bluuebunny/crossref_metadata_2025_split huggingface dataset:
FIP200 and Rb1 expression in CNS metastasis from breast cancer (CNS met): Potential predictors of patient outcome.
Authors: Hashemi Sadraei Nooshin , Ulasov Ilya , Burgett Monica , Nowacki Amy S , Prayson Richard , Weil Robert J. , Kar Niladri , Ahluwalia Manmeet Singh , Muller-Greven Ga‘lle , Shi Ting , Lesniak Maciej S. , Gladson Candece 
Published: March 2020

2014 Background: Patients with CNS met have a poor outcome with significant variation in overall survival. No marker to predict survival exists. Rb1 is a negative regulator of the cell cycle, and FiP200 is an upstream signaling node that is distributed between the nucleus and cytoplasm. Nuclear FIP200 inhibits cell proliferation by promoting expression of Rb1, whereas cytoplasmic FIP200 promotes cell survival through autophagy. Previously FIP200 deletion/mutation has been reported in 20% of primary invasive breast cancer [BR ca] patients. FIP200 cellular localization and genetic alterations have not been examined in CNS met. Methods: A retrospective analysis of BR ca and CNS met was performed based on tissue availability from 2 institutions. FIP200 and Rb1 expression and localization was evaluated by immunohistochemistry. Genetic alterations were evaluated by DNA array analysis. Results: 80 patients (42 BR ca and 38 CNS met) were identified. Overall CNS met samples had significantly higher levels of cytoplasmic FIP200 as compared to BR ca (52% vs 24% respectively, p=0.0002) and increased expression of FIP200 around areas of hypoxia/necrosis, consistent with increased autophagy. There was also a significant increase in expression of nuclear FIP200 and Rb1 in the CNS met compared to BR ca (p=0.0007 and p=0.0055 respectively). Median survival from development of CNS met was longer in the group with high levels of nuclear Rb1; 14 (3-27) vs 20 (12-33) months (low expression < 20% vs high ≥ 20%, p=0.1). The same finding was observed with FIP200, longer survival was observed with high nuclear expression; 16 (7-33) vs 19 (0.4-27) months (low expression <20% vs high ≥ 20%, p=0.2). Our DNA analysis for copy number variation and LOH in CNS met revealed no deletion in Rb1 or FIP200. Conclusions: The pattern of expression of Rb1 and FIP200 in CNS met is different from BR ca. Notably, cytoplasmic FIP200 which promotes cell survival is highly expressed in CNS mets vs BR ca. This suggests metastatic breast cancer cells utilize autophagy as a survival mechanism. In addition, there is a trend to better survival of those patients with CNS met who express high nuclear FIP200 and Rb1, both of which have anti-proliferative roles in the nucleus.
Vorinostat, temozolomide, and bevacizumab for patients with recurrent glioblastoma: A phase I/II trial.
Authors: Peters Katherine B. , Vredenburgh James J. , Desjardins Annick , Friedman Henry S. , Herndon James Emmett , Coan April D. , McSherry Frances , Lipp Eric S , Brickhouse Alise , Massey Woody C , Reardon David A. 
Published: March 2020

2027 Background: Prognosis for recurrent glioblastoma (GBM) remains poor with median survival between 3 to 6 months. Use of anti-vascular endothelial growth factor inhibitor, bevacizumab (BEV), has advanced this area of research, but continued studies have focused on whether the addition of other chemotherapies can improve efficacy in recurrent GBM. Vorinostat, a small molecule inhibitor of histone deactylase (HDAC), has anti-tumor activity directly through HDAC inhibition and indirectly by promoting anti-angiogenesis. Its good oral bioavailability and favorable toxicity profile make it a promising additive agent to standard therapy. Thus, we evaluated the efficacy of vorinostat in combination with BEV and daily temozolomide (TMZ) in recurrent GBM. Methods: This was a phase I/II open-label, single arm study in recurrent GBM patients. Primary endpoint was 6-month progression free survival (PFS). Secondary endpoints were safety/tolerability, radiographic response, PFS, and overall survival of recurrent GBM patients treated with BEV plus daily TMZ and vorinostat. Chief eligibility criteria included age ≥ 18 years, KPS ≥ 70, time interval ≥ four weeks from previous treatment, and maximum of 2 prior progressions. Dosing regimen was as follows: BEV 10 mg/kg IV every two weeks, TMZ 50 mg/m2 po daily, and vorinostat 400 mg po for 7 days on then 7 days off in a 28 day cycle. Results: 46 recurrent GBM patients were enrolled with 42 of those patients receiving a vorinostat dose of 400 mg. Most common grade 2 and above toxicities were leukopenia (36%), neutropenia (29%), fatigue (24%), and thrombocytopenia (19%). Serious toxicities included 4 grade 4 toxicities (grade 4 hyperglycemia, pulmonary embolism, bowel perforation and intracranial hematoma) and 1 patient expired on day of informed consent due to pulmonary embolism (grade 5). With a median follow-up of 11.3 months (95% CI: 10.1, 13.1 months), the 6-month PFS was 52.4% (95% CI: 36.4%, 66.1%). Best radiographic responses were 2 complete responses, 17 partial responses, 20 stable responses, and 1 radiographic progression. Conclusions: In summary, combination of BEV, daily TMZ, and vorinostat has promising efficacy on recurrent GBM with reasonable toxicity/safety.
Concurrent intrathecal methotrexate and liposomal cytarabine for the treatment of leptomeningeal metastasis from solid tumors.
Authors: Scott Brian J. , Feely Homira , Brown Tiffany , Van Vugt Vincent , Kim Ryan , Fanta Paul Timothy , Bazhenova Lyudmila , Kesari Santosh 
Published: March 2020

2052 Background: Leptomeningeal metastasis (LM) from solid tumors is typically a late manifestation of disease with a median survival of weeks to a few months. Treatment is palliative, with no widely accepted standard of care. Options include intrathecal (IT) or systemic chemotherapy, radiation therapy or ventriculoperitoneal shunting. Randomized trials comparing single agent IT methotrexate to liposomal cytarabine have shown similar efficacy and tolerability. There is limited data, however, on the use of combination IT chemotherapy in solid tumor LM. Methods: We conducted a retrospective cohort study of 19 subjects treated for LM from solid tumors at a single institution. In addition to therapies directed at active solid tumor sites, each subject received IT liposomal cytarabine plus IT methotrexate injections every two weeks. Survival data and treatment-related toxicities were determined by systematic chart review. Results: LM was diagnosed by CSF cytology in 12/19 (63%), while the remainder were diagnosed by clinical and MRI findings. The most common cancer types were breast 7(37%), glioblastoma 6(32%) and lung 3(16%). The majority 18(95%) had active systemic or parenchymal brain disease at the time of treatment, requiring systemic chemotherapy 18(95%) or radiation therapy 13(68%). The median number of IT treatments was 4(range 1-9). Treatment was interrupted due to toxicity in 3(17%), while 7(37%) experienced ≥ CTCAE grade III toxicities, most commonly meningitis 3(16%). Treatment was stopped in 7/19(37%) following complete cytologic response 6/11(55%) or radiographic clearance 1/7(14%). The median overall survival was 96 days(n=6; range 29-158), median time to neurologic progression was 46 days (n=9; range 6-101) and the most common cause of death was progression of systemic disease 4(67%). Conclusions: Combination IT chemotherapy was reasonably well-tolerated, even in a population also receiving chemotherapy for progressive systemic disease. IT-related adverse events occurred at rates similar to previously reported single agent trials. Prospective evaluation is necessary to determine whether there is a survival benefit compared to single agent IT chemotherapy.
Correlation of large brain edema with favorable prognosis in patients with single brain metastases.
Authors: Preusser Matthias , Berghoff Anna Sophie , Dinhof Carina , Hutterer Markus , Woehrer Adelheid , Hackl Monika , Bartsch Rupert , Birner Peter , Zielinski Christoph , Widhalm Georg , Marosi Christine , Prayer Daniela , Spannberger Thomas 
Published: March 2020

2053 Background: The sub-cohort of brain metastases (BM) patients (pts) with single BM has relatively favorable survival times, but novel prognostic factors are needed to individualize patient management. Methods: We retrospectively evaluated pre-operative magnetic resonance images in patients, who underwent neurosurgical resection of a single BM. The localization and largest diameter of the BM was recorded. The extent of brain edema (BE) was graded on contrast-enhanced T1, T2 and fluid-attenuated inversion recovery (FLAIR) images as follows: BE <1cm, BE >1 cm without affection of the contralateral hemisphere, BE >1cm with affection of the contralateral hemisphere. Further, immunohistochemically assessed expression of hypoxia-induced factor 1 alpha (HIF1a) was analyzed in each BM tissue specimen. Results: 159 pts were studied (81 male, 78 female; age range 24 to 80 years, median 58). The primary tumors were lung carcinoma in 74, breast cancer in 26, kidney cancer in 13, colorectal cancer in 11, melanoma in 9 and other tumor types in 26 cases. At univariate analysis, we found a significant positive correlation of overall survival time (OS) with young age, Karnofsky index >80, non-melanoma histology, and, surprisingly, large BE (p<0.05, log-rank test). At multivariate analysis, pts age, histological diagnosis and extent of BE remained independent prognostic parameters (Cox regression model, p<0.05). We found a significant positive correlation of extent of BE with expression of HIF1a (Mann-Whitney-U test, p=0.003). Conclusions: Large BE positively and independently correlates with favorable prognosis in pts operated for single BM. Peritumoral BE correlates with HIF1a expression, indicating a possible role of tumor hypoxia in its formation. [Table: see text]
Rising incidence of glioblastoma and meningioma in the United States: Projections through 2050.
Authors: Johnson Derek Richard 
Published: March 2020

2065 Background: In the absence of proven environmental or behavioral risk factors, patient age and sex remain the most important predictors of primary brain tumor risk. In coming years, an increasing incidence of brain tumors in the United States can be anticipated based on shifts in the demographic structure of the population. This study provides estimates of glioblastoma and meningioma incidence through 2050. Methods: Group-specific glioblastoma and meningioma incidence rates based on age (eleven categories) and sex were calculated from National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) data for the period 2004-2008. United States Census projections based on data from the 2000 census were used to compute the size of the twenty-two demographic subpopulations of interest in 2010, 2020, 2030, 2040, and 2050. The estimated number of new glioblastoma and meningioma diagnoses for each of these years was calculated from the defined incidence rates and population size. Results: Crude annual tumor incidence rates were 3.13 per 100,000 persons for glioblastoma and 6.81 per 100,000 persons for meningioma. While the overall size of the population is expected to increase only 42% between 2010 and 2050, the number of Americans over 65 years of age, the group at highest risk of glioblastoma and meningioma, is expected to increase by 120%. We estimate that the number of new glioblastoma diagnoses will rise from 10,688 in 2010 to 18,466 in 2050, a 72% increase. Likewise, the number of new meningioma diagnoses will rise from 22,946 to 40,680 over the same period, a 77% increase. Conclusions: The number of new glioblastoma and meningioma diagnoses will increase substantially in the future. This analysis, which assumes a fixed incidence rate, may underestimate the true magnitude of the coming change given reports suggesting that incidence rates of glioblastoma and meningioma are rising over time.
The impact of bevacizumab on the occurrence and recurrence of intracranial brain metastases in non-small cell lung cancer (NSCLC) patients.
Authors: Salem Mohamed E. , Szerlip Nicholas , Pennell Nathan A. , Ali Khaled B. , Altshuler David , Taylor Stephanie , Hallock Abhirami , Sukari Ammar , Gadgeel Shirish M. , Wozniak Antoinette J. 
Published: March 2020

2081 Background: Patients (pts) with brain metastases (BM) have a poor prognosis and limited treatment options. Approximately 40-50% of pts with NSCLC will develop BM during the course of their disease. A better understanding of the pathobiology of BM and the development of targeted agents hold promise for improved prophylaxis and therapy of BM which could have significant impact on disease progression and pt's survival. Vascular Endothelial Growth Factor has been implicated in setting up a metastatic niche allowing cells to seed and grow in the brain parenchyma. Inhibition of this signaling has been studied and shown to be effective in reducing BM in animal models. Methods: The objective of this retrospective study was to determine whether bevacizumab decreases the incidence and or the recurrence of BM in pts with NSCLC. We retrospectively identified NSCLC pts with and without BM treated with bevacizumab. The primary endpoint was the proportion of patients who developed BM on or after bevacizumab therapy. Secondary endpoints were rate of local or regional recurrence after stereotactic radiosurgery (SRS). Occurrence of BM was evaluated by retrospectively reviewing MRI and or CT scans. Results: A total of 30 pts with stage IV non-squamous NSCLC who had no BM at diagnosis treated with bevacizumab (Non-BM group, NBMG) and 85 pts with non-squamous NSCLC who had BM and underwent SRS (BM group, BMG) were studied (46%M; median age 60 years (range 32-84). In the NBMG, 28% of pts developed BM. Median time to development of BM was 10.5 months. In the BMG, 4 pts were treated with bevacizumab following SRS. Of these 4 pts, 3 pts (75%) had no recurrence while 1 pt (25%) developed local then regional recurrence at 7 and 9 months, respectively. Of the remaining 81 pts who underwent SRS but never received bevacizumab, 27% of pts had local recurrence and 41% had regional recurrence at median time of 4 and 4.5 months, respectively. Conclusions: Bevacizumab may have a role in the treatment of NSCLC in regards to development and recurrence of brain metastases. These results support the need for further prospective investigation in a larger patient population with matched controls.
An investigator-initiated monocentric phase I dose escalation trial of temsirolimus and irinotecan (TEMIR) in patients with relapsing glioblastoma multiforme (reGBM).
Authors: Scheulen Max E. , Richly Heike , Kalkavan Halime , Hoffmann Andreas-Claudius , Virchow Isabel , Hilger Ralf A. , Koeppen Susanne , Sure Ulrich , Schuler Martin H. , Hense Joerg 
Published: March 2020

2086 Background: Deregulation of the PI3K/AKT pathway has been preclinically involved in the pathophysiology of GBM. The mammalian target of rapamycin (mTOR) is an important downstream mediator of PI3K/AKT signalling. The mTOR-inhibitor temsirolimus (Tem) achieves significant drug levels in brain. Thus, Tem may be effectively combined with irinotecan (Iri) which has shown promising results in combination with bevacizumab in patients (pts) with reGBM refractory to temozolomide (Tmz) in phase II. Exposure to Tem as well as Iri is substantially reduced in pts receiving CYP3A4 enzyme-inducing anticonvulsants (CYP3A4-Ind). Methods: TEMIR is a phase I trial of escalating doses of Tem in combination with Iri in pts with reGBM refractory to Tmz depending on the cotreatment with CYP3A4-Ind. In pts without CYP3A4-Ind dose escalation of Tem was performed according to the “3+3 protocol” from 15 via 20 to 25 mg iv wkly together with 85 mg/m2 Iri iv wkly. In pts with CYP3A4-Ind the doses of Tem were 30, 40 and 50 mg iv wkly together with 170 mg/m2 Iri iv wkly, respectively. The determination of the pharmacokinetics (PK) of Tem and its influence on the PK of Iri and its active metabolite SN38 was performed by validated RP-HPLC methods with fluorescence detection. Results: Up to now, 14 pts [4 female and 10 male, median age 47 yrs (range 41-65 yrs), 9 without and 5 with CYP3A4-Ind] have been treated. All 9 pts without CYP3A4-Ind (3 pts on 15, 20 and 25 mg Tem each) are evaluable for safety with only mild toxicity [highest CTC-grade ≥2 (gr) per pt]: diarrhea 4 (gr2) and 1 (gr3), neutropenia 1 (gr3), thrombopenia 1 (gr2), anemia 1 (gr2), pneumonia 2 (gr2), rash 1 (gr2). PK parameters of Iri and SN38 were in agreement with previously published studies and there was no significant effect of 15 to 25 mg Tem combined with 85 mg/m2 Iri on the PK of Iri and SN38. In 7 pts evaluable for efficacy there was no remission (RECIST) and median time to symptomatic and/or MRT progression was 10 wks (7, 9+, 10, 10+, 11, 15, 20 wks). Conclusions: The combination of Tem in standard dose of 25 mg iv wkly with 85 mg/m2 Iri wkly is safe in pts with reGBM without CYP3A4-Ind. Tem has no significant effect on the PK of Iri and SN38.
Anaplastic oligodendroglial tumors: The Cleveland Clinic experience.
Authors: Hashemi-Sadraei Neda , Robles Irizarry Lizbeth , Patel Mital , Tekautz Tanya M. , Murphy Erin Sennett , Recinos Violette , Chao Samuel T. , Suh John H. , Peereboom David M. , Stevens Glen , Weil Robert J. , Vogelbaum Michael A. , Barnett Gene H. , Ahluwalia Manmeet Singh 
Published: March 2020

2100 Background: Anaplastic oligodendroglial tumors include both anaplastic oligodendroglioma (AO), and anaplastic oligoastrocytoma (AOA), histological categories of WHO grade 3 gliomas. There is limited data on specific prognostic factors for patients with these tumors. Methods: After obtaining IRB approval, the Cleveland Clinic Brain Tumor and Neuro-Oncology Center’s database was used to identify patients with histologically confirmed AO and AOA at the time of diagnosis. Multivariable analysis was conducted with use of a Cox proportional hazards model and a stepwise selection algorithm that used p<0.05 both as the criteria for entry and retention in the model to identify independent predictors of survival. Results: Chart records of 139 patients, 52% of whom were male, diagnosed between 1992 and 2009 were included for analysis. Median age at presentation was 47 years (range, 18-83 years). 22% of patients had biopsy only, 35% had gross total resection, 43% had near total resection or subtotal resection. Following surgery, 30% of patients were treated with chemotherapy (CT) alone, 14% were treated with radiotherapy (RT) and 47% received both CT and RT. Median progression free survival and median overall survival (OS) were 29.0 and 58.7 months respectively. On multivariate analysis, four factors were identified as independent predictors of OS: age at diagnosis (≥50 vs. <50, p=0.004), Hypothyroidism (p=0.009), multifocal disease (p=0.005) and 1p 19q co-deletion (p<0.001). Choice of initial therapy did not impact survival in this cohort of patients. Conclusions: Older age, hypothyroidism and multifocal disease were associated with higher mortality. 1p, 19q co-deletion was associated with lower mortality. [Table: see text]
Correlation between CD4 lymphocytes count and the opportunistic infections in treated glioblastoma.
Authors: Begin Marie Josee , Belanger Karl , Florescu Marie 
Published: March 2020

2102 Background: Less than 200 CD4 lymphocytopenia happens frequently with temozolomide treatment of glioblastoma. This immunosuppression is associated with many opportunistic infections and antibiotic prophylaxis is given in some centers to prevent Pneumocystis pneumonia. Methods: We analyzed the association between documented culture-proved infections and CD4 lymphocytes level in 140 patients treated with temozolomide in first-line glioblastoma in Notre-Dame Hospital from 2006 to 2009. Demographic and treatment data were collected and analyzed with Kaplan-Meier survival plots and Log Rank tests. Results: The cohort of infected patients was represented by 31 patients who developed 49 culture-proved infections: 21 urinary origin, 8 pulmonary (1 Pneumocytis and 2 Aspergillosis), 5 brain, 5 bacteremia and 2 other. The infected cohort (n=31) had similar demographs, but also similar outcome compared to our control non infected glioblastoma treated patients cohort (n=109) with a 2 year survival of 40.8% vs 50.2% (p=). The median CD4 lymphocytes level was 260, but clearly infections were associated with less than 200 CD4 lymphocytes. During their infection, 20 patients had a CD4 level less than 200, compared with 11 patients with more than 200 CD4 lymphocytes count. Conclusions: CD4 lymphocytopenia less than 200 is associated with increase in number of documented culture-proven infections in patients treated with temozolomide, but the survival is not altered by the infection.
Anti-CD3 immunotoxin to induce remissions in cutaneous T-cell lymphoma patients.
Authors: Frankel Arthur E. 
Published: March 2020

2505 Background: The anti-CD3 immunotoxin, AdmDT390bisFv(UCHT1), composed of the catalytic and translocation domains of diphtheria toxin (DT390) fused to two anti-CD3 sFvs showed selective cytotoxicity to normal and malignant human T cells in vitro and in vivo and was prepared for a phase I clinical study (Woo, Protein Exp Purif 58, 1, 2008). FDA approval (BB IND#100712), and IRB approval was obtained. Methods: Nineteen T cell lymphoma patients were screened, and 12 patients treated. Median age was 62 years (range, 39-84 years) with 6 males and 6 females. Disease was previously treated with one (6), two (3), three (1) or four (2) systemic therapies. One patient had stage IV PTCL and the other patients had CTCL (stage IB in 5, IIB in 4, IIIB in 1, and IV in 1). Six patients were treated with 2.5µg/kg x 8; five patients were treated with 5µg/kg x 5 - 8 and one patient treated with 7.5µg/kg x 8. Results: Drug-related toxicities were mild in 11/12 patients and were not dose dependent with transient fevers, chills, lymphopenia, transaminasemia, CMV and/or EBV viremia, and hypoalbuminemia. One 69 year old male with pre-existing heart failure treated at the 5µg/kg x 5 suffered severe vascular leak syndrome and heart failure. Immunotoxin Cmax was 1 – 60ng/mL, and mean half-life was 42min. Four patients had pre-treatment anti-immunotoxin titers >10µg/mL, and the others had lower pre-treatment antibody levels. All evaluable patients except two had increases of antibody titer between day 12 to 30 of 4 – 2000-fold. Among 10 evaluable patients, there were 2 complete remissions (CRs) of 17 and 41+ months durations and 4 partial remissions (PRs) of 1+ - 32+ months. Conclusions: The immunotoxin has exciting clinical efficacy in this heavily pretreated group of patients. Dose escalation is proceeding.