tbuckley/cabot-search huggingface dataset:
Enhancement of Fluorouracil Uptake in Human Colorectal and Gastric Cancers by Interferon or by High-Dose Methotrexate: An In Vivo Human Study Using Noninvasive <sup>19</sup>F-Magnetic Resonance Spectroscopy
Authors: Cary A. Presant, Walter Wolf, Victor Waluch, Charles L. Wiseman, Ilene Weitz, Jashovam Shani
Journal: Journal of Clinical Oncology (2000)

PURPOSE: To study whether two modulators, high-dose methotrexate (MTX) and interferon alfa-2a (IFNα-2a) will alter the intratumoral pharmacokinetics of fluorouracil (5-FU). PATIENTS AND METHODS: Five patients, two with gastric cancer and three with colorectal cancer, who had metastatic tumor nodules in their livers were studied dynamically in vivo after 5-FU injection. In a magnetic resonance imaging unit, noninvasive 19 F-magnetic resonance spectroscopy (MRS) was used to detect 19 F signals from 5-FU and its metabolites. RESULTS: The intratumoral half-life (t 1/2 ) of 5-FU in these tumors ranged from 18.8 minutes to 42.3 minutes. Four of the five patients exhibited increases in the t 1/2 of 5-FU after intravenous (IV) administration of MTX or IFNα-2a. In the two patients with gastric cancer who received IV high-dose MTX followed by IV 5-FU, increases were seen in either the total t 1/2 of 5-FU (41.8%) or in the t 1/2 of the α phase (150%). In the three patients with colorectal cancer who received IV IFNα-2a followed by IV 5-FU, the two patients with partial responses had increases in the t 1/2 of 5-FU of 41% and 30.2%, whereas the nonresponder had a nonsignificant increase (5.6%) in the t 1/2 of 5-FU. CONCLUSIONS: These results document that the in vivo modulation of the tumoral pharmacokinetics of 5-FU can be measured noninvasively by 19 F-MRS and suggest that such information correlates with subsequent clinical outcomes. The findings also indicate that IFNα-2a and high-dose MTX can increase the intratumoral 5-FU in some patients. Such information, obtained prospectively in vivo, may assist in better individual cancer patient management and in developing novel drug combinations.
A mouse-human phase 1 co-clinical trial of a protease-activated fluorescent probe for imaging cancer
Authors: Melodi Javid Whitley, Diana M. Cardona, Alexander L. Lazarides, Ivan Spasojevic, Jorge M. Ferrer, Joan Cahill, Chang-Lung Lee, Matija Snuderl, Dan G. Blazer, E. Shelley Hwang, Rachel A. Greenup, Paul J. Mosca, Jeffrey K. Mito, Kyle C. Cuneo, Nicole A. Larrier, Erin K. O’Reilly, Richard F. Riedel, William C. Eward, David B. Strasfeld, Dai Fukumura, Rakesh K. Jain, W. David Lee, Linda G. Griffith, Moungi G. Bawendi, David G. Kirsch, Brian E. Brigman
Journal: Science Translational Medicine (2016)

A first-in-human phase 1 clinical trial of the PEGylated protease-activated fluorescent probe, LUM015, enables tumor imaging at a safe and tolerable dose in humans.
Idiopathic retroperitoneal fibrosis.
Authors: P Greco, A Vaglio, L Manenti, D Corradi, S Ferretti, P Cortellini, F Ferrozzi, C Buzio
Journal: BMJ (1981)

Retroperitoneal fibrosis is an uncommon disease, characterized by the replacement of normal retroperitoneal tissue with fibrosis and/or chronic inflammation. In two thirds of the cases retroperitoneal fibrosis is idiopathic (IRF), whereas in the remaining ones it is secondary/associated to cancer, infections, drugs, autoimmune disease and vasculitis. IRF appears as a dense, fibrous plaque that usually arises between the level of the lower aorta and the common iliac arteries. As the plaque progresses, it engulfs the adjacent structures (e. g., ureters). In its early stages IRF is characterized by a rich infiltrate of lymphocytes, plasma cells and macrophages interspersed within fibroblasts and collagen bundles. In its advanced stages it becomes relatively avascular and acellular with abundant collagen bundles and scattered calcifications. The pathogenesis is unknown: some Authors suggest that IRF is a consequence of a local autoimmune reaction against atherosclerotic plaque antigens whereas others propose that it is the manifestation of a systemic autoimmune disease. The presenting signs and symptoms are non-specific; systemic manifestations (fever, anorexia, weight loss), often associated with local symptoms, are usually found to be related to the entrapment of retroperitoneal structures. The most common local symptom is lumbar and/or abdominal pain. The treatment can be surgical and/or medical: the former is required when obstructive complications are present; the latter, associated or not with surgery, can significantly improve the outcome of IRF patients and usually modifies the natural history of the disease. Steroids and tamoxifen are the most used drugs, whereas other agents such as azathioprine, methotrexate and cyclosporine are usually given to non-responder patients.
Amyloid plaques are still main target for Alzheimer’s drugs
Authors: Nigel Hawkes
Journal: BMJ (2016)

John Hardy, the UK geneticist behind the amyloid hypothesis of Alzheimer’s disease, still believes that drugs targeted at the amyloid plaques formed in the brain may slow progression of the disease despite previous disappointing trial results.

Giving the New Year lecture at the University College London School of Pharmacy on 12 January, Hardy was optimistic that a new trial of Eli Lilly’s drug solanezumab or a recently launched trial of Biogen’s aducanumab would produce positive results.

“We’re hopeful, but we don’t want to overstate or mislead people,” he said. “These trials will report in about 18 months, and if they are successful it tells us immediately we’re on the right road and that will lead a massive investment by those two companies and …
Is biopsy Gleason sum an independent predictor of biochemical progression following radical prostatectomy after adjusting for the pathological Gleason sum?
Authors: N. J. Fitzsimons, S. Freedland, J. Presti, C. Amling, C. Kane, M. Terris, W. Aronson
Journal: Journal of Clinical Oncology (2006)

4652 Background: Biopsy Gleason sum is a known important predictor of PSA failure following radical prostatectomy (RP). However, it is unclear whether it remains predictive of outcome after surgery when the pathological Gleason sum is known. Methods: We determined the association between biopsy Gleason sum and biochemical progression after correcting for both pre-operative and post-operative characteristics including pathological Gleason sum among 1,931 men treated with RP between 1988 and 2005 within the SEARCH Database. Gleason sum was examined as a categorical variable of 2–6, 3+4, and ≥4+3. Results: Higher biopsy Gleason sums were associated with increased prevalence of extra-capsular extension (p &lt; 0.001), positive surgical margins (p &lt; 0.001), seminal vesicle invasion (p &lt; 0.001), positive lymph nodes (p &lt; 0.001), and biochemical progression (log rank, p &lt; 0.001). After adjusting for only pre-operative characteristics, both biopsy Gleason sums of 3+4 (p = 0.004) and ≥4+3 (p &lt; 0.001) were associated with increased risk of biochemical progression when compared to biopsy Gleason sums of 6 or less. After further adjusting for multiple pathological characteristics including pathological Gleason sum, the association between higher biopsy Gleason sum and risk of progression was little changed in that men with biopsy Gleason sums of 3+4 (p = 0.001) and ≥4+3 (p &lt; 0.001) were significantly more likely to progress. Furthermore, when stratified by pathological Gleason sum, higher biopsy Gleason sums were associated with increased risk of biochemical progression within each pathological Gleason sum category (log-rank, p ≤ 0.007). Conclusions: Biopsy Gleason sum remains a strong predictor of outcome even when the pathological Gleason sum is known. If confirmed at other centers, incorporation of biopsy Gleason sum into post-operative nomograms designed to predict risk of progression might improve model precision. No significant financial relationships to disclose.
A dose finding phase I study of temozolomide (TMZ) and BCNU combined regimen (TEMOBIC) as a treatment of high grade glioma (HGG) in adult chemo-naïve patients
Authors: M. Fabbro, L. Bauchet, C. Kerr, P. Sabatier, V. Rigau
Journal: Journal of Clinical Oncology (2005)

1550 Rationale: Glioblastoma Multiforme (GBM) such as Oligodendroglioma (ODG) are associated with an non negligible chemo-sensitivity. The combination of BCNU (nitrosourea) and TMZ (alkylating agent) may offer a significant impact of tumor control throughout an additive mechanism of action on the tumor cells. Objective: To define the Maximal Tolerated Dose (MTD) and the efficacy of the BCNU-TMZ regimen in diagnosed and measurable HGG. Study design: Patients with a non operable or incomplete resection HGG, or in relapse after radiotherapy were enrolled in this study. Treatment consisted on 6 groups of patients with 3 dose level of BCNU 100, 120 or 150mg/m2 day 1, and 2 dose level of TMZ 150 and 200 mg/m2/d d 2–6. The Limited Dose Toxicity (DLT) was defined as a toxic death, any grade 4 toxicity over than 7 days duration and delayed treatment over than 14 days. The MTD was defined as the dose responsible of > 10% of death, or > 30% grade IV toxicities. Results: 24 patients were included. Median age: 43 years (26–71); median PS 1 (0–2) WHO criteria; ODG 13 pts, GBM 3 pts, Transformed Astrocytoma 7 pts, and ependymoma 1 pt. 122 cycles of treatment were delivered. 75% of patients received 4 to 6 cycles. The main toxicity is haematologic, particularly on platelets. BCNU (120) was stopped after 3 cycles in one patient for thrombopenia gr 3 lasting more than 3 weeks without transfusion. One gr 4 neutropenia, 5 gr 4 thrombopenia and minor anemia gr 1–2 were noted. No other gr 3–4 toxicity was noted. Median interval between 2 cycles varies to 28 to 41 days. 70% of the pts received their treatment at d 28 to 35. No lung toxicity was observed. At the level 6, toxicity gr 4 was observed in all the 4 pts, representing the MDT. 22 patients were eligible for efficacy: 11 PR, 3 SD, 8 PD. Conclusion: The recommended dose for the TEMOBIC protocol is BCNU 120 mg/m2 d 1,and TMZ 200 mg/m2 d2–6 which is planed to be used in a phase II study. No significant financial relationships to disclose.
Association between glutathione S-transferase (GST) P1 polymorphisms and survival of patients with advanced non-small cell lung cancer (NSCLC)
Authors: C. Lu, H. Zhao, M. Truong, Q. Dong, M. R. Spitz, X. Wu
Journal: Journal of Clinical Oncology (2004)

7009 Background: Glutathione S-transferase (GST) P1 is a detoxification enzyme with substrate specificity for both exogenous carcinogens and therapeutic compounds. Genetic polymorphisms of GSTP1 exon 5 (Ile105Val) and exon 6 (Ala114Val) appear to reduce this enzyme's activity. Previously, we reported that the exon 6 variant genotypes were associated with an increased risk of lung cancer, particularly among men, younger patients, and ever smokers. Increased cancer risk is due to reduced detoxification capacity of carcinogens. The variant genotype may also be associated with better chemotherapy response due to reduced inactivation of chemotherapy agents, and thus better survival in advanced-stage NSCLC patients, a group that is more likely to receive platinum-based chemotherapy. Methods: Stage III and IV NSCLC cases enrolled in a molecular epidemiology study at our institution were identified and genotyped for GSTP1 exons 5 and 6 by PCR-RFLP. There were 425 subjects. Results: Patients with the exon 6 variant genotype (C/T + T/T) had significantly better survival compared to patients with the wildtype genotype (CC) (P=0.037). The median survival time was 16.1 months for patients with the variant genotypes and 11.4 months for those with the wildtype. The better survival was especially apparent in patients who were younger than 55 years old (P=0.020), male (P=0.037), and ever smokers (P=0.032) but not in patients who were older than 55 years females, and never smokers. When we performed multivariate analysis using a Cox proportional hazards model, we detected a reduced hazard ratio (HR) of death associated with the exon 6 variant genotype of 0.8 (95% CI 0.55–1.16). This protective association was statistically significant among younger patients (< 55 years) (HR 0.47, 95% CI 0.23–0.94) and among males (HR 0.65, 95% CI 0.39–1.07). Conclusions: GSTP1 exon 6 variant genotypes may be associated with improved survival among stage III and IV NSCLC patients, particularly in subsets of younger patients, males, and ever smokers. Further studies are warranted. No significant financial relationships to disclose.
Decitabine low-dose schedule (100 mg/m<sup>2</sup>/course) in myelodysplastic syndrome (MDS). Comparison of 3 different dose schedules
Authors: S. O’Brien, J.-P. Issa, F. Ravandi-Kashani, F. Giles, S. Faderl, G. Garcia-Manero, J. Davis, E. Estey, H. Kantarjian
Journal: Journal of Clinical Oncology (2005)

6545 Background: Decitabine (DAC), a hypomethylating agent, has shown activity in MDS. DAC 150 mg/m2 by continuous infusion has been associated with CR rates of 10% to 20%. We investigated optimizing the dose schedule of DAC in MDS. Study Group and Methods: Patients (pts) with IPSS intermediate 1–2 & high risk MDS were randomized to one of 3 schedules of DAC: 1) 20 mg/m2 IV over 1 hour daily x 5; 2) 10 mg/m2 IV over 1 hour daily x 10; or 3)10 mg/m2 subcutaneously (SQ) BID x 5. A total of 90 pts are to be treated; Bayesian randomization is implemented based on CR rates. Courses were given every 28 days. Delays to allow counts recovery were permitted every 3 courses, or if myelosuppression without disease, or severe myelosuppression complications. Pts were allowed to receive erythropoietin 40,000 units weekly for anemia, or G-CSF if needed. Response criteria for CR & PR were as for AML (PR requiring also ↓ blasts by >50%). Clinical benefit (CB) referred to one or more of: platelets ı̂ by ≥ 50% and >30 x 109/L, or granulocytes increase by ≥ 100% and to >109/L, or hemoglobin ı̂ by ≥ 2 g/dl or transfusion independence, or splenomegaly ↓ by 50% or more, or monocytes ↓ by 50% or more (pretreatment >5 x 109/L). Results: 54 pts have been treated; median age 64 yrs; 61% >60 yrs old. IPSS: intermediate-1 32%; intermediate-2 33%; high 19%; CMML 15%. Cytogenetic abnormalities 57%; secondary MDS 21%; marrow blasts > 10% in 30%. 20 pts had prior erythropoietin; 14 had prior GCSF; 15 had other prior therapies. Presently, 52 pts have received 1 course. Results: 18 CR (35%); 4 PR (8%); 13 marrow CR + CB (25%); 8 CB (15%); overall response 43/52=83%. Median courses to CR 2 (range 1 to 5). Median follow-up of 5 months; 36 pts continue on DAC. Compared with a 114 pts with MDS who received intensive chemotherapy (2000–2004), CR rate was lower with DAC (35% vs. 45%), overall response rate was favorable; 6-week mortality was lower with DAC (2% vs. 21%); and estimated survival favorable (p = 0.02). CR rates by schedule: 5 days IV 10/21 (48%); 5 days SQ 4/14 (28%); 10 day IV 4/17 (24%). There was more myelosuppression with 10 day IV. Conclusions: DAC has significant anti-MDS activity; 2) optimal schedule being defined; 3) timely repeated courses needed for optimal response. No significant financial relationships to disclose.
Detection of antibodies to the HPV16 proteome in head and neck cancer patient sera.
Authors: K. S. Anderson, J. Wong, M. R. Posner, A. B. Riemer, J. H. Lorch, R. I. Haddad, J. Bryan, M. Mclean, K. Kelsey
Journal: Journal of Clinical Oncology (2010)

5545 Background: Human papillomavirus (HPV) type 16 is associated with a subset of oropharyngeal carcinomas (OPC). Of the 8 proteins encoded in the HPV genome, antibodies (Ab) to the early genes E6 and E7 have been detected in patients with HPV16-associated OPC, and are associated with improved prognosis. It is not known whether antibodies to other HPV-derived proteins are potential biomarkers of HPV-associated malignancies. Methods: Antibodies to the HPV16 and HPV18 antigens E1, E2, E4, E5, E6, E7, L1, L2 were quantified using a novel multiplexed bead array assay. Full-length genes were expressed as c-terminal GST fusion proteins in a cell-free transcription translation system and captured onto anti- GST Luminex beads. Blinded sera were obtained from head and neck cancer patients with known antibodies to HPV16 L1 (N=10) or HPV18 L1 (N=10) by Merck competitive Luminex immunoassay (cLIA). Healthy control samples were age- and sex-matched (n=20). The ratio of median fluorescent intensity (MFI) values for each antigen to control p21-GST fusion proteins was determined. P-values were calculated by Wilcoxon rank-sum test. Results: Antibody responses to multiple HPV-derived early genes were detected in patient sera. HPV16 E1, E2, E4, E6, E7, and L1 antibody levels (but not E5 or L2) were elevated in HPV16 L1 Ab+ patients (defined by Merck assay) compared to healthy control samples. Median MFI ratios were: E1 39 vs. 2.0, p<0.0001; E2 2.7 vs. 1.4, p<0.0001; E4 9.1 vs. 1.4, p<0.001; E6 10 vs. 2.1, p<0.0001; E7 3.9 vs. 2.0, p<0.01; and L1 10.8 vs. 2.4, p<0.0001. For patients with HPV18 L1 Abs defined by Merck assay, only Abs to HPV18 E1 (11.9 vs. 2.3, p<0.001); E2 (20.7 vs. 1.9, p=0.0016), and L1 (9.8 vs. 2.7, p<0.0001) were specifically detected. There was no cross-reactivity detected between HPV16 and HPV18-specific antibodies. Conclusions: We developed a custom multiplexed bead array for the rapid detection of HPV16 and HPV18-specific antibodies in patient sera. Patients with head and neck cancers have detectable antibodies to multiple early genes derived from HPV. These antibodies are potential biomarkers for HPV-associated malignancies. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck Merck
Trends in stage distribution for patients with non-small cell lung cancer: A National Cancer Database Survey
Authors: D. Morgensztern, B. Goodgame, P. Chitneni, M. Q. Baggstrom, F. Gao, R. Govindan
Journal: Journal of Clinical Oncology (2007)

7598 Background: We have previously reported a significant change in stage distribution for non-small cell lung cancer (NSCLC) among patients diagnosed at our institution (ASCO 2006 # 7205). To confirm this observation, a larger sample population was evaluated. Methods: Patients with NSCLC registered at the National Cancer Database (NCDB) and diagnosed between the years 1998 and 2003 were evaluated for demographic characteristics including age, race, gender, and stage at presentation. Results: 551,248 patients were identified. Patients with stage 0 or unknown stage were excluded from the study, leaving 510,942 eligible for the final analysis. The annual proportions of stage IV disease at the time of diagnosis are described in the table below. Stage distribution remained stable from 1998 to 2000, but a sharp increase in the percentage of stage IV was noticed between 2000 and 2001 (35.7% to 38.9%). This increase in the percentage of stage IV patients was sustained in the subsequent years and present across the other demographic variables. Conclusions: We have documented a significant change in the NSCLC stage distribution over the last six years. The NCDB is the largest database available and currently captures approximately 62% of all NSCLC patients diagnosed in the United States. The increase in stage IV disease coincides with the widespread adoption of FDG-PET, suggesting an earlier diagnosis of metastatic disease and confirming our previous findings. No significant financial relationships to disclose. [Table: see text]
18F-fluorodeoxglucose (FDG) positron emission tomography (PET) versus FLIPI as a predictor of therapy response in follicular lymphoma (FL) patients.
Authors: D. M. Lamonica, T. Hahn, D. Drumsta, M. Achakzai, M. S. Czuczman, F. J. Hernandez-Ilizaliturri
Journal: Journal of Clinical Oncology (2010)

8102 Background: Tracer retention on post-therapy 18F-fluorodeoxglucose (FDG) positron emission tomography (PET) is associated with worse prognosis in Hodgkin lymphoma or diffuse large B-cell lymphoma. The role of FDG PET as an indicator of clinical outcome in indolent lymphoma is understudied; therefore we evaluated complete response rate (CRR) and progression free survival (PFS) in relation to the maximum standardized uptake value (SUV) by body weight with staging PET in newly diagnosed FL treated with chemo-immunotherapy. Methods: The study included 42 patients with FL grades 1 (n=23), 2 (n=4), 3 (n=13), or unknown (n=1). Median age was 56 years (range, 35-84), 60% male, FLIPI risk category was low (n=15)/intermediate (n=17)/high (n=10), 76% stage III-IV disease. Patients were treated with rituximab (N=7) alone or chemotherapy + immunotherapy with CD20-directed monoclonal antibody (i.e. rituximab [N=28], ofatumumab [N=3] or I131 tositumomab [N=4]). SUV was categorized as <5 vs. >5; <7 vs. >7; or <9 vs. >9, and ranged from 3 to 17.4. Results: In all patients, the CRR was 71% and 3-year PFS was 76% (95% CI 62-90%) at a median follow-up of 3 years (range, 0.5-5.1 years). FLIPI score at diagnosis was significantly associated with PFS, but not CRR. SUV was significantly associated with CRR, but not PFS. FLIPI score and SUV were not correlated with each other. Patients with SUV<5 had a CRR=100% in contrast to >5 (CRR=55%, p=0.008). Sensitivity analyses also yielded significant results with an SUV cutoff of 7 or 9 (Table). Conclusions: SUV predicts response to front-line chemo-immunotherapy, but does not correlate with PFS in FL. Given the natural history of the disease, longer follow-up may be needed to determine if low SUV at diagnosis correlates with improved long-term PFS after chemo-immunotherapy for FL. SUV at diagnosis and response rate SUV cutoff CRR p value SUV <5 100% p = 0.008 SUV ≥5 59% SUV <7 90% p = 0.017 SUV ≥7 55% SUV <9 83% p = 0.026 SUV >9 46% No significant financial relationships to disclose.
The application of serum protein fingerprints in the postoperative follow-up of colorectal cancer
Authors: W. Xu, Y. Chen, S. Zheng, S. Zhang
Journal: Journal of Clinical Oncology (2008)

15044 Background: The objectives of this are to detect the serum protein fingerprints of postoperative colorectal cancer patients by using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry and ProteinChip, to screen cancer progressive biomarkers. Methods: Between April 2002 and April 2005, seventy-two postoperative CRC patients with curative resectable colorectal cancer were followed-up. At a mean follow-up of 16 months, 42 patients diagnosed as postoperative recurrences or metastases and 30 patients diagnosed as no postoperative recurrences or metastases. The serum protein fingerprints of the 72 samples were detected. The data were pretreated and the discrepant proteins were screened to identify cancer progressive biomarkers. The protein fingerprints of the 30 patients survived free from cancer after their operations and the 42 patients with postoperative recurrences and metastases were compared by Biomarker Wizard 3.2.0. software and SPSS 13.0 software. Results: Ten discrepant proteins were screened in the comparison (P<0.05). The expression of m/z: 5908, 28092, 5341, 2957and 8566Da of the 30 patients who survived free from cancer after their operations were higher than that of the patients with cancer progression after their operations (P<0.05). Whereas, five proteins (m/z: 2107, 6114, 2131, 2162 and 2389 Da) were up regulated when cancer progression than those without cancer progression (P<0.05). Using SPSS 13.0 software, 5908 m/z protein was selected whose AUC values were more than 0.7. Gamma-CTF (50) protein may be the cancer progression biomarker whose MW is 5908Da. Conclusions: The method showed great potential for the screening postoperative colorectal cancer patients. It is worth studying further. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Funded by the National Natural Science Foundation of China (Grant Number: 30471987), The National Natural Science Foundation of China (Grant Number: 30471987)