tbuckley/cabot-search huggingface dataset:
A phase IIa study of PEGylated glutaminase (PEG-PGA) plus 6-diazo-5-oxo-L-norleucine (DON) in patients with advanced refractory solid tumors
Authors: C. Mueller, S. Al-Batran, E. Jaeger, B. Schmidt, M. Bausch, C. Unger, N. Sethuraman
Journal: Journal of Clinical Oncology (2008)

2533 Background: Our phase IIa study evaluated the safety and clinical activity of the glutamine depleting enzyme PEG-PGA in combination with DON. DON as a glutamine antagonist irreversibly inhibits key enzymes in the purine and pyrimidine synthesis. Based on the competitive mechanism, effectiveness of DON is greatly enhanced if plasma glutamine level is significantly depleted by PEG-PGA. Methods: In this multicenter study, patients (pts) with advanced solid tumors refractory to standard treatments were enrolled. Pts were treated with 120 I.U./m2 PEG-PGA (once weekly) and 140 mg/m2 DON (twice weekly) both as 15 min intravenous infusions. Three weeks were considered one cycle and tumor assessment (RECIST) was performed every two cycles. The primary endpoint was safety. Results: Fifty-five pts (20f/35m) were enrolled. Median age was 60 years (range 31–84). 30% had an ECOG PS <1. Pts were heavily pretreated and all had progressive disease at study entry. Treatment duration ranged from 1 to 379 days. Glutamine levels were depleted below 10% of baseline after the 2nd infusion of PEG-PGA and remained depleted in >90% of the patients. The treatment was very well tolerated. Most frequent (>2%) possibly related NCI-CTC grade 3 or 4 non-hematological toxicities were fatigue in 5 (9.1 %), nausea in 3 (5.5%), vomiting in 2 (3.6%) and diarrhea in 2 (3.6%) pts. Grade 3 or 4 hematological side effects were also rare, with neutropenia and thrombocytopenia being observed in 1 patient (pt), each. One pt with metastatic colorectal cancer (mCRC) experienced a confirmed partial response. One additional pt (mCRC) had a prolonged stable disease lasting > 12 months under treatment despite multiple lung metastases (>30). Among the pts with mCRC, 9/17 (53%) pts 5/17 (29%) pts were progression-free at 3 and 5 months, respectively. Signs of activity were also observed in pts with lung cancer. Five of six (83%) pts with lung cancer were progression-free 3 months after inclusion. Conclusions: PEG-PGA and DON were well tolerated and demonstrated activity in late stage colorectal and lung cancer. The therapeutic approach warrants further investigations. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Medical Enzymes AG
Long-term toxicity and associated cost of initial treatment and subsequent toxicity-related intervention for patients treated with prostatectomy, external beam radiotherapy, or brachytherapy: A SEER/Medicare database study.
Authors: Jay P. Ciezki, Chandana A. Reddy, Kenneth Angermeier, James Ulchaker, Kevin L. Stephans, Rahul D. Tendulkar, Andrew Altman, Nabil Chehade, Eric A. Klein
Journal: Journal of Clinical Oncology (2012)

4 Background: Treatment-related toxicity for prostate cancer (CaP) is rarely reported more than 5 years after therapy. We examined the SEER-Medicare linked database with the potential of having 16 years of follow-up data on toxicity requiring procedural intervention. Methods: The SEER-Medicare database was queried for CaP patients treated with prostatectomy (RP), external beam radiotherapy (EBRT), or brachytherapy (PI) between 1991-2007. We identified procedural billing codes associated with toxicity-related treatments. We obtained information on the Medicare reimbursement rates for the initial treatment and any toxicity-related interventions. We then computed the cost per patient-year within each treatment modality over time. Results: A total of 137,427 patients who were 65 years or older at the time of CaP diagnosis and who had CaP as their only cancer diagnosis were retrieved from the SEER/Medicare database: 59,559 (43.3%) treated with RP, 60,806 (44.2%) treated with EBRT, and 17,062 (12.4%) treated with PI. No patient received combined therapy. The median follow-up is 71 months. Overall, 10,585 (7.3%) patients experienced a toxicity requiring intervention. Within treatment modalities, the percentages receiving toxicity-related intervention were: RP 6.9%, EBRT 8.8%, and PI 3.7%. The gastrointestinal (GI) and genitourinary (GU) toxicity comparisons are listed in the table. Dilation of a urethral stricture was the most common GU toxicity (3.6% of all patients) while cauterization of rectal bleeding was the most common GI toxicity (0.8% of all patients). Conclusions: The long-term toxicity and cost per patient-year of the major prostate cancer treatment modalities differ. EBRT is the most toxic and most costly. [Table: see text]
Association of epithelial-mesenchymal transition with an immunosuppressive, inflammatory tumor microenvironment with elevated levels of checkpoint inhibitors in lung adenocarcinoma.
Authors: Yanyan Lou, Lixia Diao, Edwin Roger Parra Cuentas, Warren Denning, Limo Chen, You Hong Fan, Jaime Rodriguez, Lauren Averett Byers, Jing Wang, Vassiliki Papadimitrakopoulou, Carmen Behrens, Ignacio Ivan Wistuba, Patrick Hwu, John Heymach, Don Lynn Gibbons
Journal: Journal of Clinical Oncology (2015)

3030 Background: Promising results in the treatment of NSCLC have been seen with agents targeting immune checkpoints, such as programmed cell death 1 (PD-1) or programmed cell death 1 ligand (PD-L1). However, only a select group of patients respond to these interventions. The identification of biomarkers that predict clinical benefit to immune checkpoint blockade is critical to successful clinical translation of these agents. Epithelial-mesenchymal transition (EMT) is a key process driving metastasis and drug resistance. Previously we have developed a robust EMT gene signature, highlighting differential patterns of drug responsiveness for epithelial and mesenchymal tumor cells. Methods: We conducted an integrated analysis of gene expression profiling from three independent large datasets, including The Cancer Genome Atlas (TCGA) of lung and two large datasets from MD Anderson Cancer Center, Profiling of Resistance patterns and Oncogenic Signaling Pathways in Evaluation of Cancers of the Thorax (PROSPECT) and the Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE-1). Comprehensive analysis of mRNA gene expression, reverse phase protein array (RPPA), immunohistochemistry and in vivo mouse models were analyzed. Results: EMT is highly associated with an inflammatory tumor microenvironment in lung adenocarcinoma, independent of tumor mutational burden. We found immune activation co-existent with elevation of immune checkpoint molecules, including PD-L1, PD-L2, PD-1, TIM-3, BTLA and CTLA-4, along with increases in tumor infiltration by Foxp3+ regulatory T cells in lung adenocarcinomas that displayed an EMT phenotype. Similarly, IL-6 and indoleamine 2, 3-dioxygenase (IDO) were elevated in these tumors. Furthermore, we demonstrate that in murine models, many of these changes are recapitulated by modulation of the miR-200/ZEB1 axis, a known regulator of EMT. Conclusions: This study demonstrates EMT might represent a potential biomarker to select the patients who will benefit from immune checkpoint blockade agents and other immunotherapies in NSCLC and possibly other cancers.
Risk of Injurious Fall and Hip Fracture up to 26 y before the Diagnosis of Parkinson Disease: Nested Case–Control Studies in a Nationwide Cohort
Authors: Helena Nyström, Anna Nordström, Peter Nordström
Journal: PLoS Medicine (2016)

Background Low muscle strength has been found in late adolescence in individuals diagnosed with Parkinson disease (PD) 30 y later. This study investigated whether this lower muscle strength also may translate into increased risks of falling and fracture before the diagnosis of PD. Methods and Findings Among all Swedish citizens aged ≥50 y in 2005, two nested case–control cohorts were compiled. In cohort I, individuals diagnosed with PD during 1988–2012 (n = 24,412) were matched with up to ten controls (n = 243,363), and the risk of fall-related injuries before diagnosis of PD was evaluated. In cohort II, individuals with an injurious fall in need of emergency care during 1988–2012 (n = 622,333) were matched with one control (n = 622,333), and the risk of PD after the injurious fall was evaluated. In cohort I, 18.0% of cases and 11.5% of controls had at least one injurious fall (p < 0.001) prior to PD diagnosis in the case. Assessed by conditional logistic regression analysis adjusted for comorbid diagnoses and education level, PD was associated with increased risks of injurious fall up to 10 y before diagnosis (odds ratio [OR] 1.19, 95% CI 1.08–1.31; 7 to <10 y before diagnosis) and hip fracture ≥15 y before diagnosis (OR 1.36, 95% CI 1.10–1.69; 15–26 y before diagnosis). In cohort II, 0.7% of individuals with an injurious fall and 0.5% of controls were diagnosed with PD during follow-up (p < 0.001). The risk of PD was increased for up to 10 y after an injurious fall (OR 1.18, 95% CI 1.02–1.37; 7 to <10 y after diagnosis). An important limitation is that the diagnoses were obtained from registers and could not be clinically confirmed for the study. Conclusions The increased risks of falling and hip fracture prior to the diagnosis of PD may suggest the presence of clinically relevant neurodegenerative impairment many years before the diagnosis of this disease.
Renal Handling of Circulating and Renal-Synthesized Hepcidin and Its Protective Effects against Hemoglobin–Mediated Kidney Injury
Authors: Rachel P.L. van Swelm, Jack F.M. Wetzels, Vivienne G.M. Verweij, Coby M.M. Laarakkers, Jeanne C.L.M. Pertijs, Jenny van der Wijst, Frank Thévenod, Rosalinde Masereeuw, Dorine W. Swinkels
Journal: Journal of the American Society of Nephrology (2016)

Urinary hepcidin may have protective effects against AKI. However, renal handling and the potential protective mechanisms of hepcidin are not fully understood. By measuring hepcidin levels in plasma and urine using mass spectrometry and the kidney using immunohistochemistry after intraperitoneal administration of human hepcidin-25 (hhep25) in C57Bl/6N mice, we showed that circulating hepcidin is filtered by the glomerulus and degraded to smaller isoforms detected in urine but not plasma. Moreover, hepcidin colocalized with the endocytic receptor megalin in proximal tubules, and compared with wild-type mice, megalin-deficient mice showed higher urinary excretion of injected hhep25 and no hepcidin staining in proximal tubules that lack megalin. This indicates that hepcidin is reaborbed in the proximal tubules by megalin dependent endocytosis. Administration of hhep25 concomitant with or 4 hours after a single intravenous dose of hemoglobin abolished hemoglobin-induced upregulation of urinary kidney injury markers (NGAL and KIM-1) and renal Interleukin-6 and Ngal mRNA observed 24 hours after administration but did not affect renal ferroportin expression at this point. Notably, coadministration of hhep25 and hemoglobin but not administration of either alone greatly increased renal mRNA expression of hepcidin-encoding Hamp1 and hepcidin staining in distal tubules. These findings suggest a role for locally synthesized hepcidin in renal protection. Our observations did not support a role for ferroportin in hhep25-mediated protection against hemoglobin–induced early injury, but other mechanisms of cellular iron handling may be involved. In conclusion, our data suggest that both systemically delivered and locally produced hepcidin protect against hemoglobin-induced AKI.
Cost of chronic lymphocytic leukemia (CLL) in Medicare patients
Authors: M. Danese, M. Gleeson, C. Reyes, M. Pao, K. B. Knopf
Journal: Journal of Clinical Oncology (2008)

17531 Background: About 15,000 new cases of CLL are diagnosed annually in the United States but the direct medical costs attributable to CLL have not been delineated. Methods: We analyzed the CLL cost of care using SEER-Medicare data. Patients with CLL (including small lymphocytic lymphoma) as their first primary cancer were diagnosed from 1998–2002 with follow up through 2005. Patients had to have ≥ 1 year of prior non-HMO Medicare coverage. Costs were taken from claims for inpatient, outpatient and physician services. Control comparisons were made both to the pre-diagnosis 12 month period and to a 5% sample of Medicare patients without a cancer diagnosis. Linear regression models with robust standard errors were adjusted for age, co-morbidity score, diagnosis year, gender, and county of residence. Results: There were 3,999 patients who met the inclusion criteria. The median time from diagnosis to first chemotherapy was 199 days. The unadjusted mean monthly cost was similar regardless of control groups (∼$2,700). This cost declined over time but did not reach the pre-diagnosis level. Most costs were for inpatient and provider charges with chemotherapy representing 6.9% of 1st year and 8–10% of later year costs. After adjustment the incremental cost of CLL was $2,773/month for the first year compared to the 5% Medicare sample (p<0.05). Increasing age, male gender, and non-white race were significantly associated with increased monthly costs (p<0.01) Conclusions: CLL is associated with increased costs of care in the Medicare population, particularly in the first year after diagnosis where it is over $33,000 per patient. Mean monthly cost ($) relative to diagnosis date Health Service 12 Months Before 12 Months After 12–24 Months After 24–36 Months After Medicare 5% Sample Inpatient facility 287 2244 1038 1005 227 Provider 172 901 573 753 133 Outpatient facility 11 25 20 23 5 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genentech Genentech Genentech
Irreversible encephalopathy with ifosfamide/mesna.
Authors: E Salloum, F Flamant, M Ghosn, N Taleb, C Akatchereian
Journal: Journal of Clinical Oncology (1987)

Article Tools Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1987.5.8.1303 Journal of Clinical Oncology - published online before print September 22, 2016 PMID: 3114437 Irreversible encephalopathy with ifosfamide/mesna. E SalloumxE SalloumSearch for articles by this author , F FlamantxF FlamantSearch for articles by this author , M GhosnxM GhosnSearch for articles by this author , N TalebxN TalebSearch for articles by this author , C AkatchereianxC AkatchereianSearch for articles by this author https://doi.org/10.1200/JCO.1987.5.8.1303 PDF "Irreversible encephalopathy with ifosfamide/mesna.." Journal of Clinical Oncology, 5(8), pp. 1303–1304© 1987 by American Society of Clinical Oncology
Identification of SGK1 as a novel predictive marker for treatment response in medulloblastoma
Authors: D. Sturm, M. Remke, S. Pleier, H. Witt, G. Reifenberger, J. Felsberg, A. Kulozik, A. Korshunov, P. Lichter, S. Pfister
Journal: Journal of Clinical Oncology (2009)

10006 Background: We have recently demonstrated that both gains (5-year OS 16%) and losses (5-year OS 100%) of chromosome 6q define distinct clinical and biological subgroups of medulloblastoma. However, the underlying molecular mechanisms accounting for the prognostic impact of these aberrations so far remained unclear. Methods: To identify potential candidate genes on chromosome 6q targeted by these genomic aberrations, a genome wide mRNA expression profiling study was performed for 47 well-characterized medulloblastoma samples and correlated to chromosome 6q DNA copy-number status. Results were validated by real-time quantitative PCR (RTQ-PCR). SGK1 protein expression was examined by immunohistochemistry on a tissue-microarray which represents a large independent cohort of uniformly treated medulloblastoma patients (n = 260). Results of both studies were correlated with survival data available for all investigated samples. Results: Expression profiling revealed the AKT homologue SGK1 as an interesting candidate gene on chromosome 6q showing very close correlation to 6q copy-number status. Direct correlation could be confirmed by RTQ-PCR showing that SGK1 mRNA levels were significantly upregulated in tumors with gain of chromosome 6q (median log2-ratio when normalized against normal cerebellum = 3.88) and, in contrast, downregulated in cases carrying deletions of this region (median log2-ratio = -1.97). On protein level, we found high SGK1 protein levels to be highly associated with poor overall survival as assessed by immunohistochemistry (Kaplan-Meier method; p &lt; 0.00001). Conclusions: We identified SGK1 as an interesting novel candidate gene on chromosome 6q contributing to the striking differences in overall survival of cases with chromosome 6q gain or loss, who are known to have a very poor or especially good prognosis, respectively. The fact that SGK1 encodes for a serum- and glucocorticoid inducible kinase which is both structurally and functionally homologous to the antiapoptotic kinase AKT further underlines the potential role of this gene. Based on the reported results, we propose SGK1 protein expression as a novel prognostic marker in medulloblastoma. No significant financial relationships to disclose.
Myeloproliferative neoplasms and inflammation: whether to target the malignant clone or the inflammatory process or both
Authors: S Koschmieder, T I Mughal, H C Hasselbalch, G Barosi, P Valent, J-J Kiladjian, G Jeryczynski, H Gisslinger, J S Jutzi, H L Pahl, R Hehlmann, A Maria Vannucchi, F Cervantes, R T Silver, T Barbui
Journal: Leukemia (2016)
A phase II clinical trial utilizing maximum medical and surgical cytoredutive treatments for patients with metastatic colorectal cancer to the liver
Authors: S. D. Glisson, R. V. LaRocca, J. B. Hargis, A. Cervera, G. Goldsmith, B. Cornell, D. D. Repishti, J. E. Sunderland
Journal: Journal of Clinical Oncology (2009)

e15130 Background: The median overall survival (‘OS‘) for patients with mCRC treated with chemotherapy is about 20.4 months. Combination chemotherapy with surgical cytoreduction for patients with liver metastases are evaluated in a phase II clinical trial. Methods: Patients with newly diagnosed mCRC to the liver or recurrent CRC after 5FU failure were consented to receive further chemotherapy with at least irinotecan-based chemotherapy, oxaliplatin-based chemotherapy, and with the intention to treat the liver metastases with either RFA and/or liver resection between chemotherapy regimens whenever possible. Bevacizamab and cetuximab were considered options for treatment after their respective FDA approvals. Chemotherapy was given until there was treatment failure. The primary endpoint was OS. Results: Between 2001 and 2004 thirty-seven patients aged 41 to 79 were consented. One remained alive by December 2008. Only patients with an ECOG performance status of 0–1 were consented. Twenty had been treated with 5FU for a stage III CRC befored developing mCRC. All patients received irinotecan in the form of FOLFIRI, IFL, or as a single agent. Thirty-six also received oxaliplatin in the form of either FOLFOX4 or 6. Twenty-two patients received cetuximab as a single agent. Some regimens were augmented with bevacizumab. Fourteen patients could not undergo resection or RFA because of performance status or progression. Three required radiation to the CNS or distant bone. There were eleven patients who underwent RFA of at least one liver metastasis. There were ten patients who underwent liver resection. One patient underwent both RFA and liver resection at two different times. Another patient underwent RFA, adrenalectomy and wedge resection of the lung at three different times. He remained alive at 78 months at the time of submission. Median OS was 34.5+ months at the time of submission. Patient survival ranged from 15 to 86 months. There were no deaths associated with any surgical intervention. Conclusions: OS was improved in mCRC patients or recurrent CRC patients who had potentially ablatable or resectable liver lesions at the time of their diagnosis and who were treated with available aggressive medical and surgical therapies. [Table: see text]
Updated activity and safety results of a phase II randomized discontinuation trial (RDT) of AV-951, a potent and selective VEGFR1, 2, and 3 kinase inhibitor, in patients with renal cell carcinoma (RCC)
Authors: P. Bhargava, B. Esteves, D. A. Nosov, O. N. Lipatov, A. A. Lyulko, A. A. Anischenko, R. T. Chacko, P. Lee, M. Al-Adhami, J. Ryan
Journal: Journal of Clinical Oncology (2009)

5032 Background: AV-951 is a potent inhibitor of VEGFR-1, 2 &amp; 3 kinases (IC 50 0.21, 0.16 and 0.24 nM respectively), and inhibits cKit and PDGFR at 10-times higher concentrations (IC 50 1.63 and 1.72 nM respectively). In a phase II RDT of AV-951 (1.5 mg/day; 3 wks on, 1 wk off) in RCC, preliminary ORR at wk 16 was 28% (ASCO GU. 2008; abstract #283). Methods: Pts with locally advanced or metastatic RCC (any histology) and no prior VEGF-targeted therapy received AV-951 for 16 wks, after which further treatment was assigned based on response. Pts with ≥ 25% tumor shrinkage continued treatment with AV-951, while pts with &lt; 25% change from baseline were randomly assigned to receive AV-951 or placebo for 12 wks (double-blinded). The primary end points were (1) objective response rate (ORR) at 16 wks, (2) percentage of randomly assigned pts remaining progression free at 12 wks following randomization, (3) safety profile. Results: 272 pts were enrolled: 70% male, 93% white, median age 56 yrs. 53% pts were treatement naïve, 72% had undergone nephrectomy and 83% had RCC with clear cell component. With a median duration of treatment of 5 mo (range 0–12 mo), the investigator assessed ORR (CR+PR) is 27.2% (30% in clear cell RCC), SD 60.5% and Disease Control Rate (CR/PR + SD) 88%. 118 (43%) pts were randomized to AV-951 or placebo. The most common treatment-related AEs (all grades) were hypertension (HTN, 42%) and dysphonia (16%). Guidelines for management of HTN were provided to investigators, and 52% pts received anti-hypertensives. Minimal (all grades) diarrhea (9%), fatigue (8%), stomatitis (3%) and hand-foot syndrome (2%) were observed. Laboratory abnormalities (all grades) were notable for minimal neutropenia (8%) and elevations of AST (21%) and ALT (21%). AEs led to dose reduction in 4% and treatment discontinuation in 5.5% of pts. Conclusions: Interim results of this phase II study demonstrate that AV-951 is active in RCC. The AE profile of AV-951 is consistent with that of a selective VEGFR inhibitor, with minimal off-target toxicities. Updated results of ORR (including independent radiology assessment), safety, percentage of randomly assigned pts remaining progression free at 12 wks, and overall PFS will be presented. [Table: see text]