bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Egyptian National Breast Screening Program: Priorities, challenges, and results of the pilot phase
Authors: Salem D. S. , Kamal R. , Said N. H. , Adel I. , Talaat S. , Adel L. , Abdel Razek N. , Helal M. , Selim A. 
Published: August 2020

1523 Background: According to the World Health Organization,the number of breast cancercases in developing countries will increase dramatically by the year 2050. Egypt is likely to see an increase in this disease burden unless effective programs for early detection and control are implemented. Many women, especially those who are medically underserved, still do not understand the importance of regular mammograms, or how and where to get one. Methods: Four mobile mammography vans were launched in October 2007, to screen women over 45 years old in the underserved areas of Cairo. Each van was equipped with a full field digital mammography (FFDM) machine, dedicated computer system linked to the National Breast Screening Center via video SAT & ADSL, sphygmomanometer, blood glucose measuring kit, and spring scale and meter to measure weight and height. Based on positive findings, patients were directed to Cairo University Hospital to receive appropriate treatment. Mobile units continued to operate through October, 2008. Results: From October 2007 through October 2008, 11,414 women were screened for breast cancer, hypertension, diabetes, and obesity. Two hundred forty four (2.13%) women were radiologically positive for cancer; of these, only 112 (45.9%) women agreed to be recalled for assessment; of these, 49.1% were confirmed to be true positive with BI-RADS 4,5 (61% cases were mass, with 27.9 % 1–2 cm in size; 16.4% cases were microcalcifications alone; multicentricity in 6.6 %; bilaterality in 2.5% of cases). 36.6% were false positive, and 14.2% are under further investigation. Conclusions: Although Cairo is the most developed city in Egypt, there is lack of breast cancer awareness, especially in the underserved areas. Breast cancer is now a priority for the Ministry of Health, with four more vans and 10 fixed FFDM units to be implemented during the next year. A 5-year plan has been established to cover all 29 Egyptian Governorates. No significant financial relationships to disclose.
Detection of human papillomavirus DNA from the breast carcinomas and the cervix: Are they correlated?
Authors: Choi J. , Lim H. , Kim W. , Lee S. , Kim S. , Kim S. , Kim D. , Cho E. , Lee J. , Nam S. , Yang J. 
Published: August 2020

1544 Background: The association between human papillomavirus (HPV) and cervical cancer is well known. However, it remains unclear whether there is also a correlation between HPV infection and human breast cancer. The aim of this study is to investigate the hypothetic association between HPV infection and breast carcinoma through the comparison of the type of HPV infection in the breast and cervix. Methods: From April to December 2008, 106 patients who were diagnosed as breast cancer and underwent mastectomy were analyzed. Their breast tissue (tumor, normal parenchyme, and nipple-areolar complex) and cervix smear were analyzed for HPV infection with DNA chip microarray method. Results: 24 patients (23.1%) showed HPV infection in their cervix smear; high-risk type of HPV was found in 12 patients. But only six patients (5.8%) revealed the HPV infection in breast cancer; half of them were high-risk group (HPV-16, 31); the same types of HPV was found at the normal breast tissue in two patients of them. However, there were no patients with HPV infection in both breast and cervix concurrently. Conclusions: There were no positive results for HPV infection of cervix in HPV-infected breast cancer patients. Also, we cannot find that the presence of high-risk HPV in the breast might be related to the breast carcinogenesis. We concluded that HPV infection is not correlated to the carcinogenesis of breast. No significant financial relationships to disclose.
Phase I/II study of sorafenib and temsirolimus for patients with recurrent glioblastoma (GBM) (NABTC 05–02)
Authors: Wen P. Y. , Cloughesy T. , Kuhn J. , Lamborn K. , Abrey L. E. , Lieberman F. , Robins H. I. , Wright J. , Prados M. D. , Gilbert M. 
Published: August 2020

2006 Background: The activity of targeted molecular therapy with single agents has been disappointing in GBM. Combination therapy simultaneously targeting both the PI3k/Akt/mTOR and the MAP kinase pathway may be more effective. Methods: The North American Brain Tumor Consortium conducted a phase I/II study of sorafenib (VEGFR/PDGFR/Raf inhibitor) in combination with temsirolimus (mTOR inhibitor) in recurrent GBM. Eligibility criteria included histologically proven GBM, radiologic progression, > 18 years old, KPS > 60, adequate bone marrow reserve, and organ function. There was no limit on the number of prior relapses for phase I and no more than two prior relapses for phase II. No enzyme-inducing antiepileptic drugs were allowed. Dose-finding used a standard 3 + 3 design with the MTD defined as the dose with DLTs in 1/6 or fewer patients. The primary endpoint for the phase II component was PFS6 (p0 = 15%; p1 = 35%). A 2-stage design was used. If > 4 of the initial 19 patients achieved PFS6, an additional 14 patients would be accrued for a total of 33 patients. Results: In phase I, 13 patients were enrolled. Median age was 50 years (32–59); median prior chemotherapy 1 (1–3). The initial doses were sorafenib 200 mg bid and temsirolimus 25 mg intravenously once weekly. The MTD was 400 mg bid of sorafenib daily combined with 25 mg of temsirolimus weekly. At this dose 1/6 patients had a DLT (grade 3 thrombocytopenia). Other grade 3 or 4 toxicities included transaminitis, hypophosphatemia, fatigue, diarrhea, and hyperlipidemia. Pharmacokinetic data were similar to that for single agent sorafenib and temsirolimus suggesting that there were no significant interaction between the two drugs. In phase II, 19 patients were accrued to stage I. Median age 50 years (24–64); median prior relapses 1 (range 1–2). One patient was found not to have GBM on central review. No patient remained progression free at 6 months, although two patients stopped treatment prior to 26 weeks for other than progression (alternative therapy, cerebral ischemia). As result, the study was terminated and did not proceed to the second stage. Conclusions: The combination of sorafenib and temsirolimus was moderately well-tolerated but did not demonstrate sufficient efficacy in recurrent GBM to warrant further investigation. No significant financial relationships to disclose.
Safety of bevacizumab in patients with metastases to the central nervous system
Authors: Rohr U. P. , Augustus S. , Lasserre S. F. , Compton P. , Huang J. 
Published: August 2020

2007 Background:. The background rate of CNS hemorrhage (CH) in cancer patients with brain metastases not receiving bevacizumab (BV) treatment is 5%-29%, depending on tumor type. Patients with CNS metastases were routinely excluded from most BV late-stage clinical trials, following the occurrence of CH in one hepatocellular carcinoma patient with occult CNS metastasis in a BV phase I trial. In this particular tumour type, up to 87.5% has been reported as a background rate of CH without BV use. Available safety information in BV-treated patients with CNS metastases has been reviewed to determine whether the exclusion of these patients from trials is still justified. Methods: A retrospective exploratory analysis was conducted using safety data from three datasets: A.) 13 randomized controlled phase II or III trials (RCTs); B.) Two ongoing open-label trials MO19391 (ATHENA) and MO19390 (SAIL). While patients with known CNS metastases, based on imaging or clinical signs and symptoms, were excluded from trial in A and B datasets, patients who were found to have CNS lesions had either unrecognized CNS metastases at study entry or had developed these during the trial.; C.) 2 ongoing open-label studies AVF3752g and AVF3671g in patients with NSCLC, where inclusion of patients with treated CNS metastases was allowed. Incidence of CH in patients with brain metastases was quantified in each dataset. Results: A.) In 13 RCTs, with a total of 8443 patients with locally advanced, unresectable, or metastatic breast, renal, pancreatic, colorectal cancer, or NSCLC, brain metastases were identified in 187 patients (91 in BV-arms and 96 in control arm). Three of 91 (3.29%) BV-treated patients developed grade 4 CH, and one in 96 patients in the control arm (1.04%) developed grade 5 CH; B.) In open-label studies no CH was reported in 68 patients with CNS metastases, out of 3,252 patients enrolled. C.) In two studies in patients with treated CNS metastases, one subject in 83 (1.2%) BV treated patients developed a grade 2 CH. Conclusions: In this retrospective review, the rates of CH in BV-treated patients with CNS metastases is low, and appears consistent with historical rates of CH in these patient populations. Ongoing trials are expected to provide additional data regarding the risk of CH in patients with primary and metastatic CNS tumors. [Table: see text]
A phase I study of ABT 510 and concurrent temozolamide and radiotherapy for patients with newly diagnosed glioblastoma multiforme
Authors: Kekan M. , Fiveash J. , Markert J. M. , Gillespie G. Y. , Kuo H. , Meleth S. , Gladson C. L. , Nabors L. B. 
Published: August 2020

2023 Background: ABT-510 (Abbott Laboratories, Abbott Park, IL, USA) is a Thrombospondin-1 (TSP-1) mimetic drug with anti-angiogenic properties. This phase I dose escalation trial was designed to study the maximum tolerated dose (MTD) of ABT 510 when used concurrently with temozolomide (TMZ) and radiotherapy (RT) in patients with newly diagnosed glioblastoma multiforme (GBM). Methods: A total of 23 patients with newly diagnosed, histologically verified GBM were enrolled between April 2005 and January 2007, after obtaining written consent. The study was approved by the University of Alabama at Birmingham (UAB) Institutional Review Board. Four cohorts with three patients in each, receiving subcutaneous ABT 510 injection at doses of 20, 50, 100, and 200 mg/day were studied. The starting dose was primarily based on preclinical findings from animal studies and phase I studies on healthy subjects and cancer patients. Treatment plan included 10 weeks of induction phase (TMZ and RT with ABT 510) followed by a maintenance phase (ABT 510 and TMZ) of 14 cycles each consisting of 28 days. Patients were monitored with brain MRI along with laboratory values for dose limiting toxicities (DLT) defined as grades 3–4 non-hematological toxicities and grade 4 hematological toxicities (neutropenia or thrombocytopenia). In the absence of a DLT in at least two of the three patients, the dose was increased by 50% in the next cohort of patients. Therapy was discontinued if 14 maintenance cycles were completed, disease progression occurred, or if the patient requested withdrawal. Disease progression and survival statistics were analyzed. Results: During this trial, grade 3/4 DLT were not observed even after the dose was increased to 200 mg/day, hence, the last cohort was expanded to include 14 patients. A MTD was not defined. The median time to tumor progression (TTP) was 220 days and the median overall survival was 422 days. Gene expression analysis of the tumor pathology will be performed to evaluate the relationship between the expression of TSP-1, TSP-2, and patient response to the drug. Conclusions: ABT 510, at subcutaneous doses up to 200 mg/day, is tolerated well with concurrent TMZ and RT in patients with newly diagnosed GBM. No significant financial relationships to disclose.
Intra-CSF trastuzumab in patients with neoplastic meningitis from breast cancer or primary brain tumors
Authors: Allison D. L. , Glantz M. , Werner T. L. , Kirkegaard S. L. , Murdock K. , Jensen R. 
Published: August 2020

2066 Background: Neoplastic meningitis is a devastating complication of extra-CNS malignancies and primary brain tumors with few available treatments and none of outstanding efficacy. Trastuzumab, a large molecule monoclonal antibody directed against the HER-2/neu receptor (overexpressed on some breast cancers, glioblastomas, and medulloblastomas), has negligible access to the CSF after intravenous administration. Intra-CSF administration could circumvent this barrier. Methods: Sixteen patients with neoplastic meningitis (11 GBM, 4 breast cancer, 1 medulloblastoma) and progressive neurologic deterioration were treated with intra-CSF trastuzumab (20–60 mg per dose, either weekly or every other week) for four treatments. Age ranged from 35 to 74 (median 51) years; KPS ranged from 60 to 90 (median 70). Patients who were neurologically and radiographically stable or improved after four treatments were continued on every other week therapy until neurologic progression. CSF cytology, neurologic status, and KPS were assessed at each treatment. MRI scanning of sites of previously demonstrated leptomeningeal tumor was performed after four treatments and then at 8 week intervals. HER-2/neu status of the primary tumors was also evaluated. Results: Two of the four patients with breast cancer (both HER-2/neu+) are responding clinically and cytologically 4 and 14 weeks after initiating treatment. The patient with medulloblastoma (also HER-2/neu+) continues to respond clinically and cytologically after 6 weeks. Seven of 11 patients with GBM have responded (two cytologically, two radiographically, all seven clinically), with response durations ranging from 4 to 12+ weeks. HER-2/neu status is being assessed. There were no adverse events related to the trastuzumab. Conclusions: Trastuzumab can be safely administered into the CSF in patients with solid tumor neoplastic meningitis. Sustained clinical and cytologic responses may occur in patients with breast cancer and primary brain tumors. HER-2/neu status may predict response. Further study to establish the biologically optimum dose and efficacy of this agent may be warranted. No significant financial relationships to disclose.
A long-term open-label extension study examining the steroid-sparing effects of corticorelin acetate in patients with cerebral tumors
Authors: Mechtler L. , Wong E. T. , Hormigo A. , Pannullo S. , Hines V. , Milsted R. , O'Connor P. C. , Ryan R. P. , Recht L. 
Published: August 2020

2079 Background: Corticorelin acetate (CrA) is a synthetic peptide formulation of corticotropin-releasing factor, which is undergoing clinical trials as a treatment for peritumoral edema. The objective of this study was to evaluate long-term safety, tolerability and steroid-sparing potential of CrA in patients with primary or secondary brain tumors and peritumoral edema. Methods: Patients from two randomized double-blind controlled studies who received either CrA (CrA-CrA group) or placebo (PLA) (PLA-CrA group) were permitted to receive open-label CrA 1 mg SC bid after participation in the initial studies. Treating physicians were requested to attempt and maintain the maximum possible reduction of the dexamethasone (dex) dose without knowledge of their patients’ prior treatment regimen in the controlled feeder studies. During this extension study, patients’ dex doses and adverse events were monitored monthly; neurologic function and clinical status were recorded 3 monthly. For this analysis, data up to October 17, 2008, are reported from this ongoing study. Results: Of the 110 patients enrolled, 47 (43%) reduced their dex dose to zero and 67 (61%) were able to reduce their dose to ≤1 mg/day. At entry to this extension study, the daily baseline dex dose was lower for patients who had previously received CrA (3.9 mg; n = 59) than for those who had previously received PLA (6.2 mg; n = 51). The PLA-CrA group showed a greater percent decrease in dex dose than the CrA-CrA group at Week 4 (24.0% vs. 12.6%). At week 8 the mean prescribed dex dose was similar in the two groups (PLA-CrA 3.7 mg vs. CrA-CrA 3.4 mg). Long-term treatment with CrA has been well tolerated with no reported safety concerns. To date, 48 patients remained on study for ≥6 months, 27 patients for ≥12 months, 5 patients for >2 years; 31 patients remain on study. Conclusions: These findings indicate that CrA is safe and well-tolerated, and may enable substantial reduction or cessation of dex therapy for many patients with cerebral tumors. [Table: see text]
Pharmacology and safety factors affecting use of flat (rather than weight-based) dosing of tesetaxel, an orally administered taxane
Authors: Warrell R. P. , Beeram M. , Spindler E. , Papadopoulos K. , Patnaik A. , Tolcher A. W. 
Published: August 2020

2510 Background: As a class, taxanes have wide interpatient (pt) pharmacokinetic (PK) variability at their effective dose, which has been associated with adverse reactions, especially neutropenia. Tesetaxel is an oral taxane with Phase 2 activity in pretreated pts with colorectal, non-small cell lung, gastric, and breast cancers. Tesetaxel is not a substrate for P-glycoprotein; it is associated with lower neurotoxicity at equi-myelotoxic does, and it displays a long terminal half-life in plasma (∼180 hrs). We explored PK and clinical safety to determine the feasibility of using flat dosing in future studies. Methods: PK parameters were evaluated in 21 pts treated at the maximum tolerated dose (27 mg/m2) either alone or in combination with capecitabine. We then compared actual dose (total mg) with the weight-based dose and correlated the incidence and severity of Grade 3–4 neutropenia with weight-based vs. flat dosing. Results: A total of 174 pts were treated with tesetaxel in Phase 2 trials at doses of 27 or 35 mg/m2 once every 3 weeks. For pts prescribed with weight-based dosing (27 mg/m2), mean Cmax in 3 separate cohorts was 24.6, 42.5, and 47.9 μg/L, with AUC0-inf of 1363, 1592, and 1663 h*μg/L, respectively. In 103 pts prescribed a dose of 27 mg/m2, 17% and 16% of pts received doses of 40 mg or 60 mg, respectively, whereas 67% received 50 mg. Correlations between drug exposure AUC0-inf and actual dose (mg and mg/m2) across the entire range of administered doses showed r2 values of 0.455 and 0.492, respectively. Similar correlations after a second repeat dose showed r2 values of 0.731 and 0.653, respectively. The incidence of Grade 3–4 neutropenia at 27 mg/m2 was 33%. Conclusions: PK and clinical safety suggest that weight-based dosing offers no substantial advantage compared with flat dosing. Future studies could incorporate a starting dose of 50 mg administered once every 3 weeks. Flat dosing should also be tested using different schedules, including weekly x 3 weeks and “metronomic dosing” (1–2 mg/d). [Table: see text]
Proportion of subjects with an ethically acceptable reason for enrolling in a phase I trial
Authors: Pentz R. D. , Khuri F. , Kauh J. , Owonikoko T. , White M. M. , Harvey R. D. 
Published: August 2020

2512 Background: Concern persists that phase I subjects, who frequently enter trials for personal benefit, are deluded. They may suffer from therapeutic misconception (TM) - conflating research and clinical care, or from therapeutic misestimation (TMis) - misestimating benefits or risks. Methods: To estimate the proportion of phase I subjects who have an ethically acceptable reason for participation, we both interviewed and surveyed subjects to obtain qualitative and quantitative data. Ethically acceptable reasons included 1) Altruism (sole motive for entering trial was to help others or advance science); 2) Self-regarding motives but no TM (correctly identifying that the trial mostly intends to help research and gain knowledge, the study decides the treatments and the subjects get different doses of drug); 3) Self-regarding motives, TM but no TMis (chance of benefit < 20% and chance of risk > 0%); or 4) Self-regarding motives, TM, overestimation of benefits but broad view of benefit (with collateral benefits like getting careful disease monitoring or access to an academic center listed) and chance of risk > 0%. This generous interpretation of ethically acceptable reasons hinges on the view that subjects at least must recognize there is some risk, that chance of disease benefit is not high and that collateral benefits count. Results: The 86 subjects were mostly white, male, with incomes more than $60,000. 49% were college educated with a mean age of 60. 53.5% had an ethical reason for participation, with 10.5% altruistic, 16.3% no TM, 8.1% TM but no TMis, and 18.5% overestimating benefit but including collateral benefits. In both univariate and multivariate analyses age younger than 60 yo and having at least a college education were the only characteristics significantly correlated with having an ethically acceptable reason for participation. Those who reported strong religious beliefs (p = 0.01) were significantly more likely not to have an ethically acceptable reason. Conclusions: With almost half of participants lacking an ethically acceptable reason for participation, interventions are necessary to bolster understanding. Older participants lacking a college education are particularly at risk and could be the target for an intervention trial. No significant financial relationships to disclose.
Novel phase I design for oncology research
Authors: Lupinacci L. , Anderson K. , Sun L. , Tymofyeyev Y. 
Published: August 2020

2517 Background: Phase I studies in oncology patients seek to identify a dose of a new investigational agent that is tolerable and has the potential to be effective. Toxicity data are the key to defining dose levels of the new agent that are acceptable for further study. Several Phase I designs are available to researchers. Some are practical and easy to implement. Others are complex but yield better information on the toxicity of studied doses. We sought a Phase I design that had a high probability of selecting a dose with acceptable toxicity, allowed adaptation based on observed dose-limiting toxicity (DLT) data and did not create considerable enrollment delays. Methods: We compared the 3+3 design, an algorithmically-determined adaptive method proposed by Ji, et al. (2007), and variations on Ji's design including a 2-stage design combining a 3+3 with a modified Ji design. We simulated Phase I trials with 6 dose levels and 12 dose response relationships and studied the properties of the designs including how often the dose with the target toxicity level was selected, the expected percentage of patients with a DLT and the expected sample size. We also implemented operational conventions on top of the preferred design to enhance the practicality and clinical usefulness of the design. Results: In general, the adaptive, Ji-based designs outperformed the 3+3, selecting the target dose up to 18% more often. The 2- stage and other Ji-based designs were comparable in most scenarios and performed the best when the target dose was among the middle doses in the dose range tested. When the target dose was the highest dose or higher than all of the doses tested, the 3+3 and 2-stage designs outperformed some of the other Ji-based designs. Conclusions: For single agent studies, we prefer a 2-stage design in which a 3+3 is implemented until a preliminary maximum tolerated dose (MTD) is identified. Then, a modified Ji design (target toxicity rate = 20%) is used to confirm the MTD and allow further dose refinement. While this design may underperform slightly compared with the complex continuous reassessment methods, this design is easier to implement and more intuitive to investigators and ethical and regulatory review boards. In addition, it maximizes enrollment continuity while ensuring appropriate patient safety. [Table: see text]