bluuebunny/crossref_metadata_2025 huggingface dataset:
Sensitivity of 6-[F-18]fluoro-L-dihydroxyphenylalanine positron emission tomography for localizing tumors causing catecholamine excess
Authors: Fiebrich H. , Brouwers A. H. , Kerstens M. N. , Pijl M. E. , Kema I. P. , de Jong J. R. , van der Wal J. E. , Sluiter W. J. , de Vries E. G. , Links T. P.
Published: August 2020

11064

Background: Positron emission tomography (PET) using the catecholamine precursor 6-[F-18]fluoro-L-dihydroxyphenylalanine (18F-DOPA) has emerged as promising technique to localize tumors with catecholamine excess. This study investigated the sensitivity of 18F-DOPA PET, compared to 123I-metaiodobenzylguanidine (123I-MIBG) scintigraphy and computer tomography (CT)/ magnetic resonance imaging (MRI) in patients with catecholamine excess. Methods: In a single center prospective study 18F-DOPA PET was compared to 123I-MIBG and CT/MRI in patients with catecholamine excess. The performance of each imaging modality was analyzed for individual patients and individual lesions. 18F-DOPA PET, 123I-MIBG, and CT/MRI were compared using a composite reference standard derived from all available imaging, clinical and histological information. Sensitivities were calculated and discordance between imaging techniques was compared. 18F-DOPA PET uptake was measured to determine whole body metabolic burden. Correlations between 18F-DOPA PET imaging and biochemical data were evaluated. Results: 48 patients were included. The tumor localization was found in 45 patients, 43 with 18F-DOPA PET, 31 with 123I-MIBG and 32 with CT/MRI, resulting with surgery in final diagnosis of pheochromocytoma in 40, adrenal hyperplasia in 2, paraganglioma in 2, ganglioneuroma in 1 and 3 unknown (as yet no lesion detected). Per patient based analysis showed sensitivities for 18F-DOPA PET, 123I-MIBG and CT/MRI of 90, 65 and 67% (P<.01 18F-DOPA PET vs 123I-MIBG, P<.01 18F-DOPA PET vs CT/MRI, P=1.0 123I-MIBG vs CT/MRI). Corresponding sensitivities in the lesion based analysis were 73, 48 and 44%, respectively (P<.001 for both 18F-DOPA PET vs 123I-MIBG and vs CT/MRI, P=.51 123I-MIBG vs CT/MRI). The 8F-DOPA PET+CT/MRI combination was superior to 123I-MIBG+CT/MRI (93 vs 76%, P<.001) Whole body metabolic burden measured with 18F-DOPA PET correlated with plasma free normetanephrine (r=.82) and 24h urinary total normetanephrine (r=.84) and metanephrine (r=.57). Conclusions: The sensitivity of 18F-DOPA PET to localize tumors with catecholamine excess is superior to either 123I-MIBG scintigraphy or CT/MRI.

No significant financial relationships to disclose.
Significance of serum colony-stimulating factor-1 as a breast cancer marker
Authors: Aharinejad S. , Thomas A. , Singer C. , Kubista E. , Paulus P. , Miksovsky A. , Abraham D.
Published: August 2020

11071

Background: A specific and sensitive biomarker that indicates the presence of breast cancer is highly desirable, yet available markers are of limited value. Colony-stimulating factor-1 (CSF-1) is involved in mammary gland development and mediates breast cancer progression. Earlier work indicated correlation of serum CSF-1 with breast cancer staging, and a recent report suggests that CSF-1 is a potential breast cancer marker, however the data reported so far await validation. Methods: In a prospective study in 799 women with no history of malignant disease undergoing surgery, serum CSF-1 levels were measured by a commercially available ELISA. In this cohort, 312 patients had breast cancer and 487 age-matched women had benign tumors. The tumor size, nodal and metastasis status, histological tumor type, hormone and human epidermal growth factor receptor 2 (HER2) and menopausal status were evaluated. Mean CSF-1 serum concentrations were compared between the patient groups by non-parametric Wilcoxon two-sample and Kruskal-Wallis test. The area under the receiver operating characteristic curve was calculated by logistic regression. Results: Mean serum CSF-1 concentrations were significantly higher in all patients with malignant tumors (502±429 pg/mL) as compared to those with benign tumors (382±344 pg/mL) (p<0.0001, Wilcoxon). Increased CSF-1 concentrations were significantly related to malignant versus non-malignant disease in logistic regression and receiver operating characteristic analysis (p<0.0001, AUC=0.6). Increased CSF-1 levels in patients with malignant tumors were associated with postmenopausal (p=0.0038) but not premenopausal (p=0.94) status (Wilcoxon). Serum CSF-1 concentrations did not correlate significantly with tumor size, nodal and metastasis status, hormone receptor and HER2 status of patients (Kruskal-Wallis). Conclusions: Our data suggest that serum CSF-1 could serve as a breast cancer marker in postmenopausal women. While its serum levels are not related to breast cancer stage at diagnosis, they might be useful for breast cancer screening in postmenopausal women.

No significant financial relationships to disclose.
Predicting risk of developing invasive breast cancer in the African American female population
Authors: Wheeler A. J. , Zhang A. Y. , Drohan B. , Lawrence C. , Roche C. , Kopans D. B. , Moore R. H. , Smith B. L. , Sharko J. , Kevin H. S.
Published: August 2020

11080

Background: African Americans (AA) have a lower incidence of breast cancer with a poorer prognosis than Caucasians. It is unclear whether AA women have fewer known risk factors for breast cancer or that risk factors have a lesser effect in AA. We evaluated the accuracy of the race-based modification Gail Model in predicting the risk of developing invasive breast cancer in the AA population. Methods: With IRB approval, we performed a retrospective analysis of data obtained from women (n=15,973) ages 40–79 presenting to our Breast Center(5/2003 to 7/2005) for a screening mammogram. The five-year probability of breast cancer for AA (n=702) versus Caucasians (n=15,721) was calculated for each individual using 3 methods: 1) the race specific Gail model, 2) the Gail model ignoring race (AA using the Caucasian model), and 3) age and race matched SEER projection using DevCan (v6.1.1) software. Results: There was no significant difference between the 5-year probability of breast cancer for Caucasians as calculated by the Gail model vs. the SEER prediction (p=NS), suggesting our population was representative of the larger study population from which SEER data was derived. As compared to SEER prediction, the modified Gail model underestimated the breast cancer risk for all age groups of AA (p<0.0001). When the Gail Model without the race-based modification was applied to the AA population, the projected risk was not significantly different from the SEER prediction (p=0.1049). Conclusions: This study suggests that the race-based modification of the Gail Model underestimate the risk of breast cancer in AA women. When the model is applied to AA women without incorporating the modification for race, the Gail model accurately reflects SEER 5-year projections of risk of invasive cancer in AA women. Differences in risk factor distribution among race, rather than a differential effect of those factors on risk, may have a substantial role in explaining the lower incidence in AA women as compared to Caucasian women over 40.

[Table: see text]

No significant financial relationships to disclose.
A functional procedure using fresh samples to select patients with acute myeloid leukemia prior to treatment with the novel targeted cytotoxic agent F14512
Authors: Barret J. , Dumontet C. , Annereau J. , Brel V. , Breillout F. , Guminski Y. , Imbert T. , Guilbaud N. , Bailly C.
Published: August 2020

11087

Background: The Polyamine Transport System (PTS) is an energy-dependent machinery generally hyper-active in cancer cells with a high demand for polyamines. This system can be viewed as a suitable molecular gate to deliver selectively polyamine-based molecules into cancer cells. We exploited this strategy to target to PTS-positive cancer cells, F14512 , a novel polyamine-epipodophyllotoxin conjugate, that exhibits significant anti-tumor activity and has been selected for further clinical development. This study was undertaken to investigate the potential of N-methyl-spermine-NBD, a proprietary fluorescent polyamine conjugate, designed to select patients with PTS-positive leukemic cells. Methods: The uptake of this probe was first measured by flow cytometry in a panel of human leukemia cell lines. The procedure was then adapted and optimized to measure N-methyl-spermine-NBD fluorescence in blood samples from healthy donors. After the selection of the optimal CD gating, median value of fluorescence of our probe was measured by flow cytometry in lymphocytes and blastes of each patient. Results: Data showed that high level of fluorescence was detected in F14512 -sensitive cancer cell lines whereas leukemia cells responding poorly to F14512 generally exhibited very low levels of PTS. We then demonstrated that human leukocytes incorporate N-methyl-spermine-NBD in a time, concentration and temperature dependent manner, confirming the active transport of polyamines in these cells. The incorporation in lymphocytes was found low and with a weak inter-individual variation. A panel of 50 fresh human acute myeloid leukemia samples showed a larger inter-individual variation and, interestingly, incorporation of the fluorescent probe was generally higher in leukemia blasts than in lymphocytes. Median values of fluorescence intensity were similar in blood and bone marrow samples, suggesting that these two sources might be used for this analysis. Conclusions: The data show that the PTS can easily be evaluated in fresh AML blasts and provides a simple means to identify patients for future enrollment in clinical trials with F14512.

[Table: see text]
Model-based prediction of defective DNA mismatch repair using clinicopathological variables in stage II and III colon cancers
Authors: French A. J. , Sinicrope F. , Foster N. R. , Thibodeau S. N. , Sargent D. J. , O'Connell M. J.
Published: August 2020

11093

Background: Defective DNA mismatch repair (MMR) results in microsatellite instability (MSI) and is detected in approximately 15% of sporadic colon cancers. MMR status has been shown to provide prognostic and predictive information in primary colon cancers. We sought to develop a model to predict MMR deficiency using clinically available data, and thereby facilitate patient selection for MMR or MSI testing. Methods: TNM stage II and III colon carcinomas (n= 982) were studied from six 5- fluorouracil-based adjuvant therapy trials conducted by the North Central Cancer Treatment Group. MMR status in tumors had been analyzed by MSI (using mono- and dinucleotide markers) or by immunohistochemistry for MMR proteins (hMLH1 and hMSH2). Logistic regression and a recursive partitioning and amalgamation (RPA) analysis was used to identify important predictive factors of MMR status. Factors explored included age, gender, histologic grade, tumor site, stage, lymph node metastases, and T-stage. Results: Defective MMR was found in147 (15%) cancers. Tumor site was the most important predictor of MMR status followed by histologic grade. Distal tumors had a low likelihood of defective MMR (3% rate overall; 13/468), whereas proximal tumors had a greater likelihood of defective MMR (26%; 130/506). For patients with proximal tumors, the addition of histologic grade and gender increased the prediction of defective MMR ( Table ). Using tumor site, histologic grade, and gender, the logistic regression model showed excellent discrimination (c- statistic = 0.81). Conclusions: Tumor site is an important predictor of defective MMR that is rare in distal and increased in proximal tumors. The combination of proximal site, poor differentiation, and female gender resulted in a 51% likelihood of defective MMR. Therefore, this model can facilitate the selection of sporadic colon cancers for MMR or MSI testing to enable its use in clinical decision-making. [Table: see text]

No significant financial relationships to disclose.
Translational disequilibrium as an interference marker to study miRNA and methylation silencing of APRIN, a stem cell regulator in breast cancer microchimerism
Authors: Geck P. , Denes V. , Pilichowska M. , Makarovskiy A. , Carpinito G. A.
Published: August 2020

11109

Background: Gene silencing is universally observed in cancer and involves promoter DNA methylation. We found that a cohesin-related stem cell regulator, APRIN (Pds5B) was silenced in breast cancer clinical samples. Surprisingly, in 40% of these samples DNA methylation was not involved. Furthermore, in some breast cancer cell lines the APRIN protein was silenced without transcript downregulation or promoter methylation. This “translational disequilibrium” has been frequently reported with other proteins, but without mechanistic explanations. Recent results with RNA interference indicate that gene repression through microRNAs (typically mismatched) is mostly translational without transcript degradation. We propose, therefore, that the puzzling translational disequilibrium phenomenon is a new form of epigenetic silencing by miRNA mechanisms. We aim (i) to verify miRNA epigenetics of APRIN silencing in breast cancer cell lines; (ii) to study clinical breast cancer samples for methylation vs. miRNAs mechanisms in APRIN translational disequilibrium; and (iii) to investigate if miRNA silencing of APRIN affects a fetal embryonic stem cell pool in breast cancer (microchimerism). Methods: (i) We used miRNA mimics and miRNA inhibitors in breast cancer cell lines to verify specific miRNA involvement in APRIN silencing. (ii) We used immunohistochemistry with bisulfite converted DNA for methylation and microdissected RNA for microRNA interference studies from 56 clinical breast cancer samples. (iii) We used Y-chromosome markers on microdissected DNA for fetal microchimerism studies. Results: (i) We found that in breast cancer cell lines with APRIN translational disequilibrium a set of microRNAs correlate with APRIN silencing. (ii) We found miRNA related mechanisms in about 35 percent of breast cancer samples where APRIN was silenced and (iii) APRIN may specifically affect stem cells of fetal origin in the mother's mammary gland and contribute to cancer. Conclusions: The novel miRNA-based mechanism maybe a new epigenetic factor of gene silencing in cancer. We experimentally confirmed a set of APRIN specific miRNAs and established preliminary correlations with fetal microchimerism in breast cancer.

No significant financial relationships to disclose.
Association of increase in thymidine uptake relative to tumor cell proliferation in indolent NHLs and DNA repair
Authors: Juweid M. E. , Buck A. K. , Ponto L. L. , Mottaghy F. M. , Syrbu S. , Moller P. , Vose J. M.
Published: August 2020

11116

Background: Uptake of radiolabeled thymidine (tdR) or its analogs is frequently used to assess tumor cell proliferation as well as tumor DNA repair synthesis after inhibition of tumor cell proliferation with certain drugs. We determined whether the relationship between thymidine (td) uptake and tumor cell proliferation may be different between indolent and aggressive NHLs. Methods: Twenty-four patients with histologically confirmed aggressive (n=16; all DLC) or indolent NHLs (n=8; 7 FL gr I-II, 1 MZL) underwent pretherapy imaging with the td analog 18F-fluorothymidine (FLT) and biopsy to determine the proliferative cell fraction by the Ki-67 index. Tumoral FLT uptake was determined by the maximum standardized uptake values (SUVmax) and correlated with the Ki-67 index. The FLT-SUV to Ki-67 ratio was also compared between indolent and aggressive NHLs. Results: Disproportional increase in FLT-SUVmax relative to tumor cell proliferation was found in indolent NHLs: median %Ki-67 was 5% in indolent vs. 80% in aggressive NHL whereas median FLT-SUVmax was 3.6 vs. 9.4, respectively. The disproportional increase in FLT-SUV in indolent NHLs could not be explained by nonspecific FLT uptake in tumor extracellular space estimated to account for <0.2 SUV unit. Difference in the ratio of FLT-SUVmax to Ki-67 index between indolent and aggressive NHLs was highly significant (1.21 ± 0.77 vs. 0.18± 0.20; P=0.006). These data are in line with a previous study using tdR where the ratios of median tdR (in cpm) to median %-Ki-67 or %-S phase cells in indolent were ∼1.5x those in aggressive NHLs which was associated with relatively increased expression of DNA repair proteins (PCNA) in indolent NHLs (Holte et. al. Acta Oncologica, 1999) Conclusions: Disproportional increase in td uptake relative to %proliferating tumor cells in indolent NHLs likely reflects enhanced DNA repair in quiescent cells or, less likely, constitutively increased Tk1 expression. Studies are underway to determine expression of proteins that, unlike Ki-67, are associated with both DNA repair and replication (e.g., RFA, PCNA). If enhanced DNA repair is confirmed in indolent NHLs this could have major implications with respect to understanding their natural course and treatment options.

No significant financial relationships to disclose.
Multifactorial CNS relapse susceptibility in HER2-positive breast cancer patients: First results from a population-based registry study
Authors: Musolino A. , Ciccolallo L. , Panebianco M. , Fontana E. , Zanoni D. , De Lisi V. , Sgargi P. , Ceci G. , Ardizzoni A.
Published: August 2020

1117

Background: A series of retrospective studies have reported a higher incidence of central nervous system (CNS) metastases in HER-2-positive (HER-2+) metastatic breast cancer. Trastuzumab, which does not cross the blood-brain barrier, has been associated with this increased risk. Methods: The aim of this study was to evaluate incidence, survival, and risk factors of CNS metastases in the incident breast cancer population systematically collected by the Tumor Registry of Parma Province over the 4-year period, 2004–2007. Study endpoints were: any distant metastasis as first event; CNS metastasis as first event; CNS metastasis at any time. Associations between CNS metastases and HER-2 status in the entire population and between trastuzumab and CNS metastases in HER-2+ patients (pts) were estimated. A multivariate analysis was performed to test the effect of covariates. Results: We evaluated the total resident population (n = 1500) of breast cancer pts diagnosed during the period 2004–2007 in Parma Province. Two-hundred and twenty-five pts (15%) were HER-2+ (IHC 3+/FISH amplified). Of these, 100 pts were treated with adjuvant trastuzumab-based therapy. At a median follow-up of 36 months from the diagnosis, the incidence of CNS relapse was 3% (1.3% as first recurrence). The median time to death from the diagnosis of CNS metastases was 25 months. Among the HER-2+ pts, there was a significant association between trastuzumab and subsequent CNS metastases (p = 0.02). However, in multivariate analysis, HER-2 status regardless of trastuzumab therapy was found to be the only independent predictive factor for CNS metastases (either as first or as subsequent recurrences; p < 0.01). Conclusions: This is the first population-based registry study analyzing CNS metastases in breast cancer in relation to tumor biological features, systemic treatment, and clinical outcome. Based on our results, HER-2 status independently distinguishes pts with a higher risk of CNS metastases. It is however presumable that, in some cases, improvements in systemic control and overall survival associated with trastuzumab-based therapy lead to an “unmasking” of CNS relapse that would otherwise have remained clinically silent prior to a patient's death.

No significant financial relationships to disclose.
Assessment of uterus, bone, serum lipids, and hormones in postmenopausal breast cancer patients treated with TAS-108, a novel steroidal antiestrogen: Results of a randomized phase II study
Authors: Nakayama T. , Inaji H. , Iwata H. , Yamamoto N. , Sato Y. , Tokuda Y. , Aogi K. , Saji S. , Ikeda T. , Noguchi S.
Published: August 2020

1120

Background: TAS-108, a novel steroidal antiestrogen, has demonstrated a favorable safety profile, including lower agonistic activity on uterus than tamoxifen and supportive effect on bone in preclinical studies. The potential tissue-specific effect of TAS-108 was investigated in postmenopausal breast cancer patients included in a randomized phase II study. (The clinical efficacy and safety results were presented at the 31st San Antonio Breast Cancer Symposium). Methods: Postmenopausal women aged 20–80 years with hormone receptor-positive metastatic breast cancer were eligible for this study and treated with oral TAS-108 (40, 80, or 120 mg/day) once a day. Endometrial thickness (ET) was measured by ultrasonography. The change in Bone Mineral Density (BMD) at lumber spine was assessed by dual energy X-ray absorptiometry. Hormone levels, bone metabolism markers, and serum lipid parameters were also measured at regular intervals. Wilcoxon signed-rank test was used to assess the significance of changes or percentage changes from baseline. Results: Ninety one patients with a median age of 62 years (range 44–80) were included in the analysis population. TAS-108 did not cause significant endometrial thickening (median baseline ET 3.3 mm, last point ET 3.6 mm; n = 36). In particular, after at least 1 year of treatment in 13 cases, no clinically significant increase in ET was found. No change was observed in median BMD (+0.74%; n = 20). Serum carboxy-terminal telopeptide of type I collagen (I CTP) levels remained unchanged although the decrease in osteocalcin levels was significant (p = 0.019; n = 49) in patients without bone metastasis. Median triglyceride levels significantly decreased from 104.0 to 85.0 mg/dl (p = 0.000) after 4 weeks of treatment, while there were no changes in other lipid parameters. An increase in sex hormone-binding globulin and testosterone levels were observed. Conclusions: TAS-108 may have no harmful effects within these parameters and could be used safely. However, further study in a greater number of cases is needed to identify the effect of the long-term use of TAS-108 on the uterus and bone.

[Table: see text]
Bevacizumab combined with taxanes in second-line or more for metastatic breast cancer: Efficacy and predictive factors of response
Authors: Vanneuville A. , Gentil J. , Vautravers-Dewas C. , Guiu S. , Favier L. , Causeret S. , Mayer F. , Coudert B. , Fumoleau P.
Published: August 2020

1122

Background: In metastatic breast cancer (MBC), bevacizumab (BEVA) and taxanes (TAX) (paclitaxel or docetaxel) are very efficient as first line metastatic therapy. However, such combination is questionable in subsequent lines of therapy. Aims: evaluate the efficacy and the factors of response of BEVA and TAX combination in second line or more for MBC. Methods: A retrospective study was done on all the MBC patients treated with BEVA combined with TAX, between July 2007 and November 2008, in the medical oncology department. Statistics were descriptive for the population and the efficacy. Univariate and multivariate analysis were used to determine the predictive factors of response. Results: 31 patients received BEVA combined with paclitaxel in 30 cases (96.7%) or docetaxel in one case (3.3%). Mean age was 55.3 years (IC95% [50.8–59.7]). Median number of previous lines was 4 (range [2–10]). 14 patients had already progressed under TAX therapy. Mean follow up was 7.1 months (IC 95% [5.9–8.4]). Thirteen (41.9%) patients had a clinical response, partial in 12 (38.7%) and complete in 1 (3.2%) patients. Four (12.9%) additional patients were stabilized therefore clinical benefit (CR+PR+SD) was obtained in 17 (60.7%) patients. The mean duration of the clinical benefit, measured as the delay between the first day of BEVA-TAX treatment and the date of progression or last news date, was of 5.8 months (IC95% = [4.4–7.1]). The progression delay, for patients who presented a progression and needed the introduction of a new therapy, was of 2.4 months (IC95% = [1.7–3.1]). Eleven (35.5%) patients had no clinical benefit and readily progressed under therapy. Multivariate analysis showed that age less than 65 (OR = 14.5 IC95% = [1.6–128.7]; p = 0.016) and a number of previous lines less than 6 (OR = 11.0 IC95% = [1.2–102.7]; p = 0.036) were related to the clinical benefit. Previous TAX resistance had no significant influence on the efficacy of the combination. Conclusions: In pretreated MBC patients, the combination of BEVA and TAX can be effective with a mean duration of clinical benefit around 6 months. Age over than 65 and a number of previous lines over 5 could be considered as factors of resistance to such a combination. These results have to be confirmed in larger studies.

[Table: see text]
Evaluation of Ki-67 measured in benign breast tissue acquired from premenopausal women treated with a flaxseed derivative
Authors: Fabian C. J. , Khan Q. J. , Sharma P. , Baxa S. , Metheny T. , Zalles C. M. , Kimler B. F.
Published: August 2020

1507

Background: The lignans enterolactone and enterodiol are derived from the action of gut bacteria on ingested secoisolariciresinol diglycoside (SDG) which is commonly found in flaxseed. Enterolactone and enterodiol are thought to impair mammary carcinogenesis via reduction in aromatase activity and the mid-cycle surge of luteinizing hormone. We assessed the modulatory activity of 1 year of SDG on a number of risk biomarkers for breast cancer in a prospective phase II pilot study. We report the effect of SDG on the primary endpoint, proliferation in benign breast tissue as measured by Ki-67 immunocytochemistry, in the first 35 women completing study. Methods: Premenopausal women age 21 to 55 at increased risk for breast cancer underwent a baseline random periareolar fine needle aspiration (RPFNA) between the first and tenth days of their menstrual cycle. Those with RPFNA evidence of hyperplasia and Ki-67 greater than or equal to 2% were invited to participate. Women taking flaxseed or oral contraceptives were ineligible. All women took one Brevail (lignan research) capsule containing 50 mg of SDG daily. Ki-67 staining was performed with DAKO M7240 antibody on hematoxylin counterstained slides and the number of cells staining positive in 500 cells within hyperplastic clusters was counted. Results: Forty-nine women were enrolled on study between February 2006 and June 2008. Of these, four stopped prematurely, 10 women have not completed, and 35 have completed study and undergone follow-up RPFNA. Baseline characteristics of the 35 women completing study are as follows: median age 44 (range 29–50), median baseline 5-year Gail model risk 1.6% (range 0.1%-5.7%), median Ki-67 4.2% (range 2.0%-16.8%). Thirty seven percent had hyperplasia without atypia, and 63% had atypia. At repeat RPFNA, Ki-67 expression was reduced (median value of 2.0%, range 0%-15.2%); with 29 of the 35 women demonstrating a decrease (median relative reduction of 0.70). Conclusions: Based upon reduction in Ki-67 expression in hyperplastic benign breast tissue after 12 months, 50 mg of SDG administered daily as Brevail appears promising as a preventive. Supported in part by grant R21 CA117847 from the National Cancer Institute.

No significant financial relationships to disclose.
Telephone disclosure of BRCA1/2 test results? Experience and opinions of genetic counselors and consumers
Authors: Patrick-Miller L. J. , Fetzer D. , Schmidheiser H. , Daly M. , Toppmeyer D. , Olopade O. , Bradbury A.
Published: August 2020

1510

Background: BRCA1/2 test results have historically been disclosed in person (IPD) by a certified genetic counselor (GC). Greater consumer demand and access to BRCA1/2 testing, and greater prevalence and acceptance of telemedicine, have interested providers in conducting BRCA1/2 testing and disclosing results by telephone (TD) and internet. GC and consumer experiences and opinions about TD have not been well described. Methods: To determine experience, opinions and interest in TD of BRCA1/2 test results we conducted semi-structured interviews with 194 GC recruited via NSGC Cancer Special Interest Group and with 30 consumers (to date) less than 9 months post IPD of BRCA1/2 test results at two cancer centers. Descriptive statistics characterize GC and consumer experiences and opinions. Results: 98% GC had provided TD; 46% rarely. Most frequent reasons for TD: perceived consumer hardship of IPD (n = 190); consumer preference (n = 49) and medical benefit (n = 30). GC comfort with TD varied by test result (true negative [TN] 77%, indeterminate [IND] 49%; mutation carriers [MC] 37%; variant of unknown significance [VUS] 33%). GC cited consumer convenience (n = 132), medical (n = 71) and psychological benefit (n = 42), and greater GC counseling capacity (n = 33) as TD advantages. No nonverbal communication (n = 161), poorer communication/understanding (n = 67), and difficulty explaining complex results (n = 41) were disadvantages GC most frequently reported. 46% post-IPD consumers reported interest in TD; interest varied by test result (VUS 67%; IND, 63%; TN 57%; MC 25%). Consumers’ perceived advantages: convenience (n = 22) and medical benefit (n = 9); and disadvantage to TD; lack of visual and personal connection with GC (n = 18). Conclusions: Results of the ongoing study suggest many consumers of BRCA1/2 testing are interested in, and nearly all GC have conducted, TD. GC and consumers share perceptions of TD convenience, and of challenges of lack of visual cues, however, GC comfort with, and consumer preference for, TD vary differently by test result. Given consumer and provider interest, longitudinal study of TD impact on knowledge, risk perception, communication, and health behaviors, and their mediators will be critical to develop policy and procedures optimizing adaptive responses to TD.

No significant financial relationships to disclose.
A short-term biomarker modulation prevention study of anastrazole in women at increased risk for breast cancer
Authors: Arun B. , Valero V. , Brewster A. , Gutierrez A. , Green M. , Esteva F. , Buzdar A. , Hortobagyi G. N. , Sneige N.
Published: August 2020

1514

Background: Selective estrogen receptor modulators (SERMs) reduce the risk of breast cancer. Acceptance of SERMs is low due to toxicities. Agents with a better toxicity profile and surrogate endpoint biomarkers to evaluate the effect of preventive agents are needed. In addition to reducing the risk of recurrence of breast cancer, the aromatase inhibitors (AI) have been shown to reduce the risk of contralateral breast cancer in large phase III adjuvant studies. Our objective in this prospective short-term prevention study was to evaluate the effect of anastrozole on surrogate endpoint biomarkers in breast tissue and serum of women with breast cancer who are at increased risk for developing a contralateral second primary breast cancer. Methods: Women with a history of stage I, II breast cancer who were scheduled to start anastrozole for standard adjuvant treatment were eligible. After signing informed consent, patients underwent baseline fine needle aspiration (FNA) of the unaffected breast and serum collection for biomarker analysis before starting anastrozole at 1 mg per oral /day. A repeat FNA and serum collection were performed after 6 months of therapy. Biomarker endpoints included changes in ER and KI-67 expression in breast tissue analyzed by immunohistochemistry and insulin-like growth factor binding protein (IGFBP-1) in serum analyzed by ELISA. The difference in biomarkers before and after treatment was assessed using a Wilcoxon signed-rank test. Results: Forty two patients were enrolled and accrual has been completed. Median age was 58.8 (range 48–75). There was no change in ER or Ki-67 expression in pre- and posttreatment FNA samples. However, there was a statistically significant difference in pre- and posttreatment serum IGFBP-1 levels (p = 0.014); with pre-and post- mean treatment levels being 9.2 ng/mL and 13.5 ng/mL, respectively. Conclusions: We found a significant modulation of IGFBP-1 levels with 6 months of anastrozole treatment in women at increased risk of developing contralateral breast cancer. Anastrozole is currently being studied as a prevention agent in a large phase III trial, and our results provide support for continued evaluation of IGFBP-1 as a surrogate endpoint biomarker in prospective breast chemoprevention studies.

[Table: see text]
Stage-size relationship in long-term repeated CT screening for lung cancer: Anti-Lung Cancer Association project
Authors: Seki N. , Eguchi K. , Kaneko M. , Ohmatsu H. , Kakinuma R. , Matsui E. , Kusumoto M. , Tsuchida T. , Nishiyama H. , Moriyama N.
Published: August 2020

1540

Background: We have investigated the individualized benefit of CT screening as Anti-Lung Cancer Association projects (presented at ASCO 2006–2008). However, there has not been enough information about the relationship of lung cancer stage to tumor size in repeated CT screening. Therefore, we evaluated the stage-size relationship of these asymptomatic lung cancer cases diagnosed by long-term repeated screening with low-dose helical CT. Methods: Among 2,120 participants (mean age 63 years, 87% male, and 83% smoker) at baseline screening, 1,877 underwent semiannually repeated screening from 1993 to 2004. Nineteen (0.90%) prevalence cancers and 57 (0.32%) incidence cancers were detected. Within categories of tumor size, the distribution of pathological stage, histology, lymph node status, and distant metastases was determined. Results: Pathological stage has a strong relationship to tumor size at baseline screening (spearman r = 0.63, p = 0.013) and repeated screening (r = 0.65, p < 0.001). In the analysis of all 76 cases, lymph node status (r = 0.59, p < 0.001) and distant metastases (r = 0.55, p = 0.005) have also a strong relationship to tumor size. The percentages of cases with no metastases (N0M0) were 100% (0/21), 89% (17/19), 62% (8/13), 83% (10/12), 50% (4/8), and 33% (1/3) for the categories 10 mm or less, 11 mm to 15 mm, 16 mm to 20 mm, 21 mm to 30 mm, 31 mm to 40 mm, and 41 mm or greater, respectively. Histology for the categories 15 mm or less was localized bronchioloalveolar carcinoma in 13 cases, adenocarcinoma with mixed subtype in 11 cases, invasive adenocarcinoma in five cases, other non-small cell carcinoma in 10 cases, and small cell carcinoma in one case. Accumulated 10-year hazard ratio of above histology was 2.4, 2.5, 2.6, 4.1, and 0.7. In multivariate analyses, pathological stage was related to only tumor size (standardized regression coefficient beta = 0.59, p < 0.001) whereas histology was related to tumor size (beta = 0.43, p < 0.001) and smoking index (beta = 0.28, p = 0.016). Conclusions: These results provide direct evidence of a stage-size relationship in long-term repeated CT screening for lung cancer. Furthermore, early detection of lung cancer of 15 mm or less in diameter leads to the detection of early-stage (N0M0) lung cancer in repeated CT screening.

No significant financial relationships to disclose.
Web-based resources for sun protection information: A French-language evaluation
Authors: Mahé E. , Beauchet A. , Saiag P.
Published: August 2020

1549

Background: With the dramatic increase in ultraviolet-induced skin damage, including melanomas and skin carcinomas, advocating the benefits of reasonable and moderate exposure to sunlight is a public health priority in most Western countries. Objective: The aim of this study was to investigate the nature and quality of the information posted on the Internet about the effects of the sun on health and about sun protection. Methods: We used eight terms with eight search engines to identify relevant websites providing sun protection advice on the French-speaking web. This information was compared to the recommendations issued by nine official organizations. Influence of website quality and commercial links on the quality of the advice provided was evaluated. For the purposes of this comparison, we attributed marks to the following four criteria: 1) risks and benefits of sun exposure; 2) sun avoidance; 3) clothing recommendations; and 4) sunscreen use. Results: The search identified 1,551 links. After exclusion of sites duplicated either within or between search engines, and of websites used as references, we found 129 web pages dedicated to sun protection advice. Data on the effects of the sun and sun protection were deficient in most websites in comparison to official organization websites. It was even better than the web pages or websites respecting quality criteria. Commercial links tended to score poor marks for 1, 2, and 3 but better marks for 4 (sunscreen use). Conclusions: We showed the limits of web-based resources on the French-speaking web regarding sun protection advice. Poor quality of most of the websites and commercial conflict of interest with sunscreen manufacturers may explain these limits.

No significant financial relationships to disclose.
A phase II study of chemoradiation followed by adjuvant temozolomide and poly-ICLC in patients with newly diagnosed glioblastoma: 12- and 18-month survival data (NABTT 0501)
Authors: Rosenfeld M. R. , Chamberlain M. , Grossman S. A. , Peereboom D. M. , Lesser G. J. , Batchelor T. T. , Desideri S. , Salazar A. M. , Ye X.
Published: August 2020

2002

Background: Polyinosinic-polycytidylic (poly-ICLC), is a double-stranded RNA that stimulates a variety of host defense mechanisms including T-cell and natural killer cell activation, cytokine release and specific anti-proliferative and anti-viral effects. The objective of this study was to determine the safety and efficacy of poly-ICLC when added to adjuvant treatment for newly diagnosed glioblastoma. Methods: Newly diagnosed patients > 18 years with histologically proven glioblastoma received standard external beam radiation with concurrent low-dose temozolomide (TMZ) (75 mg/m2) followed by adjuvant cycles of TMZ for 5 days (150–200 mg/m2) (week 1) then intramuscular injections of poly-ICLC (20 mcg/kg) 3 times a week (weeks 2–8; total 21 injections) with week 9 off and no limit to the number of adjuvant cycles (TMZ + poly-ICLC). Imaging evaluations were performed before every cycle. Results: There were 97 patients enrolled (60 men); median age 56 yrs (range 21–85); median KPS 90 (range 60–100). Fourteen patients did not start adjuvant treatment (5 patient request and 4 investigator withdrawal; 2 progressive disease; 1 death; 1 toxicity; 1 other). The most frequent CTC grade 3–4 toxicities occurring in > 5% of subjects at least possibly related to poly-ICLC were leukopenia (20%), thrombocytopenia (14%), anemia (13%), neutropenia (10%), and SGPT (9%) or alkaline phosphatase (7%) elevation. Two deaths during adjuvant treatment were considered unlikely related to poly-ICLC. To date 71 of 97 patients have survived at least 12 months from diagnosis. The estimated median survival for the entire cohort was 17.2 months (95% CI: 15.5–19.3 months). Overall survival for the cohort at 12 months was 73.2% (95% CI: 63%-82%) and at 18 months 47.4% (95% CI: 37–58%). For only those subjects 18–70 years, overall survival at 18 months was 51.8% (95% CI: 41–63%). This is contrasted with EORTC 26981/22981 that reported an 18 month overall survival of 39.4% (95% CI: 33.8–45.1). Conclusions: The addition of poly-ICLC to a modified adjuvant treatment regimen for newly diagnosed GB is well-tolerated. Survival data at 12 and 18 months suggest increased efficacy compared to chemoradiation with adjuvant TMZ only.

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Bevacizumab in combination with temozolomide in the adjuvant treatment of newly diagnosed glioblastoma multiforme: Preliminary results of a phase II study
Authors: Nicholas M. K. , Lucas R. V. , Arzbaecher J. , Paleologos N. , Krouwer H. , Malkin M. , Omar A. , Vick N. A.
Published: August 2020

2016

Background: Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. Current standard treatment consists of fractionated radiotherapy (RT) with daily oral temozolomide (TMZ) chemotherapy followed by 6 months of adjuvant TMZ chemotherapy. Median survival is 14.3 months. Because GBM is characterized by vascular proliferation and produces high levels of vascular endothelial growth factor (VEGF), attempts to better control the disease with targeted anti-angiogenesis therapies are underway. Here, we report preliminary safety and tolerability data of bevacizumab (BV) when added to monthly TMZ chemotherapy. Methods: Subjects received standard regional RT to a dose of 60 Gy in 30 fractions with dailyconcurrent TMZ (75 mg/m2) within 3–5 weeks of diagnosis. Four weeks after RT/TMZ, subjects received 5 consecutive daily TMZ doses (150–200 mg/m2) administered every 28 days. BV (10mg/kg) was given every 14 days. Treatment continued until either disease progression or unacceptable toxicity occurred. Results: 42 of 48 planned subjects were enrolled as of 12/30/08. Twenty-three remained on study. Of these, 4 were receiving RT/TMZ, 18 were receiving TMZ/BV and 1 was delayed post-RT/TMZ due to local wound infection. Nineteen were off-study. Eleven of those off-study never received BV due to: study withdrawal (n = 2), toxicity during RT/TMZ (n = 3) and post-RT/TMZ progression (n = 6). Seven subjects progressed while receiving TMZ/BV. Twenty-six of the 42 enrolled received at least one 28-day cycle of TMZ/BV (range 1 - 16 cycles). Duration of treatment, inclusive of RT/TMZ, ranged from 27 to 523 days. Best radiographic responses of evaluable subjects, using MacDonald criteria were: 5 complete, 9 partial, 13 stable and 7 progressive disease. Of those taken off study, 13 were due to disease progression. Of those removed from study due to toxicity, none were unexpected and only 1 (a GI bleed) occurred during the TMZ/BV phase. A statistical analysis of response and survival is pending. Conclusions: The co-administration of TMZ/BV following RT/TMZ for newly diagnosed GBM is safe and well-tolerated.

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Phase I study of vandetanib with radiation therapy and temozolomide for newly diagnosed glioblastoma
Authors: Drappatz J. , Norden A. D. , Wong E. T. , Lassman A. B. , Doherty L. , LaFrankie D. , Gerard M. , Phan P. , Schiff D. , Wen P. Y.
Published: August 2020

2031

Background: There is increasing evidence that angiogenesis inhibition may potentiate the effects of radiation therapy (RT) and chemotherapy in patients with glioblastoma (GBM). In addition, inhibition of the epidermal growth factor receptor (EGFR) may be of therapeutic benefit, as EGFR is often upregulated in GBM and contributes to radiation resistance. We conducted a phase I study of vandetanib, an inhibitor of VEGFR2 and EGFR, in patients with newly-diagnosed GBM in combination with RT and temozolomide (TMZ). Methods: Using a standard 3 + 3 dose escalation design, 13 newly-diagnosed GBM patients received vandetanib with RT (60 Gy) and concurrent TMZ 75 mg/m2 daily, followed by adjuvant TMZ for up to 12 cycles (150–200 mg/m2 on days 1–5 of each 28 day cycle). The maximum tolerated dose (MTD) was defined as the dose with ≤1/6 dose-limiting toxicities (DLT). Eligible patients were adults with newly-diagnosed GBM or gliosarcoma, Karnofsky performance status of ≥60%, normal organ function, and not taking enzyme-inducing anti-epileptic drugs. MTD was determined by evaluation of DLTs during the first 12 weeks of therapy. Results: Six patients were treated with vandetanib at 200 mg daily. 2/6 patients developed DLTs (grade 5 gastrointestinal hemorrhage and grade 3 thrombocytopenia in one patient and grade 4 neutropenia in one patient). Seven patients were treated at 100 mg daily with no DLTs observed, establishing 100 mg daily as the MTD. Of 10 evaluable patients, one had a minor response (10%), defined as 25% to <50% reduction in enhancing area for 8 weeks; eight had stable disease (80%), defined as <25% increase or decrease; and one had progressive disease (10%). Conclusions: These data suggest that vandetanib may be combined with RT and TMZ in GBM patients. A randomized phase II study in which patients receive RT and TMZ with or without vandetanib 100 mg daily is underway.

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A phase I trial of surgical resection with biodegradable carmustine (BCNU) wafer placement followed by vaccination with dendritic cells pulsed with tumor lysate for patients with malignant glioma
Authors: Rudnick J. D. , Phuphanich S. , Chu R. , Mazer M. , Wang H. , Serrano N. , Francisco M. , Black K. L. , Wheeler C. , Yu J.
Published: August 2020

2033

Background: Our prior immunotherapy trials demonstrated efficacy in generating a tumor specific immune response in malignant glioma and the potential for high tumor-specific toxicity and sustained tumoricidal activity. Immunotherapy may synergize with chemotherapy and biodegradable carmustine (BCNU) wafers extend overall survival from 11.6 to 13.9 months. Methods: We exploited this synergistic effect to maintain a cytotoxic environment around the tumor milieu. Patients with high-grade glioma were eligible after maximal resection with biodegradable carmustine (BCNU) wafer placement. Screening leukapheresis is used to isolate mononuclear cells which are differentiated into dendritic cells, pulsed with tumor lysate, and then 3 intradermal vaccines are administered at 2-week intervals. Patients continued systemic chemotherapy after vaccine or at progression. Results: Eighteen patients have been enrolled (7 Male, 11 Female) between April 2007 and February 2009 with one screen failure and two patients with clinical progression prior to vaccination. The median patient age was 57 years (26 to 74 ) and median Karnofsky performance status was 90% (80–100). The histology included 3 newly diagnosed glioblastoma multiforme (GBM), 8 recurrent GBM, 2 newly diagnosed anaplastic astrocytoma (AA), and 2 recurrent AA. 15 patients were successfully treated by vaccine injections with 12 patients receiving vaccine every 2 weeks x 3 followed by adjuvant chemotherapy. Our preliminary data on 15 patients and 39 courses of Dendritic Cell vaccines demonstrate one grade 3 toxicity of fever/chest pain. A stable disease interval of 13 to 90 weeks was observed for patients who received vaccine. The 3 newly diagnosed GBM patients have stable disease (18 to 71 weeks). In the recurrent GBM cohort 7/8 patients had progression within 6 months from the post-vaccination MRI. Conclusions: This phase I study demonstrates the safety, feasibility of dendritic cell vaccination with biodegradable carmustine (BCNU) wafers with one grade 3 AE. Immunological data is pending to determine potential synergy of dendritic cell vaccination with intracranial chemotherapy.

No significant financial relationships to disclose.