tbuckley/cabot-search huggingface dataset:
Expression of the leukocyte chemoattractant chemerin in human prostate tumors.
Authors: Russell Kent Pachynski, Brian Zabel, Weng-In Leong, Robert Crowder, Donna Peehl, Eugene Butcher
Journal: Journal of Clinical Oncology (2015)

81 Background: The infiltration of immune cells into the tumor microenvironment can regulate growth and survival of neoplastic cells. Several studies have shown a correlation between increases in the number of effector immune cells present in a tumor and clinical outcomes in many human tumors, including prostate. The field of prostate cancer immunotherapy continues to grow, with sipuleucel-T already approved and a recombinant vaccinia-PSA (Prostvac) currently in a Phase III clinical trial. Recent studies have shown immune cell infiltration into prostate tumors after systemic administration of sipuleucel-T, suggesting infiltration of these cells may be a key step in the mechanism of action. Methods: Here, in a survey of public whole genome expression datasets we found that the gene for chemerin (RARRES2), a widely expressed endogenous chemoattractant protein for immune cells, is downregulated in prostate cancer. In mouse models, we have previously shown that forced re-expression of chemerin at sites of tumor results in an increase in immune cell infiltration (e.g. NK and T cells), as well as significantly reduced tumor growth (Pachynski JEM 2012). Results: In addition to this published analysis, using RT-qPCR we have gone on to confirm that human prostate tumors have significantly less chemerin (RARRES2) compared to normal prostate tissue. Preliminary immunohistochemistry results in human tumors using an anti-human chemerin antibody, are consistent with our qPCR results, suggesting human prostate tumors downregulate chemerin during their malignant transformation. Conclusions: We have shown, for the first time, that human prostate tumors downregulate chemerin compared to normal prostate tissue. We hypothesize that this is one mechanism of “immune escape.” Therapeutic forced re-expression of chemerin in human tumors may restore anti-tumor immunity within the tumor microenvironment resulting in slowed growth and regression of established tumors. Additionally, chemerin’s ability to recruit NK and T cells into the tumor microenvironment may make it an ideal therapy to combine with other treatments aimed at boosting the immune response, such as sipuleucel-T or checkpoint inhibition (e.g. anti-CTLA4, anti-PD1/PDL1).
Expression of the p16<sup>INK4a</sup> tumor suppressor correlates with adverse clinical outcome in follicular lymphoma
Authors: C. Foster, T. Baetz, R. Sidhu, P. Farmer, H. E. Feilotter, D. P. LeBrun
Journal: Journal of Clinical Oncology (2008)

22078 Background: Follicular lymphoma (FL) is an attractive model for discovering biomarkers and elucidating mechanisms of tumor progression. We hypothesized that alterations in the expression of proteins with known roles in hematological cancers might correlate with clinical outcome and thereby shed light on biological mechanisms. Methods: Sections from a tissue microarray (TMA) containing FL samples from 67 patients were immunostained for candidate biomarkers, including p53, p16INK4a, bcl-2, bcl-6, MUM1, p65, PML, pERK, and p27. The Kaplan-Meier method and log-rank test were used to identify markers that correlate significantly (p<0.05) with overall survival (OS). The χ2 or Fisher exact test were used to examine associations between histological markers and baseline clinical features, including the FLIPI score. Multivariate analysis of significant variables was undertaken using a stepwise Cox proportional hazard method. Results: Expression of p16INK4a or p53, or absent CD10 expression correlated with poor survival. Patients with p16-negative tumors had a median OS of 13.4 years (95% CI: 1–26) compared to 8.3 years (95% CI: 0–17) for those with p16- positive tumors (p=0.006). Expression of p16INK4a was significantly associated with low hemoglobin, elevated serum LDH, high histological grade, high cell proliferation index, presence of associated diffuse large B-cell lymphoma (DLBCL) and high-risk FLIPI classification. Multivariate analysis identified lack of CD10, low hemoglobin, elevated LDH, high histological grade and the presence of DLBCL as significant and independent predictors of OS. Conclusion: Our observation of a positive association between p16INK4 expression and indicators of tumor aggressiveness is novel and perhaps surprising since loss of the INK4a tumor suppressor gene is one of the most frequently observed lesions in human cancers, including lymphoma. Expression of p16INK4a may reflect induction consequent to unidentified pro-mitotic mutations associated with more aggressive instances of FL. No significant financial relationships to disclose.
Abstract 13078: Central Glucagon-like peptide-1 Receptor Activation Counteracts Hypertension with Suppression of Sympathetic Nerve Activity in Spontaneously Hypertensive Rats
Authors: Kenichi Katsurada, Yuko Maejima, Masanori Nakata, Toshihiko Yada, Kazuomi Kario
Journal: Circulation (2014)

Introduction: Incretin related medicines, such as glucagon-like peptide-1 (GLP-1) receptor agonists, are widely used to treat type-2 diabetic patients. Recently, several clinical studies using meta-analysis reported that GLP-1 receptor agonists reduce blood pressure. It has been postulated that GLP-1 reduces blood pressure by acting directly on blood vessels and kidney to promote vasodilation and natriuresis, respectively. In addition to these direct effects on the end effectors, GLP-1 may also regulate blood pressure via the central action. GLP-1 receptors are expressed in the hypothalamus and brain stem regions related to sympathetic and cardiovasucular control including the paraventricular nucleus (PVN), nucleus tractus solitarius (NTS) and rostral ventrolateral medulla (RVLM). The present study explored the central action of GLP-1 on blood pressure and underlying mechanisms. Methods and Results: Spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats aged 8 weeks were intracerebroventricular...
Prognostic role of serum Ca 15–3 and circumstances of diagnostic in advanced breast cancer: Data from a prospective randomized trial
Authors: R. Rouzier, K. Slimane, J.-R. Garbay, R. Arriagada, H. Marsiglia, M.-C. Mathieu, F. Andre, S. Delaloge, M. Spielmann
Journal: Journal of Clinical Oncology (2004)

810 Background: The routine use of CA 15.3 for monitoring breast cancer is controversial. The aim of this study was to evaluate the prognosis of metastatic breast cancer patients included in a randomised trial according to the circumstances of diagnosis. Methods: Among a cohort of 926 patients included in a randomised trial comparing ovarian function suppression versus not after surgery and chemotherapy, 217 patients who have presented a distant recurrence and who were treated at the Institut Gustave Roussy comprised the study population. Survival was evaluated according to the circumstances of diagnosis (group 1: elevation of CA 15.3 (n=55, including 25 patients without initial clinical or radiological evidence of metastasis), group 2: symptoms (n=95), group 3: clinical examination (n=34), group 4: radiological test (n=33)). Results: The 4 groups did not differ in terms of clinico-pathological characteristics, treatments received and metastasis sites. Median interval between initial treatment and metastasis was 54 months in the group 1 versus 47, 40 and 31 months for group 2,3 and 4 (p=.03). After the diagnostic of metastasis, the 2-year survival of group 1 was 69% versus 48%, 37% and 44% for group 2,3 and 4 (p=.07). In the multivariate analysis, interval between initial treatment and metastatis occurrence, metastasis site, estrogen receptor status and initial tumor size were related to survival after metastatic event whereas circumstances of diagnosis and CA 15.3 level were not. When metastatic status was diagnosed because of CA 15.3 elevation, patients could receive 3.2 lines of therapy versus 2.6 for other patients (p=.01). When considering only patients with more than 4 years of disease free survival after diagnosis, median survival was 41 months for group 1 patients versus 31 for other groups (p=.03). Conclusions: Our study suggests that routine use of CA 15.3 is of few interest before 4 years after initial treatment but after 4 years, the number of lines of therapy received and the survival are higher for the 40% of patients with a metastatic status diagnosed following the routine use of CA 15.3. No significant financial relationships to disclose.
Phase II trial of old age acute myeloid leukemia treatment by arsenic trioxide and low-dose subcutaneous cytosin arabinoside
Authors: A. Ghavamzadeh, S. Hashemi, K. Alimoghaddam, Z. Nasri Moghaddam, M. Shadpour, M. Jalili
Journal: Journal of Clinical Oncology (2009)

7075 Background: AML is a disease of old age, but unfortunately due to several factors standard treatment can not be delivered to these patients. Here we tried to achieve to bet possible response to these patients. Methods: Eleven old age patients selected for this trial. Patients couldn't tolerate standard treatment of AML due to old age or comorbid disorders. Treatment consist of best supportive care plus administration of low dose ARA-C (20mg/day as SQ) for 10 days each months and arsenic trioxide 10 mg/day as 2 hour iv infusion each month. Patients followed by CBC and BMA/B when peripheral blood normalized or every other month. Results: This cohort consist of 8 men and 3 women. Median age was 75 y/o (55–80). Median WBC count Hb level and platelet count at presentation were 42,860μl, 8.3g/dl and 30,500/μl, respectively. Complete remission observed in 6 and partial remission in one patient (RR = 63.6%), but remission was short live, after 6 months one patient was in CR and one in PR. After 12 months, only one patient was in PR. Median survival was 6 months and 6 patients survive more than 6 months. Two patients are alive after 12 months. Conclusions: Although prognosis of old age AML remain poor, but with this type of treatment RR is acceptable. In this very high-risk group of very old AML, combination of ATO and ARA-C possibly could improve survival. No significant financial relationships to disclose.
Phase III study of vinflunine versus docetaxel in patients (pts) with advanced non-small cell lung cancer (NSCLC) previously treated with a platinum-containing regimen
Authors: M. Krzakowski, J. Douillard, R. Ramlau, J. Jassem, A. Szczesna, P. Zatloukal, J. von Pawel, O. Hansen, X. Sun
Journal: Journal of Clinical Oncology (2007)

7511 Background: Vinflunine (VFL) is a new microtubule inhibitor of the vinca alkaloid class with clinical activity in NSCLC (J. Bennouna, BJC, 2006). Single-agent efficacy and safety of VFL and docetaxel (DTX) were compared in the 2nd line chemotherapy. Methods: Open-label, multi-center, randomised, phase III study in platinum pre-treated locally advanced/metastatic NSCLC pts. At least 275 pts were to be randomized by arm to receive VFL (320 mg/m 2 , 20-min IV infusion) or DTX (75 mg/m 2 , 1-hour IV infusion with dexamethasone over 3 days) every 3 weeks. The primary endpoint was progression free survival (PFS), with a non-inferiority analysis based on a 10% difference (types I and II error rates: 5%, 20%). Results: From 06/03 to 03/05, 551 pts were randomized (VFL: 274; DTX: 277) and 547 treated (411 men, 136 women); median age 61 years [range 22–83]; ECOG PS 0–1: 89%; metastatic: 90%. All pts were platinum pre-treated, in combination with a vinca alkaloid (22%), paclitaxel (21%), or gemcitabine (48%). A total of 950 [1–20] and 1,025 [1–18] cycles were given with VFL and DTX respectively. Grade 3/4 toxicities were low in both arms: neutropenia (33% vs 30%), anemia (8% vs 3%), thrombocytopenia (2% vs &lt;1%), febrile neutropenia (3% vs 5%), fatigue (11% vs 6%), vomiting (2% vs 1%), abdominal pain (4% vs &lt;1%), constipation (7% vs &lt;1%). Overall incidence of alopecia was: 20% vs 35%, nail disorders 1% vs 6%, injection site reaction 25% vs 1%, peripheral neuropathy 11% vs 15%, diarrhea 6% vs 12%. Efficacy: All efficacy endpoints were similar: median PFS (2.3 vs 2.3 months, HR:1.004 [95% CI: 0.841–1.199]), independent review response rate (4.4% vs 5.5%), stable disease (36.0% vs 39.6%), disease control (40.4 vs 45.1), median overall survival (6.7 vs 7.2 months, HR: 0.973 [0.805–1.176]). Conclusion: VFL shows efficacy equivalent to docetaxel in 2nd line NSCLC chemotherapy. Low, manageable but different toxicity profiles were observed in either arm. Vinflunine offers a new and useful alternative for the 2nd line treatment of pts with this disease. No significant financial relationships to disclose.
Phase I study of MK-3475 (anti-PD-1 monoclonal antibody) in patients with advanced solid tumors.
Authors: Amita Patnaik, Soonmo Peter Kang, Anthony W. Tolcher, Drew Warren Rasco, Kyriakos P. Papadopoulos, Muralidhar Beeram, Ronald Drengler, Cong Chen, Lon Smith, Crystal Perez, Kevin Gergich, Manfred Lehnert
Journal: Journal of Clinical Oncology (2012)

2512 Background: Programmed death-1 (PD-1) is an inhibitory T-cell coreceptor that may lead to suppression of antitumor immunity. MK-3475 is a humanized monoclonal IgG4 antibody against PD-1. Preclinically, MK-3475 has shown antitumor activity in multiple tumor types. This first-in-human phase I trial explored safety, PK, PD, and antitumor activity of MK-3475. Methods: An open-label, dose escalation study was conducted in patients with advanced malignancy refractory to standard therapy. Cohorts of 3-6 patients were enrolled (3+3 design) at escalating IV doses of 1, 3, and 10 mg/kg. Following an initial dose and 28-day Cycle 1, patients were allowed to subsequently receive multiple doses given every 2 wks. Radiographic assessment was conducted every 8 wks using RECIST 1.1 guidelines. Results: Nine patients, 3 at each dose level, completed the dose-limiting toxicity (DLT) period (28 d). Patients had non–small cell lung cancer (NSCLC, n=3), rectal cancer (n=2), melanoma (MEL, n=2), sarcoma (n=1), or carcinoid (n=1). To date, a total of 63 doses were administered (median 7/patient; max 12) without DLT. Drug-related adverse events (AEs) across all doses included Grade 1 fatigue (n=3), nausea (n=2), diarrhea (n=1), dysgeusia (n=1), breast pain (n=1), and pruritus (n=1). One drug-related Grade 2 AE of pruritus was reported. No drug-related AEs ≥ Grade 3 were observed. PK data are shown in the table. Based on RECIST, 1 patient with MEL on therapy &gt;6 mths had a partial response, and preliminary evidence of tumor size reduction (stable disease) was observed in 3 additional patients with advanced cancer. Conclusions: MK-3475 was well-tolerated without DLT across 3 tested dose levels. Evidence of antitumor activity was observed. Enrollment continues to obtain additional safety, PK, and efficacy data; updated data will be presented at the meeting. [Table: see text]
Multicenter analysis of activity and safety of trastuzumab plus chemotherapy in advanced breast cancer in elderly women (≥ 70 years)
Authors: A. Brunello, S. Monfardini, D. Crivellari, F. Puglisi, O. Nascimben, G. Scattolin, A. Molino, G. Mustacchi, M. Beda, U. Basso
Journal: Journal of Clinical Oncology (2008)

1096 Background: Despite the high prevalence of breast cancer (BC) in elderly pts, no specific trial of activity and safety of trastuzumab (T) has addressed pts older than 70 years, and the only available data are taken from subgroup analyses. Methods: Charts of pts ≥70 with inoperable locally advanced/metastatic BC overexpressing HER2 treated with chemotherapy (CHT) and T in 9 Italian Centers were reviewed. Primary endpoints were response rate (RR), time to progression (TTP), toxicity and cardiac events. Results: Fifty pts were eligible, median age 73.8 years (range 70–92). ECOG PS range was 0–2. Twenty-four pts (48%) were ER negative. 38 pts (76%) had G2-G3 tumors. Cardiovascular risk factors are reported (Table). Taxane-based regimens were used in 28 pts (56%), vinorelbine-based in 18 pts (36%). Basal LVEF was 65% (range 54–78%). A comprehensive geriatric assessment had been done in 10 pts. Partial or complete response was obtained in 29 pts out of 43 evaluable (RR= 67%). Other 12 pts had disease stabilization (30%). No difference in RR was seen among subgroups (taxane vs vinorelbine; age <80 vs ≥ 80 years; previously treated vs naïve pts; high vs low grade), yet a trend for increased response for pts with ER-negative disease was observed (80 vs 53%, p = 0.06). Median TTP was 8.7 months at a median follow-up of 14 months. Toxicity did not correlate with CHT regimen or age. After a median of 11.5 months of treatment, two hypertensive crises and an episode of chest pain occurred in 3 pts. A reduction of LVEF >10% but < 20% was observed in 3 pts out of 34 (9%) in whom serial echocardiograms were available. None of these cases required treatment interruption. Conclusions: RR and TTP for elderly pts receiving CHT plus T appeared to be comparable to published data. Taxanes and vinorelbine seem to have comparable activity and toxicity. No serious cardiac event was observed but periodical assessment of cardiac safety is strongly recommended in this category of pts due to frequent concomitant cardiovascular comorbidity. Cardiovascular risk factors (other than hypertension alone) # pts % Previous anthracyclines 21 42% Diabetes, obesity, hyperlipemia, hypertension 9 18% Smoking 6 12% Deep vein thrombosis 3 6% Cardiac arrythmias 3 6% Ischemic cardiopathy 2 4% Cor pulmonale 1 2% No significant financial relationships to disclose.
Analysis of 46 patients with nasopharyngeal carcinoma treated with hyperfractionated radiotherapy in a single institution
Authors: M. Majem, M. Martinez, R. Galiana, A. Montes, F. Cardenal, J. Rodon, J. Nogues, F. J. Perez, J. Gomez, R. Mesia
Journal: Journal of Clinical Oncology (2004)

5616 Background: New fractionations in radiotherapy (RT) on head and neck cancer have emerged to increase local control. Addition of chemotherapy (CT) in advanced nasopharyngeal tumors tries to decrease local and distant recurrence. We report our results in non-Asiatic patients (pts) with advanced nasophayngeal carcinoma treated with induction CT and hyperfractionated RT (hfRT). Methods: Forty-six pts with nasopharyngeal carcinoma have been treated from 10/94 to 05/02: 79% male and 21% female, median age: 51 years (18–76). Hystologic subtypes: 33% keratonizing squamous cell carcinoma (KSCC), 8% nonKSCC, 59% undifferentiated carcinoma. Stage (2002 UICC Classification): 4 IIa, 11 IIb, 14 III, 10 IVa and 7 IVb. Karnofsky index was > 50% in all pts. All patients were treated with hyperfractionated radiotherapy (HfRT). The median HfRT dose was 80.4 Gy administered at 1.2 Gy/ fraction twice day. Additionally 26 pts (55.3%) received induction CT with platinum-based regimens. Results: Median number of CT cycles: 3 (2–5). Grade 3–4 toxicity related to CT: G3 mucositis 27%, G3 emesis 19%, G3–4 afebrile neutropenia 27%. Global Response to CT: 81 % (23% CR, 58% PR). Grade 3–4 acute toxicity related to HfRT: mucositis 59% (20% required enteral support), epithelitis 17%. Late side effects related to HfRT were mainly cervical fibrosis, xerostomy and trismus. There was 1 toxic death (aspirate pneumonia). Surgical neck dissection was performed in 3 pts. Final response: 83% CR, 11 % PR, 6% no evaluated (1 toxic death, 1 suicide during RT, 1 lost of follow up). A total of 14 pts have died: 12 (26%) due to progressive disease. Recurrence rate: 30% (14 pts): 7 local only, 1 nodal only, 3 both and 3 distant. Two of these pts (1 local, 1 nodal) are free of disease with salvage therapy. Second tumors: 2 (none tobacco-related). With a median follow up of 64 months, the 5-year PFS and overall survival were 66.7% (51.3–82.1) and 75.7% (61.9–89.5) respectively. Conclusions: hfRT might be an effective treatment for nasopharyngeal carcinoma. It's unknown the role of CT added to hfRT but the high acute toxicity observed in our series difficulties the use of CT concurrent with hfRT. No significant financial relationships to disclose.
Normal cardiac biopsy results following co-administration of doxorubicin (A), Cyclophosphamide (C) and trastuzumab (H) to women with HER2 positive metastatic breast cancer
Authors: V. Valero, E. Gill, V. Paton, H.-Y. Chang, A. U. Buzdar, G. Park, G. Hortobagyi, M. Ewer
Journal: Journal of Clinical Oncology (2004)

572 Background: Trastuzumab (Herceptin, H) extends overall survival when administered with chemotherapy (CT) to patients (pts) with HER2+ metastatic breast cancer (MBC). An increase in cardiac dysfunction (CD) was seen in pts who received H + CT (paclitaxel or AC) in a phase III study. The mechanism by which H contributes to CD may include a pharmacokinetic (PK) interaction or increased cardiac sensitivity to A. This phase I study evaluated the PK of A, C, and H; the utility of CD monitoring by LVEF (echocardiogram (EC)/nuclear multigated cardiac scan (NCS)), by cardiac biopsy, and cardiac serum marker surveillance. Methods: Inclusion criteria: ages 18–60, no prior internal mammary/mediastinal XRT, no prior A or prior CT for HER2+ MBC. Pts received weekly H (4mg/kg load, 2mg/kg weekly) with AC (60/600) q3w x 6. Cardiac evaluations included physical examination, LVEF, and cardiac biopsy after C4 and/or at s/sx of CD. Biopsies were graded using published methods. Plasma for cardiac markers and PK was obtained. Results: 10 pts were enrolled. Median age: 43 years (range 29–55); Patients received a median of 35 H doses and a median A dose of 360 mg/m2 (range 240–360 mg/m2). The med baseline LVEF by EC was 63.5% (range, 57% - 70%) and 62%,65%,61%,60%,57%,53% at weeks 4,7,10,13,16,22, respectively. These results were confirmed by NCS. Cardiac biopsies (n=10) were grade 0 (no cardiac abnormalities) following C4. Two pts had CD (NYHA, grade II n=1, IV n=1) that was not predicted by prior LVEF results, and one asymptomatic LVEF decline from baseline ≥ 20%.(76% to 48%). Cardiac function normalized in all patients. There were no cardiac deaths. Cardiac marker and PK results will also be presented. The ORR was 100% (1 CR, 9 PR). Conclusion: The lack of significant cardiac biopsy findings coupled with some clinical evidence of short-lasting cardiac dysfunction established that the mechanism of CD from AC+H is different from anthracycline-induced CD. These findings may help explain the different clinical course when CD follows H treatment. 10 add'l pts will enroll and receive A over 72hrs Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Genentech; Pfizer Genentech Bristol-Myers Squibb; Genentech Genentech