tbuckley/cabot-search huggingface dataset:
PDTB-12. CNS PENETRATION OF THE CDK4/6 INHIBITOR RIBOCICLIB (LEE011) IN NON-TUMOR BEARING MICE AND MICE BEARING ORTHOTOPIC PEDIATRIC BRAIN TUMORS
Authors: Yogesh Patel
Journal: Neuro-Oncology (2016)

Pediatric patients with brain tumors have limited treatment options and poor long-term survival. CDK4/6 bound with Cyclin D regulates cell proliferation by phosphorylating retinoblastoma protein (Rb) and releasing E2F, a positive regulator of the G1/S transition. Ribociclib, a CDK4/6 inhibitor is under clinical evaluation for treatment of pediatric malignancies. We evaluated its CNS penetration in two pediatric brain tumor models (diffuse intrinsic pontine glioma [DIPG] and Group 3 medulloblastoma [G3MB]) and in normal mouse brain using cerebral microdialysis. A plasma pharmacokinetic study of 100 mg/kg orally-administered ribociclib was performed in CD1 nude mice bearing orthotopic DIPGx7 xenografts (n=9) using population-based sampling scheme to determine ribociclib plasma exposure and pharmacokinetic parameters to derive a limited sampling model (LSM) for subsequent microdialysis studies. A cerebral microdialysis study of ribociclib (100 mg/kg, oral) was performed in CD1 nude mice bearing either orthotopic glioma (DIPGx7) xenografts or G3MB allografts, or in non-tumor bearing CD1 nude mice. Plasma samples at LSM derived time-points and microdialysis samples for every 1-hr interval were collected up to 7 or 24 hrs. Plasma and microdialysis samples were analyzed using a validated LC-MS/MS method. A one-compartment plasma model with two-compartment tumor model was fitted to all data using NONMEM. The ribociclib unbound area under the plasma concentration time curve was similar to that which was observed at tolerable clinical doses (e.g., 600 mg). The unbound tumor to plasma partition coefficient (Kp,uu) for ribociclib was 0.12 ± 0.09, 0.16 ± 0.11, and 0.07 ± 0.07 for normal brain, G3MB, and DIPG tumors, respectively. Using our pharmacokinetic model we simulated daily oral dosing, and observed that it did not accumulate in the brain/tumor after multiple dose administration. Overall, our results show ribociclib penetrates into the CNS and tumors, and warrant further preclinical investigation in treating pediatric CNS tumors.
Impact of newer treatment strategies on end of life chemotherapy for advanced NSCLC
Authors: J. M. Koeller, P. Kwan, R. Smith, J. Simon
Journal: Journal of Clinical Oncology (2004)

8076 Background: In one report of 144 patients (pts) with a variety of tumor types (27% lung cancer), 26% of pts received chemotherapy (chemo) within the last month (mo) of life (Aragon-Ching et al. Proc ASCO 22: #3119, 2003). For advanced (adv) NSCLC, 2nd-line treatment (tx) is now considered standard of care and 3rd-line tx was recently approved. With overall survival at 8 - 10 mo., chemo at the end of life may now be more common than previously thought. Methods: An on-site retrospective chart review of expired pts was carried out by a 4-member team in this adv NSCLC disease mapping research trial. Ten community oncology clinics participated. Results: We report on 417 pts treated with chemo for adv NSCLC (27% stage IIIb/73% stage IV). Fifty-seven per cent of pt records came from 2003/02, 27% from 2001 and 15% from 2000. The mean age was 67 yo. (median 62 yo.) and included 54% males. Fourty per cent of pts were >69 yo. and 35% were P.S. 2 or 3. First-line tx included combination chemo in 84% of pts. Second-line tx was given to 56% of pts (42% received combinations), 26% 3rd-line (23% received combinations), 10% 4th-line (21% combinations) and 5% 5th-line or greater. Pts received a mean of 6.1 cycles of chemo. Toxicity that caused a drug or dose change or tx delay was seen in 26% of 1st-line cycles, 25% of 2nd-line cycles, 19% of 3rd-line cycles, 17% of 4th-line cycles and 19% of 5th-line or greater cycles. The mean survival was 8.6 mo. (median 6.0 mo.) Chemo was given within one month of death to 30.4% of pts. The mean time from last chemo to death for all pts was 3.1 mo., with a median of 1.7 mo. Conclusions: With 2nd-line tx now common and 3rd-line tx recently approved for adv NSCLC, one can expect chemo near the end of life to become a more common practice even with a consistant degree of toxicity in community oncology practice. We found 30% of pts in the community treated within one month of death. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration MGI MGI
Serum Urate Levels Predict Joint Space Narrowing in Non‐Gout Patients With Medial Knee Osteoarthritis
Authors: Svetlana Krasnokutsky, Charles Oshinsky, Mukundan Attur, Sisi Ma, Hua Zhou, Fangfei Zheng, Meng Chen, Jyoti Patel, Jonathan Samuels, Virginia C. Pike, Ravinder Regatte, Jenny Bencardino, Leon Rybak, Steven Abramson, Michael H. Pillinger
Journal: Arthritis & Rheumatology (2017)

The pathogenesis of osteoarthritis (OA) includes both mechanical and inflammatory features. Studies have implicated synovial fluid uric acid (UA) as a potential OA biomarker, possibly reflecting chondrocyte damage. Whether serum UA levels reflect/contribute to OA is unknown. We investigated whether serum UA levels predict OA progression in a non-gout knee OA population.Eighty-eight patients with medial knee OA (body mass index [BMI] <33 kg/m2 ) but without gout were studied. Baseline serum UA levels were measured in previously banked serum samples. At 0 and 24 months, patients underwent standardized weight-bearing fixed-flexion posteroanterior knee radiography to determine joint space width (JSW) and Kellgren/Lawrence grades. Joint space narrowing (JSN) was calculated as the change in JSW from 0 to 24 months. Twenty-seven patients underwent baseline contrast-enhanced 3T knee magnetic resonance imaging for assessment of synovial volume.Serum UA levels correlated with JSN values in both univariate (r = 0.40, P < 0.01) and multivariate (r = 0.28, P = 0.01) analyses. There was a significant difference in mean JSN after dichotomization at a serum UA cut point of 6.8 mg/dl, the solubility point for serum urate, even after adjustment (JSN of 0.90 mm for a serum UA ≥6.8 mg/dl and 0.31 mm for a serum UA <6.8 mg/dl; P < 0.01). Baseline serum UA levels distinguished progressors (JSN >0.2 mm) and fast progressors (JSN >0.5 mm) from nonprogressors (JSN ≤0.0 mm) in multivariate analyses (area under the receiver operating characteristic curve 0.63 [P = 0.03] and 0.62 [P = 0.05], respectively). Serum UA levels correlated with the synovial volume (r = 0.44, P < 0.01), a possible marker of JSN, although this correlation did not persist after controlling for age, sex, and BMI (r = 0.13, P = 0.56).In non-gout patients with knee OA, the serum UA level predicted future JSN and may serve as a biomarker for OA progression.
Optimal Treatment Sequencing In Multiple Myeloma: An Exploratory Modeling Approach
Authors: Bart Heeg, Michel van Agthoven, Johan Liwing, Ulf-Henrik Mellqvist, Torben Plesner, Floris Logman, Verena Donatz, Johan Aschan, Hermann Einsele, Martin Kropff, Maarten Treur, Mirjam Barendse, Jean-Luc Harousseau, Antonio Palumbo, Pieter Sonneveld
Journal: Blood (2010)
GENT-35. MicroRNA miR100 INHIBITS GLIOBLASTOMA GROWTH BY TARGETING SMARCA5 AND ERBB3 IN GBM STEM-LIKE CELLS VIA TWO DISTINCT TRANSCRIPTS
Authors: Bahauddeen Al-Rfaei, Raghu Vemuganti, John Kuo
Journal: Neuro-Oncology (2016)

Glioblastoma (GBM) is the most aggressive brain cancer with a high recurrence rate and poor patient survival. miRNAs are powerful controllers of protein translation which can be therapeutically modulated to alter outcome in various diseases. We previously reported the role of microRNA-100 (miR100) in reducing GBM tumorigenicity. Here we analyze the effects of miR100 in patient-derived GBM stem-like cells (GSC), and uncover the roles of the two miR100 transcripts (miR100-5p, miR100-3p). Four patient-derived GSC lines were isolated and rigorously validated for stem marker expression, multipotent differentiation and tumor initiation. qPCR showed downregulated miR100 expression (50-80%) in all GSC lines compared to normal neural stem cell controls. miR-100 overexpression in GSCs by transient transfection resulted in inhibition of cell growth (20-50%) and proliferation (20-40%). SMARCA5 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 5) is highly expressed in stem-like cells, and inactive after terminal differentiation. We identified SMARCA5 in silico as a putative miR100-5p target, and verified via a SMARCA5 3’-UTR luciferase reporter assay. ERBB3 (Her3) is a member of the oncogenic epidermal growth factor receptor tyrosine kinase family that was identified in silico as a putative miR100-3p target, and verified via reporter assay. Overexpression of pre-miR100 (encodes both transcripts) mediated anti-tumorigenic activity via miR100-5p (upregulation of the cell cycle inhibitor p21, and inhibition of STAT3 phosphorylation), and miR100-3p (ERBB3 inhibition causes decrease in AKT and ERK phosphorylation). Inhibition of both SMARCA5 and ERBB3 by pre-miR-100 also reduced expression of GSC stem cell markers (L1CAM, Nestin). Orthotopic implantation of stably transfected miR-100-expressing GSCs show reduced tumor xenograft formation, and xenografts show decreased ERBB2 and ERBB3 activation. This study increases our understanding and reveals the potential tumor suppressor activities of two distinct miR-100 transcripts in GBM.
Acute and Chronic Renal and Hepatic Disease in Rats Fed Mirex: Reply
Authors: Borge M. Ulland
Journal: JNCI Journal of the National Cancer Institute (1977)

Journal Article Acute and Chronic Renal and Hepatic Disease in Rats Fed Mirex: Reply Get access Borge M. Ulland, D.V.M. Borge M. Ulland, D.V.M. Hazleton Laboratories America, Inc.9200 Leesburg Pike Vienna, Virginia 22180 Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 59, Issue 4, October 1977, Pages 1052–1053, https://doi.org/10.1093/jnci/59.4.1052 Published: 01 October 1977
Post-Treatment (not interim) PET-CT Scan Status Is Highly Predictive of Outcome In Mantle Cell Lymphoma Treated with R-Hypercvad or ASCT
Authors: Anthony R Mato, Tania Zielonka, Tatyana Feldman, Jakub Svoboda, Harry Agress, David Panush, Mitchell Miller, Patrick Toth, Elise A Chong, Emeline R Chong, Drew Torigian, Paul M Lizott, Stephen J. Schuster, Scott D Rowley, Michele L Donato, Stuart L Goldberg, Andrew L Pecora, Andre Goy
Journal: Blood (2010)
Gut Microbiota Promotes Obesity-Associated Liver Cancer through PGE2-Mediated Suppression of Antitumor Immunity
Authors: Tze Mun Loo, Fumitaka Kamachi, Yoshihiro Watanabe, Shin Yoshimoto, Hiroaki Kanda, Yuriko Arai, Yaeko Nakajima-Takagi, Atsushi Iwama, Tomoaki Koga, Yukihiko Sugimoto, Takayuki Ozawa, Masaru Nakamura, Miho Kumagai, Koichi Watashi, Makoto M. Taketo, Tomohiro Aoki, Shuh Narumiya, Masanobu Oshima, Makoto Arita, Eiji Hara, Naoko Ohtani
Journal: Cancer Discovery (2017)

Obesity increases the risk of cancers, including hepatocellular carcinomas (HCC). However, the precise molecular mechanisms through which obesity promotes HCC development are still unclear. Recent studies have shown that gut microbiota may influence liver diseases by transferring its metabolites and components. Here, we show that the hepatic translocation of obesity-induced lipoteichoic acid (LTA), a Gram-positive gut microbial component, promotes HCC development by creating a tumor-promoting microenvironment. LTA enhances the senescence-associated secretory phenotype (SASP) of hepatic stellate cells (HSC) collaboratively with an obesity-induced gut microbial metabolite, deoxycholic acid, to upregulate the expression of SASP factors and COX2 through Toll-like receptor 2. Interestingly, COX2-mediated prostaglandin E2 (PGE2) production suppresses the antitumor immunity through a PTGER4 receptor, thereby contributing to HCC progression. Moreover, COX2 overexpression and excess PGE2 production were detected in HSCs in human HCCs with noncirrhotic, nonalcoholic steatohepatitis (NASH), indicating that a similar mechanism could function in humans.Significance: We showed the importance of the gut-liver axis in obesity-associated HCC. The gut microbiota-driven COX2 pathway produced the lipid mediator PGE2 in senescent HSCs in the tumor microenvironment, which plays a pivotal role in suppressing antitumor immunity, suggesting that PGE2 and its receptor may be novel therapeutic targets for noncirrhotic NASH-associated HCC. Cancer Discov; 7(5); 522-38. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 443.
A prospective observational study of the impact on bone metabolism of short-term periodic steroid premedication of chemotherapy for gastrointestinal cancer. (ESPRESSO-01 study): pre-planed subgroup analysis
Authors: M. Nakamura, A. Ishiguro, T. Muranaka, S. Yuki, K. Ohno, T. Murai, C. Matsuda, A. Oba, K. Itaya, M. Yagisawa, Y. Koike, A. Endo, Y. Tsukuda, Y. Ono, T. Kudo, A. Nagasaka, S. Nishikawa, Y. Komatsu
Journal: Annals of Oncology (2016)
Phase I study of ribociclib plus cetuximab in patients with recurrent or metastatic squamous cell carcinoma of the head and neck
Authors: E. Seront, S. Schmitz, S. Rottey, S. Henry, C. Lonchay, G. van Caloen, A. Gilain, J.-P. Machiels
Journal: Annals of Oncology (2016)
Disease-Free Survival After Cord Blood (CB) Transplantation Is Not Different to That After Related or Unrelated Donor Transplantation in Patients with Hematologic Malignancies.
Authors: Doris Ponce, Junting Zheng, Anne Marie Gonzales, H.R. Castro-Malaspina, Katharine C Hsu, Ann Jakubowski, Robert R. Jenq, Guenther Koehne, Esperanza B Papadopoulos, Miguel-Angel Perales, Marcel R.M. van den Brink, James W. Young, Farid Boulad, Nancy A. Kernan, Rachel Kobos, Susan E Prockop, Andromachi Scaradavou, Trudy N Small, Richard J O'Reilly, Juliet Barker
Journal: Blood (2009)
Efficacy and circulating tumor DNA (ctDNA) analysis of the BRAF inhibitor dabrafenib (D), MEK inhibitor trametinib (T), and anti-EGFR antibody panitumumab (P) in patients (pts) with BRAF V600E–mutated (BRAFm) metastatic colorectal cancer (mCRC)
Authors: R.B. Corcoran, T. André, T. Yoshino, J.C. Bendell, C.E. Atreya, J.H.M. Schellens, M.P. Ducreux, A. McRee, S. Siena, G. Middleton, M. Gordon, Y. Humblet, K. Muro, E. Elez, R. Yaeger, R. Sidhu, M. Squires, S. Jaeger, F. Rangwala, E. Van Cutsem
Journal: Annals of Oncology (2016)
Mutational Analysis of Chronic Myeloid Leukemia (CML) Clones Reveals Heightened BCR-ABL1 Genetic Instability and Wild-Type BCR-ABL1 Exhaustion in Patients Failing Sequential Imatinib and Dasatinib Therapy.
Authors: Alfonso Quintás-Cardama, Don L. Gibbons, Hagop Kantarjian, Moshe Talpaz, Nick Donato, Jorge Cortes
Journal: Blood (2007)
Mandatory parental consent to abortion. Council on Ethical and Judicial Affairs, American Medical Association
Journal: JAMA (1993)

This report analyzes the ethical issues raised by requirements that parents be involved when minors seek an abortion. Parents are generally supportive and understanding and can provide helpful guidance to their children. In some cases, however, parents may respond abusively to the knowledge that their minor child is pregnant or is considering an abortion. In addition, privacy in matters of health care is a profound need of minors as well as adults. Accordingly, the Council concludes that, while minors should be encouraged to discuss their pregnancy with their parents and other adults, minors should not be required to involve their parents before deciding whether to undergo an abortion.
A swollen red finger
Authors: Wim Opstelten, Ruth Klaasen
Journal: BMJ (2017)

Thank you for your interest in spreading the word about The BMJ.NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address. Username * Your Email * Send To * You are going to email the following A swollen red finger Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
ReCaTuR -Rare Cancer Network Calabria -“Implementing a software system based on showing of 3D stereoscopic imaging data”
Authors: S. Turano, R. Biamonte, E. Zumpano, P. Veltri, G. Confessore, F. Dattola, I. Pellegrino, P. Iaquinta, M. Iusi, R. De Stefano, F. Romeo, S. Palazzo
Journal: Annals of Oncology (2016)
A multi-center, randomized, double-blind phase II trial of FOLFIRI + regorafenib or placebo for patients with metastatic colorectal cancer who failed one prior line of oxaliplatin-containing therapy
Authors: B. O'Neil, S. O'Reilly, S. Kasbari, R. Kim, R. McDermott, D. Moore, W. Grogan, A. Cohn, T. Bekaii-Saab, A. Ivanova, O. Olowokure, N. Fernando, J. McCaffrey, B. El-Rayes, A. Horgan, T. Ryan, G. Sherrill, G. Yacoub, R.M. Goldberg, H. Sanoff
Journal: Annals of Oncology (2016)
STMC-26. MULTIVALENT CATIONIC LIPOSOMES FOR siRNA TRANSFECTION OF PATIENT DERIVED GLIOMA INITIATING CELLS
Authors: Vagisha Ravi, A.B. Madhankumar
Journal: Neuro-Oncology (2016)

Glioma initiating cells (GICs) have been implicated as the root cause of treatment failure and tumor recurrence in glioblastoma multiforme (GBM). Therapeutic targeting of GICs is therefore essential to ensure effective treatment without relapse. A novel approach to modulate protein expression in cancer cells is the delivery of siRNAs using liposomes. However, past attempts to transfect cells using neutral liposomes have proven challenging and inefficient owing to the highly refractory nature of these cells. We therefore sought to develop a multivalent cationic liposome (MVCL) formulation for efficient and reproducible transfection of cancer initiating cells. The high valency and cationic charge on these liposomes allows binding to more siRNA molecules while increasing endocytosis into the cell due interactions with the negatively charged cell membrane. To test the ability of these liposomes to transfect GICs in vitro, we transfected CD133+ patient derived GICs with siRNA against the iron storage protein H-ferritin (Hft). Using this method of siRNA delivery, we were able to knockdown the expression of Hft in GICs compared to controls. The most effective Hft knockdown was observed at 48 and 72hours post transfection and was accompanied by a compensatory increase in the expression of light chain subunit of ferritin, L-ferritin. Past studies using Hft shRNA show reduced cell proliferation in GICs upon Hft downregulation. Consistent with this finding, we observed increased release of LDH in Hft siRNA treated GICs versus control and vehicle treated cells. These data suggest that Hft downregulation by itself might be lethal to GICs; a finding that is different from our previous report using astrocytoma cell lines. Thus, we show that MVCL liposomes possess the ability to efficiently transfect and deliver siRNA to patient derived cancer initiating cells providing a new means to modulate protein expression in GICs and a potential new target in H-ferritin.
P07.19 Fractal structure on gadolineum-enhanced MRI scans correlates with oxidative metabolism and VEGF expression in glioblastoma
Authors: S. Berendsen, K. J. Miller, W. G. M. Spliet, W. Van Hecke, T. Seute, K. Yeom, M. G. Hayden, G. A. Grant, P. A. Robe
Journal: Neuro-Oncology (2016)

AbstractIntroduction:In glioblastoma, VEGF expression promotes angiogenesis and has been reported to correlate with contrast enhancement on MRI scans. However, clinical results of anti-angiogenic therapy seem limited and there is a need to identify glioblastoma patients that might benefit from this treatment. Fractal structure is found throughout many processes in nature, and often arises from sets of simple growth rules. In this study, we examined the contrast enhancement patterns in MRI scans of glioblastoma patients for evidence of fractal structure and correlated these to biological tumor characteristics.Materials and Methods:For 39 glioblastoma patients, volumetric T1 post-contrast MRI scans were obtained before surgical resection. For each tumor, we calculated the fractal dimension (Minkowski-Bouligand dimension) using a box-counting (cubic scaling) approach. VEGF expression was determined with use of immunohistochemistry on tissue microarrays. RNA expression microarrays from fresh frozen tissue were explored with gene set enrichment analysis (GSEA).Results:We found robust evidence for fractal structure in the contrast enhancement pattern, with an average fractal dimension of 2.17 ± 0.10, with a visually apparent split at 2.10. High fractal dimension significantly correlated with increased VEGF expression. Additionally, GSEA analysis showed a clear association between high fractal dimension and a decrease of gene sets involved in oxidative phosphorylation.Conclusion:The presence of fractal dimensionality presents a new way to analyse classic gadolineum-enhanced T1 MRI scans of glioblastoma patients. The fractal dimension of the contrast enhancement pattern provides significant information on the tumor’s metabolism and might be used as a future biomarker for hypoxia or reponse to anti-angiogenic therapy.
P14.05 Bilateral hypoglossal palsy after radiation therapy for nasopharyngeal carcinoma: a case report
Authors: A. Silvani, A. Salmaggi, A. Rigamonti, L. Stanzani, V. Mantero, G. Rossi
Journal: Neuro-Oncology (2016)

BACKGROUND: Oxaliplatin (OXA) is the first-line chemotherapy agent in the treatment of colorectal (CRC).OXA-induced neuropathy is the most frequent long-term side-effect.Retreatment with OXA is frequently considered in patients as salvage treatment.MATERIAL: Patients receiving OXA-based chemotherapy regimen twice in our institution between 2009 and 2015 were reviewed.The aim of this study was to investigate whether retreatment with OXA increases the risk of developing or worsening previous OXA-induced peripheral neuropathy.The severity of neuropathy was measured by National Cancer Institute (NCI), Total Neuropathy Score (TNS) and nerve conduction studies (NCS).RESULTS: Sixty CRC patients were included in the analysis.Median age at OXA-based treatment was 61 years.29, 27, 2 and 2 patients received FOLFOX-4, FOLFOX-6, CAPOX and other OXA-based regimen, respectively, the first time, and 0, 53, 3 and 4 patients in the retreatment, respectively.After the first-line OXA-based chemotherapy, 56.8% of patients developed peripheral neuropathy, after a median of 11 [1-14] cycles.Severity of neuropathy was grade 1 (24.1%),grade 2 (29.3%), and grade 3 (3.4%).Mean time to retreatment with OXA was 29.46 ± 11.9 months.Frequencies of neuropathy before retreatment were as follows: 66.7% grade 0, 25% grade 1 and 8.3% grade 2. After retreatment, severities of neuropathy were 35.1% grade 1, 19.3% grade 2. No patient developed grade 3. 45.6% of patients did not develop neuropathy (grade 0).Peripheral neurotoxicity was the reason for stopping treatment prematurely after first-line and retreatment in 15% and 5 % of patients, respectively.Worsening of previous NCI score was observed in 23% of patients.The great majority of patients (77%) remained within the same NCI score than before retreatment.Median cycles in the retreatment were 7.5 [1-14].Among those patients that did not develop neuropathy according NCI (grade 0) after first treatment with OXA (n=26), only 4 (15%) and 2 (7%) patients developed grade 1 and 2, respectively, after a median of 7 [1-14] cycles.Among those patients who initially developed grade 2 and 3 neuropathy and had TNS assessment (n=19), no differences in median TNSc just before and after finishing retreatment with OXA were identified (6 [4-10] vs 6.5 [4-12], p=0.408).CONCLUSION: Retreatment with oxaliplatin in CRC patients is a feasible option even in patients who developed moderate or severe OXAinduced neuropathy previously.Lack of worsening of previous neurotoxicity is observed in the great majority of patients.Neurological monitoring of patients candidates to retreatment with OXA should be recommended to ensure the safety. P14.