tbuckley/cabot-search huggingface dataset:
Current status and future directions of anti-angiogenic therapy for gliomas
Authors: Wolfgang Wick, Michael Platten, Antje Wick, Anne Hertenstein, Alexander Radbruch, Martin Bendszus, Frank Winkler
Journal: Neuro-Oncology (2015)

Molecular targets for the pathological vasculature are the vascular endothelial growth factor (VEGF)/VEGF receptor axis, integrins, angiopoietins, and platelet-derived growth factor receptor (PDGFR), as well as several intracellular or downstream effectors like protein kinase C beta and mammalian target of rapamycin (mTOR). Besides hypoxic damage or tumor cell starvation, preclinical models imply vessel independent tumor regression and suggest differential effects of anti-angiogenic treatments on tumorous and nontumorous precursor cells or the immune system. Despite compelling preclinical data and positive data in other cancers, the outcomes of clinical trials with anti-angiogenic agents in gliomas by and large have been disappointing and include VEGF blockage with bevacizumab, integrin inhibition with cilengitide, VEGF receptor inhibition with sunitinib or cediranib, PDGFR inhibition with imatinib or dasatinib, protein kinase C inhibition with enzastaurin, and mTOR inhibition with sirolimus, everolimus, or temsirolimus. Importantly, there is a lack of real understanding for this negative data. Anti-angiogenic therapies have stimulated the development of standardized imaging assessment and the integration of functional MRI sequences into daily practice. Here, we delineate directions in the identification of molecularly or image-based defined subgroups, anti-angiogenic cotreatment for immunotherapy, and the potential of ongoing trials or modified targets to change the game.
Changes in metabolic rate in patients with severe emphysema after lung volume reduction surgery.
Authors: T Mineo, Ambrogi, E Pompeo, D Ciarapica, A Polito
Journal: European Respiratory Journal (2003)

Background. Resting metabolic rate (RMR) increases in severe emphysema.   Lung volume-reduction surgery (LVRS) proved effective therapy in palliating symptoms and improving lung function, but the mechanism underlying the improvement is not yet elucidated. We hypothesized that the improvement after surgery may be related to a RMR saving due to more effective act of breathing. The aim of our study is to evaluate changes in RMR after LVRS and explain possible correlations with symptoms amelioration.
Methods. In 14 patients, mean age 63.8±10.2, body mass index (BMI) 24.3±4.4kg/m2, who underwent LVRS, RMR was measured using a whole body respiratory chamber. Anthropometric measurements, nutritional status, respiratory parameters, ergometric tests and quality of life scales were also assessed. The baseline values were compared with a homogeneous non-emphysematous population of 10 subjects (65.5±7.9, BMI 26.8±3.3kg/m2). Height, weight, skinfold thickness, forced expiratory volume 1 second (FEV1), residual volume, 6-minute walking and quality of life measurements were also assessed. Basal transversal and 6-month longitudinal comparisons were performed according to the more appropriate statistical tests.
Results. At the baseline the emphysematous patients showed a more elevated fat free mass RMR (128.4±10.8 Vs 116.7±11.6 kJ/kg/die, p=0.007) than the control group. At 6 months forced expiratory flow in one second (FEV1) (0.90 Vs 1.29L, p=0001), residual volume (RV) (4.98 Vs 3.43L, p=0.0001), and quality of life scores (p=0.0001) significantly improved. Accordingly, RMR was significantly decreased for absolute (4.339±0.6, p=0.05) and fat free mass (117.3±11.8, p=0.01) values and reached the predicted values calculated from the Harris-Benedict equation. RMR saving was significantly related with RV decrement (p=0.001).
Conclusions. RMR improves with lung function and symptoms after LVRS, thus outlining a more elevated cost of breath
Invasive breast cancer: Ki-67 evaluation in 3909 early breast cancer patients
Authors: A. Auriemma, A. Mercanti, E. Fiorio, M. Mandarà, M. Giovannini, M. Pavarana, A. Caldara, R. Micciolo, G. L. Cetto, A. Molino
Journal: Journal of Clinical Oncology (2005)

678 Background: The rate of cell proliferation correlates with the response of breast cancer to chemotherapy and disease outcome. The Ki-67 protein is a useful histopathological marker for assessing the growth fraction of tumour cells during all of the active phases of the cell cycle. The measurement of Ki-67 levels by means of immunohistochemistry (MIB-1 antibody) is the most widely used method of evaluating cell proliferation and the biological aggressiveness of a tumour. High Ki-67 levels usually correlates with a poor prognosis in breast cancer. The aim of this study was to verify the relationshoip between Ki-67 levels and tumour characteristics. Patients and Methods: We analysed 3909 women who underwent surgery for an invasive breast tumour between 1992 and 2003, and correlated Ki-67 expression (low:0–15%; medium:16–25%; high:26–100%) with the clinical (menopausal status, disease presentation and age), biological (ER and PgR expression, c-erbB2 overexpression, and p53, p21 and bcl-2 expression) and pathological parameters (tumour size, node status, grading and lymphovascular invasion). The data were analysed using the chi-squared test and correlations with a p value of ≤0.05 were considered statistically significant. Results: Ki-67 levels were higher in women with a symptomatic diagnosis (p<0.01), ER and PgR negativity (p<0.01), c-erbB2 overexpression (p<0.01), p53 mutations (p<0.01), bcl-2 expression (p<0.01), larger tumour diameters (p<0.01), axillary node involvement (p<0.01), lymphovascular invasion (p<0.01), and G2–3 tumours (p<0.01). Conclusions: On the basis of our experience, Ki-67 closely correlates with the parameters of tumour aggressiveness; despite all of the new biological parameters, it should still be considered an important prognostic factor in breast cancer and it can be useful in therapeutic decision making. We are now calculating the survival curves, which will be presented at the meeting. No significant financial relationships to disclose.
Testicular Function After Cytotoxic Chemotherapy: Evidence of Leydig Cell Insufficiency
Authors: S. J. Howell, J. A. Radford, W.D.J. Ryder, S. M. Shalet
Journal: Journal of Clinical Oncology (1999)

PURPOSE: To evaluate testicular function in men after treatment with cytotoxic chemotherapy. PATIENTS AND METHODS: We measured testosterone, sex hormone–binding globulin (SHBG), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) levels in 209 men after treatment with mechlorethamine, vinblastine, procarbazine, and prednisone, hybrid chemotherapy, or high-dose chemotherapy and in 54 healthy age-matched controls. RESULTS: The mean age of the patients was 38 years (range, 19 to 68 years), and all patients had received chemotherapy between 1 and 22 years previously. Patients had significantly higher mean LH (7.9 v 4.1 IU/L; P &lt; .0001) and FSH levels (18.8 v 3.1 IU/L; P &lt; .0001) than controls. There was no significant difference in mean total testosterone level between the patients and controls, but there was a trend toward a lower mean testosterone/SHBG ratio in the patients (0.63 v 0.7; P = .08). Analysis of the hormonal parameters using a model that allowed for the effects of increasing age on testicular function showed evidence of significant recovery of gonadal function in the first 10 years after treatment. Fifty-two percent of patients had LH levels at or above the upper limit of normal, and 32% of patients had increased LH with testosterone levels in the lower half of the normal range, suggesting a degree of Leydig cell impairment. CONCLUSION: In a significant proportion of men, there is good evidence of Leydig cell dysfunction after cytotoxic chemotherapy. The clinical significance of this Leydig cell dysfunction is not clear, but some of these men may benefit from testosterone replacement. Further studies are warranted.
Different clinical behavior of nodular melanoma (NM) compared to superficial spreading melanoma (SSM) at New York University from 1972 to present
Authors: M. A. Warycha, J. Z. Yu, P. Christos, F. Darvishian, H. Kamino, R. L. Shapiro, R. S. Berman, A. W. Kopf, D. Polsky, I. Osman
Journal: Journal of Clinical Oncology (2008)

20001 Background: The high recurrence and mortality rates associated with NM are generally attributed to its advanced thickness at presentation; nevertheless, we and others have recently reported that NM may have distinct biologic characteristics independent of thickness. Here, we examine the differences in clinical behavior of NM compared to SSM at NYU, a tertiary referral center, over three decades. Methods: 1,684 melanoma patients (pts) prospectively enrolled were studied. 1,143 pts were diagnosed 1972–1982 (median thickness 1.3mm; 793 (69%) SSM, 126 (11%) NM, and 224 (20%) other). 541 pts were diagnosed 2002-present (median thickness 0.9mm; 299 (55%) SSM, 125 (23%) NM, 117 (22%) other). Differences between the features of NM and SSM within each time period as well as changes over time were analyzed using the t-test, Wilcoxon rank-sum test, or chi-square test, as appropriate. Results: Median age at diagnosis of NM increased from 51 years of age in 1972–1982 to 63 years of age in the current time period (p<0.01). No significant stage migration or change in median NM thickness over time was observed. In comparison, SSM pts in the current time period are diagnosed at earlier stages and as thinner lesions (p<0.01 and p<0.01, respectively). The rate of ulcerated NMs did not significantly change over time (p=0.29), while the proportion of ulcerated SSMs decreased significantly (p<0.01). The rate of lymph node positivity was 21.3% in NM pts in the current time period compared to only 11.3% in SSM pts (p=0.04), however this was insignificant after controlling for tumor thickness (p=0.76). Nevertheless, 20% (17/85) of NM pts who had negative sentinel lymph node biopsies (SLNB) and/or completion dissections later developed recurrent disease, compared to 3.9% (4/102) of SSM pts (p<0.01). Conclusions: Our data suggest that NM presents with aggressive histological features and advanced stages of disease that may not be solely attributed to thickness. Older patients may need more frequent screening for NM. Furthermore, SLN status may not accurately predict risk of metastasis in these patients. The distinct clinical behavior of NMs supports further research into the underlying biologic differences among histopathologic subtypes. No significant financial relationships to disclose.
Phase II study of CT-322, a targeted biologic inhibitor of VEGFR-2 based on a domain of human fibronectin, in recurrent glioblastoma (rGBM).
Authors: D. Schiff, D. A. Reardon, S. Kesari, T. Mikkelsen, J. F. De Groot, L. Fichtel, T. E. Coyle, E. Wong, C. Eaton, B. Silver
Journal: Journal of Clinical Oncology (2010)

2011 Background: VEGF signaling through VEGFR-2 is the major factor in glioblastoma angiogenesis. CT-322, a pegylated protein engineered from the tenth type III human fibronectin domain, binds the VEGFR-2 extracellular domain with high specificity and affinity to block VEGF-induced VEGFR-2 signaling. This study evaluates CT-322 in an open-label phase II setting to assess its efficacy and safety in rGBM. Methods: Eligibility: age ≥ 18; histologically confirmed rGBM in 1st to 3rd relapse; no prior anti-angiogenic therapy; measurable disease on contrast-enhanced MRI; KPS ≥ 70; ≥ 12 weeks from RT completion; no CNS hemorrhage; and no anticoagulants. This noncomparative trial assigned pts to IV weekly CT-322 at 1 mg/kg or 2 mg/kg and within each dose randomized pts to ± irinotecan (I) (125 mg/m2 q2w if no enzyme-inducing antiepileptics [EIAEDs]; 340 mg/m2 IV q2w if on EIAEDs). One cycle is 4 weeks. Primary end point is 6-mo progression-free survival (PFS-6). Planned enrollment is 75 pts. All results are ITT population. Results: Demographic and safety data (N = 42): Age median 56, range 33-77; 27 M/15 F; prior temozolomide/RT, all; first/second/third relapse, 24/14/4. CT-322 1 mg/kg, 21 pts (14 monotherapy; 7 combined with I); CT- 322 2 mg/kg, 21 pts (13 monotherapy; 8 combined with I). The most frequent treatment-emergent AEs (≥ 20% pts) are fatigue (52%), diarrhea (36%), nausea (31%), headache (26%), and hypertension (24%); ≥ grade 3 at least possibly related AEs include fatigue/failure to thrive (n = 3); CNS hemorrhage, headache, hypertension (n = 2 per event); hypophosphatemia, increased lipase, lymphopenia, thrombocytopenia, increased urine protein:creatinine ratio (n = 1 per event). Efficacy (only available for CT-322 1 mg/kg cohort): investigator-assessed PFS-6: CT-322 mono, 21.4% (95% CI, 0- 42.9%); CT-322 + I , 57.1% (95% CI, 20.5-93.8%); both 1 mg/kg groups combined, 32.1% (95% CI 11.7-52.6%). Two 1 mg/kg monotherapy pts remain on treatment at 12+ and 19+ mo, the latter with 51% tumor reduction on MRI. Conclusions: CT-322 ± I is clinically active and tolerable for rGBM at 1 mg/kg IV qw. Independent centralized response review and continuing accrual at CT-322 dose of 2 mg/kg are ongoing. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Adnexus Adnexus, Bristol-Myers Squibb Bristol-Myers Squibb Adnexus Adnexus, Bristol-Myers Squibb
Elevated extracellular fluid in the "at risk" arm from taxane-based chemotherapies in women treated for early breast cancer.
Authors: Sharon Lynn Kilbreath, Jane McNeil Beith, Kathryn M. Refshauge, Leigh C. Ward, Owen Ung, James French, Louise Koelmeyer, Katrina Kastanias, Judy M. Simpson, Jasmine Yee
Journal: Journal of Clinical Oncology (2013)

126 Background: Taxane-based regimes has improved survival in early breast cancer and now is used routinely. A common side effect is oedema which potentially increases the risk of lymphoedema in the arm after surgery. This has not been assessed prospectively. The aim of this study was to determine the effect of taxane-based regimens on extracellular fluid (ECF) in the arm on the side of surgery. Methods: Women (n=441) aged 56.8 (SD 11.2) years enrolled prior to surgery for early breast cancer and were reassessed within 1 month and 6, 12, and 18 months following surgery. Assessment included bioimpedance spectroscopy which quantifies ECF in each arm and used to derive the ECF ratio. Based on the ECF ratio, women were categorised as having, or not, swelling preferentially in their at risk arm at each time point and having no taxane-based chemotherapy (n=269), paclitaxel (n=73) or docetaxel chemotherapy (n=88). Results: Pre-surgery, the ECF ratio was not significantly different in women who later did or did not receive taxane-based chemotherapy. Following surgery but prior to commencing chemotherapy, 45 (11%) women had increased ECF in their at-risk arm. Both taxane-based chemotherapies and elevated postoperative arm swelling were associated with swelling at each follow-up timepoint (Table). Conclusions: In addition to pre-existing swelling, both taxel chemotherapies were associated with swelling preferentially in the at-risk arm between 6 and 18 months following surgery. Strategies to prevent or minimise this swelling need to be developed. [Table: see text]
Fibroblast growth factor 23 and PTH are strong determinants of the bone mineral density changes occuring within the first post-renal transplantation year
Authors: Kathleen Claes, Nada Kanaan, Jean-Pierre Devogelaer, Dirk Vanderschueren, Eric Goffin, Pieter Evenepoel
Journal: Journal of the American Society of Nephrology (2008)
164. Allogeneic Lymphocyte-Licensed DCs Expand TCR/CAR-Engineered T Cells, Which Are Insensitive To Oxidative Stress and Immunosuppressive Factors
Journal: Molecular Therapy (2014)

Allogeneic Lymphocyte-Licensed DCs Expand TCR/CAR-Engineered T Cells, Which Are Insensitive To Oxidative Stress and Immunosuppressive Factors
Effects of everolimus (EVE) on disease progression in bone and bone markers (BM) in patients (pts) with bone metastases (mets).
Authors: Michael Gnant, José Baselga, Hope S. Rugo, Shinzaburo Noguchi, Kathleen I. Pritchard, Howard A. Burris, Martine J. Piccart-Gebhart, Lowell L. Hart, Janice F. Eakle, Hirofumi Mukai, Hiroji Iwata, Mona El-Hashimy, Shantha Rao, Tanya Taran, Tarek Sahmoud, David Edward Lebwohl, Gabriel N. Hortobagyi
Journal: Journal of Clinical Oncology (2012)

512 Background: BOLERO-2, a multinational, double-blind, placebo-controlled, phase III study in postmenopausal women with estrogen-receptor–positive breast cancer (BC) refractory to non-steroidal aromatase inhibitors (NSAIs), showed significant clinical benefits with the addition of EVE to exemestane (EXE) (Baselga J, et al. NEJM. 2011 Epub). As bone resorption is an important factor in BC mets, it is interesting to study bone-related effects of EVE. In preclinical studies, mTOR inhibition was associated with decreased osteoclast survival and activity. Exploratory analyses in BOLERO-2 evaluated the effect of EVE vs placebo (PBO) on BM levels and BC progression in bone in pts with bone mets at baseline. Methods: Eligible pts were treated with EXE (25 mg once daily) and randomized (2:1) to EVE (10 mg once daily) or PBO. Bone turnover markers were exploratory endpoints analyzed at 6 and 12 wks after treatment initiation, and included bone-specific alkaline phosphatase, amino-terminal propeptide of type I collagen, and C-terminal cross-linking telopeptide of type I collagen. Progressive disease in bone (PDB) was defined as worsening of a pre-existing bone lesion or a new bone lesion. Results: Baseline disease characteristics, including bone mets at baseline (n = 370, 76% EVE vs n = 184, 77% PBO), were well balanced between arms (N = 724), and baseline bisphosphonate use was not (44% EVE vs 55% PBO). At 12.5 mo median follow-up, progression-free survival (primary endpoint), overall response rate, and clinical benefit rate (P &lt; .0001, all) were significantly higher with EVE (n = 485) vs PBO (n = 239). BM levels at 6 and 12 wks increased vs baseline with PBO, but decreased with EVE. The cumulative incidence rate of BC PBD was lower for EVE vs PBO at day 60 (3.03% vs 6.16%, respectively) and this trend was sustained beyond 6 months. Updated results will be presented. All bone-related adverse events reported were grade1/2 and occurred with similar frequency in EVE- (2.9%) and PBO- (3.8%) treated patients. Conclusions: Exploratory analyses from BOLERO-2 suggest that adding EVE has beneficial effects on bone turnover and BC progression in bone in pts receiving EXE therapy for NSAI-refractory BC.
Outcome of patients receiving chemotherapy for advanced biliary tract or gallbladder cancer
Authors: P. A. Cassier, C. Thevenet, J. Souquet, T. Ponchon, J. Baulieux, C. Partensky, J. Scoazec, C. Lombard-Bohas
Journal: Journal of Clinical Oncology (2008)

15627 Background: Patients with cholangiocarcinoma or gallbladder cancer have poor overall prognosis, and their management is often complex. There is currently no standard chemotherapy for this disease, but several single agents and combinations have shown promising activity. Patients and Method: We conducted a retrospective analysis of all cases of biliary tract of gallbladder cancer treated at 2 academic centres in Lyon, France: 127 cases were identified, 67 underwent primary surgery, 13 of whom were dimmed unresectable upon surgical exploration and were treated medically, 60 patients received medical treatment only. Overall 76 patients received chemotherapy for locally advanced or metastatic disease and are the subject of this report. Results: 43 patients received upfront chemotherapy for unresectable disease, 15 received chemotherapy for disease recurrence within 3 months of surgery and 18 for disease recurrence more than 3 months after surgery. Among the patients receiving chemotherapy for recurrence, 4 had previously received adjuvant chemotherapy. 38 patients received gemcitabine-oxaliplatin (GEMOX) combination, 26 patients received single agent gemcitabine (GEM) and 11 patients received 5FU based regimens, one patient received gemcitabine-cisplatin combination and was analysed with patients receiving GEMOX (=>n=39). Median progression-free survival was 4.1 (95%CI: 2.9–5.3) months for the whole cohort (n=76), 4.9 (95%CI: 2.9–6.9) months for patients receiving GEMOX, 4.2 (95%CI: 1.8–6.5) months for patients receiving GEM and 2.1 (95%CI: 0.8–3.4) months for patients receiving FU-plat ( p=.4341 for GEMOX vs GEM and p=.0004 for GEMOX or GEM vs FU-plat, 4.3 vs 21 months). Eleven patients (14%) interrupted their treatment for toxicity, in 6 cases for neurological toxicity of oxaliplatin (16% of patients receiving GEMOX). Median overall survival was 11.5 (95%CI: 7.9- 15.1) months for the whole cohort. Conclusion: Although retrospective, these data support the use of gemcitabine containing regimens in patients with advanced biliary tract or gallbladder cancer. The benefit of adding oxaliplatin in this setting remains unclear. No significant financial relationships to disclose.
Prognostic factors for patients with lymphoma requiring intensive care
Authors: A. Scheliga, F. M. Vieira, N. Spector, S. Romano, J. I. Salluh, R. D. Bello, M. Soares
Journal: Journal of Clinical Oncology (2006)

17519 Background: Prognosis of patients (pts) with hematological malignancies (HM) in the intensive care unit (ICU) seems to be improving, despite different biological behaviors and outcomes. The study of homogenous groups of pts might provide useful clinical insights. The aim of this study was to evaluate the outcomes of critically ill patients with lymphomas (CIPL). Methods: During 66 months, all consecutive CIPL admitted to an oncologic ICU were studied. Variables collected were: age, gender, performance status, type and status of lymphoma, neutropenia, infection at admission, use of mechanical ventilation (MV), the Acute Physiology and Chronic Health Evaluation (APACHE) II score, comorbidities and number of acute organ failures (AOF). Variables selected in the univariate analysis (p &lt; 0.25) and those clinically relevant were entered in a multivariable logistic regression analysis [results expressed as odds-ratios (OR), 95% confidence interval (CI)]. The end-point was hospital mortality. Results: A total of 120 CIPL were studied. Mean age was 51 ± 20 years and 54% were males. APACHE II was 19 ± 7 points. Diagnoses were High Grade Non-Hodgkin’s Lymphoma (77.5%), Hodgkin’s disease (17.5%) and Low Grade Non-Hodgkin’s Lymphoma (5%). Reasons for ICU admission were severe sepsis (62%) and acute respiratory failure (22%). During ICU stay 90% pts received MV, 71% vasopressors and 27.5% dialysis. Twenty-three (19%) pts had neutropenia. End-of-life decisions were implemented in 31% pts and all of them died at the ICU. The ICU and hospital mortality rates were 53% and 67% respectively, with no difference among the groups of lymphomas (p = 0.877). Variables identified in the multivariate analysis were: age [OR = 1.03 (95% CI = 1.01–1.06)], male gender [3.72 (1.27–10.90)], uncontrolled disease [OR = 6.28 (1.80–21.95), for pts with newly diagnosed disease and OR = 5.33 (1.45–19.47), for those with recurrence/progression, sepsis [OR = 5.31 (1.62–17.37)] and AOF [OR = 2.35 (1.53–3.61)]. Conclusions: Higher age, male gender, the severity of organ failures, sepsis and disease status were the main adverse factors. Type of lymphoma and neutropenia had no impact in the outcome. The appropriate use of such easily available clinical characteristics may avoid forgoing intensive care for lymphoma pts with a chance of survival. No significant financial relationships to disclose.
Relationships between pleural plaques, lung asbestos content and asbestos exposure in Australians with or at risk of lung cancer
Authors: J. D. Thomas, O. Mohammed, R. E. Slaughter, M. Feuntes, J. Crossin, H. Marshall, C. M. Wright, M. U. Martins, M. E. Tan, I. A. Yang, K. M. Fong, R. V. Bowman
Journal: Journal of Thoracic Oncology (2011)