tbuckley/cabot-search huggingface dataset:
Endosialin/TEM1: Cellular localization and prevalence in soft-tissue tumors and carcinomas
Authors: C. Rouleau, W. Weber, R. Bagley, S. D. Morgenbesser, S. Kataoka, N. Honma, K. Hasegawa, I. Ishida, B. L. Thurberg, B. A. Teicher
Journal: Journal of Clinical Oncology (2007)

20520 Background: Tumors grow more slowly in endosialin/TEM1 KO mice compared to WT, suggesting that host endosialin/TEM1-positive stroma promotes malignancy (Nanda, PNAS, 2006). Methods: We surveyed 92 human clinical samples by IHC (52 epithelial tumors, 40 sarcomas) to measure the extent of endosialin/TEM1 expression and assess cellular localization. Expression was also studied in primary cell cultures and 49 cancer lines. Results: 46/52 adenocarcinomas and carcinomas (88.5%) expressed endosialin/TEM1 mainly in pericytes (7/7 bladder, 7/11 breast, 5/5 colon, 7/8 ovarian, 7/7 renal, 2/2 liver, 4/5 lung, and 7/7 gastric). In some tumors, endosialin/TEM1 was present in pericytes and in fibroblasts (2/7 bladder, 4/11 breast, 5/5 colon, 5/8 ovarian, 2/7 renal, 2/2 liver, 1/5 lung and 7/7 gastric cancers). 32/40 sarcomas (80%) expressed endosialin/TEM1 mainly in pericytes (10/11 synovial sarcomas, 9/10 malignant fibrous histiocytomas, 3/5 Ewing's sarcomas, 3/5 angiosarcomas, 3/4 rhabdomyosarcomas, 2/2 pleiomorphic sarcomas, 1/1 Kaposi's sarcoma, 0/1 leiomyosarcoma and 1/1 liposarcoma). Synovial sarcomas displayed intense fibroblast staining. Endosialin/TEM1 was expressed by sarcoma cells in a few samples. In culture, we previously showed expression in human fibroblasts, endothelial precursor cells, pericytes and mesenchymal stem cells (MSC). We now report that endosialin/TEM1 mRNA is present in MSC during osteogenic and adipogenic differentiation. In 49 human tumor lines, expression was restricted to sarcoma cells (7/15 sarcoma, 0/5 melanoma, 0/2 neuroblastoma, 0/4 breast, 0/1 ovarian, 0/3 prostate, 0/1 renal, 0/1 liver, 0/3 pancreatic, 0/6 colorectal and 0/8 hematopoietic cancer lines). Conclusions: Endosialin/TEM1 is frequently expressed in clinical cancer (85% of 92 samples), both in epithelial and mesenchymal tumors. Cellular expression is mesenchymal in clinical samples and in culture. In tissues, endosialin/TEM1 is present in pericytes and fibroblasts, with some expression in sarcoma cells. The importance of endosialin/TEM1-positive stroma in experimental animals and prevalence in patient samples warrant further investigation. Endosialin/TEM1 may be a useful therapeutic target. [Table: see text]
In vivo biological effects of panitumumab + chemotherapy in advanced colorectal cancer patients
Authors: K. Bencardino, M. Ronzoni, M. Manzoni, B. Rovati, S. Mariucci, S. Delfanti, S. Chatzileontiadou, E. Villa, M. Danova
Journal: Journal of Clinical Oncology (2008)

14576 Background: Panitumumab, a fully human monoclonal antibody against EGFR, has demonstrated efficacy in the treatment of metastatic colorectal carcinoma (mCRC). Multiple links have been found between angiogenesis and both the EGFR pathway and the immunoresponse in human tumors, influencing the properties of these new anticancer agents with molecular targets. Flow cytometric (FCM) determination of circulating endothelial cells (CECs) and progenitor cells (CEPs) has been proposed to monitor anti-angiogenetic drug activity. We have focused on the impact of a first-line Panitumumab-based combination therapy on CECs and CEPs as well as on the both peripheral blood (PB) lymphocyte and dendritic cell (DC) immunophenotype, in order to identify non-invasive biomarkers of efficacy. Methods: We utilized multiparameter FCM to quantify the absolute numbers of CECs (rCEC, resting and aCEC, activated) and CEPs, PB lymphocytes and DC subsets in 11 mCRC pts (M/F:7/4, median age: 71 yrs, range 61–75), before and during a 1st-line, biweekly treatment with Oxaliplatin/5FU/LV + Panitumumab. Baseline data were compared with reference values obtained by 50 healthy subjects (M/F: 25/25, median age:43 yrs, range 21–65). Results: With respect to normal donors, we observed at baseline: a significant decrease of the total lymphocytes, CD4 T-lymphocytes, CD19 and CD20 B-lymphocytes and of NK cells, while DCs (in both DC1 and DC2 subsets) and CECs did not show significant differences. In 8 evaluable pts, after 3 courses of CT + Panitumumab, a trend was shown toward a progressive increase of all (but not CD19 and CD20) lymphocyte subsets, total DCs, DC subsets and total CECs, particularly in their resting form. This trend was confirmed after the 6th course when the increase of both aCECs and rCECs became highly statistically significant vs the baseline. No significant variations were shown on CEPs levels probably due to their extreme rarity. Conclusions: Panitumumab-based, first-line treatment of mCRC has a significant impact on both CECs levels and the in vivo T-cell mediated response. This suggests a potential usefulness of the combined FCM determination of CECs and PB / DC immunophenotype, as predictive biomarkers of efficacy in the clinical setting. No significant financial relationships to disclose.
Post-traumatic stress in patients with acute leukemia.
Authors: C. Zimmermann, C. Lo, A. Rydall, A. Chan, J. Andrews, M. Minden, A. Schimmer, J. Brandwein, G. Rodin
Journal: Journal of Clinical Oncology (2010)

9143 Background: Acute leukemia is marked by discrete, life-threatening events (diagnosis, relapse and refractory disease), which may evoke symptoms of post-traumatic stress (PTS). However, PTS has not been evaluated systematically in these patients. This study was undertaken to evaluate PTS in patients with acute leukemia to determine the impact of physical distress, psychosocial factors and communication with the medical team. Methods: Patients with recently diagnosed or relapsed acute myeloid, lymphocytic and promyelocytic leukemia were recruited from hematology clinics and inpatient units at Princess Margaret Hospital, Toronto. Using multivariate regression analysis we evaluated demographic factors, past psychiatric history, disease/treatment variables (leukemia type, new onset vs. relapse, active treatment vs. supportive care, duration of illness), and communication with the medical team as predictors of PTS. Self-report measures included: Stanford Acute Stress Reaction Questionnaire (SASRQ), Memorial Symptom Assessment Scale, Karnofsky Performance Status, and CARES Medical Interaction Subscale. Results: Of 118 subjects recruited, 61% were male, mean age was 51.4±15.1 years, 82% were recently diagnosed, and 97.5% were receiving active treatment. At baseline, subjects reported significant physical distress with a mean of 8.2±4.1 concurrent physical symptoms, including lack of energy (78%), difficulty sleeping (56%), loss of appetite (55%) and pain (44%). Mean SASRQ score was 26.7±20.3 (range 0-89), with 9.3% of patients meeting criteria for acute stress disorder. In regression analyses, PTS was predicted by higher physical symptom distress (Beta= .389, p<.0001), past psychiatric history (Beta=.217, p<.01), and poorer ratings of communication with the medical team (Beta=.272, p<.002) (adjusted R2=0.29). Conclusions: A significant minority of patients with acute leukemia suffer from PTS, which is associated with higher reported physical distress, past psychiatric history, and poorer communication with the medical team. Future longitudinal findings from this study will allow testing of a causal model for the emergence and course of PTS and help to identify timing and targets for proactive palliative care intervention. No significant financial relationships to disclose.
Prediction is no panacea: The key to language is in the unexpected
Authors: Hugh Rabagliati, Douglas K. Bemis
Journal: Behavioral and Brain Sciences (2013)

Abstract For action systems, the critical task is to predict what will happen next. In language, however, the critical task is not to predict the next auditory event but to extract meaning. Reducing language to an action system, and putting prediction at center, mistakenly marginalizes our core capacity to communicate the novel and unpredictable.
Evolutionary history of the COII/tRNALys intergenic 9 base pair deletion in human mitochondrial DNAs from the Pacific.
Authors: A J Redd, N Takezaki, S T Sherry, S T McGarvey, A S Sofro, M Stoneking
Journal: Molecular Biology and Evolution (1995)

Length changes in human mitochondrial DNA (mtDNA) are potentially useful markers for inferring the evolutionary history of populations. One such length change is a nine base pair (9-bp) deletion that is located in the intergenic region between the COII gene and the Lysine tRNA gene (COII/tRNALys intergenic region). This deletion has been used as a genetic marker to trace descent from peoples of East Asian origin. A geographic cline of the deletion frequency across modern Pacific Islander populations suggests that the deletion may be useful for tracing prehistoric Polynesian origins and affinities. Mitochondrial DNA sequence variation within two variable segments of the control region (CR) permits a number of inferences regarding the evolutionary history of the 9-bp deletion that cannot be determined from frequency data alone. We obtained CR sequences from 74 mtDNAs with the 9-bp deletion from Indonesia, coastal Papua New Guinea (PNG), and American Samoa. Phylogenetic and pairwise distribution analysis of these CR sequences pooled with previously published CR sequences reveals that the deletion arose independently in Africa and Asia and suggests possible multiple origins of the deletion in Asia. A clinal increase of the frequency of the 9-bp deletion across the three Pacific populations is associated with a decrease in CR sequence diversity, consistent with founder events. Furthermore, analysis of pairwise difference distributions indicates an expansion time of proto-Polynesians that began 5,500 yr ago from Southeast Asia. These results are consistent with the express train model of Polynesian origins.
Phase I experience with c-MET inhibitor XL880 administered orally to patients (pts) with solid tumors
Authors: J. P. Eder, E. Heath, L. Appleman, G. Shapiro, D. Wang, L. Malburg, A. x. Zhu, T. Leader, A. Wolanski, P. LoRusso
Journal: Journal of Clinical Oncology (2007)

3526 Background: XL880 is a sub-nM inhibitor of the hepatocyte growth factor receptor (Met) and VEGF receptor family with low in vitro nM inhibition of PDGFRβ, KIT, FLT3, Tie-2 and Ron. Methods: The safety of XL880 was evaluated in two phase 1 studies. XL880 was administered mass-based on a 5 days on / 9 days off schedule (study 1) or as a fixed daily dose (study 2). Inclusion criteria include ECOG performance status = 2, adequate liver, cardiac, and renal function and no brain metastases. Tumor response is assessed every 8 wks by RECIST criteria. Pharmacokinetics, pre and post treatment tumor biopsies and plasma markers of angiogenesis (VEGF, sVEGFR and Ang2) were collected. Results: To date, 51 pts have been dosed in studies 1 &amp; 2. In study 1, dose limiting toxicities (DLT) included reversible Gr3 elevations of lipase, hepatic transaminases and proteinuria. The maximum tolerated dose (MTD) was 3.6 mg/kg. In study 2, the MTD has not been defined. Common adverse events include hypertension and fatigue with loss of concentration. In study 1, 5 of 40 pts had partial responses (2+ -12+ months[m]), 3 pts had minimal responses and 8 pts had stable disease (SD) &gt; 3 m. In study 2, 5 of 8 evaluable pts had SD &gt; 3 m (4 ongoing) and 3 are too early to evaluate. Correlative studies in tumor biopsies show marked inhibition of phospho (p)-met, p-RON, p- ERK, p-AKT and increased apoptosis at less than the MTD. Patients in study 2 pts showed lower XL880 Cmax values with consistent mean concentrations (Css)compared with study 1 MTD pts. Css levels are reached in 15 d. Conclusions: XL880 as daily oral or 5 day on / 9 day off administration is generally well tolerated for &gt; 1 year, although hypertension is nearly universal but manageable. XL880 has demonstrated substantial phase I antitumor activity with both dosing regimens. Correlative studies indicate significant activity against Met and Ron signaling. Enrollment continues on study 2. Phase II trials in gastric cancer and head and neck cancer will begin soon. No significant financial relationships to disclose.
Pattern of gastric cancer resection in the Memphis metropolitan area (MMA).
Authors: M. Evangelist, J. C. Sachdev, A. G. Khattak, J. Denbo, W. S. Orr, M. Ul-Haq, A. Berry, T. O'Brien, R. A. Dilawari, R. U. Osarogiagbon
Journal: Journal of Clinical Oncology (2010)

e14633 Background: Quality of cancer surgery impacts patient outcomes. We evaluated the pattern and quality of gastric cancer resections and correlated them with postoperative and long term survival in the MMA. Methods: Institutional review of all curative-intent gastric cancer resections from 1999-2008 excluding those who received preoperative therapy. Good quality resection (GQR) was defined as R0 with ≥ 15 lymph nodes (LN) examined. Log rank test for survival comparisons, Wilcoxon Mann Whitney for comparison between medians and proportional hazard models were employed. Results: Table: Cohort characteristics (N=112). GQR rate: 26%. Only 6% of patients had preoperative endoscopic ultrasound (EUS) or laparoscopic staging. Unexpected metastatic disease was discovered intraoperatively in 25% of the patients. R-status (p< 0.001), but not number of LN examined, correlated with survival. Tumor stage independently predicted survival on univariate analysis, while GQR, age, and number of comorbidities did not. Conclusions: R0 resection was associated with better survival in our MMA gastric resection cohort. The proportion of patients who had ≥ 15 LN examined was low. Increased utilization of preoperative staging modalities like EUS and laparoscopy, and emphasis on more thorough pathological examination of resection specimens can improve GQR rates. (%) P value Median age 66 (25-93) Sex Female 43 Male 57 Race Black 63 White 30 Other 7 Stage I 24 II 22 III 30 IV 22 Preoperative staging CT 71 EUS 3 Laparoscopy 3 Not reported 23 Gastrectomy Proximal 5 Distal 66 Total 28 R status R0 72 R1/R2 28 Median margin distance (mm) 10 (0-340) LN status Nx 4 N0 29 N1-3 66 Median LN examined Overall 14 (0-55) LN-negative patients 9 (1-43) p < 0.01 LN-positive patients 15 (0-55) # LN examined 0 5 < 15 54 ≥15 41 GQR p = 0.61 Overall 26 Stage I 20 Stage II 30 Stage III 28 Stage IV 25 60-day postoperative survival rate (%) 93 5-year survival rates (%) Overall 44 Stage p <0.01 I 74 II 35 III 39 IV 21 R status p < 0.001 R0 55 R1/R2 17 LN examined p = 0.61 < 15 49 ≥ 15 38 GQR p = 0.51 Yes 42 No 51 No significant financial relationships to disclose.
Phase I/II trial of carboplatin (CBDCA)/ weekly paclitaxel in patients with advanced non-small cell lung cancer in Japanese population: WJTOG 9907
Authors: H. Saka, N. Nogami, S. Kitaguchi, M. Yamamoto, M. Fukuoka, Y. Ariyoshi
Journal: Journal of Clinical Oncology (2005)

7341 Background: Weekly paclitaxel is superior to conventional every-three week delivery in metastatic breast cancer (Seidman D, et al. ProcASCO 2004). Peripheral neuropathy and arthralgia were less frequent with weekly doses in non-small cell lung cancer (Belani CP, et al. ProcASCO 2004). Methods: In the phase I part, the doses of paclitaxel were increased 70, 80, 90, and 100 mg/m2 on days 1, 8, and 15 q4w with the fixed dose of CBDCA (AUC=6 mg/mL · min) on day 1. The phase II was followed. Eligibility included ECOG PS 0 to 1, advanced IIIB-IV chemo-naïve non-small cell lung cancer. Results: The Phase I part was consisted of 12 patients (pts), 3 pts in each step. Recommended dose of paclitaxel was 90 mg/m2. In the phase II part, 26 pts (male/female 19/7) were entered. Median age was 63.5 (range 42–74). Pts with IIIB/IV/relapsed after resection were 6/16/4, respectively. PS 0 in 10 pts, adeno in 20 pts, and weight loss (< 5%) in 21 pts. Response rate was 37% (n=19). Grade 4 leukopenia, neutropenia, anemia were observed in 1, 4, 1 pt(s) respectively. No grade 3 or 4 non-hematologic toxicity was observed except 1 pt with grade 3 infection. No toxic death was reported. Conclusions: The antitumor effect was moderate. Grade 3 or 4 peripheral neuropathy was not observed in Japanese population. No significant financial relationships to disclose.
In vivo changes in gene expression profiles (GEP) after bortezomib (V) for multiple myeloma (MM): Differential effects on plasma cells (PC) and micro-environment (ME)
Authors: J. D. Shaughnessy, F. Zhan, Y. Huang, B. Barlogie
Journal: Journal of Clinical Oncology (2006)

7603 Introduction: V, a proteasome inhibitor with potent anti-myeloma activity, is thought to act through effects on malignant PC and the ME. However, the in vivo effects of this drug have never been examined at the molecular level. Methods: Serial GEP analyses were performed of paired purified PC and bone marrow biopsies from 46 patients, obtained prior to and 48hr following administration of a single V dose at 1mg/m 2 . RNA was isolated from whole biopsies and purified PCs from each sample, converted to cRNA, and hybridized to Affymetrix U133 Plus2 microarrays. SAM analysis with 5% false discovery rate was employed to identify drug-altered genes. Results: Following V, 36 ME-associated genes (MAGs) were up-regulated, among them the osteoinductive factor osteoglycin (OGN), consistent with a V effect on osteoblastogenesis; CYR61, an angiogenesis inducer, significantly over-expressed in myeloma relative to normal marrow, was one of only 3 significantly down-regulated genes. V is known to induce expression of proteasome genes and PSMA6, PSMA1, and PSMA14 were among 15 genes up-regulated in PC. In contrast, early growth response (EGR1, EGR2, and EGR3), Krupple-like factor (KLR4, KLR5, KLR6, and KLR7) and nuclear receptor (NR4A1, NR4A2, and NR4A3) family members were down-regulated in PC by V. These differential PC and ME expression changes were only noted in low-risk MM, lacking over-expression of CKS1B. Conclusion: We report here, for the first time, on the differential molecular consequences of a single in-vivo dose of V on both tumor cells and cells of the microenvironment. The clinical implications of these findings are being further investigated and will be presented. [Table: see text]
Bevacizumab (B) plus irinotecan (I) in progressive multiple pretreated and temozolomide (T) refractory glioblastoma multiforme (GBM): A single center experience using a low dose regimen
Authors: A. Dresemann, A. Hobbold, G. Dresemann
Journal: Journal of Clinical Oncology (2008)

13007 Background: Standard treatment consisting of surgery, irradiation plus concomitant and following T is established in GBM with median survival of 15.6 months, indicating the need for further effective treatment. In several phase II studies B plus I showed impressive objective response rates (>50%) in pre-treated GBM pts with low toxicity rate, duration of response, however, was moderate. Therefore B plus I might be an effective induction regimen for T resistant GBM patients as basis for further treatments. In colo-rectal cancer a lower dose of B plus I was effective therefore B and I dose was reduced. Methods: From December 2006 to October 2007, 44 pts with progressive GBM resistant to T were treated with B 4 mg/kg body weight intravenously (iv) followed by I 80 mg/m2 iv repeated every 2 weeks. ECOG performance status (PF) was 0–2 in 43 pts, 3 in 1 patient. MRI scans were required at baseline (no haemorrhage was allowed) after 4 weeks and afterwards every 6 weeks. Treatment was given until progressive disease (PD) or intolerable toxicity occurred. Results: All 44 pts were eligible for toxicity and efficacy, median follow up was 7 months, 33 pts were male, 11 female, median age was 45 years (21–79), 32 pts had primary GBM, 12 pts secondary GBM. All pts had prior irradiation (56–60 Gy) 4 pts 4 prior chemotherapy regimens, 11 pts 3, 22 pts 2 and 7 pts T only. The only patient with PF 3 died of clostridium sepsis during grade IV leucopenia after the first treatment, 1 patient developed grade III leucopenia and 2 pts grade III thrombopenia, 1 patient grade III pneumonia, 2 pts asymptomatic intracerebral bleeds requiring treatment delay and 1 patient grade III fatigue. In 22 pts a partial response (PR) was achieved, in 15 pts disease stabilization for at least 2 months, 7 pts showed primary PD. Median duration of PR was 3 months (2–8), best MRI response was acchieved after 4 to 8 weeks of treatment. Data will be updated. Conclusion: B plus I seems to be the most effective regimen for induction of objective response in multiple pretreated GBM pts with excellent toxicity profile. Efficacy of the low dose regimen was comparable to other published regimen. Confirmation is required. A following maintenance treatment should be considered. No significant financial relationships to disclose.
Preliminary results of a phase I study of external beam radiation therapy (EBRT), oxaliplatin (OX), bevacizumab (BV), and capecitabine (CAP) for locally advanced or metastatic adenocarcinoma of the rectum
Authors: B. Czito, J. Bendell, C. Willett, G. Vaccaro, M. Morse, D. Yu, W. Honeycutt, A. Franklin, H. Hurwitz
Journal: Journal of Clinical Oncology (2006)

3543 Background: BV, a monoclonal antibody against vascular endothelial growth factor, increases survival when added to first and second line chemotherapy for metastatic colorectal cancer. Preclinical studies suggest BV may enhance tumoral radiation sensitivity. Preliminary studies of OX and 5-FU based chemoradiation therapy for rectal cancer have suggested improved pathologic CR rates compared to 5-FU/ radiation alone. CAP allows fluoropyrimidine treatment without the inconvenience of an infusion pump. We investigated CAP + BV + OX + EBRT for pts with rectal cancer to evaluate for the MTD and preliminary efficacy results. Methods: Pts with adenocarcinoma of the rectum and no prior pelvic irradiation received 5040 cGy EBRT (180 cGy/fx), CAP (625–825 mg/m 2 PO BID on EBRT days), BEV (15 mg/kg d1 and 10 mg/kg d8 and d22), and OX (50–75 mg/m 2 /week during radiation, weeks 1–5) in dose-escalating fashion. DLT was defined as any grade 3 heme tox ≥ 7d, grade 4 heme tox, grade 4 non-heme tox during chemoradiation, or inability to deliver &gt;85% of planned treatment. Pts eligible for surgical resection could have surgery 6–8 wks after treatment completion. After recovery from surgery, patients could be treated with CAP, BV, and OX. Results: 11 patients (5 men/6 women) have been enrolled. All have completed chemoradiation and resection. At dose level 1 (CAP 625 mg/m 2 BID, OX 50mg/m 2 ) there were no DLT’s in 3 pts. 1/3 pts had G3 subarachnoid hemorrhage during adjuvant chemotherapy. At dose level 2 (CAP 825 mg/m 2 , OX 50 mg/m 2 ) 2/2 pts had DLT (1 G4 diarrhea; 1 G2 rectal pain, causing treatment hold for study-defined DLT). 6 more pts were treated at dose level 1. 1pt had DLT of G3 diarrhea. G2 toxicities included diarrhea (3/11), fatigue (2/11), skin changes (2/11), and pain (2/11). 9/11 patients were downstaged. 2/11 patients had pCR at surgery and 2/11 microscopic disease only. Conclusions: CAP + BEV + OX + EBRT is a well-tolerated, active regimen for the treatment of rectal cancer. MTD was determined to be CAP 625 mg/m 2 BID + BEV 15 mg/kg d1 + 10 mg/kg d 8 and 22 + OX 50 mg/m 2 /week. Further study of efficacy at the MTD is warranted. [Table: see text]