doses (2 × 108 cells priming and 1 x 108 cells boost). The second cohort (Pts 4–6) was to receive at higher doses (5 x 10^8 cells priming and 3 x 10^8 cells boost). Toxicity was assessed using the CTC v3.0. Results: To date, 6 Pts, 3 males, 3 females, median age 59 (range 50–66) were treated. Two Pts completed all 12 injections. Others received 9, 6, 6 and 4 injections, respectively. To date no serious adverse events can be attributed to the vaccine. Adverse events (≤CTC grade 2) attributable to the vaccine include injection site pain/discomfort and local skin reaction in all Pts. Other adverse events (≤grade 2) include hyperkalemia, fever and increased LDH levels in one Pt. One Pt with non-malignant hepatic lesions at the time of initial surgery was removed from the study after confirmation of metastatic disease in the liver. At this point the median 6.5 (range 9–4) months in the study all remaining (5/6) patients have no evidence of recurrent disease. Conclusions: Preliminary data indicate that antitumor vaccination with genetically altered allogeneic human pancreatic cancer cells expressing a(1, 3) galactosyltrasferase is safe and feasible

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A phase II study of FolateImmune (EC90 with GP1–0100 adjuvant followed by EC17) with low dose cytokines interleukin-2 (IL-2) and interferon-α (IFN-α) in patients with refractory or metastatic cancer
Authors: Messmann R. , Amato R. , Hernandez-McClain J. , Conley B. , Rogers H. , Lu J. , Low P. , Bever S. , Morgenstern D.
Published: March 2020

13516

Background: FolateImmune is a folate-receptor (FR)-targeted immunotherapy that induces an immune response against tumor cells by marking them with a folate-hapten conjugate. The conjugate is specifically designed to target FR, which is over-expressed in a variety of cancers. FolateImmune therapy is comprised of a vaccine fluorescein conjugate (EC90), an adjuvant (GP-0100), and a folate-hapten conjugate (EC17). Patients (pts) receive a series of subcutaneous (SQ) injections of EC90 vaccine to stimulate the production of antibodies to the fluorescein-hapten, followed by SQ injections of EC17, which forms a molecular bridge between the tumor cell and the endogenous circulating anti-fluorescein IgG antibody. This is thought to initiate an Fc-mediated immune response leading to antibody-dependent cellular cytotoxicity and/or phagocytosis. IL-2 and IFN are utilized at low doses (7 MIU and 3 MIU, respectively) to further promote an immune response. The Phase Ib objective is to determine the safety of EC90 vaccine/EC17 folate-targeted therapy in combination with IL-2 and IFN. The previous phase I trial explored the safety of FolateImmune without cytokines. Methods: This phase 1b safety study treated eligible patients with FolateImmune therapy at dose levels of 1.2 mg EC90 and EC17 of 0.3 mg/kg. Results: As of Jan 2, 2007, all patients have tolerated therapy without significant toxicity. Grade 1–2 toxicity included: chills, fever, and nausea. One patient has had a minor response and continues on study. Laboratory studies revealed decline in circulating FR+ cells. Of 6 pts enrolled, 5 had a pathologic classification of renal cell cancer (RCC). Conclusion: Preliminary data suggest that FolateImmune therapy, with the addition of low dose cytokines, may be administered in a safe and well-tolerated manner. Phase II trials are planned for RCC.

No significant financial relationships to disclose.
Activation of the AMPK regulated metabolic stress response by a small molecule HER2/EGFR tyrosine kinase inhibitor protects cardiac myocytes from apoptotic stimuli
Authors: Bacus S. S. , Hill J. E. , Trusk P. , Seger R. , Spector N. L.
Published: March 2020

14000

Background: The HER2 receptor tyrosine kinase is a survival factor for human cardiomyocytes, providing a potential explanation for the increased incidence of cardiomyopathy associated with anti-HER2 monoclonal antibody trastuzumab. Here we show that GW2974, a HER2/EGFR TKI, but not trastuzumab activates AMP kinase (AMPK), initiating a metabolic stress response in human cardiomyocytes that protects against TNFa induced cell death. GW2974 stimulates calcium dependent fatty acid oxidation in vitro resulting in upregulation of ATP and in myocardium of GW2974 treated rodents. Methods: Western blot: p-Akt, p-Erk1/2, p-AMPKa and p- eEF2 (Cell Signaling); ERRa, ERR? (R&D Systems); PGC-1 (Chemicon); MCAD (Cayman Chemicals); Heregulin, NF?B, and Actin (Sigma). ATP was performed utilizing a bioluminescence assay kit H52 (Roche). Lipid staining was done with Oil Red O (Sigma). Cells: Au565 breast cancer and primary human cardiomyocytes (HMC) were grown in RPMI supplemented with 15% BFS treatments. BAPTA/AM and Compound C (Calbiochem); GW2974 and TNFa (Sigma); trastuzumab (Genentech). Results: Our results show that treatment with GW2974 activates catabolic pathways by activation of AMPK. AMPK is a key regulator in mitochondrial energy producing pathways in human cardiac cells. Phosphorylation of AMPK resulted in phosphorylation of eEF2, upregulation of ERRa and PGC-1 and upregulation of ATP levels. AMPK activation depends on Ca++ as the calcium chelation abolished it. Trastuzumab and Gleevec failed to activate AMPK survival pathways. In addition, GW2974 protected cardiac cells from TNFa killing, whereas treatment with TNFa and trastuzumab resulted in pervasive cellular death. Inhibition of AMPK by Compound C or siRNA resulted in cardiomyocyte killing. Conclusion: Activation of AMPK and its effects on metabolic pathways and energy production in HMC may explain the apparent reduced risk of cardiotoxicity associated with HER2 TKI compared with trastuzumab in treating patients with HER2 overexpressing breast cancers. Although activation of AMPK protected normal cardiac myocytes, this effect appears to be lethal to sensitive HER2 overexpressing breast cancer cells, which are “addicted” to glycolysis.

No significant financial relationships to disclose.
Phase I trial of intratumoral administration of reovirus type 3 with radiation in patients with advanced malignancies
Authors: Vidal-Boixader L. , Karavasilis V. , Beirne D. , Twigger K. , White C. , Pandha H. , Nutting C. , de Bono J. , Melcher A. , Harrington K.
Published: March 2020

14009

Background: Reoviruses are RNA viruses that replicate preferentially in cells with aberrant Ras-pathway signaling. Preclinical data have shown that the combination of reovirus (REO) and radiation (RT) significantly increases RT-induced cytotoxicity. Methods: Patients (pts) with measurable disease amenable to treatment with localised short-course palliative RT were enrolled in cohorts of 3. In the first stage, pts received local tumour RT (20 Gy in 5 fractions) in combination with two intratumoural injections of escalating REO doses to a maximum of 1010 TCID50. If no dose-limiting toxicity (DLT), pts received local tumour RT (36 Gy in 12 fractions) in combination with two, four or six doses of REO at TCID50. Endpoints were safety, viral replication, immunogenicity and antitumoral activity. Results: Eighteen pts have been treated to date with a variety of solid tumours.Two pts, one at the 1 x 109 dose and one at 1 x 1010 refused to receive the second REO injection due to grade 2 flu-like symptoms. Other toxicities have been mild (grade 1–2) and have included fever, sweating, skin erythema. There has been no evidence of exacerbation of the acute RT reaction. Reverse transcription polymerase chain reaction (RT-PCR) studies of blood, urine, stool and sputum on day 8 post-REO administration were negative for viral shedding for all treated pts. The induction of neutralising anti-REO antibodies was attenuated compared with previous experience in pts receiving intravenous infusions. Three pts (oesophageal ,skin squamous and colorectal carcinoma) had significant partial responses. In addition, the pt. with metastatic oesophageal cancer had a volume reduction of 15% in non-irradiated mediastinal disease for more than 6 months. Intratumoral viral replication by electron microscopy and immunohistochemistry of pre- and post-treatment tumour biopsies was performed. Conclusions: The combination of intratumoral REO and radiation is well tolerated. Promising indicators of synergistic effect are observed. Recruitment is ongoing at the last cohort of the trial.

No significant financial relationships to disclose.
Phase I evaluation of tipifarnib in combination with low-dose Ara-C (LDAC) in high-risk myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML): Interim results
Authors: Cortes J. E. , Feldman E. J. , Douer D. , Raza A. , Fruchtman S.
Published: March 2020

14014

Background: Tipifarnib (T) is a farnesyltransferase inhibitor with clinical activity in MDS and AML. LDAC has utility in the elderly with MDS/AML; hence its use in combination with the investigational agent T to improve outcomes is warranted. Methods: The primary objective of this ongoing phase I, dose finding, multicenter, open-label study was to determine the maximum tolerated dose (MTD) based on dose limiting toxicities (DLT) of T+LDAC observed during the first 28 day cycle. MDS (IPSS Int 1, 2 or High) and untreated AML pts (age =75y or =65y with preceding MDS) or relapsed/refractory AML (age >18y) were included. Planned sample size was up to 57 pts with a traditional 3+3 dose escalation and a minimum of 3 pts enrolled per cohort. T (Dose Level 0) was administered initially at 200mg PO BID x 21 days in combination with LDAC 10mg SC BID x 10 days; both repeated every 28 days. Efficacy will be assessed by bone marrow and peripheral blood count studies. Results: 15 pts have been enrolled to date: 2 MDS (Int 1 n=1, High n=1) and 13 AML (7/13 pts with no previous therapy); all 15 pts were evaluable. Mean baseline characteristics for the entire cohort were: age 76.2y, 67% men, Hb 9.4 ± 0.9 g/dL, WBC 8.7 ± 11.3 x 103/μL, platelets 96.8 ± 96.6 x 103/μL. The observed DLT for T+LDAC was generalized rash seen at Dose Level 3. The MTD was therefore determined to be T 300mg and LDAC 15mg. The most common grade 3/4 adverse events were neutropenia, thrombocytopenia, anemia, and rash. Conclusions: These interim findings show the combination of T at 300mg PO BID x 21 days and LDAC at 15mg SC BID x 10 days to be the MTD in this study. Assessment for efficacy is ongoing.

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No significant financial relationships to disclose.