bluuebunny/crossref_metadata_2025_split huggingface dataset:
Metabolic profiles of ketolysis and glycolysis in malignant gliomas: Possible predictors of response to ketogenic diet therapy.
Authors: Chang Howard T. , Olson Lawrence Karl , Schwartz Kenneth A. 
Published: March 2020

e13048 Background: The enzymatic differences in energy metabolism between normal brain tissues and malignant gliomas formed the basis for animal model studies that showed increased survival in mice with orthotopically transplanted glioblastoma multiforme (GBM) treated with energy restricted ketogenic diet (ERKD). To test the hypothesis that human brain tumors may also be sensitive to ERKD, we used immunohistochemistry reactions on formalin fixed paraffin embedded tumor samples to evaluate for the presence of enzymes important for the metabolism of ketones and glucose. Methods: Immunoreactivities were graded using a semi-quantitative scale based on the percentage of positive cells: low positive<5% (LOW); intermediate (INT) 5-20%; and highly positive (HIGH) >20%. Focal non-neoplastic “normal” brain tissue present within the specimens served as positive internal controls. Results: Succinyl CoA: 3-oxoacid CoA transferase (OXCT1) and 3-hydroxybutyrate dehydrogenase 1 (BDH1) are mitochondrial enzymes important for metabolizing beta hydroxy butyrate, the main ketone in blood. Both of these enzymes were either decreased or absent (INT or LOW) concordantly in 14 of the 17 (82%) GBMs, and in 1 of 6 (17%) anaplastic astrocytomas (AA). Two of the enzymes in the glycolytic pathway hexokinase-2 and pyruvate kinase M2 were concordantly LOW or INT in only 3 of the 17 GBMs that also were LOW or INT for both OXCT1 and BDH1. The remaining brain tumors were positive for at least one of these glycolytic enzymes. Mitochondrial enzymes were not globally deficient. The mitochondrial enzyme acetyl CoA transferase (ACAT1) was present in 9 of the 14 GBM specimens that were LOW or INT for the mitochondrial enzymes OXCT1 and BDH1. Conclusions: Our data showing that many, but not all, malignant gliomas lack ketolytic enzymes, support the rationale of ERKD as investigational treatment for patients with malignant gliomas. Moreover, we hypothesize that it is important to test individual tumor samples for the expression of these enzymes prior to ERKD, as patients with malignant gliomas that have diminished capacity to metabolize ketones likely may derive the most benefit from ERKD.
Final results of a phase I study evaluating the combination of linsitinib, a dual inhibitor of insulin-like growth factor-1 receptor (IGF-1R), and insulin receptor (IR) with weekly paclitaxel (PAC) in patients (Pts) with advanced solid tumors.
Authors: Harb Wael A. , Sessa Cristiana , Hirte Hal W. , Kaye Stanley B. , Banerjee Susana N. , Christinat Alexandra , Simantov Ronit , Singh Margaret , Sternberg David W. , Light Rebecca , Poondru Srinivasu , Naumann R. Wendel 
Published: March 2020

e13502 Background: Linsitinib (OSI-906) is an oral inhibitor of IGF-1R and IR. Increased IGF-1R and IR activity is observed in human cancers and implicated in resistance to chemotherapy. In preclinical studies, linsitinib blocked IGF-1R/IR-AKT pathway activity evoked by PAC treatment. This study combines linsitinib + a cytotoxic agent. Methods: Pts with advanced solid tumors received weekly IV PAC (80mg/m2) in 21-day cycles with intermittent linsitinib (Arm A, d1-3q7d) or continuous linsitinib (Arm B, B2 and B3, twice daily (BID) d1-21). The primary objective was to determine the maximum tolerated dose (MTD) of linsitinib + PAC using a standard 3+3 phase I design. Results: 58 pts were treated (49F:9M, median age 58 yrs). Linsitinib doses of 300mg to 600mg daily (QD) d1-3q7d in Arm A and 75mg to 150 mg BID in Arm B were evaluated. Dose limiting toxicities in Arm A (n=27) were grade G3 neutropenia, G2 neuropathy and G3 deep vein thrombosis (DVT), and in Arm B (n=31) were G3 hyperglycemia, G3 fatigue (n=2) and G4 pulmonary embolism (PE). DVT and PE were reported as unrelated to linsitinib. MTD: Arm A = 600mg QD d1-3q7d Arm B = 150mg BID. Most common drug-related toxicities in ≥20%were (any grade; G3): fatigue (60%; 15.5%), nausea (48%; 0%), alopecia (48%; 0%), diarrhea (36%; 5%), drug eruption (21%; 2%), neuropathy (26%; 2%) and dysgeusia (24%; 0%). The median duration of exposure (days) for Arm A was 64.5, 91.0, 132.0 and 159.5 for the 300mg, 400mg, 450mg and 600mg doses, respectively. In Arm B, median duration of exposure (days) was 232.0 and 87.5 for the 75mg and 150mg doses, respectively. Partial response was achieved in 6 pts (10%)-3 ovarian, 1 primary peritoneal, 1 endometrial, and 1 esophageal. Stable disease was achieved in 25 pts (43%) - 10 ovarian, 2 primary peritoneal, 1 endometrial, and 12 pts in other tumor types. Pharmacokinetic (PK) results suggested no substantial PK interaction when linsitinib was administered 2 hours prior to PAC. Conclusions: Linsitinib + PAC did not show any unexpected safety concerns given the known mechanism of action, at doses up to the single agent MTDs. Clinical trial information: NCT00889382.
Effect of treatment with hedgehog inhibitor, PF-04449913, on leukemia-initiation potential in acute myeloid leukemia cells.
Authors: Minami Yosuke , Fukushima Nobuaki , Naoe Tomoki 
Published: March 2020

e13520 Background: Aberrant activation of the Hedgehog (Hh) signaling pathway is involved in a variety of cancers, and required for maintenance of the leukemic stem cell population in several experimental systems. PF-04449913 (PF) is a novel oral small molecule inhibitor that targets Smoothened (SMO) in the Hh pathway. Treatment with PF has shown promising results regarding safety, tolerability, and early signs of efficacy in a phase 1 study of hematologic malignancies including acute myeloid leukemia (AML) (Jamieson C, et al. ASH, 2011). Methods: We used AML cell lines and primary AML cells in order to elucidate mechanisms and biomarkers in PF treatment. We also used a co-culturing system with HS-5 stromal cells, and an immunodeficient NOD/SCID/IL2rγnull (NOG) mouse model serially xenotransplanted with primary AML cells to evaluate effects of PF on AML propagation. Results: In vivo-treatment with PF attenuated leukemia-initiation potential in acute myeloid leukemia cells through the serial transplantation system, while limiting reduction of tumor burden in the primary leukemia system. Ex vivo-treatment with PF inhibited proliferation and minimally induced cell death in leukemia cell lines and primary AML cells increased expression of the myeloid differentiation marker, CD11b. In addition, PF treatment down-regulated mRNAs encoding downstream effector GLIs in the canonical Hh pathway using RQ-PCR assays and decreased nuclear expression of GLI-2 using immunofluorescence assays. Moreover, combined treatment with PF abrogated resistance to Ara-C in MOLM-14 cells co-cultured with HS-5 stromal cells. We are also investigating biomarkers in these models including CD markers (such as CD44) as well as the toxicity for normal cord blood cells with PF treatment. Conclusions: These results imply that PF treatment can attenuate leukemia-initiation potential in acute myeloid leukemia cells and improve AML therapy through overcoming the resistance to chemotherapy in the bone marrow microenvironment.
Personality disorders as a result of symptom of chemotherapy-related cognitive impairment (CRCI) antiangiogenic treatment for metastatic renal cancer: A case report of 71-year-old women.
Authors: Wachula Ewa , Zok Jolanta , Ziomek Marzenna , Wysocki Piotr Jan , Rogowski Wojciech 
Published: March 2020

e13560 Background: Chemotherapy-related cognitive impairment, known also as chemo brain, is defined as cognitive changes experienced by patients undergoing chemotherapy, especially in aspects of visual and verbal memory, attention and psychomotor functions. Cognitive changes and dysfunction after common cancer chemotherapy and recently appearing after biologic agents are increasing as a disturbing side-effect in cancer survivors. The etiology of this phenomenon is not well understood. Methods: We present the case of 71-year- old female, with metastatic renal cancer who are exposed to anti-angiogenic treatment for years.From 2005 to 2009 the patient was treated by combination therapy which consisted of bevacizumab and INF-alfa.The anti-angiogenic therapy was discontinued prematurely because of cardiac toxicity. Partial response of metastatic lesions was achieved as a result of the treatment. In 2010, new metastases were found, and a second line therapy by m-TOR inhibitor everolimus was commenced. Because of hematological toxicity of CTC grade 3, the patient required a 50% dose reduction. During anti-angiogenic treatment some psychiatric symptoms such as paranoid personality disorders, memory impairment, dementia, emotional coldness and social withdrawal were observed. Results: In laboratory tests any electrolytes and metabolic imbalance were noticed. The CT and the MR imaging of the head excluded any structural damages and focal brain parenchymal lesions. Psychotherapy and pharmacotherapy were suggested.The patient is still on everolimus until now in order to maintain stabilization. Conclusions: The chemotherapy-related cognitive impairment can be problematic for survivors. Better understanding factors that contribute to chemotherapy-related cognitive dysfunction is important because this information could identify patients at risk and inform treatment.
Pharmacologic differences in taxanes leading to difference in clinical activity and toxicity.
Authors: Deshmukh Chetan Dilip , Divekar Ganesh , Jain Minish Mahendra , Bondarde Shailesh Arjun , Bhatt Niraj 
Published: March 2020

e13567 Background: Paclitaxel and docetaxel share major parts of their structures and mechanism of action, but differ in several aspects. Both paclitaxel and docetaxel act at microtubule causing tubulin polymer generation but exhibit pharmacodynamic differences. These pharmacological differences may account for the differences observed between taxanes in their clinical activity and toxicity. Methods: Review of articles providing details of taxane pharmacology was conducted to evaluate pharmacological basis. Results: Greater uptake and slower efflux of docetaxel from tumor cells leads to longer retention time; whereas equal uptake and efflux of paclitaxel shorter retention time for paclitaxel. Hence, apoptotic and mitotic responses of paclitaxel is complete within 4 days implying that more frequent (weekly) administration of paclitaxel will be superior. High affinity to β-tubulin with docetaxel (1.9) than with paclitaxel (1.0) allows higher inhibition of tumor growth. Secondly, drug concentration causing maximum polymerization is 0.2 µM and 0.4 µM for docetaxel and paclitaxel, respectively; indicating that docetaxel is twice as potent as paclitaxel in causing microtubule polymerization. Docetaxel arrests cells in the radiosensitive G2/M phase of the cell cycle making it a potent radiosensetizer than paclitaxel. Mechanisms consistent with allosteric modulation of the reductases increase doxorubicinol formation at clinically relevant concentrations of paclitaxel when it is administered with doxorubicin. Enhanced formation of doxorubicinol aglycone, a metabolite potentially involved in the reversible phase of cardiotoxicity causes higher cardiotoxicty when doxorubicin is administered with paclitaxel than with docetaxel. Non linear pharmacokinetics and hypersensitivity with paclitaxel and fluid retention with docetaxel is attributed to excepient of the drug rather than drug itself. Conclusions: Influx and efflux mechanism support superior weekly administration of Paclitaxel. Pharmacological differences between taxanes justify the incomplete resistance seen between taxanes. The incomplete cross resistance is specifically related to docetaxelactivity in paclitaxel resistant cases.
Incidence of mucositis in patients treated with mTOR inhibitor-based regimens and correlation to treatment response.
Authors: Liu Xiaochun , Hong David S. , Fu Siqing , Piha-Paul Sarina Anne , McQuinn Lacey , Falchook Gerald Steven , Williams Jessica , Karp Daniel D. , Subbiah Vivek , Tsimberidou Apostolia Maria , Janku Filip , Zinner Ralph , Wheler Jennifer J. , Wolff Robert A. , Kurzrock Razelle , Naing Aung 
Published: March 2020

e13575 Background: Mucositis is a well-known side effect of mTOR inhibitor (temsirolimus) treatment of cancer patients, limiting the use of mTOR inhibitors. We investigated whether combination treatment of temsirolimus with another agent that was not known to cause mucositis would result in a higher or lower incidence of mucositis. We further investigated if there was an association between the severity of mucositis and tumor response to the temsirolimus-based combination treatment. Methods: This retrospective data review was approved by IRB and conducted in the department of Investigational Cancer Therapeutics at MD Anderson Cancer Center. We reviewed the electronic medical records of 87 patients who were enrolled in temsirolimus-based combination phase I trials (n=3), including physician notes from the date they enrolled on the study to the date they came off treatments. We first examined the incidence of mucositis during the course of study and its severity. We assessed patient response to the study treatment with severity of the mucositis. Results: The overall incidence of mucositis in the 3 temsirolimus-based combination trials was 46%, similar to the published data for the single agent of 41%. The grades of mucositis were: for grade 1 (n=14), grade 2 (n=17) and grade 3 (n=9). No grade 4 mucositis was observed. Neither gender nor ethnicity altered the incidence of mucositis. The median onset time was 14 days after the start of the studies. Of 87 patients, 20 responded to the study treatments with at least stable disease for longer than 6 months or a partial or complete response. The incidence of the mucositis was not associated with the response to temsirolimus-based treatment. Severity of mucositis did not correlate with response to the temsirolimus-based regimen. (grades 1/2 vs. ≥ grade 3; p=0.512). Conclusions: The incidence of mucositis did not increase significantly in patients who received a temsirolimus-based regimen compared to single-agent temsirolimus. Severity of mucositis did not correlate with tumor response to the temsirolimus-based regimen. Future study is warranted to optimize management for mTOR inhibitor-induced mucositis.
Paclitaxel in combination with AT-101 induces apoptosis via supressing Bcl-2, bcl-XL, mcl-1 proteins in human breast cancer cells.
Authors: Cakar Burcu , Gursoy Pinar , Atmaca Harika , Kisim Asli , Bozkurt Emir , Uzunoglu Selim , Sezgin Canfeza , Sanli Ulus Ali , Karabulut Bulent , Uslu Ruchan , Karaca Burcak 
Published: March 2020

e13578 Background: Paclitaxel, a microtubule stabilizing agent, has been a standard of care for breast cancer. AT-101, is an -/- enantiomer of gossypol, inhibits the Bcl-2 family proteins which contain BH3 domain. We reported previously that Paclitaxel in combination with AT-101 showed strong synergistic cytotoxic and apoptotic effects in human breast cancer cells. In this study, to elucidate the molecular mechanisms involved in the apoptotic effect of AT-101/Paclitaxel combination treatment in breast cancer cells, we investigated the possible roles of anti-apoptotic Bcl-2, Bcl-XL and Mcl-1 proteins which contain BH3 domain. Involvement of caspase 3 and 7 activation was also investigated. Methods: Human breast cancer cells were treated with increasing concentrations of drugs alone or with the synergistic combination doses of AT-101 and Paclitaxel. Cell Death Detection Elisa Plus Kit (Roche) was used to detect apoptosis. Caspase 3/7 activity was evaluated by Caspase-Glo 3/7 (Promega, Madison, WI) kit. Changes in the mRNA levels of Bcl-2, Bcl-XL and Mcl-1 genes were evaluated by qRT-PCR. Expression levels of these proteins were also investigated by Western blot analysis. Results: Combined treatment was shown to have strong synergistic apoptotic effects in MCF-7 and MDA- MB-231 human breast cancer cells. mRNA levels of Bcl-2, Bcl-XL and Mcl-1 molecules were reduced by the combination treatment in both cell lines. In parallel with mRNA levels, Bcl-2, Bcl-XL and Mcl-1 protein levels were significantly reduced after this novel drug combination. Combined treatment also induced caspase 3/7 activation in breast cancer cells. Conclusions: These preliminary data suggest that anti-apoptotic proteins such as Bcl-2, Bcl-XL and Mcl-1 may play important role in the underlying mechanistic rationale of apoptotic effect of AT-101/paclitaxel combination, while pro-apoptotic Bcl-2 related genes (Caspase-3 and Caspase-7) also seem to regulate this synergistic interaction.
The radiosensitization effect of mTOR inhibitior in human tongue squamous cell carcinoma.
Authors: Su Yu-Chieh , Hung Shih-Kai , Yu Chi-Chia , Lee Ching-Chih , Li Szu-Chin , Lai Hung-Chih 
Published: March 2020

e13585 Background: mTOR plays a critical role in malignant phenotype in many tumors. Everolimus [RAD001 (40-O-(2-hydroxyethyl)-rapamycin)] is a rapamycin rapalog that is being developed as an antitumor agent and is approved for various cancers. Recently, RAD001 has also been reported to increase the radiosensitization following for amplifying the autophagic pathway; however, it could promote an alternative mechanism that leads to apoptosis. In HNSCC, radiation therapy is a common form of cancer treatment, but locoregional recurrence and/or distant metastasis is the most cause of failure after RT and it results in HNSCC significant morbidity. Evidence from previous studies showed that RAD001 enhanced the cytotoxic effects of radiation in HNSCC cell lines. The molecular mechanism of radiosensitization by RAD001 in HNSCC has not cleared.Our aim is to evaluate the role of molecular mechanism of RAD001-mediated radiosensitization in HNSCC. Methods: Radiosensitivity effects of RAD001 were assays on human oral squamous cell carcinoma cell lines (SCC4 and DuFa). RAD001 (30 and 300 nM)and radiation (0~8 Gy) alone and in combination were evaluated for antitumor activity in the clonogenic assay. Next, we also evaluated the RAD001 on radiation-induced signal transduction by western blot analysis. Results: Here, we show that 300nM RAD001 plus 6 Gy cohort with significant HNSCC cell line growth suppression compared to 6 Gy alone (p=0.004) or 30n MRAD001 plus 6 Gy (p=0.008). RAD001 treatment effectively reduces mTOR downstream effector p-S6 protein compared with the vehicle or irradiated alone. RAD001 + 6 Gy significantly increases p53 and PARP cleavage, which facilitates apoptosis. Unexpectedly, autophagy pathway, such as beclin 1 and LC3II were not affected by RAD001. Addiationlly, we discover that Akt phosphorylation (Ser473) is up-regulated after RAD001/and irradiation of HNSCC cells. Conclusions: These findings suggest radiosensitization by the RAD001 involves the induction of apoptosis in HNSCC. Notwithstanding, Akt signaling is increased under RAD001 and it could attenuate anticancer efficacy instead, contribute to the development of resistance.
Patient compliance to oral anticancer chemotherapy evaluated in breast and colorectal cancer patients receiving capecitabine: The OCTO study.
Authors: Henin Emilie , Bourmaud Aurelie , Colomban Olivier , Schwiertz Vérane , Regnier Veronique , You Benoit , Ranchon Florence , Guitton Jerome , Maraval-Gaget Raymonde , Girard Pascal , Chauvin Franck , Freyer Gilles , Tod Michel , Rioufol Catherine , Trillet-Lenoir Veronique N. 
Published: March 2020

e13594 Background: Given the expanding use of oral chemotherapies, optimal compliance to treatment is critical to achieve the best clinical outcome in terms of efficacy and safety. The aim of the OCTO clinical study was to measure patient compliance, either electronically or by self-assessment, to capecitabine-based treatment. Methods: A cohort of patients with either locally advanced or metastatic, breast or colorectal, cancer were monitored for 6 cycles, and ambulatory treated with monotherapy of capecitabine (Xeloda). Treatment was prescribed at 1250 mg/m² as a combination of 500 and 150 mg pills, taken twice daily for 14 days every 3-week cycle. Tumor response was evaluated after 3 and 6 cycles using the RECIST criteria. Toxicity was evaluated using the NCI CTC scale. Compliance was assessed in all patients by self-completed questionnaires on disease, treatment and ambulatory management of side effects; and in half of the cohort by electronic medication event monitoring systems (MEMS) recording the opening times of the pill bottle. Results: Forty patients were enrolled between November 2008 and September 2011 and treated by capecitabine for an average of 4.75 cycles (range: 1-6). 63% patients completed 6 cycles, 22% and 15% patients discontinued due to respectively disease progression and adverse events. Best tumor response was evaluable in 35 patients: 23% had partial response, 54% stable disease and 23% progressed. Hand-foot syndrome was the most reported toxicity (77% patients), and to a lesser extent diarrhea (45%), nausea (30%) and vomiting (30%). In the MEMS cohort, 20 patients were included. Patient compliance was excellent with very few missing occasions (23/2272 records). Timing of morning doses was less variable (p=0.03) than timing of evening ones. Thirty-eight questionnaires were returned. Autonomy of ambulatory oral treatment was appreciated by 54% patients, while resulting in anxiety in 6%. Only 39% patients were concerned by the potential impact of non-compliance while 45% declined answering the question. Conclusions: Compliance to oral anticancer chemotherapy was found excellent in this population, with few deviations from prescription.