tbuckley/cabot-search huggingface dataset:
The timing of breast cancer recurrence after mastectomy and adjuvant CMF chemotherapy supports a dormancy-based model for metastatic development
Authors: R. Demicheli, G. Bonadonna, W. J. M. Hrushesky, A. Moliterni, M. W. Retsky, P. Valagussa, M. Zambetti
Journal: Journal of Clinical Oncology (2004)

9573 Background: Adjuvant chemotherapy may be regarded as a probe revealing features of the metastasis development, by changes induced in the recurrence timing. Methods: Two randomized clinical trials and a historical group of axillary node positive patients undergoing mastectomy, all treated at the Ist. Naz. Tumori of Milan, were analyzed. Study 1 involved 386 women (no further treatment vs. 12 cycles of CMF), Study 2 involved 459 women (6 vs. 12 cycles of CMF) and the historical group involved 575 patients (mastectomy alone). Discrete hazards of early recurrence (over 4 years), and recurrence risk reductions for treated patients relative to controls were estimated. Results: 1) recurrence rate reduction by CMF is mainly restricted to specific, temporally separate recurrence clusters at the first and third year, while the second-year recurrences are weakly affected; 2) prolonging adjuvant treatment from 6 to 12 months partially changes the recurrence timing, without affecting the overall treatment effectiveness; 3) findings are menopausal status independent. Conclusions: At least two different proliferative events, resulting in clinical appearance of the two metastasis clusters, should be assumed as occurring during treatment administration, when some other metastases are in a rather refractory status. The time distributions of both post treatment recurrence risk and CMF effectiveness are similar for both menopausal statuses, suggesting that the metastatic mechanisms may be substantially the same, although differently modulated. Cytotoxic chemotherapy changes differing recurrence dynamics of pre and post menopausal women to a common later recurrence pattern. These findings give further support to a metastasis development model based on tumour dormancy in specific micro-metastatic phases (single cells and avascular foci) and on acceleration of the metastatic process due to surgery. No significant financial relationships to disclose.
CaMKII is a RIP3 substrate mediating ischemia- and oxidative stress–induced myocardial necroptosis
Authors: Ting Zhang, Yan Zhang, Mingyao Cui, Li Jin, Yimei Wang, Fengxiang Lv, Yuli Liu, Wen Zheng, Haibao Shang, Jun Zhang, Mao Zhang, Hongkun Wu, Jiaojiao Guo, Xiuqin Zhang, Xinli Hu, Chun-Mei Cao, Rui-Ping Xiao
Journal: Nature Medicine (2016)
Gefitinib (ZD1839) treatment for adult patients with progressive high-grade gliomas (HGG): An open label, single-arm, phase II study of the Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO)
Authors: E. Franceschi, S. Lonardi, A. Tosoni, D. Grosso, L. Scopece, C. Berzioli, B. Urbini, G. Cavallo, L. Crinò, A. A. Brandes
Journal: Journal of Clinical Oncology (2005)

1564 Background: HGG comprehend a heterogeneous group of brain tumors with different histologies and prognosis. However, at second relapse, the response rate and PFS-6 are always discouraging for all subtypes. Methods: Adult pts with histologically confirmed HGG recurrent following first-line chemotherapy, were eligible. Pts were treated with Iressa 250 mg/day continuously until disease progression or unacceptable toxicity/pt refusal. Primary endpoint was disease-control rate (DCR=CR+PR+SD). Secondary endpoints were TTP, PFS-6, PFS-12, safety and OS. Results: Twenty-eight pts were enrolled and all were evaluable for activity and safety (median age: 55 years (range 29–70), male/female: 17/11, PS0/1/2: 3/21/4). Sixteen pts had GBM, 3 pts had anaplastic oligodendrogliomas and 9 pts had anaplastic astrocytoma. One pt had an unconfirmed PR (3.6%), 5 pts (17.9%) had confirmed SD, 3 pts (10.7%) had unconfirmed SD. The overall mTTP was 56 days (range 4–472) and PFS-6 and PFS-12 were 14.3% and 7.1%, respectively. In GBM pts subgroup the DCR was 12.5% (2/16), the mTTP was 60 days (range 28–472), PFS-6 and PFS-12 were both 12.5%. mOS was 172 days (range 28–607+), OS at 6 months was 50% and OS at 12 months was 14.3%. G3–4 toxicities consisted in: G3 diarrhoea in 1 pt, G3 neutropenia in 1 pt, G4 acute pulmonary oedhema in 1 pt, G4 pulmonary thromboembolism in 1 pt, G4 CNS hemorrage in 1 pt. G1–2 dermatological toxicity was common (32.1%). Conclusions: In our trial Iressa as second line treatment in HGG at the dose of 250 mg/day achieved interesting DCR and PFS-6. In the GBM subgroup, these data seem to confirm the results of the 500 mg/day previous study in terms of PFS-6. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Schering-Plough
Abstract 15052: Cardiovascular Event Reduction Versus New-Onset Diabetes During Atorvastatin Therapy: Effect of Baseline Risk Factors for Diabetes
Authors: Jennifer E Ho, David D Waters, David A DeMicco, Benoit J Arsenault, S. Matthijs Boekholdt, Michael Messig, John J Kastelein, Terje R Pedersen
Journal: Circulation (2012)

Background:  Statins reduce cardiovascular (CV) events but increase the incidence of new-onset diabetes (NOD). We previously reported that in each of 3 large randomized trials using atorvastatin 80 mg/day, 4 risk factors were independent predictors of NOD: baseline fasting glucose >100 mg/dl, fasting triglycerides >150 mg/dl, body-mass index >30 kg/m 2 , and a history of hypertension. We sought to compare CV event reduction and NOD in 15,056 non-diabetic patients with coronary disease in the TNT (n=7,595) and IDEAL (n=7,461) trials.   Methods and Results:  Patients were randomized to atorvastatin 80 vs 10 mg/day (TNT) or atorvastatin 80 vs simvastatin 20-40 mg/day (IDEAL) and followed for a median of 5 years in both trials. CV events included coronary heart disease death, myocardial infarction, stroke and resuscitated cardiac arrest. High-dose atorvastatin was associated with an increased odds of NOD among participants with 2-4 risk factors (OR 1.24, 95% CI 1.08-1.42, P=0.003), but not in those with 0-1 risk factors for NOD (OR 0.97, 95% CI 0.77-1.22, P=0.77), when compared with low-dose atorvastatin or simvastatin ( Figure ). In contrast, high-dose atorvastatin was associated with a decreased odds of CV events regardless of the number of NOD risk factors present ( Figure ). There was a suggestive interaction between treatment and risk factor group in the prediction of NOD (P=0.07).   Conclusion:  Compared to low-dose statin therapy, treatment with atorvastatin 80 mg/day was not associated with an increased risk of NOD in patients with 0-1 NOD risk factors. Among patients with 2-4 NOD risk factors, atorvastatin 80 mg was associated with a 24% increase in NOD. CV events were significantly reduced with atorvastatin 80 mg regardless of NOD risk factors.
Phase II trial of lapatinib for brain metastases in patients with HER2+ breast cancer
Authors: N. U. Lin, L. A. Carey, M. C. Liu, J. Younger, S. E. Come, E. Bullitt, A. D. Van Den Abbeele, X. Li, F. H. Hochberg, E. P. Winer
Journal: Journal of Clinical Oncology (2006)

503 Background: One-third of women with HER2+ metastatic breast cancer develop central nervous system (CNS) metastases. This study evaluated the safety and efficacy of lapatinib, an oral inhibitor of EGFR and HER2, in patients with HER2+ brain metastases. Methods: Eligible patients (pts) had HER2+ breast cancer, new or progressive brain metastases, and at least one measurable (LD ≥1.0cm) lesion. Pts received lapatinib 750 mg PO BID. Tumor response was assessed by MRI every 8 wks. FDG-PET scans were performed at baseline, and repeated at wks 1 and 8. The primary endpoint was objective response (CR+PR) in the brain by RECIST. Secondary endpoints included safety, quality-of-life (QOL), and PET changes. Sample size was calculated using a 2-stage design to distinguish objective response of 5% (H 0 ) vs 20% (H A ); ≥ 4 objective responses were required to reject the null hypothesis. Results: 39 pts were enrolled, mean age 52 yrs (range 31–76). All pts developed CNS disease on trastuzumab; 38 progressed after prior radiation. Toxicity data are available for 38 pts; the most common AEs were diarrhea (grade 3, 21%), fatigue (grade 3, 16%), and rash (grade 3, 5%). Three pts remain on active treatment. Two pts achieved a PR by RECIST, and remained on study for 158 and 347 days. An additional pt achieved &gt;30% decrease in LD of her CNS lesion but, upon central radiology review, did not meet RECIST criteria for measurable disease and was excluded from analysis of the primary endpoint. Five additional pts achieved SD≥16 wks. Median time to treatment failure was 3.2 mo (95% CI 2.3 to 3.8). Preliminary volumetric analysis of 20/39 pts demonstrates 5 pts with ≥30% volumetric decline in CNS lesions, and an additional 3 pts with 15–30% volumetric decline. Analyses of QOL and correlation of PET with clinical outcomes will be presented. Conclusion: Lapatinib is well-tolerated in this population. Although the study failed to demonstrate the hypothesized level of activity as assessed by RECIST, there is sufficient evidence of clinical effect, albeit preliminary, to suggest that lapatinib can penetrate the CNS. Further investigation of lapatinib in HER2+ CNS disease is warranted and ongoing. Acknowledgements: AVON PFP award; NCI-SPORE in Breast Cancer at DF/HCC(CA89393), UNC(CA58223), Georgetown; ASCO YIA. [Table: see text]
Feasibility of an exercise program for aromatase inhibitor-related arthralgia (AIRA) in breast cancer survivors.
Authors: J. Katz, D. C. Savior, P. Gilman
Journal: Journal of Clinical Oncology (2010)

TPS101 Background: Aromatase inhibitors (AIs) are standard adjuvant treatment for postmenopausal hormone-sensitive breast cancer. Multiple studies have demonstrated that 40% of women on AIs develop AIRA. The etiology of AIRA is unclear. Studies have shown tendon changes on MRI and ultrasound (Morales L et al. abstract 4056, Breast Cancer Res Treat 100 [sup 1] 2006). Estrogen's effects on joint inflammation and nociceptors are implicated (Felson D et al. Arthritis & Rheumatism 52:2594-2598, 2005) and recently 4 SNPs in the TCL1A gene were associated with AIRA (Ingle J et al. abstract 15; SABCS; San Antonio, TX, 2009). Quality of life (QOL) decreases with AIRA. The AI discontinuation rate is 5%. Most women have mild to moderate symptoms; 25% have severe symptoms (Crew K et al. J Clin Oncol 25:3877-3883, 2007). While conventional therapies are useful, some women have no relief. Acupuncture was shown to improve symptoms in one study (Crew KD et al. abstract 5071, Breast Cancer Res Treat 100 [suppl 1] 2006). Physical activity improves cardiac function and bone health in breast cancer survivors (Holmes MD et al. JAMA 293: 2479-2486, 2005). The effect of exercise on AIRA is unknown. A nonpharmacologic intervention to improve the QOL of patients on AIs could have a substantial impact. Methods: A feasibility trial of 20 postmenopausal women (PMW) with AIRA is planned. The primary aim is retention of women to an exercise program. The secondary aim is response of AIRA to exercise. Inclusion criteria are PMW with early-stage hormone-responsive breast cancer on AI with AIRA. Exclusion criteria include significant comorbidities, disease progression, and participation in another exercise program. After medical clearance, women start a reproducible and defined exercise program 2-3 times a week for 8 weeks. Sessions are supervised by a personal trainer who emphasizes strength and aerobic training. Background and demographic data are collected. Women answer a questionnaire at weeks 0, 4, and 8 to assess location and timing of joint symptoms. Common adverse reactions are also assessed. Information on the women's experience in the program is taken upon completion. Currently 11 women have enrolled. No significant financial relationships to disclose.
Loss of plakoglobin immunoreactivity in intercalated discs in arrhythmogenic right ventricular cardiomyopathy: protein mislocalization versus epitope masking
Authors: Sebastian Kant, Claudia A. Krusche, Anna Gaertner, Hendrik Milting, Rudolf E. Leube
Journal: Cardiovascular Research (2015)

To examine the relevance and cause of reduced plakoglobin IF in intercalated discs for arrhythmogenic right ventricular cardiomyopathy (ARVC) and ARVC-like disease in mouse and human. Normalized semi-quantitative IF measurements were performed in a standardized format in desmoglein 2-mutant mice with an ARVC-like phenotype (n = 6) and in cardiac biopsies from humans with ARVC and non-ARVC heart disease (n = 10). Reduced plakoglobin staining was detectable in ARVC only with one antibody directed against a defined epitope but not with three other antibodies reacting with different epitopes of plakoglobin. Reduced plakoglobin staining in intercalated discs of heart tissue from human ARVC patients and in a murine ARVC model is caused by alterations in epitope accessibility and not by protein relocalization.
Hepatic arterial infusion of mitoxantrone in the treatment of primary hepatocellular carcinoma.
Authors: F A Shepherd, W K Evans, M E Blackstein, S Fine, J Heathcote, B Langer, B Taylor, F Habal, G Kutas, K I Pritchard
Journal: Journal of Clinical Oncology (1987)

Twenty-three patients (16 male, seven female) with hepatocellular carcinoma (HCC) were treated by hepatic arterial infusion (HAI) of mitoxantrone every 4 weeks. At each treatment, a catheter was inserted percutaneously into the main hepatic artery via the femoral artery under image intensification. Treatment consisted of a 24-hour continuous HAI of mitoxantrone, 6 mg/m2/d X 3 (eight patients) or 10 mg/m2/d X 3 (14 patients) without heparin. Eight patients had only one infusion, nine patients four infusions, five patients three infusions, two patients two infusions, and one patient five infusions. A partial response was seen in six patients, with a median duration of 20 weeks (range, 18 to 38 weeks). Five patients achieved stable disease, with a median duration of 20 weeks (range, 11 to 42 weeks). The median survival of the overall group was 22 weeks. Survivals of responding, stable, and nonresponding patients were 32 weeks, 24 weeks, and 9 weeks, respectively. Complications of catheter placement included asymptomatic dissection of the hepatic artery (one patient), and asymptomatic thrombosis of the hepatic artery (five patients). Three patients experienced mild nausea and vomiting, and six patients had mild to moderate alopecia. Granulocytopenia was frequent at both dose schedules. The granulocyte nadir was greater than 1,000/microL in 34% of evaluable courses, 500 to 1,000/microL in 32%, and less than 500/microL in 34% of courses. Two patients developed neutropenia-associated fever. A platelet nadir below 100,000/microL was seen after only 10% of courses, and only two patients had platelets below 50,000/microL. Seven patients received doxorubicin after progression on mitoxantrone. Four received systemic doxorubicin, 50 mg/m2, and three HAI of doxorubicin, 25 mg/m2, for three days. Two patients achieved partial response (18 weeks and 32 weeks) to HAI doxorubicin. Mitoxantrone has activity in HCC and is well tolerated when administered by HAI. It is not entirely cross-resistant with doxorubicin.
Effect of rituximab (R) on clinical outcomes after autologous stem cell transplantation (ASCT) in pts with relapsed or refractory diffuse large B-cell lymphoma (DLBCL)
Authors: O. Adegbola, C. Andreadis, S. J. Schuster, E. A. Chong, S. D. Nasta, D. L. Porter, S. M. Luger, D. E. Tsai, K. Cunningham, E. A. Stadtmauer
Journal: Journal of Clinical Oncology (2007)

8122 Background: First-line chemotherapy cures ∼50% of pts with DLBCL, while salvage therapy followed by ASCT can cure another ∼30%. R significantly improves response rates to 1 st line therapy. This retrospective study was designed to test the hypotheses that: 1) ASCT is effective in pts relapsed after R-chemotherapy and 2) addition of R to salvage improves outcomes after ASCT. Methods: We identified 84 pts with relapsed/refractory DLBCL who underwent ASCT at our institution between 1990 and 2006. In all, 32% received a R-chemo 1 st line regimen and 27% received R with salvage. The median age at ASCT was 49 yrs and the median time from diagnosis to ASCT was 16 mos. High-dose regimens included BCV (48%), BEAM (8%) and alkylator/TBI (20%). Results: Overall response rate (ORR) after ASCT was 52%, with 37% of pts in CR by day 100. Among those in CR, 16% had a CR pre-ASCT, 72% had a lesser response, and 9% were chemo-resistant. The addition of R to salvage (23/84 pts) was favorably associated with ORR after ASCT (OR: 5.2, 95% CI: 1.1 - 25, p=0.029), even in pts who had failed a prior R regimen (p=0.013). Other factors favorably associated with ORR were response to salvage (p=0.046) and time to ASCT &gt;12 mos (p=0.017). At last f/u (med: 22 mos, iqr: 7 - 55 mos), event-free (EFS) and overall survival (OS) were both 35%. The only factor associated with EFS and OS in univariate and multivariate analyses was ORR after ASCT (HR: 0.16, 95% CI: 0.07 - 0.37, p&lt;0.001 and HR: 0.12, 95% CI: 0.05 - 0.28, p&lt;0.001 respectively). Age at ASCT, time to ASCT, year of ASCT, mobilization/conditioning regimen, and failure of a R-chemo regimen were not associated with EFS or OS. Conclusions: Pts with DLBCL who have failed a R-chemo first-line regimen derive an equal benefit from ASCT as pts who are R-naïve, with significant long-term EFS and OS. Additionally, inclusion of R in salvage therapy prior to ASCT provides superior response rates, even after a failed prior R-chemo regimen. These results confirm the benefit of ASCT for pts with DLBCL in the rituximab era and argue for the incorporation of R and related agents in studies of high-dose therapy and ASCT. No significant financial relationships to disclose.
Contact Activation Inhibition and Platelet Rich Plasma Are Required in Order to Differentiate Bleeders from Non-Bleeders in FXI Deficiency Using the Thrombin Generation Assay
Authors: Gillian N Pike, Anthony M Cumming, Charles R.M Hay, Jecko Thachil, John Burthem, Paula H. B Bolton-Maggs
Journal: Blood (2014)
PKM2 promotes tumor angiogenesis by regulating HIF-1α through NF-κB activation
Authors: Ninel Azoitei, Alexander Becher, Konrad Steinestel, Arefeh Rouhi, Kristina Diepold, Felicitas Genze, Thomas Simmet, Thomas Seufferlein
Journal: Molecular Cancer (2016)

Initially identified as a molecule that regulates the final step of glycolysis, the M2 isoform of pyruvate kinase (PKM2) was recently reported to have a central role in the metabolic reprogramming of cancer cells as well as participating in cell cycle progression and gene transcription. Despite intensive efforts, the intricate molecular mechanisms through which PKM2 regulates tumor progression remain elusive.The proliferation and apoptosis of various pancreatic cancer cells using lentiviral-mediated PKM2 abrogation were assessed in vitro via Western blot and flow cytometric assay while the in vivo experiments involved tumor xenograft on chicken chorionallantoic membranes and immunohistochemistry on human tissue specimens. In order to decipher the molecular mechanism of HIF-1α and p65/RelA regulation by PKM2 in cancer cells cultivated in hypoxic atmosphere or normoxia we involved various biochemical assays such as Western blotting, immunoprecipitation, reporter gene assay and ELISA.Strong expression of PKM2 was observed in 68 % of human pancreatic adenocarcinoma specimens and almost all analyzed pancreatic cancer cell lines. Abrogation of PKM2 resulted in impaired proliferation and augmented apoptosis in vitro as well as impaired tumor growth and decreased blood vessel formation in vivo. Furthermore, deletion of PKM2 negatively impacted hypoxia-induced HIF-1α accumulation and promoter activity ultimately resulting in impaired secretion of VEGF.Our study suggests that in hypoxic pancreatic tumors PKM2 interferes both with NF-κB/p65 and HIF-1α activation that ultimately triggers VEGF-A secretion and subsequent blood vessel formation.
A phase I trial of PS-341 and fludarabine for relapsed and refractory indolent non-Hodgkin’s lymphoma and chronic lymphocytic leukemia
Authors: M. Snell, O. N. Koc, N. J. Bahlis, L. Liu, H. M. Lazarus, S. L. Gerson, M. J. Laughlin, J. Jacobberger, N. Horvath, S. Remick, B. W. Cooper
Journal: Journal of Clinical Oncology (2006)

7580 Background: The safety and efficacy of PS-341 (bortezomib) as a single agent in relapsed and refractory hematologic malignancies has been well documented. Fludarabine is known to be active in indolent non-Hodgkin’s lymphoma (NHL) and chronic lymphocytic leukemia (CLL). PS-341 may potentiate fludarabine activity by inhibiting DNA repair and inducing apoptosis in Bcl-2 over-expressing cells. The safety of this combination was evaluated in an ongoing phase I study. An additional dose level including rituxumab has been added to potentially improve efficacy without significant additional toxicity. Methods: Dose levels were as outlined in the table below. Each cycle was 21 days. Results: To date, 13 patients have received at least one cycle of treatment and are evaluable for toxicity. Diagnoses of patients included CLL, Waldenstom’s macroglobulinemia and MALT, lymphoplasmacytoid, mantle cell and follicular lymphomas. Patients received a median of 3 prior treatments (range 1–6). DLT’s were not observed in the first 4 dose levels, however the first patient on dose level 5 experienced grade 4 neutropenia. Three patients had doses of PS-341 held due to toxicity (2 due to neuropathy and one leukopenia; doses were held during cycles 3, 4 and 2 respectively) and two required dose reductions for grade 2 neuropathy (on cycles 2 and 3). One CRu has been documented (follicular lymphoma), 1 PR (mantle cell) and 6 patients with SD for 1.5 to 3 months. One patient was taken off the study with disease progression after 1 cycle (CLL) and two discontinued treatment due to prolonged cytopenias (MCL) and patient decision. The most 2 most recent patients are not yet evaluable for response. Conclusions: Combination PS-341 and fludarabine appears to be well-tolerated and active in relapsed and refractory NHL and CLL. Enrollment and follow-up of patients on level 5 (addition of rituxan) continues. Initiation of a phase II study of this regimen is anticipated shortly. [Table: see text] No significant financial relationships to disclose.