bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of known risk factors for breast cancer in Venezuelan patients with breast cancer, benign breast diseases, and without breast pathology
Authors: Hernandez D. E. , Hernandez A. E. , Garcia G. C.
Published: August 2020

1531

Background: Breast cancer (BC) represents the second cause of death from cancer in Venezuelan women, therefore, it is important to study the known risk factors for developing BC in Venezuelan patients. Also, little is known about the importance of these risk factors in patients with benign breast diseases (BBD). Due to this we carried out a prospective case-control study of known risk factors for developing BC in a group of female patients with BC and BBD with the purpose of defining clinical criteria which can be used to orient physicians and patients about the conducts to be followed not only by the patients, but also by their family group. Methods: We included 515 patients with BC, 507 with BBD, and 505 without breast pathology.The following risk factors were identified through a personal interview with each patient: family history of breast and ovary cancer, exposure to female hormones (exogenous and endogenous), and previous history of BBD. Results: The significant results when comparing the BC group with the BBD group were the following: strong family history of BC (p = 0.004), ingestion of oral contraceptives (p = 0.035), lactation (p = 0.00013), hormone replacement therapy (p = 0.000001), and previous history of BBD (p = 0.0000032). The significant results when comparing the BC group with the group without breast pathology were the following: family history of BC (p = 0.0000001), family history of ovary cancer (p = 0.0000001), nulliparity (p = 0.00009), age of first terminal pregnancy (p = 0.000001), number of abortion (p = 0.024), lactation (p = 0.03), and previous history of BBD (p = 0.0000001). A logistic regression model showed that the variables with the highest impact were lactation (p = 0.0001), family history of breast cancer (p = 0.0001), and family history of ovary cancer (p = 0.0001). Conclusions: Even though several hormonal factors were important, lactation and family history of breast and ovary cancer were the most important risk factors.

No significant financial relationships to disclose.
Willingness of breast cancer survivors to participate in a randomized controlled trial (RCT) of digital mammography with or without magnetic resonance imaging (MRI) as breast cancer (BC) surveillance: A feasiblity study
Authors: Warner E. , Tsoi D. , Bordeleau L. , Brezden C. , Holloway C.
Published: August 2020

1534

Background: Although no RCT of MRI screening has ever been performed, and thus its impact on survival is unknown, MRI (plus mammography) has become the standard of care for screening women at very high risk for BC due to its superior sensitivity. The current ASCO guideline for surveillance of women with a past history of BC patients for ipsilateral recurrence or contralateral BC is annual mammography; however, MRI is often being ordered as well. A RCT for this population is still theoretically feasible assuming one could recruit a sufficient number of patients. We conducted a study to evaluate the willingness of BC survivors to participate in a RCT of digital mammography with or without MRI. Methods: In this multi-center, cross-sectional cohort survey, consecutive women ages 20 to 59 with invasive BC who had completed all primary therapy (except hormonal therapy), had at least one remaining breast and no evidence of metastatic disease, were consented in clinic to complete a self-administered questionnaire. Results: 348 women at four study sites across Toronto, Canada, were enrolled over 10 months. Median age 51 years, 76% Caucasian, 69% had BC within the last 5 years, 37% had previous mastectomy. At diagnosis, 71% BC had been visible on mammogram; 45% had undergone diagnostic MRI. 22% continued to have MRI as part of surveillance imaging, especially women younger than 40 years. 58% agreed to consider participating in the proposed RCT, and 16% remained neutral. Women who had undergone mastectomy were more likely to consider the trial (71% vs. 52%). The most common reason for not considering the trial was that they were already getting surveillance MRI. Other reasons were additional false positive tests and biopsies (34%), discomfort associated with MRI (28%), and fear that their anxiety about cancer recurrence would increase (16%). Conclusions: A RCT of MRI surveillance for BC survivors younger than age 60 is still feasible at centers where annual MRI is not yet routinely recommended for this population.

No significant financial relationships to disclose.
The Love/Avon Army of Women: A “just in time” resource to encourage research in women
Authors: Love S. M. , Mills D. , Eraklis E. , Hurlbert M.
Published: August 2020

1535

Background: One of the barriers to finding the cause of breast cancer is the difficulty basic scientists have in involving healthy women and obtaining human tissues, fluids, and information processed according to their needs. The Dr. Susan Love Research Foundation has collaborated with basic scientists successfully recruiting community women for studies. These efforts led to the Love/Avon Army of Women (AOW), a new “just in time” resource seeking to partner women with scientists to find the cause and prevention of breast cancer. Methods: The AOW is a pool of volunteers who have registered online ( www.armyofwomen.org ) that they are willing to participate in research. Peer-reviewed, funded projects submitted by researchers are reviewed by the AOW Scientific Advisory Committee for eligibility. An eBlast is sent to all AOW volunteers describing the study, and eligible women RSVP to the AOW for a secondary screen. The list is then sent to the researcher. If needed, referrals are made to a regional AOW Center for specimen collection, processing, and shipment. All scientists participate in a webcast with the eligible volunteers to explain the research before the study and describe the overall results at the end, ensuring a partnership between the women and the investigators. Results: AOW recruitment was initiated October 1, 2008, by Dr. Love on national media with the goal of creating a resource of 1,000,000 women available for researchers. To date over 260,000 women have joined. All ethnicities, ages (18–89), and states are represented. The first eBlast was sent out in mid-October for the Sister Study to accrue the last 5,000 women needed from diverse backgrounds. In 48 hours, 1,600 women had responded and qualified, and in 2 months, 2,500 had signed up with a 90% enrollment rate. The second study required women who were breastfeeding and scheduled for a breast biopsy. In one week, 30 eligible women were identified. Conclusions: The Love/Avon Army of Women is a just in time resource for breast cancer scientists to obtain exactly the specimens: breast or adipose tissue, ductal fluid, urine, saliva, blood, or information processed exactly as needed. This new partnership between women and scientists promises to revolutionize research and accelerate efforts to find the cause and prevention of breast cancer.

No significant financial relationships to disclose.
Patients’ experiences and reported barriers to screening colonoscopy: A systematic review
Authors: McLachlan S. , Clements A. , Austoker J.
Published: August 2020

1537

Background: Colonoscopy is a component of most colorectal screening programs, as a primary test or as follow-up to an abnormal FOB test. Little is known about why some patients do not comply with colonoscopy after being referred. Methods: A search strategy using three themes of screening, colonoscopy, and patient acceptance was developed and used in MEDLINE, EMBASE and PSYCHinfo (1996–2008). Retrieved citations were assessed for eligibility by two reviewers using prespecified criteria. A qualitative synthesis was conducted. Results: From an initial 3,174 studies, 264 were identified as potentially eligible for review. After full text assessment, 64 studies met eligibility criteria and were included in the final analysis. Six studies examined the experience of a primary colonoscopy by eliciting patients’ views soon after they had the test. Fifty-six studies addressed patient-reported concerns and barriers to an anticipated primary colonoscopy. Most patients perceived the laxative bowel preparation to be the most burdensome part and the greatest barrier to colonoscopy. Other reported difficulties included anxiety and anticipation of pain. Feelings of embarrassment and vulnerability occurred, particularly in women, and also acted as barriers to adherence. Inadequate knowledge about screening was common and was identified as an obstacle to the uptake of screening colonoscopy as was fear of finding cancer. Physician endorsement, having a family history, knowing someone with cancer, and perceived accuracy of the test were incentives to having a colonoscopy. The most common reported practical barriers were inconvenience, transportation, scheduling, and cost. Only two studies focused on colonoscopy as a secondary procedure in the screening context. Similar procedural, personal, and practical concerns were reported by patients in this setting. Conclusions: Bowel preparation, lack of awareness of the importance of screening, and feelings of vulnerability in women are all significant barriers to colonoscopy in the screening context. These obstacles need to be addressed, and further research undertaken on barriers to second line colonoscopy.

No significant financial relationships to disclose.
Trends in screening for colorectal cancer in France
Authors: Viguier J. , Calazel Benque A. , Mahjoubi M. , Pivot X. , Morère J. , Blay J. , Coscas Y. , Roussel C. , Eisinger F.
Published: August 2020

1538

Background: In France, after a pilot population-based screening program in 23 districts (2002–2003), a national organized program was progressively implemented starting in 2005. The EDIFICE 2 survey was conducted in 2008, 3 years after EDIFICE 1, to provide a better understanding of French people's participation in colorectal screening programs and to assess the evolution between the two periods. Methods: This second nationwide observational study, EDIFICE 2, was conducted in January 2008 among a representative sample of 1,801 subjects aged between 40 and 85 years old. The analysis focused on the target population of the national screening program (50–74 years old). Results: In 2008, 38% of subjects between 50 and 74 years (N = 928) had undergone a screening test for colorectal cancer (including fecal test or colonoscopy) versus 25% in 2005 (p < 0.05); 32% of the unscreened population (N = 575) planned to undergo a test. Colorectal cancer screening increased significantly in all age groups, especially between 65 and 69 years, and for both sexes. A most significant increase can be observed in districts with pilot programme (+ 21%). Factors influencing the probability of screening were: being encouraged by the family circle, living in a couple, the existence of a case of cancer (especially colorectal cancer) in the family circle, and fear of colorectal cancer. The main reasons for not performing the screening were: not feeling concerned, no recommendation by the GP, carelessness, no symptoms, and fear of exams or results. Conclusions: The objective rate of participation (50%), can be reached by motivating the unscreened population already planning to perform a test. The results in the pilot districts show the effectiveness of an organization of the screening. This trend of increasing testing will probably be confirmed in the future if the reasons for non-attendance in an organized program are addressed.

No significant financial relationships to disclose.
Diverse cancer prevention needs in a population seeking risk assessment for gastrointestinal (GI) cancers
Authors: Hall M. J. , Rybak C. , Mazar C. , Balsham A. , Manne S. L. , Slater E. , Weinberg D. S. , Meropol N. J.
Published: August 2020

1539

Background: Demand for hereditary cancer risk assessment has increased dramatically in the past decade. However, the population seeking risk assessment for GI cancers is heterogeneous, requiring primary (PP), secondary (SP), and tertiary (TP) prevention strategies. In an effort to improve targeting of prevention resources, we examined clinical cancer prevention needs as well as 1) estimates of personal risk, 2) risk beliefs 3) interest in genetic testing (GT) among individuals seeking GI risk evaluation. Methods: The Gastrointestinal Tumor Risk Assessment Program (GI-TRAP) offers risk assessment to persons seeking evaluation for a risk of a GI or related cancer. Following informed consent, participants complete a health history questionnaire prior to counseling, education, and genetic services. Results: In total, 398 individuals from 278 families were evaluated (1999–2008)( Table 1 ). Moderate-to-high risk persons with SP needs (i.e. intensive screening, chemoprevention, and genetic testing), dominated the population (281/398, 70.6%), mainly due to significant family history (FHx) of GI-related cancer (236/281, 84.0%) and/or personal history (PHx) of colorectal polyps (128/281, 45.6%). Individuals at high-risk due to a PHx of cancer were infrequent (68/398, 17.1%); here, TP needs focused on GT were common, as interest was highest in this group (p<0.01). A low-risk group (49/411, 11.9%) with minimal PHx or FHx, had mainly PP needs (i.e. risk factor management, education related to appropriate screening). Nonetheless, prior to counseling, the magnitude of personal estimated risk in this group paralleled that of the higher risk groups. Conclusions: Perceived cancer risks and beliefs may not reflect true prevention needs. Risk stratification strategies are critical for targeting education, risk counseling, and/or GT resources while maximizing current prevention goals.

[Table: see text]

No significant financial relationships to disclose.
Evaluation of Smad2/3 and Smad4 as inhibitors of estrogens and Ski protein as a predictive factor in T1, T2 N0 breast carcinomas
Authors: Koumoundourou D. S. , Kassimatis T. I. , Tzorakoleftherakis E.
Published: August 2020

1543

Background: Smad proteins are TGF-β intracellular substrates, and Ski protein is a negative regulator of TGF-pathway. Tamoxifen's inhibition in breast cancer cells is mediated through TGF-β and Smad proteins. The purpose of our study was to investigate the activation of Smad2/3, Smad4, and Ski proteins in breast carcinomas and correlate their expression with each other and with hormonal receptors, as well as with other clinicopathological parameters such as the tumor size and grade, and the Distant Disease Free and the Overall Survival. Methods: One hundred forty-seven paraffin-embedded specimens from 22 in situ and 125 invasive ductal node-negative carcinomas were used, for which we had a mean follow-up time of 96 months. ER and PR status, as well as the expression of Smad2/3, Smad4, and Ski proteins were evaluated using immunohistochemistry. Staining of 5% of the tumor cells was adopted as a threshold. SPSS13 for windows was used for the statistical analysis of the results. Results: Smad2/3 and Smad4 were strongly correlated with each other (p < 0,001) and inversely correlated with patients’ DDFS (Kaplan-Meier plots, p = 0,004 for Smad2/3 and p = 0,026 for Smad4) and OS (Kaplan-Meier plots, p = 0,034 for Smad2/3 and p = 0,017 for Smad4). Smad2/3 was proved to be an independent prognostic factor in grade 1 tumors, while Smad4 was inversely correlated with PR expression (p = 0,028) and had a strong prognostic value in ER+ tumors (p = 0,02). Ski protein had a strong association with tumor grade (p < 0.001) and was found to be an independent prognostic factor in Cox regression analysis (p = 0,006, exp(B) = 4,98). Conclusions: Smad 2/3 and Smad 4 not only are tumor suppressor molecules, but also inhibit ER dependent gene expression. This inhibition is lost when Smad's expression is reduced, and that is a potent explanation for Smad 4 prognostic value in ER positive tumors. Moreover the correlation with PR expression, may be due to the fact that PR is an indicator of ER pathway's integrity and also to PR's enallaktiki activation by ER-β. From the other hand, Ski protein acts as an oncogene in breast carcinogenesis and contributes to the development of a more aggressive tumor phenotype.

No significant financial relationships to disclose.
Risk factors of cervical neoplasia in a low income sector under control program in a developing country
Authors: Zarba J. J. , Holgado S. , Sanchez Segura M. , Gonzalez A. , Gonzalez A. , Cano Busnelli V. M. , Lorente C. E. , Elias de Vacaflor A.
Published: August 2020

1545

Background: There are a high number of risk factors (RF) in cervical neoplasias, most of them related with human papilloma virus infection: women with history of multiple sex partners (MSP), with early onset of sexual intercourse (EOSI),and non-previous cervical Papanicolaou (Pap) smear (NPAP).Objective: To determine the presence of RF in the studied population, the frecuency and types of lesions found, and the correlation between non-previous pap smear and underlying pathology. Methods: The population included in the study were 14,021 patients from institutions of public (PU) (n = 7523) and private (PRI) (n = 6499) sectors in the province of Tucumán–the average age being 34 and 43 years old, respectively–studied between 2007 and 2008, in a routine screening for CC with Pap testing. Both sectors include mostly low income people with none or limited health insurance. All testings were performed under methodologic norms of a CC Detection Program. The RF analized were: NPAP, EOSI, and MSP. Cervical lesions were studied with Bethesda System 2001. The statistic applied was the exploratory analysis. Results: NPAP in PU n = 4562 (75.76%), PRI n = 3247 (81.66%). EOSI with mean age being in PU 17 years old (sD 3.55) and PRI 19 (sD 5.33).MSP above 4 partners PU n= 482 (6.55%) PRI n= 161 (2.75%).Frecuency of LSIL in PU n= 30 (0,40%) PRI n = 50 (0.80%).HSIL in PU n = 29 (0.39%) PRI n = 28 (0.45%).Ca INV in PU n = 6 (0.08%) PRI n = 3 (0.05%). ASCUS in PU n = 24 (0.32%) PRI n = 10 (0.16%). Asociation between NPAP and cervical pathology was found p = 0.024 < 0.05 given that 100/142 (70.42%) patients with lesion had NPAP and 42/142 (29.57%) paitents had previous Pap. Conclusions: The results in this sample indicate low Pap coverture is mantained in PU and PRI sectors and the need to approach the population under 20 years old in Tucuman, Argentina, to prevent CC.

No significant financial relationships to disclose.
The UICC Cervical Cancer Initiative: A comprehensive program for cervical cancer prevention worldwide including a fellowship program
Authors: Harford J.
Published: August 2020

1547

Background: HPV vaccines and new screening tools have the potential to make cervical cancer largely a disease of the past. The UICC Cervical Cancer Initiative (CCI) is a comprehensive program that aims to increase awareness and education, and support screening, vaccination, and treatment via four key components: advocacy; public information; professional education; and pilot projects. CCI is global in scope, but emphasis is placed on resource-poor settings where mortality and morbidity rates from cervical cancer and HPV-related infections are highest. Lack of appropriate professional knowledge has recurrently been identified as one of the major hindrances to national cancer control programs and lack of access to diagnosis and treatment. Methods: A comprehensive educational package developed by a task force of experts will serve as a basis for train the trainer courses. CCI curriculum materials are practical and reader-friendly with an interdisciplinary approach. UICC has developed a dedicated fellowship program to support the implementation of the CCI. Special attention is given to south-to-south knowledge transfer by encouraging workshops within regions and in local languages. Professional education is one of the key components of UICC projects in Tanzania and Nicaragua, which aim to showcase the impact of comprehensive education on cervical cancer control. The fellowships support these efforts via opportunities for appropriate training of health practitioners, policy-makers, educators, researchers, and technicians. Results: See www.uicc.org for information about study grants, training workshops, technology transfer, and training for nurses, investigators, and pathologists. Expert reviewers ensure each project is judged according to preset criteria. Conclusions: Knowledge transfer between professionals and a lay audience is critical for long-term sustainability. The UICC cervical cancer curriculum supported by a dedicated fellowship program and a train the trainer approach is one route to achieving success. Key factors include: identification of host institutions and reviewers, continual funding, evaluation and implementation plans per trainee, as well as a sharing best practice forum.

No significant financial relationships to disclose.
Misuse of suncare products: Toward a protocol for sunscreen application
Authors: Issachar N. , Nkengne A. , Bertin C. , Robert C.
Published: August 2020

1548

Background: Increasing awareness of the UV-induced skin carcinogenesis has led to a significant demand for improved photo-protection both in UVB and UVA ranges. Sunscreen products are subjected to strict efficacy controls relying on standardized UV protection measurements and are widely recommended by oncologists and dermatologists in order to prevent skin cancers. However, sunscreen effectiveness depends not only on the quality of the product itself but also on the way people use it in real life. Misuse of suncare products might even lead to opposite deleterious effects. We conducted three successive studies in order to validate a sunscreen application protocol. Methods: Three studies were done on healthy volunteers who were asked to apply a sunscreen product as they usually do without any guidance or following a protocol of product application. Spontaneous application was evaluated in the first study (N = 17). Two application protocols were successively tested (N = 31) where both quantity of product and quality of sunscreen spreading were assessed (without and with the protocol) by three independent evaluators using photos taken under UVA light. Results: Spontaneous application of sunscreen resulted in an heterogeneous application of only 27% of the quantity recommended following COLIPA guidelines. Two application protocols giving practical informations concerning the quantity and the way to spread the product on each body anatomical sites were successively evaluated. Use of the application protocols improved both the quantity of suncare product and the homogeneity of product spreading with an highly significant improvement resulting from the use of the final and improved application protocol tested in the third study (p < 0.02). Conclusions: The correct use of sunscreens is a public health issue about which the public still requires considerable education. We propose that, in addition to the usual photoprotection recommendations (i.e., clothing protection and avoidance of middle day exposure), population should be trained to use validated protocols for sunscreen application.

[Table: see text]
Phase II trial of bevacizumab in combination with temozolomide and regional radiation therapy for up-front treatment of patients with newly diagnosed glioblastoma multiforme
Authors: Lai A. , Nghiemphu P. , Green R. , Spier L. , Peak S. , Phuphanich S. , Fehrenbacher L. , Kolevska T. , Polikoff J. , Cloughesy T.
Published: August 2020

2000

Background: Bevacizumab (BV) is a humanized monoclonal antibody directed against the vascular endothelial growth factor (VEGF). Based on the promising activity of BV in the treatment of recurrent glioblastoma, we are conducting a phase II trial to determine whether up-front treatment of newly diagnosed GBM with BV may be more advantageous than withholding BV until recurrence. In this trial, we evaluate the safety and efficacy of BV combined with standard of care radiation (RT) and temozolomide (TMZ) and radiation (RT) for newly-diagnosed GBM. Methods: This is a phase II trial with a 10-patient pilot and 60-patient expansion phases. Newly-diagnosed GBM patients with no prior treatments are eligible. Primary outcome measure is overall survival; the secondary outcome measure is TTP and 12-month survival. Therapy began between 3–5 weeks of surgery with BV (10 mg/kg every 2 weeks), TMZ (75 mg/m2 daily), and external beam RT (30 x 200 Gy) on the same day. After completion of radiation, patients are then placed on a maintenance phase of BV (10mg/kg every 2 weeks) and TMZ (150–200 mg/m2 5 out of every 28 days) until progression or 24 months in which patients are then maintained on BV only. Results: 70 of 70 projected GBM patients have been enrolled between August 2006 and November 2008 at UCLA and Kaiser Permanente (KP) (Northern and Southern California). All patients had resections to ensure that frozen tissue (>200mg) was collected. The median age was 57.4 years (range 31–75). MGMT methylation analysis has been performed on 52/70 patients with ∼40% showing methylation. Severe adverse events to date have included ischemic stroke, pulmonary embolus, wound breakdown, GI bleeding/perforation, and renal dysfunction. Isolated cases of retinal detachment and optic neuropathy have also been observed. As of now, 35/70 patients are off study (26 due to progression and 9 due to SAE). Preliminary TTP by Kaplan-Meier analysis is promising compared to that of a UCLA/KP control group of patients that received the conventional RT/TMZ regimen. Conclusions: Addition of BV to the standard regimen of TMZ and RT for newly-diagnosed GBM is well-tolerated and shows promising efficacy. More detailed analysis of safety and efficacy will presented.

[Table: see text]
NABTT 0306: A randomized phase II trial of EMD 121974 in conjunction with concomitant and adjuvant temozolomide with radiation therapy in patients with newly diagnosed glioblastoma multiforme (GBM)
Authors: Nabors L. B. , Mikkelsen T. , Batchelor T. , Lesser G. , Rosenfeld M. , Ye X. , Piantadosi S. , Olson J. , Brem S. , Grossman S.
Published: August 2020

2001

Background: EMD 121974 (cilengitide) is a selective integrin receptor inhibitor that is well tolerated and has demonstrated biological activity in patients with malignant glioma. The objectives of this phase II trial were to determine safety when combined with chemoradiation and estimate the overall survival for two different doses in newly diagnosed GBM. Methods: A total of 112 patients were accrued onto the trial through the NABTT CNS consortium. Cilengitide was administered by one-hour infusion twice a week with 18 patients treated in a safety run-in phase of 6 patients at the tested dose levels of 500 mg, 1000 mg, and 2000 mg. After safety completion, 94 patients were randomly assigned to either 500 mg or 2000 mg groups. To date, 55 out of 112 (49%) patients have died. Overall survival was estimated using all patients in this trial regardless of their treating dose. Results: The median age was 55 years old (range: 22–88) and the median KPS was 90 (range: 60–100). 86 out of the 112 (76.8%) had a craniotomy as their initial surgical procedure and 25 patients (22%) had a biopsy. There were no DLTs during the safety run-in phase. The estimated median survival time is 18.9 months (95% CI: 16.3 -30.0 months) for patients treated with RT+TMZ+EMD. The trial was closed to accrual on December 31, 2007. To date, 89 out of 112 patients were alive 12 months from their initial diagnosis. The overall survival at 12 months for all patients is 79.5% (95% CI: 71–87%). MGMT methylation status and survival based on dose levels received are not currently available. Conclusions: EMD 121974 (cilengitide) is well-tolerated when combined with standard chemoradiation (TMZ+RT) and may improve survival for patients newly diagnosed with GBM given the substantial differences between the estimated median survival and that seen in the EORTC study (Stupp, N Engl J Med, 2005).

[Table: see text]
NABTT-0702: A phase II study of R-(-)-gossypol (AT-101) in recurrent glioblastoma multiforme (GBM)
Authors: Fiveash J. B. , Chowdhary S. A. , Peereboom D. , Mikkelsen T. , Nabors L. B. , Lesser G. J. , Rosenfeld M. R. , Ye X. , Grossman S. A.
Published: August 2020

2010

Background: R-(-)-gossypol (AT-101) is an oral bcl-2 family protein inhibitor (Bcl-2, Bcl-XL, Mcl-1, Bcl-W) and potent inducer of proapoptotic proteins. A prior study of racemic gossypol demonstrated objective responses in patients with malignant glioma. The objectives of this trial were to determine the efficacy and safety of the more active (-) enantiomer of gossypol (AT-101) in patients with recurrent GBM. Methods: Fifty-six patients with recurrent GBM were enrolled in this multi-institution phase II clinical trial through the NABTT CNS consortium designed to detect a 33% increase in overall survival (OS, primary endpoint) from 5 to 6.65 months with Power/Alpha 80%/0.01. All patients had received prior radiation and none had received more than two prior treatments. Patients taking P450-inducing anticonvulsants were not eligible. AT-101 was administered at 20 mg PO per day for 21 of 28 days in repeated cycles. Radiographic assessment of tumor response was made at q 8-week intervals. Results: Fifty-six patients were enrolled with a median age of 59 (range 34–79) and KPS of 80 (range 60–100). Grade 3 or greater adverse events possibly or probably related to AT-101 included fatigue (n = 2), ileus (n = 1), elevated cardiac troponin T levels (n = 1), elevated GGT (n = 1), and thrombocytopenia (n = 1). Response data is available for 43 patients. OS determination is ongoing. Seven patients (16%) had stable disease as the best response. One partial response (centrally reviewed) was observed. No complete responses were observed. Although treatment is ongoing, two patients are without progression after more than 7 months of therapy. Conclusions: AT-101 is well tolerated and without unique toxicities in patients with recurrent GBM. Further follow-up will determine the impact of AT-101 on OS and whether any tissue correlate is predictive of efficacy.

No significant financial relationships to disclose.
Phase II study of bevacizumab and nitrosourea in patients with recurrent malignant glioma: A multicenter Italian study
Authors: Soffietti R. , Rudà R. , Trevisan E. , Picco E. , Guarneri D. , Caroli M. , Fabrini M. , Scotti V.
Published: August 2020

2012

Background: Bevacizumab (BV) has shown a promising activity in recurrent malignant gliomas (MG) in combination with irinotecan. Few data are available on the combination of bevacizumab and nitrosoureas, that represent the standard cytotoxic option at recurrence. Methods: In this ongoing phase II study patients with MG recurrent after surgery, radiation therapy, and temozolomide are eligible. The treatment consists of an induction phase with BV at 10 mg/kg intravenously on day 1 and 15 and fotemustine (FTM) (a nitrosourea with elevated lipophilic properties) at 75 mg/m2 intravenously on day 1 and 8, followed after a 3-week interval by a maintenance phase with BV at 10 mg/kg i.v. and FTM 75 mg/m2 i.v. every 3 weeks until tumor progression or unacceptable toxicity. Patients undergo clinical and MRI assessment 1 month after the start of treatment and thereafter every 2 months. Monitoring of CBV with perfusion MRI is performed in selected centers. The co-primary endpoints are objective response rate (ORR), based on Mc Donald's criteria (CR + PR) and progression-free survival at 6 months (PFS6), with secondary endpoints of safety time to tumor progression (TTP) and overall survival. Results: From April 2008 to December 2008, 34 patients were enrolled and 31 (22 glioblastomas and 9 anaplastic gliomas) are evaluable for response. Overall response rate (2 CR and 9 PR) was 35% (glioblastomas 33%, anaplastic gliomas 41.5%). Median time to maximal response was 1 month. Steroids were reduced in 50% of patients. Sixteen of 31 patients progressed with a TTP of 2.6 months (1–8.5). Patterns of progression were local in 10/16, local + leptomeningeal spread in 3/16 and gliomatosis in 3/16. Fifteen patients are free of tumor progression (from 2 to 8 months). Toxicities included grade III-IV neutropenia in three patients, grade III-IV piastrinopenia in five, and grade III thrombosis in two. Seventeen patients developed mild to moderate fatigue, six arterial hypertension, and three grade I intratumoral haemorrhage. Conclusions: Combination of bevacizumab and fotemustine in recurrent malignant gliomas is safe and promising. Updated results, monitoring of CBV with perfusion MRI, and correlations between MGMT promoter methylation and response/outcome will be presented.

No significant financial relationships to disclose.
Targeting brain tumor stem cells using a bispecific antibody directed against CD133+ and EGFRvIII+
Authors: Wong A. , Mitra S. , Gupta P.
Published: August 2020

2022

Background: Using the marker CD133, cancer stem cells (CSCs) have been demonstrated for glioblastomas (GBMs) and medulloblastomas. However, CD133 is also present on normal neural stem cells. EGFRvIII is a tumor specific EGF receptor. We hypothesized that a recombinant bispecific antibody directed against CD133 and EGFRvIII would be a highly specific reagent. Methods: Single chain antibodies (scFv) were cloned for anti-EGFRvIII and anti-CD133 using existing hybridomas and published sequences. scFv were cloned into a bicistronic vector containing a human CH3 constant domain. The bispecific antibody (BsAb) contains the anti-CD133 (AC133) and anti-EGFRvIII single chain Fv; monospecific but bivalent reagents for anti-CD133 and anti-EGFRvIII were also constructed. Results: U87 cells were co-transfected with increasing amounts of CD133 and decreasing amounts of EGFRvIII cDNAs. The BsAb showed the highest binding for cells expressing both epitopes, whereas Di-EGFRvIII and Di-AC133 had the highest affinity for cells expressing high levels of individual antigens. When cells expressing both antigens were mixed with cells expressing high levels of either antigen alone, the BsAb only recognized CD133+/EGFRvIII+ cells. We then explored the efficiency of tumor cell killing. Using human CD16-expressing NK cells as the effectors at an effector:target ratio of 10:1 and an 83 nM antibody concentration, the BsAb induced 86% lysis of U87-EGFRvIII/CD133 cells, 42.5% in U87-vIII but only 27.3% in U87-CD133 cells. Di-EGFRvIII efficiently induced cytotoxicity in U87-EGFRvIII/CD133 and U87vIII cells but not in U87-CD133 cells. Di-CD133 was the least effective at inducing ADCC. Finally, we studied the ability of the BsAb to induce ADCC on tumor spheres and normal neurospheres. The BsAb showed at least 4X greater lysis on tumor spheres that were CD133+/EGFRvIII+ over normal neurospheres expressing CD133 alone at an E:T of 10:1. This was seen at concentrations as low as 0.83 nM. Conclusions: A recombinant bispecific antibody directed against CD133 and EGFRvIII is highly specific for cells that are positive for both antigens, but poorly targets cells expressing CD133 alone. It can potentially be used as a therapeutic agent for specifically targeting CD133+/EGFRvIII+ cancer stem cells.

No significant financial relationships to disclose.
Angiotensin-(1–7), a small molecule inhibitor of glioblastoma growth
Authors: Lesser G. J. , Carver K. A. , Newton S. J. , Tallant E. A. , Gallagher P. E.
Published: August 2020

2024

Background: Recent studies suggest that anti-angiogenic therapies may be effective in patients with glioblastoma multiforme (GBM), a highly vascular tumor. We have previously demonstrated that angiotensin-(1–7) [Ang-(1–7)], an endogenous heptapeptide with anti-angiogenic properties, significantly reduced the serum-stimulated growth of three human glioblastoma cell lines which contained mRNA for the AT(1–7) receptor mas. We now provide the first evidence that Ang-(1–7) markedly decreases the proliferation and growth of human glioblastomas in vivo using a xenograft model. Methods: Athymic mice with tumors resulting from injection of human U87 glioblastoma cells were treated for 18 days with saline or 1000 μg/kg Ang-(1–7), delivered by subcutaneous injection every 12 h. Results: The average volume of the tumors from mice treated with the heptapeptide was approximately 3-fold less than the size of the tumors from control animals (586.1 ± 94.5 mm3 vs 1845.5 ± 238.1 mm3; n = 6, p < 0.05). Further, the tumors from mice injected with Ang-(1–7) weighed almost 50% less than the tumors from mice treated with saline (1.31 ± 0.12 g vs. 2.45 ± 0.23 g; n = 6, p < 0.05). The Ang-(1–7)-mediated reduction in tumor growth was associated with a significant decrease in immunoreactive Ki67, a proliferation marker. In addition, a marked down-regulation of cyclooxygenase 2 (COX-2), prostaglandin E synthase (PGES-1) and vascular endothelial growth factor (VEGF) was observed in tumors from Ang-(1–7)-injected mice compared to saline-treated controls (COX-2: 1.00 ± 0.06 vs 0.55 ± 0.07 relative gene expression; PGES-1: 1.03 ± 0.08 vs. 0.40 ± 0.06; VEGF: 1.05 ± 0.07 vs. 0.59 ± 0.09; n = 6, p < 0.05) with no effect on COX-1 or PGI synthase mRNA. Conclusions: These results suggest that Ang-(1–7) may reduce the concentration and ratio of proliferative and anti-proliferative prostaglandins to decrease glioblastoma growth as well as attenuate angiogenesis through a reduction in VEGF. Thus, Ang-(1–7) may be a new, first-in-class small molecule inhibitor for the treatment of glioblastoma, providing combination therapy as a selective COX-2/PGES-1 and angiogenic inhibitor, targeting a specific AT(1–7) receptor mas.

No significant financial relationships to disclose.
Post-therapeutic changes in the molecular profile of glioblastomas
Authors: Horbinski C. , Mintz A. , Engh J. , Lieberman F. , Hamilton R. L. , Park D. M.
Published: August 2020

2026

Background: Glioblastoma multiforme is the most common and malignant primary brain tumor in adults. Despite aggressive surgery, radiation, and chemotherapy, average survival time after diagnosis is about 1 year. This may be partly due to development of resistance to adjuvant therapies. While the molecular alterations in pretreated glioblastomas have been the subject of much research in recent years, changes in their genetic profile after adjuvant therapy are largely unknown. Methods: Herein we describe a cohort of over 40 glioblastomas with characterization of key genetic loci (EGFR, p53, 1p, 19q, 9p, 10q, 17p) using fluorescence in situ hybridization, PCR-based loss of heterozygosity (LOH) analysis, and immunohistochemistry on formalin-fixed, paraffin-embedded tissues. Analyses were performed on tumor tissue obtained at initial diagnosis and at first recurrence. Treatment regimen during the interval consisted of external beam radiation therapy and temozolomide, an alkylating chemotherapeutic agent. Results: About 50% showed large increases or decreases in hyperploidy of chromosomes 1, 7, 9, and/or 19 after therapy. Over 70% showed changes in LOH patterns on 1p, 19q, 9p, 10q, and/or 17p. 24% of previously non-EGFR-amplified tumors acquired low-grade amplification (less than 10 copies/chromosome 7 CEP signal) after treatment, and 16% of EGFR-amplified tumors lost amplification after treatment. Conclusions: Our results suggest that the molecular profile of these tumors is dynamic and that certain key alterations, including acquisition of low-level EGFR amplification in previously EGFR-negative tumors, occurs in a subset of cases. Such alterations may contribute to therapy resistance as the glioma evolves in a changing microenvironment.

No significant financial relationships to disclose.
Change in MGMT methylation status between first and second surgery for recurrence: Clinical implications
Authors: Brandes A. A. , Franceschi E. , Tosoni A. , Fioravanti A. , Agati R. , Andreoli A. , Mazzocchi V. , Morandi L. , Bartolini S. , Ermani M.
Published: August 2020

2027

Background: MGMT promoter methylation status is known to be a potent prognostic factor in newly diagnosed glioblastoma (GBM) patients (pts). However, it is not yet clear whether and, if so, how MGMT methylation status may change; nor is it known whether the prognostic role of this epigenetic feature is retained during the disease course. Methods: A retrospective analysis was made using a database of 614 GBM pts treated prospectively from January 2000 to August 2008. We evaluated only patients who met the following inclusion criteria: age ≥18; PS 0–2; two distinct surgical procedures; histological diagnosis of GBM both at first and at second surgery for recurrence; postoperative treatment consisting of: a) radiotherapy (RT) followed by temozolomide (TMZ) until 2005, and b) TMZ concurrent with and adjuvant to RT after 2005; a time interval ≥3 month between first and second surgery. The study aim was to evaluate changes of MGMT status during the course of GBM. The log-rank test was employed to evaluate the significance of the prognostic variables. The percentages of MGMT methylated cases at first and second surgery were compared using the McNemar test. Results: MGMT status, evaluated at first and second surgery in all 44 pts (M:F 32:12, median age: 49 years, range: 27–67), was assessable in 38 (86.4%) cases: MGMT promoter was methylated in 13 (34.2%) pts at first surgery. MGMT methylation status, unchanged in 63.2% of second surgery samples, changed more frequently in methylated than in unmethylated pts (61.5% vs 24%, p = 0.03). The median survival was 24.3 months (95% CI: 20.8–27.7), being 35.2 months (95% CI: 10.1–60.2) and 21.9 months (95% CI: 17.3–26.5) for pts with methylated and unmethylated MGMT assessed at first surgery, respectively (p = 0.04). However, MGMT status at second surgery was no longer prognostic for survival (p = 0.1). Conclusions: Significant changes in MGMT methylation status during the course of GBM occur more frequently in MGMT methylated than unmethylated cases. Moreover, while MGMT methylation status is prognostic at first surgery, it appears to be of no prognostic utility at the time of second surgery.

No significant financial relationships to disclose.
A phase I evaluation of intravenous TM601 in recurrent glioblastoma: Use of perfusion MRI to monitor antiangiogenic effects
Authors: Akella N. S. , Nabors L. B. , Rosenfeld S. S. , Chamberlain M. C. , Mrugala M. M. , Jacoby D. B. , O'Neill A. M.
Published: August 2020

2041

Background: TM601, a synthetic chlorotoxin, is a peptide derived from scorpion venom. In vitro data demonstrate binding to vascular endothelial cells, and blockage of endothelial cell invasion. In vivo, intravenous infusion of TM601 decreases neovascularization. Based on this work and previous clinical trials demonstrating tumor-specific uptake of 131I-TM601 in malignant glioma after IV delivery, a phase I trial was initiated with intravenous unlabeled TM-601. Methods: Six patients with recurrent glioblastoma have been enrolled. All patients received a test dose of 10 mCi 131I-TM601 to demonstrate tumor-specific uptake prior to TM601 treatment at doses of 0.04 mg/kg IV weekly for 3 weeks in a 4 week cycle. Treatment continued until tumor progression. Patients were evaluated at week 4 of each cycle with conventional and dynamic susceptibility contrast MRI (DSC-MRI) to assess perfusion. Anatomic and perfusion MRI evaluations were performed at baseline, 1 day after the initiation of TM601 therapy, and 21 days after initiation of each treatment cycle. MRI data were post-processed to yield an arterial input function and parametric hemodynamic maps. Results: With respect to safety, there has been one intratumoral hemorrhage that was considered to be possibly related to therapy. Three other serious adverse events considered to be unrelated to therapy included disease progression on therapy, a hip fracture and renal calculi in a patient with a history of renal calculi. Two of six patients in the first dosing cohort have demonstrated a greater than 25% reduction in relative cerebral blood flow (rCBF) and/or relative cerebral blood volume (rCBV) compared to baseline. Both patients with improvement in perfusion MRI had extended response to intravenous TM601. Conclusions: Intravenous unlabeled TM601 at the initial dose schedule produces measurable changes in perfusion MRI parameters which correlate with clinical response. Perfusion MRI parameters appear to correlate with clinical response to TM601 and are consistent with angiogenic inhibition.

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Treatment of recurrent malignant glioma with G207, a genetically engineered herpes simplex virus-1, followed by irradiation: Phase I study results
Authors: Karrasch M. , Gillespie G. Y. , Braz E. , Liechty P. G. , Nabors L. B. , Lakeman A. D. , Palmer C. A. , Parker J. N. , Whitley R. J. , Markert J. M.
Published: August 2020

2042

Background: G207 is a doubly mutated (deletion of both γ134.5 loci, insertional inactivation of UL39) herpes simplex virus (HSV)-1. Safety and efficacy of intracerebral inoculations of G207 to patients suffering from recurrent malignant gliomas have been demonstrated in previous clinical trials. Methods: In this phase I clinical trial, a total of 1 x 109 plaque forming units (pfu) G207 were administered by five stereotactic injections of 0.2 mL each into regions of recurrent malignant glioma defined by MRI, followed by focal radiation therapy 24 hours post injection. Included patients suffered from inoperable pathologically proven recurrent glioblastoma multiforme (GBM) or anaplastic astrocytoma (AA) which was progressive despite radiotherapy or chemotherapy and failed external beam radiotherapy > 5 Gray prior to study enrolment. Results: 9 patients were treated in this phase I study. 5 patients were suffering from relapsed GBM, 4 patients were suffering from relapsed AA. 1 month after treatment, 3 patients (3xGBM) showed SD, 2 patients (1xGBM, 1xAA) PR, and 4 patients (1xGBM, 3xAA) PD. The 2 patients with initial PR (1xGBM, 1xAA) were re-treated with G207/Irradiation at time point of tumor recurrence, showing PR one month after re-treatment again. Median overall survival time for all 9 patients was 229 days (7.6 months), with one patient still alive at time of abstract submission. In patients suffering from relapsed GBM, mOS was 7.4 months, in patients suffering from relapsed AA, mOS was 9.25 months. 20 serious adverse events occurred in this study, only 3 were possible/probable related to G207/irradiation. Within persistent areas of tumor, HSV staining was present by using a polyclonal antibody for HSV, indicating intratumoral G207 replication (proof of concept). Conclusions: In 9 patients suffering from relapsed GBM or AA, stereotactic intracerebral G207 inoculation followed by radiation therapy was feasible, safe, and induced clinically relevant responses. G207/Irradiation re-treatment was possible and induced anew clinical responses. Median overall survival is superior to published data in this patient population. Therefore, further clinical development of G207 in GBM is medically reasonable.

[Table: see text]