bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical factors affecting HE4 and CA125 in women at high risk of developing ovarian cancer.
Authors: Raamanathan Archana , Holman Laura L. , Urbauer Diana L , Baggerly Keith A. , Shen Yu , Bast Robert C. , Lu Karen H.
Published: March 2020

1569

Background: CA125 is often used to screen high-risk patients (pts) for ovarian cancer (OC), but levels are affected by many factors, especially in premenopausal pts. In prior studies of low-risk pts, HE4 is more stable than CA125. The objective of this study was to determine how clinical variables affect CA125 and HE4 in pts at high risk for ovarian cancer. Methods: Serum from 373 pts at high risk of OC was collected every 3-12 mo from 2006-2012, for a total of 1081 samples. Serum CA125 and HE4 were measured in duplicate utilizing a commercially available multiplexed sandwich immunoassay (MagPlex). Multilevel regression models were used to examine the associations of clinical factors with CA125 and HE4, while considering the inter-correlated nature of outcomes measured periodically from the same subject. Results: The mean age was 44.6 years, 51.2% were premenopausal, 72.7% were white, 9.1% were Ashkenazi Jewish, 65.2% had a history of breast cancer, and 81.5% had a BRCA mutation. Log transformed CA125 was found to be 0.32 units higher in premenopausal pts compared to postmenopausal pts (p=0.0023), and 0.27 units higher in pts with active breast cancer (BC) compared to pts with no active BC (p=0.0044). In premenopausal pts, CA125 varied throughout the menstrual cycle, with highest levels noted at menstruation (p<0.0001). Age, smoking status, and hormone use did not affect CA125 levels. Interestingly, there was no significant association between HE4 levels and any of the evaluated variables, including age, menopausal status, active BC, smoking status, hormone use, or point in menstrual cycle (all p>0.05). Conclusions: In women at high-risk for OC, HE4 levels fluctuate less with the menstrual cycle and are less likely to be elevated in BC than CA125. This finding is important as many high-risk pts that undergo screening are pre-menopausal and have a BC history. HE4 may provide a valuable addition to the current screening regimen of high-risk pts.
Adiposity post prophylactic oophorectomy in young women at high risk for breast and ovarian cancer.
Authors: Visvanathan Kala , Huynh Minh-Huy , Al-Lozi Rawan , Oidtman Jessica , May Betty J , Ouyang Pamela
Published: March 2020

1572

Background: Bilateral prophylactic salpingo-oophorectomy (BPSO) is the current standard of care for BRCA1/2 mutation carriers and women with a strong family history of ovarian cancer. We have previously demonstrated an association between early oophorectomy, adiposity and mortality in the general population. Methods: A cross sectional study was conducted between November 2009 and January 2013 in 87 women with a family history of breast and ovarian cancer and/or BRCA1/2 mutation to identify the effect of early BPSO on multiple health outcomes. Twenty-two women who underwent BPSO within 1 to 5 years of enrollment while premenopausal and not on hormone therapy were compared to 44 premenopausal women with intact ovaries and the same age distribution and 21 postmenopausal women with intact ovaries and not on hormone therapy. Multiple anthropometric measures were taken and % body fat assessed by DEXA scan. Linear regression was used to estimate differences in these measures between the three groups. Results: The mean ages were 47, 47, and 54 years in the BPSO, premenopausal and postmenopausal groups respectively. Parity, alcohol intake, smoking and race did not significantly differ between groups. Fewer BPSO women had ever used oral contraceptives (OCP) compared to the premenopausal group (p =0.05). The BPSO group had lower mean physical activity (p = 0.05) compared to the two other groups. BMI was increased in the BPSO group but was not statistically different across groups. However, mean waist and abdominal circumference and trunk % body fat were significantly higher among women who underwent BPSO compared to both groups. In multivariate analyses adjusting for age, physical activity, and OCP use, the average waist circumference was 7.92 cm (95% CI 1.46, 14.37) higher and 8.98 cm (95% CI 0.40, 17.46) higher in the BPSO group compared to the postmenopausal and premenopausal groups, respectively. A similar pattern was seen for abdominal circumference. Association with % body fat were not statistically significant. Conclusions: This pilot study suggests that increased central adiposity, is a sequelae of BPSO in young women. Longitudinal studies are needed to confirm results and evaluate the efficacy of interventions.
The impact of family information services on genetic testing uptake among relatives in Lynch syndrome families.
Authors: Lynch Henry T. , Buxbaum Sarah G. , Snyder Carrie L. , Stacey Mark , Shaw Trudy G. , Lynch Patrick M.
Published: March 2020

1573

Background: A mismatch repair (MMR) pathogenic mutation in an index patient provides a basis for predictive mutation testing in at-risk members of Lynch syndrome (LS) families. Mutation carriers warrant aggressive surveillance. As importantly, non-carriers can safely follow general population screening guidelines. However, penetration of predictive testing has been disappointing in first-degree relatives (FDR), and has been even more limited in second- and more distant-degree relatives, even though the benefits can be as great as in FDRs. Family Information Services (FISs), involve an in-person session in which expert providers and counselors meet with multiple family members in a convenient geographical location. Education and counseling are intended to lead to testing for the family MMR mutation, followed by appropriate surveillance. Methods: LS families with a known MMR mutation (n=97) were targeted for this study. Selection for FIS was based on family size and convenient geographic location. Twenty-eight were offered an FIS and 69 received standard care (mailed educational material and invitation for testing). Data were collected on testing rates. Results: In at-risk patients that did receive FIS, 20.4% (std dev = 11.4%, 95% CI: 16.0 to 24.8%, range: 3 to 57.5%) were DNA tested, whereas in families that did not receive FIS, 12.9% (std dev = 10.8%, 95% CI: 10.2 to 15.5%, range: 0 to 43.5%) were DNA tested. The difference in proportions tested between the FIS and non-FIS families was statistically significant (p=0.003) and was more pronounced in family members whose relationship to the proband was beyond first-degree (p<0.0001). Of those individuals that attended an FIS, 81.1% were tested. Conclusions: Genetic counseling in the FIS setting facilitates uptake of predictive mutational testing in FDRs and in more distant at-risk relatives. However, the FIS is time-consuming and labor intensive; more efficient means of disseminating LS risk information and the benefits of predictive testing in more distant relatives are needed. A cost-effectiveness analysis as well as a randomized study that controls for participation bias must be done.
HIV-associated high-risk HPV infection in Nigerian women.
Authors: Akarolo-Anthony Sally Nneoma , Ogbonna Celestine C. , Famooto Oluranti Ayotunde , Dareng Eileen O. , Al-Mujtaba Maryam , Odonye George , Olaniyan Olayinka , Offiong Richard , Lawal Ishak , Wheeler Cosette , Adebamowo Clement Adebayo
Published: March 2020

1576

Background: The incidence of cervical cancer has remained stable in HIV+ women but the prevalence and multiplicity of high risk HPV (hrHPV) infection, a necessary cause of cervical cancer, appears different comparing HIV+ to HIV- women. Because this has not been well studied in Africa, we conducted this study to identify single and multiple hrHPV infection among HIV+ and HIV- women in Nigeria. Methods: We enrolled HIV+ and HIV- women presenting at our cervical cancer screening program in Abuja, Nigeria between April 2012 and August 2012. Using a nurse administered questionnaire, we collected information on demographic characteristics, risk factors of HPV infection and cervical exfoliated cells samples from all participants. We used Roche Linear Array HPV Genotyping Test to characterize the prevalent HPV according to manufacturer’s instruction and logistic regression models to estimate the association between HIV infection and the risk of high-risk HPV infection. Results: There were 278 participants, 40% (111) of whom were HIV negative, 54% (151) HIV positive and 6% (16) with HIV status unknown. Of these, 108 HIV+ women cases and 149 HIV- women controls were available for analysis. The mean ages (±SD) were 37.6 (±7.7) for HIV+ and 36.6 (±7.9) years for HIV- women (p-value = 0.34). Cases and controls had similar socio-demographic characteristics. Among HIV+ women, HPV35 (8.7%) and HPV56 (7.4%) were the most prevalent hrHPV, while HPV52 and HPV68 (2.8%, each) were the most prevalent among HIV- women. The age adjusted RR for prevalent hrHPV was 4.18 (95% CI 2.05 – 8.49, p-value <0.0001), comparing HIV+ to HIV- women. The multivariate RR for any HPV and multiple hrHPV was 3.75 (95% CI 2.08 – 6.73, p-value 0.01) and 6.6 (95% CI 1.49 – 29.64, p-value 0.01) respectively, comparing HIV+ to HIV- women, adjusted for age, and educational level. Conclusions: HIV infection was associated with increased risk of any HPV, hrHPV and multiple HPV infections. Oncogenic HPV types 35, 52, 56 and 68 may be more important risk factors for cervical pre-cancer and cancer among women in Africa. Polyvalent hrHPV vaccines meant for African populations should protect against HPV types other than 16 and 18.
U.S. Preventive Services Task Force (USPSTF) recommendations on breast cancer screening (BCS): Are they justified?
Authors: Pai Lori H. , Strauss Gary M.
Published: March 2020

1584

Background: Nine randomized population trials (RPTs) on BCS with mammography have been reported. Conclusions based upon mortality (MOR) comparisons in RPTs have long led to uncertainty about whether BCS saves lives, especially in women in their 40s. In Nov 2009, USPSTF recommended against BCS in women 40-49 and biennial BCS for women >50. By 2010, BCS fell by >4% in US. Does the evidence support USPSTF recommendations? Methods: MOR quantifies the effect of intervention across an entire population. However, the key issue is whether BCS reduces MOR among those with disease. This is reflected by survival (SUR), not MOR. While SUR is considered flawed due to conventional screening biases, the confounding influence of these biases is misunderstood. In a RPT, randomization provides an opportunity to eliminate these biases, so that (SUR) may accurately reflect screening efficacy. MOR would be biased if randomization fails to produce populations at equal risk for the target disease. Results: Among 9 RPTs, significant MOR reductions were reported only in Swedish Two-County Study in women >50 and in the Gothenburg Study in women 39-49. However, problems with randomization were responsible for MOR overestimating BCS efficacy in these trials. In 7 RPTs, significant MOR reductions were not seen. However, MOR underestimated BCS efficacy in several RPTs. The Canadian National BCS Study, the most influential RPT in women <50 yrs, showed a trend toward increased BC MOR in the screened group. However, randomization failure was likely responsible for significantly more high risk BC in the screening group, which confounded MOR comparisons. Conclusions: It’s never been possible to justify BCS based on MOR comparisons in RPTs. While meta-analyses have been widely utilized, they can be biased when MOR fails to accurately reflect BCS in individual RPTs. Abundant evidence from RPTs supports that BCS leads to significant stage and SUR advantages not attributable to conventional biases, and which more accurately reflect BCS efficacy. The magnitude of benefit is similar for women in their 40s and for those >50. USPSTF recommendations are not supported by the data. If fully implemented, these guidelines can lead to increased BC MOR in US.
Androgen deprivation therapy and survival in patients with lung cancer.
Authors: Harlos Craig Henry , Pitz Marshall W. , Musto Grace
Published: March 2020

1597

Background: The epidemiology of lung cancer differs between men and women. There exists significant evidence suggesting estrogens influence the pathophysiology of lung cancer, however the role of androgens remains unclear. This study was performed to determine if exposure to androgen deprivation therapy (ADT) has an effect on survival in male patients (pts) diagnosed with lung cancer. Methods: Using the population-based Manitoba Cancer Registry and Manitoba Health Administrative Databases, all pts diagnosed with lung cancer from January 1, 2004 to December 31, 2010 were identified. Information from the Drug Program Information Network (DPIN) and the Aria electronic record at CancerCare Manitoba were used to determine prescriptions filled for anti-androgens, 5-alpha reductase inhibitors and GnRH agonists as a measure of exposure (defined as having filled at least 2 prescriptions and/or bilateral orchiectomy). Multivariable analysis with Cox proportional hazards analysis was used to compare survival. Results: A total of 3018 men with lung cancer were identified between 2004 and 2010. Of these, 339 (10%) were identified as having used a form of ADT. The majority of pts received 5-alpha reductase inhibitors (85%), the most common being finasteride (80% of total). Multivariable analysis revealed that patients who received ADT prior to the diagnosis of lung cancer had no statistically significant difference in survival (HR: 0.97 p=0.69) compared to those who did not. Patients exposed to ADT after their diagnosis were found to have a significantly better survival than those not exposed (HR 0.36 p=0.0007). This effect was also seen in those who received ADT before and after diagnosis (HR 0.53 p<0.0001). Conclusions: In male pts diagnosed with lung cancer, exposure to ADT is associated with significantly better survival when compared with no exposure. This effect is only seen when some or all of the exposure has occurred after the diagnosis of lung cancer. This study supports the hypothesis that the androgen pathway plays a role in lung cancer pathophysiology, and that androgen deprivation may improve prognosis
NCCTG (Alliance) N0572: A phase II trial of sorafenib and temsirolimus in recurrent glioblastoma (GBM) patients who progress following prior RT/temozolomide (TMZ) and VEGF inhibitors (VEGFi).
Authors: Jaeckle Kurt A. , Schiff David , Anderson S. Keith , Galanis Evanthia , Stella Philip J. , Flynn Patrick J. , Sarkaria Jann Nagina , Giannini Caterina , Erickson Bradley J. , Buckner Jan C
Published: March 2020

2014

Background: PFS6 is low (2.3%) and med OS brief (4 mos) for recurrent GBM pts who progress after prior RT/TMZ and bevacizumab (Bev), and then receive non-Bev containing regimens (Reardon et al, Br J Canc 2012). Following VEGFi exposure, tumor cell resistance potentially may result from activation of Ras/Raf/MEK/ERK (MAPK) and PI3K/Akt/mTOR signaling pathways. Temsirolimus (mTOR inhibitor) and sorafenib (Raf, PDGFR, VEGFR inhibitor) have previously shown limited single agent activity in GBM. Methods: Recurrent GBM pts who showed radiographic progression despite prior surgery, RT + temozolomide, and VEGFi (initially or at recurrence) received sorafenib 200 mg PO bid and temsirolimus 20 mg IV weekly (the NCCTG N0572 phase I MTD) until progression. All pts had received < 2 prior chemo regimens. A two-stage design was used, with 90% power to detect an increase in PFS6 from 8% to 23%, requiring 41 evaluable pts. The primary endpoint was PFS6; secondary endpoints included OS, TTP, and ORR. Toxicity (TOX) was assessed using CTC ver 3.0. Results: 44 evaluable pts were accrued. Four of the first 40 (10%) reached PFS6, but this did not meet the pre-study threshold for success. Median TTP was 1.8 mos. (40 events, 95% CI: 1.5 – 2.3); median OS was 5 mos. (36 events, 95% CI: 6.6 – 3.1), and no objective responses were reported. Eight pts are alive; 4 have not progressed (median F/U 3.1 mos.; max, 12.2 mos.). Grade 3+ non-heme AE were observed in 51% (23/45; fatigue-5, hypophosphatemia-7, hypercholesterolemia-5, hypertriglyceridemia-5). One grade 4 hematologic AE (thrombocytopenia) occurred. 13.3% (6/45 pts) went off due to TOX, and 71.1% (32/45) due to disease progression. Conclusions: Sorafenib plus temsirolimus was tolerable, but the primary endpoint threshold for success (PFS6) was not met in post-VEGFi recurrent GBM patients. Nevertheless, PFS6 (10%) and OS (5 mos.) compared favorably to contemporary series of Bev-refractory, recurrent GBM pts who are subsequently treated with a non-Bev containing regimen. Supported by NCI CA-25224. Clinical trial information: NCT00329719.
Integrated data review of the first-in-human dose (FHD) study evaluating safety, pharmacokinetics (PK), and pharmacodynamics (PD) of the oral transforming growth factor-beta (TGF-ß) receptor I kinase inhibitor, LY2157299 monohydrate (LY).
Authors: Rodon Jordi , Carducci Michael Anthony , Sepúlveda Juan Manuel , Azaro Analia , Calvo Emiliano , Seoane Joan , Brana Irene , Sicart Elisabet , Gueorguieva Ivelina , Cleverly Ann , Pillay Sada , Desaiah Durisala , Lahn Michael M. F. , Paz-Ares Luis , Holdhoff Matthias , Blakeley Jaishri O'Neill , Baselga José
Published: March 2020

2016

Background: Activated TGF-ß signaling has been associated with poor survival in several tumors, including glioma (GM). Hence, we investigated the safety, PK and antitumor responses of the novel TGF-ß inhibitor LY in cancer patients, mainly in GM. Methods: There were 3 study parts: Part A: dose escalation of LY monotherapy in patients with solid tumor (cohorts 1 and 2, continuous dosing) and with GM (cohorts 3 to 5, intermittent dosing 14 days on/14 days off); Part B: intermittent LY dosing in combination with lomustine; Part C: monotherapy of 300 mg/day in solid tumors after completing a relative bioavailability study. Safety, antitumor activity, PK and PD were assessed as previously described (Calvo-Aller, et al. JCO 2008;26:abstract #14554; Rodon, et al. JCO 2011;29:abstract #3011; Azaro, et al. JCO 2012;30:abstract #2042). Results: 79 patients participated in this study (Part A, n = 39, 7 solid tumor, 32 GM; Part B, n = 26, all GM; Part C, n = 14 solid tumor, 9 GM, 2 hepatic cell carcinoma [HCC], 2 gastrointestinal [GI] and 1 melanoma). The integrated safety and efficacy evaluation confirms that LY has a manageable toxicity profile with antitumor activity. For GM patients the median progression-free survival (PFS) in months (range) was: 2.5 (0.0 to 36.9) in Part A; 2.5 (0.0 to 20.5) in Part B; 1.9 (0.0 to 6.4) in Part C. PFS duration in months were (range): 2.1-3.8 for HCC; 1.2-3.9 for GI and 2.2 for melanoma patient. Responders were observed in primary GM (Part A: 3/16; Part B: 2/20) and secondary GM (Part A: 3/14; Part B: 4/6). As of January 2013, 3 GM patients are still on treatment for 54, 36, and 31 months. P450-inducing medications including proton pump inhibitors or enzyme-inducing anti-epileptic drugs did not influence the PK parameters. Approximately, 90 biomarkers have been assayed and the results will be presented during the meeting. Conclusions: Because of the manageable toxicity profile of LY, the 300 mg/day dose administered as an intermittent dosing has been advanced into phase II investigation, either as a monotherapy or in combination with approved chemotherapies. Clinical trial information: NCT01682187.
BTTC08-01: A phase II study of bevacizumab and erlotinib after radiation therapy and temozolomide in patients with newly diagnosed glioblastoma (GBM) without MGMT promoter methylation.
Authors: Raizer Jeffrey J. , Giglio Pierre , Hu Jethro Lisien , Groves Morris D. , Merrell Ryan , Conrad Charles A. , Phuphanich Surasak , Puduvalli Vinay K. , Loghin Monica Elena , Paleologos Nina , Yung W. K. Alfred , Vaillant Brian D. , Rudnick Jeremy David , Chamberlain Marc C. , Vick Nicholas , Grimm Sean Aaron , Tremont-Lukats Ivo , De Groot John Frederick , Aldape Kenneth D. , Gilbert Mark R.
Published: March 2020

2019^

Background: Patients (pts) with GBM with unmethylated MGMT have a worse prognosis than those with methylated MGMT. Novel approaches for this poor risk group are warranted. The Brain Tumor Trials Collaborative (BTTC) performed a phase II trial evaluating standard chemoradiation followed by bevacizumab and erlotinib in patients with MGMT unmethylated GBM. EGFR and VEGFR are upregulated during radiation suggesting that this combination could be more effective than post-radiation adjuvant temozolomide (TMZ). Methods: After informed consent, adult patients with supratentorial GBM, KPS ≥ 70 and > 1 cm2 tumor block for MGMT promoter analysis were screened. Only tumors with confirmed unmethylated MGMT promoter were enrolled. All patients received RT + TMZ and then approximately 4 weeks after RT they received bevacizumab 10 mg/kg every 2 weeks and erlotinib 150 mg/day, continuously. One cycle was 4 weeks; evaluation by MRI was every 2 cycles. Treatment continued until disease progression or intolerable adverse events. Results: 115 patients were screened; 48 were enrolled (2 unevaluable: 1 for an infratentoral GBM and 1 withdrew after 7 days of treatment) with 29 men, 17 women. Median age was 56 yrs (29-75); median KPS was 90 (70-90). The median number of cycles was 8 (2-38) with 4 patients remaining on trial at the time of analysis. Objective responses: 4 CR, 12 PR and 30 SD. Median PFS is 7.3 months (95% CI (6.4, 11)) and median OS 14.2 months (95% CI (10.7, not reached)). There were no unexpected toxicities; grade 3/4 rate < 5%. Conclusions: Adjuvant bevacizumab and erlotinib in GBM with unmethylated MGMT is well tolerated. Preliminary efficacy data is comparable with outcomes in similar unmethylated MGMT patient populations from the EORTC/NCIC and RTOG 0525 studies. Tissue correlation is being performed. Clinical trial information: NCT00720356.
Use of DNA copy number analysis of grade 2-4 gliomas to reveal differences in molecular ontogeny associated with IDH mutation status.
Authors: Sato Mariko , Aldape Kenneth D. , Mason Clinton C , Diefes Kristin , Heathcock Lindsey , Abegglen Lisa , Schiffman Joshua David , Colman Howard
Published: March 2020

2026

Background: The genetic alterations of glioma have been studied extensively. IDH1 mutation is associated with younger age and better survival. However, differences in molecular ontogeny within glioma related to IDH1 mutation remain unknown. Here we describe a detailed analysis of copy number alterations (CNA) between IDH1mut vs IDH1wt gliomas of grade 2-3 and 4. Methods: CNA were detected by molecular inversion probes (Affymetrix) and analyzed with Nexus Copy Number Software (BioDiscovery). DNA was extracted from 94 patient FFPE samples including grade 2-3: IDH1wt (n = 17) and IDH1mut (n = 28), and grade IV: IDH1wt ( n = 25) and IDH1mut(n = 24). Chromothripsis was detected using a stringent criteria of at least ten switches of CNA in individual chromosomes. Results: We validated prior findings that IDH1wt GBM have higher frequency of Chr7 amplification (including EGFR) and loss of Chr10 (including PTEN). Other CNA across all grades were: gain of 19q12 and loss of 14q11 in IDH1wt, and gain of 11q21, 10p11, 8q21 and loss of 11p15, 19q13 in IDH1mut. Within grade 2-3 samples, few CNA were associated with mutation status: 2-3wt demonstrated higher frequencies of gain of 7q and loss of 10q, 14q11, and 22q13, while 2-3mut demonstrated higher frequencies of 11q21 gain and 19q13 loss. Grade 4 tumors demonstrated more CNA that differed by mutation status, with 4wt tumors demonstrating gain of 7 and loss of 10 and 14q11, while 4mut demonstrated gains of 8q, 10p, 12p13, 1q23, and loss of 11p15, 3p, 19q13, among others. Comparison of grade 2-3mut vs grade 4mut tumors demonstrated larger number of CNA in the grade 4mut tumors including gain of 1p, 14q, 13q33, 9p, 8q and loss of 22q, 11p15, 10q, and 3p, among others. A significantly higher incidence of chromothripsis events was observed in grade 4mut compared to grade 4wt (p = 0.0374). Conclusions: CNA analysis showed significant differences in molecular ontogeny between IDH1wt and IDH1mut, some of which may further elucidate pathogenesis. Significant CNA increases and increased chromthripsis in grade 4mut support malignant transformation of low grade gliomas through accumulation of genomic instability and genomic catastrophe.
Prognostic utility of neuraxis imaging in leptomeningeal metastasis (LM): A retrospective case series.
Authors: Chamberlain Marc C.
Published: March 2020

2037

Background: Correlate imaging of the central nervous system that includes both brain and spine MRI and radio-isotope cerebrospinal fluid [CSF] flow studies with survival in a retrospective case series of patients with LM. Methods: 240 adult patients with LM (125 non-brain solid tumor patients with positive CSF cytology; 40 non-brain solid tumor patients with negative CSF cytology and MRI consistent with LM; 50 lymphoma and 25 leukemia patients with positive CSF flow cytometry), all considered appropriate for LM-directed treatment, underwent prior to treatment brain and entire spine MRI and radio-isotope CSF flow studies. Results: Median overall survival was significantly shortened in patients with large volume MRI defined disease (defined as measurable tumor > 5 x 10 mm in orthogonal diameters) and in patients with non-corrected CSF flow obstruction irrespective of primary tumor histology. Additionally, cause of death differed wherein patients with large volume of disease or uncorrected obstructed CSF flow more often died of progressive LM disease whereas patients with normal or small volume disease and patients with normal or re-established CSF flow more often died of progressive systemic disease. Conclusions: Neuraxis imaging utilizing brain and spine MRI as well as radio-isotope CSF flow studies appears to have prognostic significance and may be predictive of median overall survival in this large cohort of patients with LM all of whom were considered for treatment with LM.
Factor Xa: PAR-1 growth loop is blocked by low-molecular weight heparins—A new perioperative and adjuvant concept in glioblastoma.
Authors: Kuhn Susanne Antje , Kratzsch Tobias , Gruenwald Viktor , Haberl Hannes
Published: March 2020

2038

Background: Glioblastoma patients suffer from thromboembolism, aggravating the disease. Recently, increased activity was shown for coagulation factors II, VIII, IX, X, XI, and XII in patient peripheral blood. In vitro, the high potential of FXa-PAR1-loop as growth factor system and significant effects of its blockade were proven. Methods: Patient samples (n=108) were analyzed for FXa and PAR-1. In immunodeficient mice, glioblastoma xenografts were established and treated with low-molecular weight heparins (LMWH) (30mg/kg SC daily for 3 wks). Phosphate buffered saline served as control. Tumor growth rates, final tumor size, tumor proliferation (Ki67), and tumor vascularization (CD31) were determined. Results: Human glioblastomas overexpressed FXa and PAR-1 in the compact tumor center (FXa: p<.001; PAR-1: p<.001) and in the invasion zone (FXa: p=.006; PAR-1: p=.005). Neoangiogenic endothelial cells disproportionately high expressed FXa and PAR-1 with rising intensity in the invasion zone (FXa: p<.001; PAR-1: p<.001), and the compact tumor mass. (FXa: p<.001; PAR-1: p<.001). Growth curves of LMWH-treated tumors slowed (p<.001). Final tumor size was reduced (s.c.: p<.001; i.c.: p<.05). Tumor cell proliferation was massively inhibited in situ (tinzaparin: p<.001; enoxaparin: p<.001) as was the number of CD31 positive endothelial cells ((tinzaparin: p<.001; enoxaparin: p<.001) and the tumor vascularization (p<.001 each). Conclusions: Glioblastoma patients display abnorm activation of coagulation factors in peripheral blood and show high levels of FXa and PAR-1 in the tumor center, invasion zone and angiogenic endothelia. LMWH caused tumor growth retardation and size reduction with blockade of proliferation and vascularization. FXa inhibition should be considered as continuous thrombosis prophylaxis and adjuvant glioblastoma treatment.
Characterization of candidate tissue and blood biomarkers in a rare cohort of myxopapillary ependymoma patients.
Authors: Ilhan-Mutlu Aysegul , Berghoff Anna Sophie , Wrba Friedrich , Marosi Christine , Wagner Ludwig , Zielinski Christoph , Preusser Matthias
Published: March 2020

2040

Background: Myxopapillary ependymoma (MPE) is a very rare tumor of the distal spinal cord. Despite benign histopathology, local recurrences occur in approximately 30% of patients and distant metastases have been described in few cases. We investigated candidate tissue and blood biomarkers in a rare MPE series. Methods: Formalin fixed paraffin embedded (FFPE) tumour tissues from 21 MPE patients were immunohistochemically investigated for expression of isocitrate dehydrogenase 1 R132H (IDH-R132H), Secretagogin, glial fibrillary acidic protein (GFAP), epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), progesterone receptor (PR), estrogen receptor (ER), Ki-67, arg, plateled derived growth factor a (PDGFRa) and b (PDGFRb), pc-kit and pc-abl. EGFR gene was evaluated using exon-sequencing. In addition, we analyzed circulating plasma-GFAP using ELISA in 3 patients with completely resected MPE, 1 patient with locally advanced MPE, 2 patients with pleuropulmonary metastases of MPE and 12 control subjects. Results: Secretagogin and GFAP were expressed in all tissue samples. arg, PDGFRa, PDGFRb, pc-kit and pc-abl were positive in 15, 1, 2, 3 and 2 patients, respectively. The Ki-67 index ranged from 1% to 12.8% (median=7.1%). We detected no expression of EGFR, IDH-R132H, HER2, PR or ER. One patient showed a silent mutation in exon 21 of the EGFR gene (c.2508C>T). We found very high concentrations of plasma-GFAP in two MPE patients with pleuropulmonary metastases, while all other MPE patients were negative. Conclusions: Our data indicate that (i) targeted tyrosine kinase inhibitors may be rational for the therapy of selected MPE patients and that (ii) circulating GFAP could be useful as circulating marker for the early detection or follow-up of distant metastases in MPE patients.
Biomarker analysis of glioblastoma and potential implications for therapy.
Authors: Xiu Joanne , Feldman-Moreno Rebecca Anne , Arguello David , Gatalica Zoran , Ghazalpour Anatole , Bender Ryan P. , Castro Michael , Reddy Sandeep K. , Basu Gargi Dan , Paul Les
Published: March 2020

2041

Background: Glioblastoma multiform (GBM), the most aggressive CNS cancer, has limited effective therapeutic options, with underlying molecular heterogeneity contributing to the differences in treatment response. Our study was designed to interrogate biomarkers from a large cohort of GBM patients to seek therapeutic implications. Methods: Data was analyzed from 570 high grade astrocytoma patients (vast majority GBM) who received tumor profiling at Caris Life Sciences from 2009 to 13. Test methodologies included IHC, FISH, CISH, Sanger SEQ, MGMT promoter methylation and NextGen SEQ (Illumina TruSeq). Results: In our patient cohort, 59% had MGMT methylation and 70% had negative MGMT IHC, predicting potential response to temozolomide. Protein expression for ERCC1, TOPO1, and TS was 53% negative, 49% positive, and 37% negative, indicating potential benefit from cisplatin, irinotecan and fluorouracil, respectively. Drug pumps PGP and MRP1, were positive by IHC in 10% and 67% of patients, suggesting possible resistance to etoposide, vinca alkaloids and methotrexate. For targeted therapies, c-Kit IHC was positive in 7% patients, mutated in 6% and PDGFRA IHC was positive in 27%, indicating potential benefit from imatinib and other TKI’s. RAS/RAF and PIK3CA/mTOR pathway activation was also noted with BRAF, KRAS, PIK3CA mutations and PTEN loss, observed in 8%, 3%, 7% and 10% of cases, respectively. TS negativity was seen in 91% of MGMT methylated patients and in 37% of MGMT unmethylated patients (p = 0.025, student’s t-test), revealing a possible novel combination therapy of fluoropyrimidines with temozolomide for a select cohort. Similarly, biomarker profiles of molecular subgroups defined by EGFR amplification (44% in our cohort) and IDH1, p53 mutations will be analyzed for therapeutic implications. Conclusions: By profiling tumor biomarkers from a large cohort of GBM patients using validated assays in a single facility, we demonstrate the vast molecular heterogeneity of GBM and highlight the importance of individualized therapy based on a patient’s unique tumor profile. Incorporating a comprehensive biomarker analysis into clinical management of this aggressive cancer allows for an informed selection of more effective therapies.
Phase I/II trial of vorinostat combined with temozolomide (TMZ) and radiation therapy (RT) for newly diagnosed glioblastoma (GBM) (N0874-ABTC0902, Alliance): Final results of the phase I trial.
Authors: Galanis Evanthia , Sarkaria Jann Nagina , Anderson S. Keith , Wu Wenting , Jaeckle Kurt A. , Giannini Caterina , Buckner Jan C. , Wen Patrick Y. ,   Alliance for Clinical Trials in Oncology
Published: March 2020

2046

Background: Vorinostat (VOR) is a histone deacetylase inhibitor that represents a rational targeted agent in GBM treatment. Given its single-agent activity in recurrent disease (Galanis,et al, 2009) and radiosensitizing properties, this phase I/II trial was designed to test the addition of VOR to standard chemoradiation in newly diagnosed GBM patients (pts): the phase I portion of the trial is the focus of this report. Methods: A standard cohorts of three design was used to assess the safety of VOR in combination with RT and concomitant TMZ and establish the phase II dose of the combination. VOR was given orally days 1 - 5 every wk beginning with the first dose of RT (total dose 60 Gy) and (75mg/m²/day). Following a 4 - 6 week rest, pts received up to 12 cycles of standard adjuvant TMZ in combination with VOR on days 1-7 and 15 – 21 of each cycle; dose was based on NABTT trial 04-03 (Lee, et al, 2012). Results: The phase I component is complete with 15 pts, 12 pts at dose level 0 (VOR 300 mg/day days 1 - 5, weekly x 6 wks), and 3 pts at dose level 1 (VOR 400 mg/day, days 1 – 5 weekly x 6 wks) in combination with RT/TMZ. Dose limiting toxicity (DLT) in dose level 1 included grade 3 fatigue in 2 pts, grade 3 wound dehiscence in 1 pt, and grade 4 neutropenia and thrombocytopenia in 1 pt. In dose level 0, 1/6 pts had DLT (gr 3 dyspnea). An MTD expansion cohort of 6 additional patients was added to dose level 0; one patient experienced grade 4 thrombocytopenia and grade 3 fatigue, and 1 patient experienced grade 3 febrile neutropenia. In the 12 pts treated in the phase II dose, most common toxicities were hematologic, including lymphopenia (gr 3/4 in 66.7%), thrombocytopenia (gr 3 in 16.7%, gr 4 in 16.7%) and neutropenia (gr 3 in 16.7%, gr 4 in 8.3%). Grade 3 fatigue was observed in 8.3% of the pts. Conclusions: MTD for VOR in combination with TMZ/RT in newly diagnosed GBM patients is 300 mg/d, days 1 - 5 weekly during RT. Toxicity was primarily hematologic. This dose was used in the recently completed phase II trial of the combination (110 pts). RNA expression profiling in patient samples is in process to assess vorinostat responsive signatures observed in preclinical models. Clinical trial information: NCT00731731.
Marrow-ablative chemotherapy followed by tandem autologous hematopoietic cell transplantation (AuHCT) in pediatric patients with malignant brain tumors.
Authors: Guerra Jhon , Dhall Girish , Marachelian Araz , Castillo Esmeralda , Malvar Jemily , Sposto Richard , Wong Kenneth , Finlay Jonathan L.
Published: March 2020

2049

Background: In an effort to both improve cure rates and quality of survival in young children with malignant brain tumors, irradiation-avoiding or at least minimizing marrow-ablative chemotherapy with AuHCT has been incorporated in both up-front as well as recurrent therapies. To decrease the toxicity of single cycle marrow-ablative chemotherapy regimens, and possibly enhance cure through overall dose intensification, use of fractionated multiple (tandem) cycles of marrow-ablative chemotherapy with AuHCT has been explored. Methods: In this retrospective analysis, we investigated the outcome of children with malignant brain tumors treated with marrow-ablative chemotherapy and tandem AuHCT at Children’s Hospital Los Angeles between June 1999 and July 2012. Results: Forty-four children (24 males) with a median age of 7.1 years (range 0.6- 19.0 years) with malignant brain tumors were studied. Twenty-one had medulloblastomas/primitive neuro-ectodermal tumors, 8 atypical teratoid/rhabdoid tumors, 5 high-grade gliomas, 4 malignant germ cell tumors, 3 ependymomas and 3 choroid plexus carcinomas. Twenty-nine patients receive 3 and 15 received 2 tandem transplants, respectively. Twenty-seven patients were newly-diagnosed and 17 recurrent disease. Thirty-one patients received irradiation at some time. The 5-year post-transplant progression-free (PFS) and overall survivals (OS) for all patients were 46.3±8.2% and 51.7±8.5% respectively. The PFS and OS for newly-diagnosed patients were 68.9 ± 9.9% and 73.5±9.3% respectively, compared with those transplanted at relapse 11.8±9.8 (p <0.001) and 15.1±12.3% (p = 0.0231) respectively. The 5-year post-transplant PFS and OS in unirradiated patients was 74.0±13.0% and 74.0±13.0% versus33.2±9.8% and 40.2+/-10.6% in irradiated patients (p = 0.11 and p = 0.239 respectively). One patient (2.3%) died of transplant-related toxicity. Conclusions: Marrow-ablative chemotherapy with tandem AuHCT is feasible and safe in children with malignant brain tumors with encouraging irradiation-free survival in newly-diagnosed children.
Phase II study of PX-866 in recurrent glioblastoma.
Authors: Pitz Marshall W. , Eisenhauer Elizabeth A. , MacNeil Mary Valeria , Thiessen Brian , Macdonald David R. , Easaw Jacob C. , Eisenstat David Daniel , Kakumanu Ankineedu Saranya , Squire Jeremy , Tsao Ming Sound , Kamel-Reid Suzanne , Tassignon Aurelie , Hausman Diana Felice , Mason Warren P.
Published: March 2020

2053

Background: Glioblastoma (GBM) is the most aggressive malignancy of the central nervous system. The majority have genetic changes that increase the activity of the phosphatidylinositol-3-OH kinase (PI3K) signal transduction pathway, critical for cell motility, proliferation, and survival. We present the results of PX-866, an oral PI3K inhibitor, in patients (pts) with recurrent GBM. Methods: A multinomial design of response and early progression (< 8 weeks on study) was used. In stage 1 (15 pts), 0 responses and ≥ 10 early progressions would stop accrual; after full accrual, ≥ 4 responses OR ≤ 13 early progressions was prespecified as of interest. Pts with histologically confirmed GBM, at first recurrence after chemoradiation and adjuvant temozolomide were given PX-866 8 mg daily on this single-arm phase II study. MRI and clinical exam were done every cycle (8 weeks). Tumour tissue was collected for analysis of potential markers of PI3K inhibitory activity (PTEN, EGFRviii, PIK3CA mutations). Results: A total of 33 pts were enrolled, eligible and evaluable. Median age was 56 (range 35-78), 12 were female; 29 had performance status (PS) 0-1 and 4 had PS 2. Median time from initial diagnosis to enrolment was 308 days (range 141-1256). Median number of cycles was 1 (range 1-7). Thirty-two pts have discontinued therapy, 26 due to disease/symptomatic progression and 6 due to toxicity (5 LFT elevation and 1 allergic reaction). Other adverse effects (AE): fatigue (16 pts/2 grade 3), diarrhea (11 pts/5 grade 3), nausea (19 pts/1 grade 3), vomiting (11 pts/1 grade 3) and lymphopenia (29 pts/7 grade 3/4). Five pts had related serious AEs (1 LFTs, 1 GI and 3 venous thromboembolism) All pts were evaluable for response; 25 had a best response of progression, 1 had partial response (overall response rate 3%) and seven (21%) had stable disease (SD, median 7.3 months; range 3.1-13.6). Six month PFS was 17%. In preliminary analyses, no statistical association was found between SD and PTEN or EGFRviii status (results pending in 16 pts). Conclusions: PX-866 was relatively well tolerated. Overall response rate was low, and the study did not meet its primary endpoint; however, 21% of pts obtained durable stable disease. Further correlative work is required to identify the predictor of this effect. Clinical trial information: NCT01259869.
Neuropilin-1 (Nrp-1) as a prognostic biomarker and potential drug target for pediatric medulloblastoma.
Authors: Riedemann Lars , Snuderl Matija , Batista Ana , Kirkpatrick Nathaniel David , Ruiz de Almodovar Carmen , Hasselblatt Martin , Rossig Claudia , Duda Gabriel Dan , Xu Lei , Fukumura Dai , Carmeliet Peter , Jain Rakesh K.
Published: March 2020

2056

Background: Medulloblastoma survival rates have significantly improved over the last decades due to surgery and chemoradiation regimens. However, pediatric patients with high-risk disease and those with recurrence often succumb to their disease. The majority of children suffer from severe adverse effects of intense therapy regimens. We recently demonstrated the role of the Placental Growth Factor (PlGF)/Nrp-1 signaling pathway in medulloblastoma progression in preclinical models (Snuderl et al., Cell 2013). The aim of this study was to evaluate the role of Nrp-1 as a biomarker and therapeutic target in medulloblastoma patients. Methods: Thirty-two surgical samples of pediatric medulloblastoma were analyzed for expression of Nrp-1 and its ligand PlGF by immunohistochemistry, array-comparative genomic hybridization and deep gene sequencing. On an independent, clinically annotated cohort of 42 medulloblastoma samples, we evaluated the correlation between Nrp-1 expression and 5-year overall survival. The therapeutic relevance of Nrp-1 signaling was tested in a D283 orthotopic human xenograft mouse model using shRNA and a monoclonal antibody against Nrp-1. Results: Nrp-1 expression was detectable in 100% and PlGF in 90% of all medulloblastoma samples. No significant differences in expression could be detected between known histological or molecular medulloblastoma subtypes. Patients with high Nrp-1 expression had a significantly worse 5-year overall survival compared to patients with a low or moderate expression (40% vs. 86%, p = 0.0058). Treatment with an antibody against Nrp-1 or genetic silencing of Nrp-1 with shRNA significantly prolonged survival in a D283 orthotopic human xenograft mouse model (for both experiments: p < 0.01). Conclusions: Nrp-1 is widely expressed across all molecular subgroups of medulloblastoma and its expression levels are inversely associated with survival of patients. Targeting Nrp-1 leads to a significant survival benefit in an orthotopic human xenograft mouse model. This data support the hypothesis that targeting the PlGF/Nrp-1 signaling pathway may be a novel therapy approach for pediatric medulloblastoma.
Evaluation of invasion patterns and their correlation with integrin alphavbeta expression in brain metastases of solid cancers.
Authors: Berghoff Anna Sophie , Rajky Orsolya , Winkler Frank , Weller Michael , Zielinski Christoph , Schittenhelm Jens , Preusser Matthias
Published: March 2020

2059

Background: Understanding the pathobiology of brain metastases (BM) could guide the establishment of new targeted therapies. Methods: We collected 57 autopsy specimens of BM (primary tumor: 27 lung cancer, 6 breast cancer, 8 melanoma, 1 kidney cancer, 2 colorectal cancer, 13 other) and histologically evaluated the patterns of invasion into the surrounding brain parenchyma. Expression of the following integrins was evaluated using immunohistochemistry: with novel antibodies for αv subunit, αvβ3, αvβ5, αvβ6 and αvβ8 integrin. Results: We observed three main invasion patterns: well-demarcated (29/57, 51%), vascular co-option (10/57, 18%) and diffuse infiltration (18/57, 32%). There was no association of invasion pattern with primary tumor type, although vascular co-option was most common in melanomas (4/10, 40%). αv subunit expression was lowest in the vascular co-option group (p = 0.05, t-test). αvβ6 levels were higher in the well-demarcated group than in the vascular co-option group (p = 0.025; t-test) and were higher in lung cancer BM than in melanoma BM (0.01, t-test). αvβ3 and αvβ5 were frequently expressed in tumoral (αvβ3: 30/57, 53%; αvβ5: 55/57, 97%) and peritumoral (αvβ3: 29/57, 51%, αvβ5: 54/57 (95%) vascular structures and 27/57 (47%) specimens showed avb5 and 6/57 (11%) αvβ3 expression on tumor cells. Prior radio- or chemotherapy did not correlate with invasion pattern or integrin expression. Conclusions: We delineate three distinct invasion patterns of BM into the brain parenchyma: well-demarcated growth, vascular co-option and diffuse infiltration. Integrin expression is frequent on tumor and vascular cells in BM and associated with distinct invasion patterns. Anti-integrin therapy could be a valid treatment option in patients with BM.
Validation of a gene expression-based diagnostic system for malignancy of glioma by multi-institute prospective-retrospective analysis.
Authors: Kato Kikuya , Shirahata Mitsuaki , Narita Yoshitaka , Muragaki Yoshihiro , Maruno Motohiko , Matoba Ryo
Published: March 2020

2066

Background: Histopathological classification of gliomas is often clinically inadequate due to the diversity of tumors that fall within the same class. Based on the strong correlation between malignancy and gene expression profile in gliomas, we constructed a diagnostic system based on gene expression profiling of 152 glioma samples (Shirahata et al., Cancer Sci, 2009, 100, 165). The diagnostic system was converted to that based on expression value of 27 genes measured with real-time PCR (Kawarazaki et al., BMC Med Genomics, 2010, 3, 52). Methods: First, the diagnostic system was validated with 75 retrospective samples from the National Cancer Center Hospital, and threshold values of the diagnostic score (PC1-score) were determined. Second, the system was evaluated by prospective-retrospective analysis of 127 samples from the four institutions using the threshold. The analysis corresponded to the category C proposed by Simon et al. (JNCI, 2010, 101, 1446). Results: In general, the PC1-score gradually increased with the grade of the glioma from grade II to IV. The prognostic classification by the diagnostic system was compared with that by WHO grade classification using 66 grade IV and 39 grade 3 samples. Harrell’s C-index was 0.673 and 0.573 for the diagnostic system and grade classification, respectively. Hazard Ratio was 5.31 and 4.97, respectively. By the system the 66 grade 4 patients were confirmed to be classified into two prognostic groups (PFS, p = 0.013; OS, p = 0.098). The 39 grade III patients were classified into two prognostic groups (PFS, p = 0.112; OS, p = 0.022).Median observation time is 12 months for PFS and 15.5 months for OS, respectively. As for grade 3 patients, IDH1 mutation had better prognostic ability (PFS, p = 0.007; OS, p = 0.002). Conclusions: Based on two retrospective and one prospective-retrospective analysis, our diagnostic system was demonstrated to be an objective prognostic indicator complementing the grade classification. The prognostic ability within grade 3 or grade 4 may be useful in therapeutic decision making.