tbuckley/cabot-search huggingface dataset:
Finnish wild berries decrease the number and size of intestinal adenomas in the Min mice
Authors: Essi M. Päivärinta, Anne-Maria Pajari, Riitta Törrönen, Marja Mutanen
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

3896 

Epidemiological studies indicate that high consumption of vegetables, fruits and berries may prevent colon cancer. These foods contain a number of different phenolic compounds which have been shown to inhibit several stages of carcinogenesis in vitro . However, only a few studies have investigated the effects of berries on colon carcinogenesis in vivo . Therefore, we studied the effects of bilberry (Vaccinium myrtillus) , lingonberry (Vaccinium vitis-idaea) and cloudberry (Rubus chamaemorus) on adenoma formation in the multiple intestinal neoplasia (Min) mice, a homologue of human familial adenomatous polyposis. At the age of 5 weeks the male and female Min mice were assigned to either a high-fat AIN93-G-based control diet or a diet containing 10% (w/w) freeze-dried bilberry, lingonberry or cloudberry. The mice were fed the experimental diets for 10 weeks. The concentrations of antocyanins and flavonols in the bilberry diet were 5532 mg and 104 mg/kg, and in the lingonberry diet 471 mg and 97 mg/kg, respectively. The cloudberry diet contained only 2 mg flavonols but 1564 mg ellagic acid/kg diet. After the feeding period, the mice were sacrified and the number, diameter and location of adenomas were determined by an inverse light microscope. All berries significantly decreased the number of adenomas in the small intestine, the average reduction being 40%. The mean number (±SD) of adenomas in the small intestine were 39 ± 17 ( P <0.05) in the bilberry, 37 ± 13 ( P <0.01) in the lingonberry and 43 ± 15 ( P <0.05) in the cloudberry group compared to 65 ± 55 in the control group. The cloudberry and lingonberry also significantly decreased the mean size of adenomas which was most pronounced in the distal small intestine: the mean diameter of adenomas were 0.77 ± 0.10 mm ( P <0.01) in the lingonberry, 0.69 ± 0.11 mm ( P <0.01) in the cloudberry, and 0.97 ± 0.14 mm in the control groups. On the contrary, the mice fed bilberry had larger adenomas in the distal small intestine than the mice fed the control diet (1.06 ± 0.23 vs. 0.97 ± 0.14 mm; P <0.05). These results suggest that all three berries studied prevent the formation of new adenomas but only lingonberry and cloudberry prevent the growth of existing adenomas in the Min mice. Because the phenolic profiles of berries are different, their effects on the intestinal mucosa may be mediated through different pathways. It is also possible that the effects of berries on adenoma formation are independent of their phenolic profiles. Further studies are required to investigate the mechanims behind the chemopreventive effects of berries.
Phase I clinical trial of pegylated liposomal mitoxantrone plm60-s: Pharmacokinetics, toxicity, and preliminary efficacy.
Authors: Yuankai Shi, Jianliang Yang, Lin Gui, Peng Liu, Xiaohong Han, Yuanyuan Song, Ning Li, Ping Du, Shuxiang Zhang, Yan Sun
Journal: Journal of Clinical Oncology (2014)

e13553 Background: Plm60-s is a novel, pegylated liposomal mitoxantrone formulation, in which mitoxantrone was loaded into small unilamellar vesicles (~60 nm) made from solid lipid membrane. This two-arm, dose-escalating phase I study was designed to determine safety and pharmacokinetics of plm60-s in patients with advanced solid tumors, and to compare its safety and pharmacokinetics with those of conventional mitoxantrone injection(c-MI). Methods: Patients received a intravenous infusion of plm60-s at 6, 10, 12, 14, 16 and 18 mg/m2 every 4 weeks. 3 or 6 patients in each group of dose level, except 2 patients in 6 mg/m2 group. If more than one patients of a group experienced dose limiting toxicity, dose climbing will stop. The control group of 3 patients received c-MI at 10 mg/m2 every 28 days. Samples for pharmacokinetic studies were collected. The analysis of the safety and tolerability was done according to the record and laboratory examination etc. Preliminary efficacy was evaluated after the completion of 3-cycle treatment. Results: Twenty patients were enrolled, treated and evaluated for safety; 12 patients were evaluated for efficacy. Grade 3 toxicities included leukocytopenia (1/17 in plm60-s group, at 16 mg/m2) and granulocytopenia (2/3 in the control group, at 10 mg/m2). Acute infusion-related reactions have occurred in one patient receiving plm60-s at 18 mg/m2. No cardiac toxicities with clinical significance were observed. Complete response (one at 14 mg/m2 and one at 16 mg/m2), partial response (one at 16 mg/m2) occurred in plm60-s group. After plm60-s therapy, total mitoxantrone was linearly cleared and mitoxantrone was predominantly in the liposomal encapsulation form. The pharmacokinetic profile of total mitoxantrone after dose 1 of plm60-s was similar to that after dose 3, indicating that repeated administration did not affect the clearance kinetics. Conclusions: At a dose of up to 18 mg/m2, plm60-s could be well tolerated and potential efficacy could be observed in the patients with advanced lymphoma and sarcoma. In addition, plm60-s was safer than c-MI at the same dose of 10 mg/m2. The pharmacokinetic profile of plm60-s was satisfactory. Further investigations are in progression. Clinical trial information: NCT02043756.
The influence of autologous stem cell transplant (ASCT) on survival in older adults with multiple myeloma (MM).
Authors: Tanya Marya Wildes, Joseph D Finney, Mark Fiala, Feng Gao, Ravi Vij, Keith Stockerl-Goldstein, Kenneth Robert Carson, Graham A. Colditz
Journal: Journal of Clinical Oncology (2013)

9559 Background: In randomized trials, ASCT improves survival in MM patients (pts) &lt; age 65. The impact of ASCT on survival in older adults with MM is unknown. Methods: In a retrospective cohort study, all pts ≥ age 65 with MM diagnosed between 2000 and 2010 were identified from the Barnes-Jewish Hospital Oncology Data Services Registry (N=199), including demographic, comorbidity (ACE-27 index) and survival data. Medical records were reviewed for stage, ECOG Performance Status (PS) and treatment. Pts &gt; age 77 or who received only steroids/supportive care were excluded (N=53). The primary endpoint was overall survival (OS), defined as time from diagnosis to death, censored at last follow-up. Univariate analyses for factors associated with undergoing ASCT were performed using Fisher’s exact test or nonparametric rank-sum test; multivariate logistic regression was used to create propensity scores for ASCT. The association between ASCT and OS was assessed using a multivariate Cox proportional hazard model with propensity scores adjustment; missing values in predictors were imputed using multiple imputations. Results: Of 146 pts included, the median age was 68 (range 65-77); 53% were male, 81% Caucasian; 43% underwent ASCT. Comorbidities were common (43.9% mild, 21.6% moderate and 9.3% severe). Durie-Salmon Stages were I – 9.5%, II-18.1%, III-72.4%. PS at diagnosis was 0 - 18.3%, 1 - 51.0%, 2 - 21.2% and 3 - 9.6%. Most received novel agents (thalidomide, lenalidomide or bortezomib) in their initial treatment (25.2% alkylators only, 58.6% novel single agents ± steroids, 16.2% novel combination regimens). Age (p&lt;0.0001) and insurance/payer (p=0.02) were associated with ASCT. On univariate analysis, ASCT [Hazard Ratio (HR) 0.54 (95% confidence intervals (CI) 0.35-0.82)] and PS [PS 1: HR 2.3 (CI 1.0-4.9), PS2: HR 3.3 (1.4-7.9); PS 3: HR 3.5 (CI 1.3-9.3)] were associated with mortality. On multivariate analysis controlling for PS, comorbidity, stage and propensity to undergo ASCT, ASCT was associated with reduced mortality [HR 0.52 (CI 0.30-0.92), p=0.02]. Conclusions: In pts over age 65 with MM, ASCT is associated with better OS after adjusting for propensity to undergo ASCT.
Retrospective, correlative study of <i>BRAF</i> mutation V600E in testicular cancer patients.
Authors: Shailesh R. Satpute, Roelof Koster, Katherine L. Nathanson, David J. Vaughn, Costantine Albany, Lawrence H. Einhorn, Nasser H. Hanna
Journal: Journal of Clinical Oncology (2013)

e15584 Background: Presence of BRAF V600E mutation forms the basis of a successful targeted therapy against malignant melanoma. While this mutation is also demonstrated in various other tumor types, its presence in germ cell tumor (GCT) is inconsistent across various studies. In one study, 9 out of 35 (26%) platinum-refractory GCTs were positive for BRAF V600E mutation (Honecker et al, JCO 2009 May 1; 27(13):2129-36). In the current study we tested tumor tissue of patients for BRAF V600E mutation in order to correlate it with known tumor subtypes and treatment outcomes. Methods: We obtained tumor specimen of 59 patients with GCT that were treated at either Indiana University or University of Pennsylvania from 2000 to 2011 and tested them for presence of BRAF V600E mutation by Sanger sequencing with exon 15 specific primers. Out of 59 tumors, 12 (20%) were seminomas and 47 (80%) were non-seminomas. 26 (44%) patients had no recurrence after first line cisplatin-based chemotherapy whereas 33 (56%) patients had either platinum-refractory disease or had a disease recurrence within 2 years of completing chemotherapy. Tumors from 10 patients contained only mature teratoma after chemotherapy. 31 (52%) patients were classified at the time of diagnosis as good risk, 8 (14%) patients as intermediate risk and 20 (34%) patients as poor risk according to international germ cell consensus classification. Results: We found that all 59 tumor tissue were wild-type or lacked BRAF V600E mutation. Appropriate positive and negative controls were used for the assay. Conclusions: BRAF V600E mutation is not a feature of GCT. In our study, we failed to observe any correlation of the mutation with tumor subtypes or with treatment outcomes. Based on this study, BRAF inhibiting drugs may not be beneficial in germ cell tumors.
Derivation and validation of the SEER-Medicare MDS risk score (SMMRS).
Authors: Hajime Uno, Angel Cronin, Deborah Schrag, Gregory Alan Abel
Journal: Journal of Clinical Oncology (2013)

7128 Background: The Surveillance Epidemiology and End Results (SEER) program has been collecting data on myelodysplastic syndromes (MDS) since 2001. These data, when linked to Medicare claims (SEER-Medicare), are an outstanding resource for MDS-related outcomes research. Unfortunately, in terms of prognostic factors at diagnosis, only morphologic subtype is available, and in about half of the registry cases, this is unclassifiable (MDS-U). We aimed to devise a prognostic risk score for use in the SEER-Medicare dataset, and compare it to the standard International Prognostic Scoring System (IPSS) using a granular MDS patient database at our institution (the DFCI/MDS CRIS). Methods: Borrowing from several validated MDS risk scoring systems, a set of candidate predictors that could be determined from claims was pre-specified. Cox proportional hazards models were then built for overall survival, using the 2001-2007 SEER-Medicare MDS dataset (n=9820). Different categorizations of each predictor were tested so that the final model would achieve the best predictive performance. The model was then validated independently using DFCI/MDS CRIS patient data (n=328). C-statistics were calculated to compare the performance of the new scoring system (SMMRS) with the IPSS. Results: The final model included cytopenias, MDS morphologic category, age at diagnosis, hospitalization at diagnosis, red cell or platelet transfusion dependence, and Charlson comorbidity score. The C-statistic for the final model in SEER-Medicare was 0.688. The table shows how the SMMRS performed in the DF/MDS CRIS database compared to, and in combination with, the IPSS. When the analyses were restricted to DF/MDS CRIS patients 65 or older (n=164), similar results were observed. Conclusions: Although missing some important clinical characteristics (eg, cytogenetics), the SMMRS can risk-stratify SEER-Medicare MDS patients with a precision similar to that of the IPSS. The SMMRS thus promises to make the large SEER-Medicare dataset much more useful for MDS clinical research. [Table: see text]
Phase I/II dose-escalation study of VB-111, an antiangiogenic gene therapy, in patients with recurrent glioblastoma multiforme.
Authors: Andrew Jacob Brenner, Yael Cohen, James J Vredenburgh, Katherine B. Peters, Eyal Breitbart, Livnat Bangio, Naamit Sher, Dror Harats, Patrick Y. Wen
Journal: Journal of Clinical Oncology (2013)

TPS2102 Background: VB-111 is an anti-angiogenic agent consisting of a non-replicating adenovirus vector (Ad-5) with a modified murine pre-proendothelin promoter leading to apoptosis of tumor vasculature by expressing a fas-chimera transgene in angiogenic endothelial cells. In a phase I/II dose-escalation study, safety and efficacy of VB-111 in patients with recurrent Glioblastoma Multiforme (GBM) were evaluated. Methods: VB-111 was administered as a single intravenous infusion at escalating doses from 1x10 12 to 3x10 12 viral particles (VPs), followed by repeat doses of 3x10 12 or 1x10 13 every 2 months. Assessments included safety, pharmacokinetics, tumor response (RANO criteria) and overall survival (OS). Results: Twenty eight patients aged 26 – 74 years at 3 medical centers in the US received up to 8 repeat doses of VB-111. The median OS was 360 [range: 70-574] and 266 days [range: 28-664] for patients receiving at least one dose of 1x10 13 VPs (high dose) vs. subjects who received lower doses, respectively (p NS). Progression free survival was 87 vs 55 days for patients who received high dose and for lower doses, respectively (p = 0.01). Median follow-up was 232 days. Three patients had a partial response (PR) at 82, 86 and 408 days post initial VB-111 dosing. Twenty one of the patients who progressed on VB-111 treatment received bevacizumab off study; 7 of the 15 evaluable patients (47%) had a PR compared to 30% expected according to literature. VB-111 was safe and well tolerated, 53 adverse events were reported, 14 were classified as possibly related to VB-111. All events were of CTCAE grade 1-2 except one grade 3 pulmonary embolism. There were no study related deaths. One patient developed peri-tumoral edema, which resolved with corticosteroid therapy. Events occurring in &gt; 10% of the patients included headache and fatigue. Conclusions: VB-111 was safe and well tolerated in patients with recurrent GBM with repeat doses of up to 1x10 13 VPs. Tumor responses were seen. Overall survival was about 3 months longer than historical data in recurrent GBM, including standard of care anti-angiogenic agents. Data suggests that VB-111 potentiates the response to bevacizumab given at further progression. Clinical trial information: NCT01260506.
Phase lb study of buparlisib (BKM120) plus either paclitaxel (PTX) in advanced solid tumors (aST) or PTX plus trastuzumab (TZ) in HER2+ breast cancer (BC).
Authors: Cristina Cruz Zambrano, Martin H. Schuler, Jean-Pascal H. Machiels, Dagmar Hess, Luis Paz-Ares, Ahmad Awada, Roger von Moos, Neeltje Steeghs, Jordi Rodon Ahnert, Peggy De Mesmaeker, Heike Richly, Catherine Herremans, Markus Joerger, Jesus Corral Jaime, Maria Alsina, Fabienne Baffert, David Demanse, Vincent Duval, Alex Morozov, Luc Dirix
Journal: Journal of Clinical Oncology (2014)

627^ Background: Preclinical data show PI3K-pathway inhibition can enhance the efficacy of anticancer therapy, such as PTX or TZ. In this 4-arm Ph Ib study (NCT01285466), buparlisib (pan-PI3K inhibitor) or BEZ235 (dual PI3K/mTOR inhibitor) was combined with PTX in pts with aST or PTX + TZ in pts with HER2+ BC. Here we report the buparlisib arms only. Methods: Pts with aST or HER2+ BC eligible for PTX ± TZ received oral buparlisib qd + PTX (70−80 mg/m2 IV) qw ± TZ (2 mg/kg IV) qw in 28-day cycles. The primary objective was to define the MTD in each arm by assessing dose-limiting toxicities (DLT) in Cycle (C) 1. Dose escalation was guided by a Bayesian logistic regression model with overdose control. Pts with PI3K-pathway alterations were enrolled in a buparlisib + PTX safety expansion cohort. Results: (2 Apr 2013) Buparlisib + PTX: buparlisib doses from 40−120 mg/d were tested in 53 pts, including 36 pts at 100 mg/d. Median no. prior regimens was 3 (1−12). DLT occurred in 5 pts: 3 at 120 mg and 2 at 100 mg. MTD was declared as buparlisib 100 mg qd + PTX (80 mg/m2 IV) qw. Drug-related G3/4 AEs (>10%) were neutropenia (13%) and hyperglycemia (11%). Median exposure was 15 wks. Primary reason for discontinuation was PD (68%). Buparlisib exposure was lower than in the single-agent study, especially at 100 mg. Buparlisib did not modify the PK of PTX. Per RECIST, there was 1 CR, 8 PR, and 27 SD (ORR = 17%). 3 pts are ongoing. Buparlisib + PTX + TZ: all 11 pts received buparlisib at 100 mg/d. Median no. prior regimens was 4 (1−10; prior taxane, 82%; prior TZ, 100%). DLT occurred in 2 pts. MTD was declared as buparlisib 100 mg qd + PTX (80 mg/m2 IV) qw + TZ (2 mg/kg IV) qw. Drug-related G3/4 AEs (>10%) were neutropenia (27%) and diarrhea (18%). 1 pt developed G4 psychosis in C2, resolving after discontinuation. Median exposure was 17 wks. Primary reason for discontinuation was PD (64%). PK of PTX and TZ were in the expected range. Per RECIST there were 3 PR (1 with prior PTX/TZ in metastatic setting) and 5 SD (ORR = 27%). 2 pts are ongoing. Conclusions: Buparlisib can be combined with PTX and TZ in pts with aST or HER2+ BC at the single-agent MTD, with early indications of activity, thus establishing the feasibility of PI3K blockade combined with PTX + TZ. Clinical trial information: NCT01285466.
Identification and activity of the novel antibody MSH-TP15 by a cell-based phage display screening approach.
Authors: Katja Klausz, Renate Burger, Christian Kellner, Matthias Peipp, Andreas Guenther, Martin Gramatzki
Journal: Journal of Clinical Oncology (2014)

e22156 Background: Multiple myeloma (MM) has a considerable incidence and high mortality. Monoclonal antibodies represent promising treatment options but candidates suitable for MM are rather limited and none has yet been approved for treatment. Therefore, it was attempted to raise an antibody against a plasma cell-specific target structure. Methods: To identify novel plasma cell surface antigens or epitopes, synthetic human single-chain fragment variable (scFv) phage display libraries were screened with a newly established subtractive cellular screening approach including pre-absorption steps and positive selection for phages binding to plasma cell lines INA-6 and JK-6L. Based on its favorable binding profile evaluated by cellular ELISA and flow cytometry, MSH-TP15 was selected and its coding sequence was used to generate a fully human scFv-Fc fusion protein (mini-antibody). Results: Screening of phage libraries with our novel strategy resulted in a number of phages with preferential binding to MM cells. The leading candidate was selected and converted into a human mini-antibody. MSH-TP15 retained its strong binding to MM cell lines as well as patient-derived CD138+ plasma cells, while showing no or only marginal binding to B and T lymphocytes, NK cells, monocytes, or granulocytes. In addition, two Burkitt lymphoma cell lines were positive. Screening of a panel of stably transfected cell lines that express antigens already considered for antibody-based MM therapy revealed no reactivity. MSH-TP15 was not capable to induce significant growth inhibition of plasma cell lines in vitro, but triggered ADCC, an important killing mechanism of therapeutic antibodies. Notably, MSH-TP15 completely prevented tumor engraftment in the INA-6 myeloma xenograft model. Conclusions: Phage display technology together with a cell-based screening approach led to an antibody that preferentially binds to MM cells, is effective in antibody-mediated killing, and prevents tumor engraftment in vivo. The recognized antigen is distinct from any of the MM antigens currently explored for antibody therapy, and thus represents a novel promising target structure for an antibody-based approach.
Evaluation of the Disease Risk Index on Outcomes Following Allogeneic Hematopoietic Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndromes
Authors: Fotios V. Michelis, Hans A. Messner, Jieun Uhm, Naheed Alam, David Loach, Laura McGillis, Anna Lambie, Vikas Gupta, John Kuruvilla, Jeffrey H. Lipton, Matthew D. Seftel, Dennis D. Kim
Journal: Blood (2014)
What is the advantage of a passive bending segment in balloon enteroscopy-assisted ERCP?
Authors: Christina Mouradides, Alaa Taha, Tom Moreels
Journal: Endoscopy (2017)

Yane et al. recently published an article on the usefulness of short-type single-balloon enteroscope (SBE) prototypes to perform balloon enteroscope-assisted endoscopic retrograde cholangiopancreatography (ERCP) [1]. They used three different short-type SBEs (152 cm), and two of these were equipped with passive bending and force transmission (SIF-Y0004-V01 and SIF-Y0015) to perform ERCP in patients with Billroth II gastrectomy, pancreaticoduodenectomy, short-limb Roux-en-Y gastrectomy, and hepaticojejunostomy. Factors determining therapeutic success were type of surgical reconstruction, second attempt ERCP, and the use of a transparent cap [1]. However, the possible advantage of the passive bending segment with force transmission is not mentioned. A passive bending segment may help to overcome sharp angulations when introducing an endoscope into a tortuous intestinal limb, an endoscopic feature that is difficult to measure [2].
Interstitial lung abnormalities in treatment-naive advanced NSCLC patients (pts): Prevalence and impact on survival.
Authors: Mizuki Nishino, Stephanie Cardarella, Suzanne Eleanor Dahlberg, Tetsuro Araki, Christine A. Lydon, Michael S. Rabin, Hiroto Hatabu, Bruce E. Johnson
Journal: Journal of Clinical Oncology (2014)

e19030 Background: Interstitial lung diseases are associated with increased risk of lung cancer. A radiographic scoring method of interstitial lung abnormalities (ILA) on CT was previously reported, which categorizes the degree of ILA into 4 groups [NEJM 2011;364:897-906]. We investigated the prevalence of ILA at the time of diagnosis of advanced NSCLC, and studied the association between ILA and overall survival (OS). Methods: The study included 120 treatment-naive stage IV NSCLC pts (53 males, 67 females; median age 64 yrs) who presented at DFCI between 8/2011 and 7/2012 and had baseline chest CT prior to the initiation of systemic therapy available for review. ILA was scored on baseline CT with a 4-point scale [0=no evidence of ILA, 1= equivocal for ILA, 2= suspicious for ILA, 3=ILA] using a sequential reading method as previously reported. ILA scores of 2 or 3 were considered to indicate the presence of ILA. Association between ILA scores vs. OS was studied. Results: ILA was present in 17 pts (14%) at diagnosis of advanced NSCLC (score 3 in 2 pts, score 2 in 15 pts). These 17 pts with ILA were significantly older (median age: 69 vs. 63 yrs, Wilcoxon p=0.04) and had a heavier smoking history (median: 40 vs. 15.5 pack-year, Wilcoxon p=0.003). Among the 4 groups of ILA, higher ILA scores were associated with shorter OS (log-rank p=0.001; Table). Median OS of the 17 pts with ILA was 7.2 mos [95%CI: 2.9-9.4] compared to 14.8 mos [95%CI: 11.1-18.4] in pts with ILA score 0 or 1 (log-rank p=0.002). In a multivariate model, the presence of ILA remained significant for increased risk for death (HR=2.09, p=0.028) after adjusting for the first-line systemic therapy (chemotherapy, p<0.001; TKI, p<0.001; each compared to no therapy) and pack years of smoking (p=0.40). Other variables were excluded because they were insignificant and not thought to be confounders. Conclusions: Radiographic ILA was present in 14% of treatment-naïve advanced NSCLC pts. Higher ILA scores were associated with shorter OS among stage IV NSCLC pts, indicating that ILA could be an additional marker of survival in advanced NSCLC. Further studies are needed to validate this finding. ILA score 0 (n=51) 1 (n=52) 2 (n=15) 3 (n=2) Median OS (mos) 18.2 12.3 7.7 4.7 (p=0.001)