tbuckley/cabot-search huggingface dataset:
Improvement of PET imaging in esophageal neoplasms by using FMISO versus FDG: A feasibility study
Authors: J. Metges, O. Pradier, V. Le Tallec-Jestin, H. Kerspern, J. Codet, D. Visvikis, C. Cheze Le Rest
Journal: Journal of Clinical Oncology (2008)

15561 Background: The use of FDG PET scan in the management of esophageal neoplasms (EN) is subject to controversies. FMISO is a new available tracer for PET imaging targeting hypoxia. No data are available in the litterature using this tracer in EN. Because hypoxia and angiogenesis are related, we designed a feasibility study using both functional imaging of hypoxia with FMISO and biological markers of angiogenesis in esophageal cancer. Material and Methods: At present, after informed consent, 8 patients with newly diagnosed esophageal cancer have been included (8 males, 62 ± 11y). 7 patients had squamous cell esophageal carcinoma and one had an adenocarcinoma. All had advanced disease (4 stage 3, 4 stage 4) and were considered for exclusive radiochemotherapy. Before treatment, all patients underwent FDG PET and FMISO PET study. FMISO PET images were acquired 2 and 3 hours after the IV injection of a mean activity of 292 MBq of FMISO. The 2 PET investigations were performed within a mean interval of 7 days (3–13). P53, HER2, epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) expressions were assessed on blood samples and tumor samples obtained before treatment. Response to therapy was evaluated using RECIST criteria by conventional imaging performed one month after treatment. Results: All patients were FDG positive with high uptake in the primary(mean SUV=8,6).The pretherapeutic FDG SUV was 8.33 (responders) vs 9.6 (non responders). FMISO uptake was statistically lower in the primary lesion (mean SUV: 0.67). The pretherapeutic FMISO SUV was 0.56 (responders) vs 0.77 (non responders). One patient had lung and liver metastases demonstrated with FDG and FMISO. FMISO uptake was only peripheric (ring aspect) in the metastases. Results concerning correlation between FMISO uptake and angiogenesis markers (EGFR,VEGF,P53,HER2) will also be presented during the meeting. Conclusions: F MISO is a new tracer for hypoxia which could help to differenciate between responders and non responders before treatment in EN. These preliminary results are to be confirmed by this ongoing study. Grants from the French PHRC. No significant financial relationships to disclose.
Association of Notch signaling pathway expression in liposarcomas with outcome, and targeting with gamma-secretase inhibitors
Authors: R. D. Meng, L. Qin, C. C. Shelton, Y. Li, R. G. Maki, E. R. Brill, S. Singer, G. K. Schwartz
Journal: Journal of Clinical Oncology (2009)

10526 Background: The Notch pathway directs normal fat cell development, but its aberrant activation may promote the development of sarcomas. The expression of the Notch pathway in liposarcoma (LPS), however, is unknown. We examined Notch signaling components in LPS's and suppressed Notch activation with drug targeting in LPS cell lines. Methods: RNA was isolated from 18 normal fat and 140 LPS tissue samples from five LPS subtypes: well-differentiated (33%), de-differentiated DD (25%), myxoid (12%), round cell (6%), and pleomorphic (13%), and were hybridized to Affymetrix U133A arrays. Microarray data were normalized with the RMA method. Correlation analysis identified genes expressed between sample classes, using Empirical Bayes t-test, and genes associated with survival, using Cox regression. The Notch pathway in two LPS lines, DDLS and LS141, was suppressed with a novel gamma-secretase inhibitor (GSI) or with siRNA to Notch receptors. Viability was assessed by colony formation, apoptosis by DAPI staining, and Notch expression by immunoblotting. Results: Expression of Notch-3 and its targets, Hes-1, Hey-1, and survivin, was increased in LPS subtypes, compared to fat tissue (p&lt;0.001). Inhibition of Notch signaling with GSI's or siRNA to Notch-1 suppressed the viability of both DD LPS lines (p&lt;0.05), inducing a G1/S arrest followed by apoptosis. Transfection of siRNA to each Notch receptor, especially Notch-3, also suppressed the viability of DD LPS's (p&lt;0.05). Expression of Notch-3 (p=0.027, HR=2.64), Notch-4 (p=0.026, HR=2.70), the ligand JAG-2 (p=0.049, HR=2.32), and Hey-1 (p=0.001, HR=4.25) was associated with reduced distant recurrence free survival in patients with DD LPS's. Expression of the negative Notch regulator Fbxw7 was associated with improved overall survival in patients with LPS (p=0.008, HR=-1.42). Conclusions: Elements of the Notch pathway (receptors, ligands, targets, and modifiers) are overexpressed in LPS's compared to normal fat tissue and associate with outcome. Suppression of Notch signaling decreased DD LPS cell line viability and induced apoptosis. Notch inhibition may represent a new therapeutic strategy for patients with LPS's and deserves further validation in a clinical trial. No significant financial relationships to disclose.
Clinical outcome of postchemotherapy salvage surgery for metastatic germ cell tumors in Japan
Authors: K. Kakimoto, T. Kinouchi, Y. Ono, N. Meguro, O. Maeda, M. Usami, N. Nonomura, D. Oka, T. Miki, Y. Mizutani
Journal: Journal of Clinical Oncology (2006)

14654 Background: Salvage surgery including retroperitoneal lymph node dissection (RPLND) following chemotherapy has been considered a critical component in the comprehensive management of advanced germ cell tumors (GCT). The objectives of this study were to determine the pathologic findings and clinical outcome of patients with metastatic GCT who underwent postchemotherapy salvage surgery. Methods: From 1980 to 2004, 157 patients with metastatic diseases underwent postchemotherapy salvage surgery at three institutions. Surgical resection was indicated in the presence of residual radiographic abnormalities. The cause-specific survival rate was calculated using the Kaplan-Meier method. Results: The histology of GCT was pure seminoma in 49 patients and non-seminoma in 108 patients. As first-line chemotherapy, 30 patients were treated with PVB (cisplatin, vinblastine and bleomycin) regimen, 107 patients with PEB (cisplatin, etoposide and bleomycin) regimen and 20 patients with other regimens. Salvage surgery was performed after first-line chemotherapy in 87 patients and after salvage chemotherapy in 70 patients. As salvage surgery, RPLND was performed in 135 patients, resection of pulmonary metastasis in 38, hepatotomy in 2 and resection of metastatic brain tumors in 3. The pathological findings at surgery were necrosis in 87 (55%) patients, mature teratoma in 34 (22%) and residual cancer in 36 (23%). Five of 36 patients with residual cancer performed salvage surgery in the state of marker positive. Of the 31 patients who had residual cancer with normalized marker, salvage surgery was performed after salvage chemotherapy in 11 patients. The sites of residual cancer were retroperitoneal lymph nodes in 34 patients, lung in 4, brain in 2 and liver in 1. The cause-specific 5-year survival rates for patients who had necrosis, mature teratoma and residual cancer were 95%, 96% and 68%, respectively. Conclusions: Residual cancer could not reliably be predicted or discriminated from necrosis or mature teratoma. Therefore, salvage surgery to remove postchemotherapy residual masses remains essential in the successful treatment of metastatic GCT. No significant financial relationships to disclose.
A multicenter prospective trial of sorafenib in patients (pts) with metastatic clear cell renal cell carcinoma (mccRCC) refractory to prior sunitinib or bevacizumab
Authors: D. R. Shepard, B. I. Rini, J. A. Garcia, T. E. Hutson, P. Elson, T. Gilligan, C. Nemec, R. Lopez, D. Borner, R. Dreicer, R. M. Bukowski
Journal: Journal of Clinical Oncology (2008)

5123 Introduction: Bevacizumab and sunitinib are common initial therapies for pts with mccRCC. The activity and tolerability of sorafenib in pts with mccRCC refractory to these agents was studied prospectively. Methods: Pts with mccRCC with disease progression by RECIST criteria after treatment with bevacizumab or sunitinib (two independent cohorts) received sorafenib 400 mg BID in a multicenter, prospective, phase II trial. Tumor burden reduction rate (TBRR), the proportion of pts with ≥ 5% reduction in the sum of RECIST-defined target lesions without other progression, was the primary endpoint. A two stage accrual design was utilized to test the hypothesis that the TBRR was > 20% versus < 5%. Results: Thirty-seven pts (n=31 evaluable) refractory to bevacizumab (n=13) or sunitinib (n=18) have been enrolled with 68% males, a median age of 64, 55% ECOG PS 0 and 84% with prior nephrectomy. Pts had received bevacizumab or sunitinib for a median of 8.5 months (range, 0.4–24.6). The median delay between stopping bevacizumab or sunitinib and beginning sorafenib was 4.4 weeks (range, 2.1–59.1). No objective responses were observed. Fifteen of 29 evaluable pts (52%) had some tumor shrinkage with ≥ 5% shrinkage in 11 pts (TBRR 38%) and ≥ 20% shrinkage in 4 pts (14%). TBRR was 33% and 41% in pts with prior bevacizumab or sunitinib, respectively. There were no significant correlations between response to prior therapy and tumor shrinkage in this trial. Median PFS is 3.8 months. Toxicities included hand foot syndrome (grade 1/2: 38%, grade 3: 31%), rash (20%, 7%), hypertension (28%, 14%), diarrhea (48%, 7%) and fatigue (38%, 17%). Overall, fifty-eight percent of pts had Grade 3 toxicity. Pts with prior bevacizumab had more hand-foot-syndrome (p=0.02) and mucositis (p=0.04) while pts with prior sunitinib had more rash (p=0.04). Conclusions: Administration of sorafenib is feasible in mccRCC pts previously treated with either bevacizumab or sunitinib, although associated with toxicity. Reduction of tumor burden was observed in pts receiving sorafenib with mccRCC refractory to bevacizumab or sunitinib. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bayer, Pfizer Oncology, Wyeth Bayer, Pfizer Oncology, Wyeth Bayer, Celgene, Genentech™ BioOncology, GlaxoSmithKline, Novartis, Pfizer Oncology, Wyeth
Abstract 17399: Twisting Motion of the Mitral Complex Assessed by Real-time 3-dimensional Echocardiography: Comparison between Normal Subjects and Functional Mitral Regurgitation.
Authors: Masao Daimon, Sakiko Miyazaki, Yoko Koiso, Yuko Onishi, Shuo-Ju Chiang, Hiromasa Suzuki, Hiroyuki Daida
Journal: Circulation (2010)

Introduction:  Left ventricular (LV) torsion has been reported. However, less is known about twisting motion of the mitral complex concomitant with ventricular torsion.   Hypothesis:  The aim of our study was to assess the hypothesis that the mitral complex has twisting motion, and examine the contribution of disturbed twisting motion of the mitral complex to the severity of functional mitral regurgitation (MR), using real-time 3-dimensional echocardiography (RT3DE).   Methods:  RT3DE was performed in 14 normal subjects and 17 patients with functional MR caused by global LV dysfunction. The short axis views at the basal level and the papillary muscle (PM) level were obtained from 3D volume data set using TomTec 3D software. Angle α between the anterior-posterior (AP) plane and the commissura-commissura (CC) plane at the basal level (figure) in 3D space was measured at both end-systole and end-diastole. Angle β between the AP plane and the PM plane at the PM level was measured as well (figure). The CC-PM angle was calculated as β-α at both end-systole and end-diastole. The MR severity was assessed by PISA method.   Results:  In normal subjects, the CC-PM angle increased at 7.3±4.4 degree during systole, suggesting the mitral complex has twisting motion. In functional MR, the change of CC-PM angle during systole was smaller than the normals (0.5±10.9 degree, p   Conclusions:  The mitral complex had twisting motion during systole. In patients with functional MR, the MR severity was associated with the angle of papillary muscle at end-systole, rather than decreased twisting motion of the mitral complex during systole.
The Metabolic Syndrome and <i>DYRK1B</i>
Authors: Hiroyuki Morita, Issei Komuro
Journal: New England Journal of Medicine (2014)

Keramati et al. (May 15 issue)1 found that the gain-of-function DYRK1B variants R102C and H90P were associated with the metabolic syndrome.These findings probably reveal one end of the phenotypic spectrum associated with DYRK1B variants.The L28P variant of DYRK1B is predicted to be "damaging,"2 and we have postulated that it may be a loss-offunction variant with a protective effect against the metabolic syndrome.We performed a phenomewide association study to examine phenotypes associated with the L28P variant of DYRK1B in a cohort of 7800 Geisinger MyCode Project participants for whom existing genotype data (obtained with the use of the Illumina HumanExome BeadChip) were available and linked to electronic medical record data.Phenotypes associated with cardiometabolic disease were identified with the use of previously validated phenomewide association study codes. 3 Our study revealed a significant protective effect of L28P (in 42 heterozygotes) against type 2 diabetes and a trend toward a protective effect against hypertension (Table 1).Two DYRK1B variants (G352A and P578S) that were predicted to be benign had no significant associations in the phenomewide association study.Some DYRK1B variants are associated with autosomal dominant protective effects.
STEAP1: A potential marker of metastatic disease for Ewing family tumors
Authors: I. Y. Cheung, Y. Feng, K. Danis, N. Shukla, P. Meyers, M. Ladanyi, N. Cheung
Journal: Journal of Clinical Oncology (2007)

10028 Background: Ewing Family Tumors (EFTs) metastasize by hematogeneous spread. Because of its dismal cure rate, targeting subclinical disease is particularly relevant. Genome-wide gene expression array analysis can uncover novel genes differentially expressed in tumors over normal marrow/blood, which may have clinical potentials as markers of minimal residual disease (MRD). Methods: Gene expression array data were obtained on 28 EFT tumors and 10 EFT cell lines using the Affymetrix U133 gene chip. Ten genes with high tumor to blood ratios were identified. Quantitative RT-PCR was performed to study (1) the dynamic range of detection of rare tumor cells (frequency of 10 -7 to 10 -4 ), (2) the gene expression in normal blood and marrow samples, (3) the gene expression among EFT tumors, and (4) the prognostic impact of marker positivity in EFT patients with histologically negative marrows. Results: Of the 10 genes, 5 genes, namely six transmembrane epithelial antigen of the prostate 1 [STEAP1], cyclin D1 [CCND1], plakophilin 1 [PKP1], transmembrane protein 47 [TMEM47], and NKX2.2 transcription factor [NKX2.2] were chosen for further analyses. This was based on their steep linear dynamic range in tumor cells seeded in normal mononuclear cells and consistently high expression among EFT tumor samples. Among 53 EFT patients with histologically negative marrow samples, a marker was classified as positive if the gene transcript level was above the upper limit of normal, defined as mean + 2SD of 26 normal blood and marrow samples. Of the 5 markers tested, STEAP1 positivity in marrow samples was highly correlated with survival with new metastasis in Kaplan Meier analysis (p=0.001). Conclusions: This gene expression array-based approach identified STEAP1 as a promising surrogate MRD marker of metastatic EFT with potential prognostic importance. Its clinical utility will need to be further tested in large patient cohorts. No significant financial relationships to disclose.
Hepatic fibrosis but not cirrhosis in hemochromatosis is reversed by iron removal by phlebotomy therapy.
Authors: LW Powell, JL Dixon, GA Anderson, VN Subramaniam, DJ Lincoln, LM Fletcher, DH Crawford, JW Searle, GA Ramm
Journal: Hepatology (2005)

Current controversy in hemochromatosis centres on the frequency of clinical expression and in particular the incidence of hepatic ﬁbrosis and cirrhosis. It is also unproven whether phlebotomy therapy reverses ﬁbrosis and cirrhosis.
Prognostic value of tyrosinase RT-PCR analysis in histologically negative sentinel lymph nodes from melanoma patients
Authors: M. Gonzalez Cao, C. Badenas, J. Malvehy, R. Martí, T. Castel, R. Rull, B. Mellado, S. Vidal, P. Gascón, S. Puig
Journal: Journal of Clinical Oncology (2004)

7562 Background: The presence of melanoma cells in sentinel lymph nodes (SN) is an important prognostic factor in patients (pts) with primary melanoma. Nevertheless, about 30% of pts with histologically negative SN will relapse. RT-PCR is a sensitive technique that can detect minimal amount of RNA in a sample tissue. Since tyrosinase is a melanocite specific enzyme, detecting melanoma minimal disease at lymph nodes could predict a worse outcome in melanoma patients. Methods: RT-PCR for tyrosinase m-RNA was performed in fresh samples of negative hematoxilin-eosin SN from 76 pts with primary melanoma. Results: 104 SN were detected after lymphoscintigraphy with colloidal 99Tc and blue-dye marker. Median number of SN harvested was 1.36 (range 1 to 3). Overall, tyrosinase RT-PCR was positive in 39 pts (51.3%), whereas in 37 pts (48.7%) was negative. After a median follow-up of 51 months (m), 5-year overall survival (OS) was 97.2% for tyrosinase negative (TN) pts versus 78.67% for tyrosinase positive (TP) pts, (p=.019). Disease free survival at five years was 80% for TN versus 66.24% in TP (p=.38). Differences in sites of disease progression, according to AJCC staging, were observed between both groups: 3 out of 4 progressing pts in the TN group relapsed as subcutaneous, soft tissue or lymph node metastases (M1a), whereas 7 out of 8 TP progressing pts presented relapse as M1c stage (p=.030). Conclusion: Positive tyrosinase RT-PCR in histologically negative sentinel nodes, predicts a more aggressive pattern of relapse, and correlates with a poor OS in these patients. No significant financial relationships to disclose.
Impact of patient and physician factors on oncologists’ recommendations for adjuvant chemotherapy in stage III colon cancer
Authors: M. K. Krzyzanowska, M. M. Regan, M. Powell, C. C. Earle, J. C. Weeks
Journal: Journal of Clinical Oncology (2006)

6051 Background: Population-based studies indicate that elderly patients with colon cancer are less likely to receive adjuvant therapy (tx). Lack of tx may reflect patient preference, appropriate consideration of comorbid illness, or physician bias. Methods: To study physician preference for tx of elderly patients with colon cancer, a vignette-based survey was developed then mailed to a nationally representative sample of 1,000 oncologists. Patient age (61/72/83 yrs), comorbidity level (none/mild/severe CHF with symptoms on minimal exertion) and preference were varied across 8 vignettes. Physician preference for recommending tx was measured using a 7-pt Likert scale; mixed effects linear regression was used to evaluate the results. Results: 485 oncologists returned the survey (RR = 49%); 363 that had seen patients with colon cancer during the previous year were included in further analyses. Median age of the respondents was 52 (range 30–77), 73 (20%) were women. Median time since graduation from medical school was 25 yrs (range 5–53); 17% were employed in academic centers, 8% in HMOs and the remainder in the community. Patient age and comorbid illness interacted to significantly influence physician recommendations. Among patients with mild comorbidity, physician preference for tx of an 83 yr old patient was 1.1 lower than for a 72 yr old (3.8 vs 4.9 on a 7-pt Likert scale) and 1.7 lower than for a 61 yr old (each p&lt;0.0001). This age effect was similar among patients with no comorbidity (p=0.30), with physicians’ preferences consistently higher by about 1.5 than for patients with mild comorbidity (p&lt;0.0001). Among patients with severe comorbidity, preference for tx of an 83 yr old was only 0.9 lower than for a 61 yr old patient (p&lt;0.0001), whereas the decrease was 2.6 for a 61 yr old with severe vs mild comorbidity. Patient preference against tx resulted in 0.3 (p&lt;.0001) decrease in physicians’ recommendations for tx. Among physician factors, only type of employment was associated with tx recommendations with a 0.3 decrease in preference for tx (p=0.0014) among academic oncologists. Conclusions: Patient rather than physician factors have the greatest effect on oncologists’ preferences for adjuvant tx with age and severe comorbidity having the strongest effect. No significant financial relationships to disclose.
Sentinel node pathology analysis in patients with breast cancer and clinical positive axilla
Authors: M. Caleffi, M. C. Biesdorf-Pretto, J. P. Viegas-Butzke, R. A. Ribeiro, M. S. Graudenz
Journal: Journal of Clinical Oncology (2008)

11520 Background: Sentinel lymph node (SLN) biopsy is an alternative method for assessing axillary status in breast cancer (BC) patients. SLN is not usually indicated when there are palpable lymph nodes in the clinical exam, even when they are mobile (N1). We have investigate in a small sample of patients with N1 the possibility of avoiding unnecessary axillaries dissections. Methods: A retrospective study was carried out between Jan/04 and Aug/07 with BC patients from 2 hospitals in Southern Brazil. All patients had clinically positive axilla (N1). All of them were submitted to SLN biopsy by the Imprint Cytology (IC) method during the procedure. Nodes that were suspicious on visual inspection during surgery were also removed. Exclusion criteria were tumor size larger than 4.0 cm, ductal carcinoma in situ, neoadjuvant chemotherapy and axillary lymph nodes classified as N2 or N3 in the clinical exam. Results: We evaluated 29 patients who presented with a N1 pre-surgical axillary lymph node. Mean age was 54 ± 12 years. 69% of patients were submitted to quadrantectomy, with median tumor size of 1.6 cm. Ductal invasive carcinoma was found in 93% and lobular invasive carcinoma in 7% of patients. Ten patients (37.9%) had positive intraoperative IC. Median number of SLN was 2, with no difference between patients with IC positive or negative. The correlation between intraoperative IC and paraffin sections were 100%, yielding sensitivity of 100% (95% CI: 68–100%) and specificity of 100% (95% CI: 78–100%). Conclusions: Our results point that the SLN technique is safe even in clinical N1 positive axilla, sparing 62.1% of patients (n=19) of having axillary clearence. This could lead to a large reduction in morbidity due to the procedure. Prospectively, we are registering all the clinical findings to present larger numbers at the meeting. No significant financial relationships to disclose.
Obesity Is An Adverse Prognostic Factor For Overall and Disease-Free Survival In Adult Acute Promyelocytic Leukemia But Not In Acute Myeloid Leukemia: A Pooled Analysis From Four Alliance Prospective Studies
Authors: Jorge J. Castillo, Flora Mulkey, Susan Geyer, Jonathan E. Kolitz, William Blum, Bayard L. Powell, Richard A. Larson, Richard M. Stone
Journal: Blood (2013)