tbuckley/cabot-search huggingface dataset:
Translational cell study exploring the role of estrogen receptor β expression as a predictive and/or prognostic factor in breast cancer patients
Authors: S. Saji, N. Honma, M. Hirose, S. Hayashi, K. Kuroi
Journal: Journal of Clinical Oncology (2009)

e22185 Background: We have reported that positive expression of Estrogen receptor β (ERβ) was associated with better prognosis in the early breast cancer patients treated with adjuvant tamoxifen monotherapy (J Clin Oncol. 2008). In addition, this was also true in the ERα-negative/PR-negative/Her-2 negative patients. We explored the biological impact of ERβ in breast cancer cell lines to determine whether these observations were due to its prognostic power or predictive power of response to the therapy. Methods: Since MCF-7 cell was ERβ-negative ERα-positive cell line, we established two stable clones of MCF-7 by introducing ERβ expression vector (β-clone 1, β-clone 2) as the model of ERβ-positive ERα-positive breast cancer. MDA-MB 231 cell was used as ERβ-positive triple-negative cell line. These cells were subjected to proliferation, expression and functional analysis. Results: In western blotting, both β-clone 1 and clone 2 showed decreased expression of PR and Her-2 than parent MCF-7, although there were no differences in ERα expression. Expression of ERβ decreased estradiol (E2) induced proliferation ability and rate of cells in S-phase cycle. PPT (ERα-specific agonist) and DPN (ERβ-specific agonist) did not show any difference in response, and IC 50 for 4 OH-tamoxifen and fulvestrant did not differ among MCF-7, β-clone 1 and clone 2 (0.05–0.1 μM). Whereas, cell death due to deprivation of E2 from 1nM to 1pM was more frequently observed in ERβ-expressing clones than in parent MCF-7 cell. These cell deaths did not involve standard apoptosis pathway with caspase-3/7 activation and PARP cleavage. E2, DPN and PPT did not affect the proliferation of ERβ-positive triple negative MDA-MB 231 cell, and IC 50 for 4-OH tamoxifen was too high (8 μM) to be achieved in clinical pharmacological dose. Conclusions: From our cell study, better prognosis of ERβ-positive breast cancer patient who treated with adjuvant tamoxifen is mainly due to its own favorable biological behavior. However, this prognostic impact may include the favorable response to the treatment, when we use estrogen-deprivation therapy such as aromatase inhibitors (AIs). Additional clinical study in AI users would be required to address this issue. No significant financial relationships to disclose.
Identifying head and neck cancer patients at risk for high symptom burden during treatment
Authors: D. I. Rosenthal, T. Mendoza, C. Cleeland
Journal: Journal of Clinical Oncology (2009)

6066 Background: Treatment for head and neck cancer (HNC) is well known to be associated with high levels of toxicity and symptom burden, but patients vary in the severity of treatment related symptom burden. The pre-treatment identification of patient characteristics most at risk for high treatment related symptom levels would be helpful for clinical and trial symptom intervention planning. Methods: 134 patients with HNC participated in the study. Patients completed the M. D. Anderson Symptom Assessment Inventory - Head and Neck module (MDASI-HN) prior to radiotherapy (RT) or chemoradiotherapy (CRT) and again six weeks after treatment began. Cluster analysis was used to identify those who were highly symptomatic due to their disease prior to treatment and those who became highly symptomatic due to treatment. We used validated MDASI-HN score ranges to define symptom severity with scores 5–6 defined as ‘moderate‘ and 7 or more as ‘severe.’ Logistic regression was used to determine which baseline symptoms may predict group membership of highly symptomatic patients at the end of therapy. Results: 18% (22/120) of HNC patients were symptomatic prior to therapy. This subset of patients reported moderate levels of pain, fatigue, sleep disturbance, feeling sad and emotional distress. At six weeks after beginning treatment, 59% (73/124) of patients were highly symptomatic. The cluster of symptoms at this point included moderate levels of pain, fatigue, nausea, mouth sores and excessive mucus and severe levels of poor appetite, dry mouth, difficulty chewing and loss of taste for food. Approximately 54% (50/92) of patients who were not symptomatic at the beginning of treatment became symptomatic at the end of treatment. Patients with moderate to severe pain before beginning treatment are 4 times more likely to be severely symptomatic at the end of treatment (p &lt; 0.009). Conclusions: As expected, only a minority of patients with HNC were highly symptomatic prior to therapy, while the majority of patients had high levels of symptoms toward the end of therapy. Patients with moderate to severe pain before beginning treatment are more likely to be have greater symptom burden at the end of treatment, so may benefit from more intensive symptom interventions. No significant financial relationships to disclose.
Limitation of prostate-specific antigen doubling time as a predictor of outcome in hormone-naive prostate cancer
Authors: J. B. Nelson, D. J. Sleep, J. D. Isaacson, M. A. Carducci
Journal: Journal of Clinical Oncology (2006)

4566 Background: Prostate-specific antigen doubling time (PSADT) is used to monitor progression after primary therapy for prostate cancer. Increasingly in this population, PSADT is an efficacy measure in therapeutic trials, many of which are uncontrolled. Examination of PSADT response on placebo in a randomized controlled study may evaluate the utility of PSADT as an outcome measure in patients with hormone-naive prostate cancer. Methods: Patients with biochemical failure post radical prostatectomy were enrolled in a randomized, double-blind, placebo-controlled trial of atrasentan 10 mg. Eligibility criteria included baseline PSA between 0.4 ng/mL and 5 ng/mL with a PSADT ≤12 months based on two PSA values at least 2 weeks apart. On-treatment PSADT was compared between treatment groups in patients with at least 3 on-treatment PSA values collected every 12 weeks while on study drug. Categorical analysis comparing PSADT between groups was performed using Cochran-Mantel-Haenszel methodology. Mean change from baseline in PSA velocity (log PSA vs time) was analyzed using a one-way analysis of variance with treatment as the factor. Results: Of 222 patients enrolled, 209 had 3 PSA values on study: N=107 for placebo; N = 102 for atrasentan. Baseline PSA was lower for patients in the placebo arm than for those in the atrasentan arm (mean of 1.4 ng/mL [SE 0.1] vs 1.8 ng/mL [SE 0.1] P =.012). On-treatment PSADT was similar between treatment arms (P =.363); the proportion of patients whose PSADT was &gt;1 year on study was 55% with placebo and 51% with atrasentan. More notably, PSADT lengthened on study for most patients in both arms (76/107, 71% for placebo and 68/102, 64% for atrasentan). PSA velocity was also protracted for patients in both treatment arms (placebo: slope = 1.47 at baseline to 0.96, P &lt; .001; atrasentan: slope = 1.56 at baseline to 1.26, P =.017). Conclusions: The fact that over 70% of patients receiving placebo experienced lengthened PSADT suggests that, in the absence of a control arm, changes in PSADT from baseline are not a reliable measure of treatment effect in trials in early prostate cancer. PSADT data from trials in this population should be interpreted with caution. [Table: see text]
Neoadyuvant therapy with dose-dense (DD) docetaxel (T) and doxorubicin/cyclophosphamide (AC) in locally advanced breast cancer (LABC)
Authors: J. G. Mata, S. Antolín, J. R. Mel, M. Ramos, A. García-Palomo, M. C. Almanza, L. De Paz, L. Calvo Martínez, E. Álvarez, A. González-Quintas
Journal: Journal of Clinical Oncology (2008)

11514 Background: Systemic and local therapy is the standard care in the management of LABC. T, A and C have proven efficacy in BC treatment. DD chemotherapy has shown improvement in clinical outcomes for BC. This study was designed to evaluate the efficacy of DD therapy with T × 4 followed by AC × 4. Main objective is pathologic complete response rate. Methods: Women with histologic confirmation of LABC, ECOG PS ≤ 2, age ≥ 18 years and adequate bone marrow, renal, hepatic and cardiac functions were included. Treatment: T 100 mg/m2 iv and prophylactic G-CSF, every 2 weeks × 4 cycles followed by A 60 mg/m2 iv and C 600 mg/m2 iv, every 2 weeks × 4 cycles. Response was evaluated every 4 cycles according to RECIST criteria. Results: Ninety-nine patients (pt) were enrolled, with a median age of 50 years (29–80), ECOG PS was 0/1 86.2/13.8%. Breast locations were left 51.5%, right 46.5% and both 2.0%. Forty-three pt (43.4%) presented stage III breast cancer, 83% had infiltrating ductal carcinoma and 50% were premenopausal. Hormone receptor status was positive in 59.4% of pt (RE+ 55.2% and RP+ 41.7%) and 28 pt of 79 with available data had Her-2 overexpression. All 99 pt received T and 95 received AC. A total of 390 cycles of T (median 4), and 378 of AC (median 4) were administered. Median relative dose intensity was 98% for T and 96% for both A and C. Of 91 evaluated pt for efficacy, 19 achieved CR and 53 PR (ORR: 79.1%; 95% CI: 70.8%, 87.5%). Surgery was performed in 95 pt; 16 of them achieved pCR (16.8%; 95% CI: 9.3%, 24.4%), 51 pPR, 20 minor responses and 8 SD, and 36% were free of malignant cells in nodes. Breast-conserving surgery rate was 43.2%. During T treatment, main grade III/IV toxicity per p were skin toxicity (12.1%), diarrhea (5.1%), elevated SGPT (4.0%), amenorrhea (3.0%) and neutropenia (2.0%); during AC treatment were neutropenia (27.4%), amenorrhea (12.6%), leucopenia (8.4%), anemia (3.2%), stomatitis (3.2%) and vomiting (2.1%). After study treatment, radiotherapy was administered in 91.7% of pt and hormonotherapy in 56.6% of pt. Conclusions: This scheme of DD neoadjuvant chemotherapy is an active regimen, even in a particular high risk cohort of LABC pt (43.4% stage III), with a manageable toxicity profile. No significant financial relationships to disclose.
Phase 2 study of combination therapy with liposomal doxorubicin and carboplatin in patients with relapsed, platinum sensitive ovarian cancer
Authors: D. A. Vorobiof, B. Rapoport, C. Slabber, R. Eek, G. Cohen, A. S. Alberts, G. B. McMichael, J. Raats, A. Uys
Journal: Journal of Clinical Oncology (2004)

5091 Background: A recent phase I study of the combination of CBDCA and Caelyx conducted at The Medical Oncology Centre of Rosebank, Johannesburg has shown that CBDCA at area under the curve (AUC) 5 and Caelyx 50mg/m2 given every 4 weeks, could be combined with acceptable toxicity Methods: The objective of this phase II second line study is to determine efficacy and toxicity of Caelyx at a dose of 50mg/m2 in combination with CBDCA (AUC = 5), in patients with recurrent ovarian cancer with a disease free interval equal or grater than 6 months. Cycles are repeated every 28 days. Results: Twenty nine patients have been entered to date. The median age is 59 years (range 45–75), the majority of patients (56%) presented with an ECOG PS of 1. Median CA 125 at presentation is 129 U/ml (range 20–8894). A total of 133 cycles have been administered, with a median of 4 cycles (range 1–8). Twenty one patients have measurable and 8 patients have evaluable disease. At this stage 21 of the 29 patients are evaluable for response. Two patients withdrew consent and 6 patients are too early for evaluation. Documented responses include 11 complete and 5 partial responses. Five patients have stable disease.Haematological toxicity includes anaemia (grade I: 5 patients; grade II: 4 patients; grade III: 1 patient), neutropenia (grade I: 5 patients; grade II: 5 patients; grade III: 8 patients; grade IV: 3 patients) and thrombocytopenia (grade I: 3 patients; grade II: 1 patient; grade III: 8 patients). No febrile neutropenia or active clinical bleeding has been documented. Non haematological toxicity includes PPE (grade I: 2 patients; grade II: 6 patients; grade III : 2 patients). Nausea and vomiting (grade I - III in 12 patients), stomatitis (grade I: 4 patients; grade II: 6 patients; grade III: 2 patients) and aesthenia (grade I-III: 20 patients). No renal toxicity has been observed. Conclusions: The combination of Caelyx at a dose of 50mg/m2 with CBDCA at an AUC = 5 appears to be a safe and active second line chemotherapy regime for advanced ovarian cancer. The study is ongoing. No significant financial relationships to disclose.
Safety and efficacy of recombinant human erythropoietin in correcting the anemia of patients with chronic renal allograft dysfunction.
Authors: N Muirhead, D C Cattran, J Zaltzman, K Jindal, M R First, A Boucher, P A Keown, L C Munch, C Wong
Journal: Journal of the American Society of Nephrology (1994)

Recombinant human erythropoietin (rHuEPO) is effective in correcting anemia in hemodialysis, peritoneal dialysis, and predialysis patients. Limited studies in patients with failing renal allografts suggest a similar efficacy but provide little information concerning benefits, dose requirements, or adverse events. This study examined these considerations in a group of 40 patients (18 men; 22 women) aged 40.3 +/- 13.8 yr with stable, chronic renal allograft failure. All patients had a hemoglobin < 95 g/L and a serum creatinine > 250 mumol/L at baseline. Patients received rHuEPO (50 U/kg sc) three times weekly for 24 wk along with iron po if serum ferritin was < 100 micrograms/L. Mean hemoglobin rose from 78.9 +/- 10.4 to 102.6 +/- 18.4 g/L after 24 wk. Mean rHuEPO dose at 24 wk was 129.8 +/- 81.9 U/kg per week. With oral iron supplementation only, serum ferritin fell throughout the 24 wk, whereas serum iron, transferrin saturation, and total iron-binding capacity remained stable. Quality of life was assessed by use of the general Sickness Impact Profile and the disease-specific Transplant Disease Questionnaire measures at baseline and every 8 wk during rHuEPO therapy. Significant improvement was noted in global Sickness Impact Profile scores and in four of five dimensions of the Transplant Disease Questionnaire. Serious adverse events were infrequent. No change in mean systolic or diastolic blood pressure was noted, although there was a significantly increased need for antihypertensive drugs in 18 patients (P = 0.0002). A significant inverse correlation was noted between baseline renal function and maintenance rHuEPO dose (r = -0.45; P < 0.05). Twelve patients returned to dialysis during the study.(ABSTRACT TRUNCATED AT 250 WORDS)
Prognostic factors for tumor histological response to preoperative chemoradiation in rectal cancer
Authors: Y. Kundel, R. Brenner, A. Abramovich, O. Purim, N. Peled, E. Idelevich, B. Nisenbaum, E. Fenig, A. Sulkes, B. Brenner
Journal: Journal of Clinical Oncology (2008)

4094 Background: Tumor histological response following preoperative chemoradiation for locally advanced rectal cancer (LARC) is a surrogate for patient outcome. However, predictive factors for this surrogate have not been fully defined as of yet. The aim of this study was to identify pretreatment patient and tumor factors that may predict tumor histological response. Methods: Between 1997 and 2007, 292 patients (pts) with LARC, defined as T3–4 Nx, TxN+ or distal (<6 cm from the anus) T2N0, underwent preoperative chemoradiation followed by surgery at the participating centers. The radiotherapy protocol was standard (50.4–54 Gy in 1.8 Gy fractions) while chemotherapy consisted of several common fluoropyrimidine-based regimens. Patients’ medical files were retrived and various epidemiological, clinical, pathological and treatment parameters were collected. The study cohort was divided into two: responders - pts achieving pathological complete response (pCR) or having only microscopic residual disease (mRD), and non-responders - those who did not achieve pCR or mRD. Results: The median age of the whole group was 67 years (range: 28–86) and 50% were males. Pretreatment TNM stage, available in 271 pts, was: T2N0–13%, T3–4N0–53%, T1-T2N1- 2%, and T3-T4N1–32%. Data on histological response was available for all pts: pCR was documented in 16% and mRD in 12%. With a relatively short follow-up (median: 40 months, range: 5–118), disease free (p=0.049) and overall survival (p=0.004) were significantly different for responders and non-responders. Survival rates of pts with pCR and mRD were equal (95% and 94% 5-year survival, respectively). On univariate analysis, lower pretreatment clinical stage (p=0.024), chemotherapy consisting of oral fluoropyrimidines (p=0.049), age >60 (p=0.017) and pretreatment hemoglobin (Hb) level >12 gr/dl (p=0.027) were associated with significantly higher rates of histological response. On multivariate analysis, all these factors retained statistical significance. Conclusions: Pretreatment clinical stage and Hb level, age, and the chemotherapy regimen can predict tumor histological response following preoperative chemoradiation in pts with LARC. The prognostic impact of histological response was again noted. No significant financial relationships to disclose.
Low-risk patients with fever and neutropenia during chemotherapy: Current clinical practice patterns
Authors: A. Freifeld, J. McNabb, J. Anderson, F. A. Ullrich
Journal: Journal of Clinical Oncology (2004)

8089 Background: Fever during neutropenia is a common complication of cytotoxic chemotherapy. There is increasing evidence that oral antibiotics, outpatient treatment, or both may be appropriate for a select group of low-risk febrile neutropenic (F&N) patients. The objective of this study is to describe the role of oral and/or outpatient therapies in clinical practice patterns of physicians treating cancer patients. Methods: A national survey of 3600 randomly selected oncologists and hematologists (ASCO members) in the U.S. was used to determine current clinical practice patterns for low-risk F&N patients. Questions included therapy choices and 4 case scenarios designed to assess factors associated with physicians' willingness to use outpatient antibiotics. Probability of willingness to use outpatient antibiotics was modeled as a function of 8 key criteria: tumor type, presenting ANC, expected neutropenia duration, comorbidities, age, renal and hepatic function, pulmonary status, and distance from the hospital. Results: Completed surveys were received from 34% of actively practicing physicians: 69% private practice, 27% academic, 3% managed care; 16 yrs (mean) in practice. 82% of respondents use outpatient antibiotics for selected low risk F&N patients - 28% of them indicated use of such treatment in ≥ 65% of their patients . For respondents indicating outpatient treatment for ≥ 5% of their F&N patients, factors predicting for outpatient antibiotic therapy were disease (breast cancer vs. leukemia/non-Hodgkin = s lymphoma), serious infection (catheter, prior invasive fungal, prior resistant bacterial vs. other) and x-ray evidence of infiltrate (present vs. absent). When outpatient monotherapy is used, oral levofloxacin is most commonly prescribed (50%), followed by ciprofloxacin alone (36%), and ciprofloxacin + amoxicillin/clavulanate (35%). 4% of physicians routinely add vancomycin to empiric regimens, 48% add G- or GM-CSF to treatment. Fluoroquinolone prophylaxis for low-risk patients is used by 45%. Conclusions: Physicians are willing to accept outpatient treatment for low-risk F&N patients, although treatment algorithms vary. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Ortho-McNeil
Use of peripheral blood CD4/CD8 ratio to predict therapy-induced durable complete response.
Authors: J. M. Bull, R. Cano, F. R. Strebel, R. W. Rowe, D. Chan, D. Q. Tran
Journal: Journal of Clinical Oncology (2010)

e21080 Background: Fever-range whole-body thermal therapy combined with oxaliplatin administered in optimized schedule and dose reproducibly induces complete, durable response in 50% of female Fischer rats bearing an aggressive primary breast cancer with lymph node metastases that closely resembles clinical inflammatory breast cancer (MTLn3 mammary adenocarcinoma). Animals that do not achieve complete response require euthanasia because of tumor growth by day 36 post implantation. In the 50% animals with complete response the tumor cannot be reinduced, suggesting an immune mechanism resulting from therapy. Methods: To investigate the immune mechanism and to predict those animals that will develop a complete response we analyzed peripheral blood monocytes (PBMC) using flow cytometry to determine changes in T-cell populations (CD4/CD8 ratio). Results: We found that complete responders had a baseline CD4/CD8 ratio of 1.36-1.45 which increased to 1.98-2.08 on day 10 (43%-46% increase). Partially or nonresponding rats demonstrated an increase in the CD4/CD8 ratio of only 15-33% from baseline (p < 0.05, responding v.s. non-responding animals), while controls with progressive tumor had an average CD4/CD8 ratio of 9.5. We are also investigating the effect of therapy on dendritic, NK, and regulatory T cells. Conclusions: The results suggest not only that the immune system is involved in the response to thermochemotherapy treatment, but additionally that changes in peripheral blood immune cells early after treatment may predict response to therapy. This noninvasive peripheral blood assay could allow early change in therapy for patients enrolled in a planned translational clinical study. No significant financial relationships to disclose.
Comparison of combination treatment with endostatin, soluble neuropilin-1 and thrombospondin-2 to single inhibitors in antiangiogenic therapy of renal cell carcinoma
Authors: G. Bartsch, K. Eggert, S. Loges, W. Fiedler, E. Laack, R. Hautmann, J. Gschwend, C. Bokemeyer, G. Schuch
Journal: Journal of Clinical Oncology (2007)

15648 Background: Combinations of cytotoxic drugs lead to increased activity and minimize resistance compared to single agents in tumor therapy. Similarly, antiangiogenic treatment could be improved by combinations targeting different pathways. We investigated a combination of endogenous inhibitors using endostatin (ES), soluble Neuropilin-1 (sNP-1), and thrombospondin-2 (TSP-2) in a model of renal cell carcinoma. Methods: Porcine aortic endothelial cells have been engineered for stable production of angiogenic inhibitors by lipofection and were encapsulated in sodium alginate microbeads. Proliferation of human umbilical vein endothelial cells or Renca renal carcinoma cells was examined after incubation with different microbeads. Similarly, effects of inhibitors on endothelial cell function were tested in tube formation and in vitro wound assays. Microbeads were implanted into SCID mice with subcutaneously growing tumors derived from Renca cells or in mice developing lung metastases after intravenous injection of tumor cells. Results: Factors released from microbeads inhibited endothelial cell function but had no effect on tumor cell proliferation in vitro. In vivo, subcutaneous tumor growth was inhibited similarly by each angiogenic inhibitor alone. After 30 days mean tumor weight was 1.3 g in controls and 0.17, 0.18, 0.18g in ES, sNP-1, and TSP-2 treated mice, respectively. Tumor weight in mice treated with all three inhibitors was further reduced to 0.03g. Histological analyses confirmed antiangiogenic activity by inhibition of microvessel density in treated tumors. In a metastastic model treatment with angiogenic inhibitors induced a significant reduction in size and number of lung metastases with additive effects when factors were used in combination. Conclusions: We conclude that combination therapy targeting multiple angiogenic pathways has synergistic activity and could help to avoid resistance to single inhibitors in tumor treatment. No significant financial relationships to disclose.