tbuckley/cabot-search huggingface dataset:
MM-013: An ongoing phase 2 trial of pomalidomide and low-dose dexamethasone (POM + LoDEX) in relapsed/refractory multiple myeloma (RRMM) with moderate or severe renal impairment (RI) including patients (pts) undergoing hemodialysis.
Authors: Pieter Sonneveld, Nils Heyne, Elisabeth Kueenburg, Axel G. Glasmacher, Claudia Kasserra, Barbara Rosettani, Pamela Joy Bacon, Katja C. Weisel
Journal: Journal of Clinical Oncology (2014)

TPS8626 Background: RI occurs in > 40% of MM pts and can be associated with poor prognosis (Knudsen, EJH 2000). Data from 2 pivotal trials (MM-002, MM-003) suggested comparable efficacy and tolerability for POM + LoDEX in pts with or without moderate RI (Siegel, ASH 2012; Weisel, ASCO 2013). However, pts with severe RI were excluded from these trials. Because POM is extensively metabolized, with < 5% of active substance eliminated in the urine, RI may not affect POM exposure in a clinically relevant manner. However, this has not been definitively tested in a clinical trial, and is under investigation in the US in MM-008. MM-013is a European, multicenter, open-label phase 2 study designed to assess the efficacy, safety, and pharmacokinetics (PK) of POM + LoDEX in RRMM pts with moderate or severe RI, including those undergoing dialysis (NCT02045017). Methods: The trial is enrolling RRMM pts (N = 80) across 3 cohorts: Cohort A (n = 33 with moderate RI, estimated glomerular filtration rate [eGFR] ≥ 30 and < 45 mL/min/1.73 m2), Cohort B (n = 33 with severe RI [eGFR < 30 mL/min/1.73 m2] and no dialysis), and Cohort C (n = 14 with severe RI requiring dialysis). Pts must have biopsy-confirmed MM-related RI and RRMM with ≥ 1 prior therapy (Tx; including lenalidomide). POM 4 mg is administered D1-21/28-day cycle and LoDEX 40 mg/day (20 mg for pts > 75 y) on D1, 8, 15, and 22 until progressive disease or unacceptable toxicity. Thromboprophylaxis is required for all pts not on dialysis; pts on dialysis should receive anticoagulants as appropriate. After Tx discontinuation, pts will be followed for survival, subsequent anti-MM Tx, and second primary malignancies for 5 y after enrollment of last pt. The primary endpoint is overall response rate; secondary endpoints include assessment of renal response (≥ 2 mos improvement in eGFR from < 15 to 30-59 mL/min/1.73 m2 [partial] + improvement from < 50 to ≥ 60 mL/min/1.73m2 [complete]), time to renal response, PFS, TTP, OS, safety, and PK. Additional analyses will examine biomarkers predictive of response or resistance to POM. MM-013 is open for enrollment across Europe. Clinical trial information: NCT02045017.
Oblimersen sodium (G3139) targeting bcl-2 mRNA overcomes acquired resistance to rituximab and sensitizes rituximab-resistant non-Hodgkin's lymphoma (NHL) cells to rituximab-associated complement mediated cytotoxicity (CMC) and antibody dependant cellular cytotoxicity (ADCC)
Authors: J. Ramanarayanan, F. J. Hernandez-Ilizaliturri, M. S. Czuczman
Journal: Journal of Clinical Oncology (2004)

3180 Background: Bcl-2 overexpression is associated with chemoresistance and poor outcome in large cell lymphoma. Recently, we demonstrated that rituximab- resistance is associated with upregulation of Bcl-2 (ASH; 2003, abstract #350). Targeting Bcl-2 expression in rituximab-resistant cell lines (RRCL) is a potential strategy to overcome acquired antibody resistance. Methods: RRCL were generated by exposing Raji cells to escalating doses of rituximab without (2R) or with (4RH) human complement. Assays were done to confirm rituximab-resistance in 2R/4RH. Bcl-2 overexpression in RRCL was demonstrated by cDNA microarray analysis and immunoblotting. 2R and 4RH were exposed to 1.2 μM G3139 or G3622 (reverse sequence) or vehicle control, under optimal transfection condition for 48hrs. Bcl-2 downregulation was shown by immunoblotting. For ADCC/CMC assays ASO-treated 2R/4RH were labeled with 51Cr and exposed to rituximab (10μg/ml) with peripheral blood mononuclear cells or human serum respectively. 51Cr-release and % lysis were analyzed by Chi-square test. Results: Following Bcl-2 downregulation, rituximab-resistance was overcome in 2R and to a lesser degree 4RH. Mean % of rituximab-associated CMC in vehicle or G3622- treated 2R was 0%. Exposure of 2R to G3139 for 48 hours prior to rituximab therapy lead to a significant increase CMC [mean % lysis 55.89%, 95%C.I.: 42.1–65.9%] [P= 0.010]. ADCC assays showed a higher, 37.3% [95%C.I. 31.2–43.4%] mean % of lysis for G3139-exposed rituximab-treated cells than rituximab-treated G3622 [26.8%, 95%C.I. 16.2–37.3, P= 0.027] or vehicle-exposed 2R cells [15.38, 95% 12.14–18.62, P= 0.004]. Conclusions: The correlation of Bcl-2 overexpression with rituximab-resistance suggests that shared pathways of resistance may exist between biological and chemotherapy agents. Our results demonstrate the possibility of significantly decreasing rituximab-resistance with G3139 by inhibition of the mitochondrial anti-apoptotic pathway. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration ASCO (Young Investigator Award)
Outcomes of patients with stage III (clinical N2) NSCLC: A VACCR analysis.
Authors: A. Ganti, W. Gonsalves, I. Aldoss, F. R. Loberiza
Journal: Journal of Clinical Oncology (2010)

7094 Background: Management of locally advanced non-small cell lung cancer (NSCLC) lacks consensus. Also, it is unclear if outcome disparities exist according to race. We conducted a retrospective analysis of patients included in the Veterans Affairs Central Cancer Registry (VACCR) to evaluate if these disparities exist. Methods: Patients with clinical N2 disease and stage 3 NSCLC diagnosed between 1995 and 2003 were included. Data abstracted included age at diagnosis, gender, race, smoking history, disease stage, tumor grade, treatment received and overall survival. Outcomes were compared using multivariate Cox proportional hazards regression analysis. Results: Ofthe 7,469 patients who met the inclusion criteria, analyses were limited to 7,238 Caucasians and African-American (AA) patients. Median age of the patients was 68 years (range: 27-93 years). Of these, 7,218 (98.5%) were male, 6,061 (82.7%) were Caucasian and 321 (4.4%) were never smokers. Median follow-up of survivors was 9 months (range: <1 – 154 months). Treatment received included: none-1,746 (23.8%), chemotherapy-1,045 (14.3%), radiation-1,689 (23%); chemotherapy and radiation (sequential or concurrent)-2,300 (31.4%), while 548 patients (7.5%) had a surgical resection (either alone or as part of multimodality therapy). Median survival (months) of the different treatments were: surgery-19.3; chemotherapy and radiation-13; chemotherapy alone-9.2; radiation alone-7.3; no treatment-4 (p<0.0001). On multivariate analysis, AA had a significantly decreased risk of mortality compared to Caucasians (HR 0.92; 95% CI, 0.87-0.98, p=0.01) while adjusting for age, disease stage and treatment type. When this was further analyzed according to type of treatment, AA had decreased mortality compared to Caucasians when chemotherapy alone was given (HR 0.81; 95% CI, 0.69- 0.96, p=0.02) and a trend towards decreased mortality when no treatment was given (HR 0.88; 95% CI 0.78-1.01, p=0.06). Conclusions: AA had a significantly better outcome when compared to Caucasians, especially when treated with chemotherapy, suggesting possibly a better tumor biology or pharmacogenomics. Surgery should be considered in conjunction with other modalities in patients with clinical N2 NSCLC. No significant financial relationships to disclose.
Effectiveness of tocilizumab with and without synthetic disease-modifying antirheumatic drugs in rheumatoid arthritis: results from a European collaborative study
Authors: Cem Gabay, Myriam Riek, Merete Lund Hetland, Ellen-Margrethe Hauge, Karel Pavelka, Matija Tomšič, Helena Canhao, Katerina Chatzidionysiou, Galina Lukina, Dan C Nordström, Elisabeth Lie, Ioan Ancuta, M Victoria Hernández, Piet L M C van Riel, Ronald van Vollenhoven, Tore K Kvien
Journal: Annals of the Rheumatic Diseases (2015)

To examine the effectiveness of tocilizumab (TCZ) with and without synthetic disease-modifying antirheumatic drugs (sDMARDs) in a large observational study.
Abstract 20373: Inhibition of Glycogen Synthase Kinase-3β Amplifies β-catenin Signaling to Promote Dedifferentiation of Endothelial Cells to Improve Neovessel Formation
Authors: Kishore K Wary, Erin E Kohler
Journal: Circulation (2014)

Rationale: Wnt signaling plays a key role in the development and the regeneration of neovessels, however, the underlying mechanisms of these processes are not clearly understood. Goal: To elucidate the mechanism of dedifferentiation of venous endothelial cells (VECs) to arterial (A)ECs. Methods and Results: Herein we demonstrate that 6-bromoindirubin-3'-oxime (BIO), an inhibitor of Glycogen Synthase Kinase (GSK)-3β elicits the stabilization and the nuclear accumulation of β-catenin, thereby its direct interaction with the transcription factor NANOG in the nucleus of ECs. In a ChiP experiment, NANOG protein bound to the NANOG-, BRACHYURY-, CD133- and VEGFR2 -promoters in these cells. In a cell-based assay, BIO induced the activation of the NANOG -promoter-luciferase reporter system. Accordingly, stimulation of VECs with BIO increased Notch-1, Ephrin-B2 and Hey2 expressions, indicating dedifferentiation these cells to AECs. While NANOG-depletion decreased BIO-induced NOTCH-1 expression and neovascularization. BIO increased Matrigel plug neovessel formation in nude mice. Immunostaining of Matrigel plug sections prepared from these mice showed increased expression of Notch-1, Ephrin-B2 and Hey2, indicating dedifferentiation of a subset of VECs into AECs. In a mouse model of hind limb ischemia, BIO induced the incorporation of VECs into collateral neovessels as characterized by Ephrin-B2- and Hey2-positivities, and smooth muscle cell recruitment. Summary: Thus, we show that a subset of mature VECs may retain the ability to dedifferentiate into AECs in vivo and suggest critical roles of GSK-3β inhibition in this process.
Can we finally use spirometry in the clinical management of infants with respiratory conditions?
Authors: Rachel E Foong, Graham L Hall
Journal: Thorax (2016)

The goal of health professionals working in respiratory medicine is to diagnose and then manage the health of individuals with respiratory conditions. This requires the engagement of a diverse range of professional disciplines, each with their own tool kit that they bring to the table. For Clinical Respiratory Scientists this tool kit revolves around the quantification of the many facets of cardiopulmonary function. We are all familiar with the use of spirometry, its measurement, reporting and interpretation, and it is often the first tool that comes to hand. Yet increasingly it is being recognised that spirometry may not be the best tool for the job1 and there is a growing awareness that a more thoughtful approach is required.2

One of the most challenging areas of clinical respiratory medicine is the management of infants with respiratory conditions. The clinical picture is often obscured by non-specific signs and symptoms, limited direct clinical trials in this clinical population and the highly complex approach needed to obtain objective measures of respiratory function during infancy. While the measurement of infant lung function (ILF) has a long tradition, its use has until recently been limited to highly specialised research centres often using research hardware and software and localised measurement protocols. These limitations have included a lack of availability of …
Surgery after initial chemotherapy for localized small-cell carcinoma of the lung.
Authors: C J Williams, I McMillan, R Lea, G Mead, J Thompson, J Sweetenham, A Herbert, M Jefferys, R Buchanan, J M Whitehouse
Journal: Journal of Clinical Oncology (1987)

Despite the high response rates induced by chemotherapy, many patients with limited small-cell lung cancer (SCLC) relapse at the site of primary disease. Failure of radiotherapy to overcome this has led to the use of surgery as part of a combined modality approach. Between December 1981 and December 1985, 189 patients with SCLC were assessed for suitability for surgery after an initial three cycles of chemotherapy (doxorubicin, cyclophosphamide, and etoposide). Fifty-seven were found to have limited disease, and of these, 19 were ineligible or unfit for surgery. Of the 38 eligible patients, 84% had an objective response to three cycles of chemotherapy and 25 were deemed suitable for surgery after restaging. At thoracotomy, four were inoperable, nine had a lobectomy, and 12 had a pneumonectomy. There was no evidence of viable SCLC in four resection specimens (one stage 1, two stage 2, one stage 3 at presentation), no viable SCLC but an entirely separate focus of viable poorly differentiated squamous carcinoma (SqLC) in one, and the remaining specimens contained viable SCLC. Survival of patients selected to undergo tumor resection was excellent (median survival, 33 months; plateau phase, 48% alive at 3 to 5 years), but survival of the entire group with limited SCLC was not dissimilar from that reported in previous series of limited-stage tumor treated with chemotherapy alone. Long-term survival appeared to be largely restricted to those with no evidence of viable SCLC at surgery (no viable SCLC, zero of five relapsed; viable SCLC, 13 of 16 relapsed and/or died). This prospective study confirms the feasibility of the combined modality approach, but suggests that any improvement in overall survival is likely to be small. Until the results from multicenter randomized trials are available, surgery, as part of a combined modality program, should be regarded as experimental.
Characteristics of young women enrolled in a high-risk breast cancer screening program
Authors: S. Tierney, J. C. Delli Carpini, M. L. Gemignani
Journal: Journal of Clinical Oncology (2009)

1512 Background: Young women at higher risk for breast cancer may benefit from enrollment in a dedicated surveillance program to ensure that their unique needs for examination, imaging, and risk modification are met. Though these programs do exist, little information is known about their effectiveness. In this pilot study, we sought to characterize the patients enrolled in our high-risk screening program. Methods: The Special Surveillance Breast Program (SSBP) at the Memorial Sloan-Kettering Cancer Center (MSKCC) was initiated in 1992 and enrolls patients in four categories: known and probable genetic mutation carriers, atypia, LCIS, and positive family history. Data is collected prospectively in an IRB-approved database and reviewed retrospectively. Patients enrolled from 1992 to March 2008 were included. Inclusion criteria included age under 40 and at least one follow-up visit. Data was validated with the patients’ medical records. Results: Four hundred and thirteen patients met inclusion criteria. The median age at enrollment was 33. The median duration of enrollment was 41 months. Defining continued participation as having a follow up visit in 2008, 193 patients (48%) were retained. At enrollment, 247 patients (60%) had ever undergone screening breast imaging. Of these, 216 patients (52%) had undergone screening in the past 2 years. At the most recent visit, 394 patients (95%) had ever undergone screening breast imaging and 376 patients (91%) had undergone screening in the past 2 years. Of the patients who had not had any radiologic screening, 18 patients (78%) were under the age of 35 at the most recent visit. Two hundred and ninety one patients (70%) reported performing self-breast exams. Two patients were diagnosed with cancer during their participation. An additional six patients underwent prophylactic surgery at MSKCC. Conclusions: Enrollment in a high-risk screening program was associated in an increase in any utilization of radiologic screening from 60% to 95%. It is unknown how this would compare to similar high-risk populations not enrolled in any program. Considering their voluntary enrollment and return for follow-up, these women are likely highly motivated regarding their health care. Further prospectively collected survey data from patients, including those who did not return after their initial visit, is planned. No significant financial relationships to disclose.
Effects of denosumab versus zoledronic acid (ZA) on health-related quality of life (HRQL) in metastatic breast cancer: Results from a randomized phase III trial.
Authors: L. Fallowfield, D. Patrick, J. Body, A. Lipton, K. S. Tonkin, Y. Qian, Q. Jiang, R. D. Dansey, K. Chung
Journal: Journal of Clinical Oncology (2010)

1025 Background: Bone metastases in patients (pts) with breast cancer can lead to skeletal related events (SREs), pain, and decreased HRQL. Denosumab, an investigative fully human monoclonal antibody against RANKL, was previously shown to be superior in delaying SREs and more effective in delaying moderate or severe pain in pts with advanced breast cancer compared with ZA. Here, we assess HRQL in this head-to-head study of metastatic breast cancer pts. Methods: Eligible pts received subcutaneous (SC) denosumab 120 mg or intravenous (IV) ZA 4 mg every 4 weeks in a double-blind, double-dummy fashion. Pts completed Functional Assessment of Cancer Therapy-General (FACT-G) questionnaires at baseline (BL), day 8, and before each monthly visit to assess overall HRQL. Higher scores (range 0–108) represent better HRQL. Improvement, maintenance, and worsening of HRQL were assessed through week 73, when 30% of pts had dropped out due to death, disease progression, or consent withdrawn. Results: BL mean FACT-G total score was 72.7 (SD 16.4) for denosumab (n=956) and 73.6 (SD 16.5) for ZA (n=952). Mean scores improved from BL through week 73 in both groups. From week 5–73, an average of 3.2% (range 1%–7%) more denosumab- treated pts experienced clinically meaningful improvement in HRQL (≥ 5-point increase in FACT-G total score) than ZA-treated pts. At week 25, 37.1% of denosumab vs. 31.4% of ZA pts experienced improvement (p=0.017). In addition, a lower proportion of denosumab pts experienced worsening in HRQL compared with ZA pts (Table). Conclusions: In bone metastases secondary to breast cancer, pts receiving denosumab or ZA showed improvement or maintenance in HRQL relative to BL, while a greater proportion of denosumab-treated pts reported a clinically meaningful improvement in HRQL. Potential benefits of SC delivery of denosumab on HRQL were not captured since both treatment arms received SC and IV administration. % of denosumab (n=787)+ and ZA (n=768)= pts reporting ≥5-point change between BL and week 25 Week 25 FACT-G total score ≥5 point improvement No change ≥5 point worsening Denosumab 37.1%* 30.2% 32.7% ZA 31.4%* 33.9% 34.8% + Pts with both BL and week 25 data . * p value < 0.02. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen Ameen, Amgen, Novartis Amgen Amgen, Novartis Amgen, Novartis Novartis
Intravenous iron improves efficacy and results in substantial savings in cost for patients receiving erythropoiesis-stimulating agents (ESAs) for chemotherapy-induced anemia
Authors: E. Doherty, J. Pappadakis, K. Ryan, M. Auerbach
Journal: Journal of Clinical Oncology (2008)

20664 Background: Annually approximately 800,000 patients receiving chemotherapy experience anemia. Of these approximately 380,000 are treated with ESAs, and many require transfusions. We conducted a retrospective review of anemia management in cancer patients receiving chemotherapy in an oncology practice in Maryland to assess the effectiveness of low molecular weight (LMW) iron dextran in reducing ESA exposure, cost of treatment, and decreasing transfusions. Methods: Living patients who recently received IV iron were screened for inclusion criteria: anemic, diagnosis of cancer <3 years prior, received chemotherapy, and ≥1 dose IV iron, with data for ≥12-weeks from first dose. Data were analyzed and compared to pooled transfusion rates from phase III epoetin trials and to published per patient per week costs of ESA and oral/no iron. Results: Forty patients met inclusion criteria: 58% received platinum-containing chemotherapy, most common cancer diagnoses were lung (38%) and breast (28%). Fifteen percent (6; all receiving platinum-chemotherapy) were transfused vs published expectations of 25% (p=0.072, z-test). Anemia management using ESA and IV iron resulted in an average cost per 12-weeks of $8,213 vs. $9,576 reported in literature (p=0.0185, t-test). Conclusions: LMW iron dextran with ESA therapy resulted in decreased blood transfusions and decreased anemia costs. Savings were most likely driven by ESA sparing effects of IV iron reported in oncology and dialysis literature. Using a back-of-the-envelope analysis, the cost savings associated with routine IV iron use could be in the range of $114 million for blood transfusions and $460 million per 12 week period for decreased ESA dosing. These findings are financially and therapeutically important and a formal prospective economic analysis is warranted. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Watson Laboratories Watson Laboratories
Abstract 17889: Estrogen Effects on Vascular Inflammation are Age-Dependent
Authors: Fadi G Hage, Meaghan Bowling, Akash Kapadia, Yiu-Fai Chen, Alexander J Szalai, Suzanne Oparil, Dongqi Xing
Journal: Circulation (2012)

Introduction: 17β-Estradiol (E2) has been shown to attenuate the inflammatory response to vascular injury in young animals. Clinical trials that enrolled older women reported increased cardiovascular risk in women treated with menopausal hormones. We hypothesize that E2 effects on vascular inflammation are age-dependent. Methods and Results: Young (10 wk) and aged (52 wk) C57BL/6 intact female mice were used as source for primary cultures of bone marrow derived macrophages (BMMs). Real-time quantitative RT-PCR showed that pro-inflammatory mediators were expressed at low levels in vehicle treated cells, and that mRNA levels increased markedly at 4 h after C-reactive protein (CRP) treatment (Table). In cells derived from young mice, E2 pre-treatment for 24 h attenuated the CRP-induced expression of inflammatory mediators. In contrast, E2 pre-treatment of cells from aged mice did not alter the response of inflammatory mediators to CRP. Using selective E2 receptor (ER) subtype agonists and antagonists, we dem...