tbuckley/cabot-search huggingface dataset:
Potential targets in prostate tumor–associated stroma
Authors: A. Richardson, A. Player, Y. Wang, J. Rodriguez-Canales, H. Erickson, E. Kawasaki, K. Woodson, R. Chuaqui, M. Emmert-Buck
Journal: Journal of Clinical Oncology (2007)

15529 Background: The past 20 years have seen a shift in the paradigm that the stromal compartment in tissues is merely a passive, supporting tissue for epithelial cells. Recent evidence shows that it plays a critical role not only in normal tissue development and homeostasis, but also in the progression of cancer. Further, as the stromal compartment is more readily accessible to vascular-delivered agents, this region might be particularly amenable to clinical intervention. As such, a broad-based study of the carcinoma-associated changes in stromal cells from patient samples could yield a wealth of information on the molecular mechansisms of tumorigenesis, and identify clinically important molecular targets. Methods: Five whole-mount frozen prostatectomy specimens were microdissected in four regions: normal epithelium, tumor epithelium, normal stroma, and tumor-associated stroma. Extracted and amplified mRNA was hybridized to the Human Genome U133 Plus 2.0 GeneChip (Affymetrix). Using the intersection of two statistical analysis packages (GCOS and RMA), we identified differentially expressed genes between the dissection groups. Quantitative RT-PCR was used to validate selected transcripts and immunohistochemistry to evaluate potential stromal molecular targets. Results: Tumor-associated stroma showed a distinctly different expression pattern compared to normal stroma with 675 differentially expressed transcripts, the majority of which were up-regulated. In contrast, tumor epithelium showed more down-regulation in the 829 transcripts that were differentially expressed relative to normal epithelium. Classes of up-regulated genes in the tumor-associated stroma showed a strong linkage to cell adhesion and migration as well as the calcium, MAPK, and TGF-beta signaling pathways. Quantitative RT-PCR was conducted to verify GeneChip findings and revealed over 80% concordance with the original data. Immunohistochemical staining further supported the expression differences. Conclusions: Global mRNA expression analysis of stromal cells within tumors provides insight into prostate cancer progression, and yields novel targets for future diagnostic and therapeutic intervention. No significant financial relationships to disclose.
Pathologic Evaluation of Total Mesorectal Excision: Big Brother Is Watching
Authors: Miguel A. Rodriguez-Bigas
Journal: Journal of Clinical Oncology (2002)

Article Tools EDITORIALS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2002.20.7.1714 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 11919224 Pathologic Evaluation of Total Mesorectal Excision: Big Brother Is Watching Miguel A. Rodriguez-BigasxMiguel A. Rodriguez-BigasSearch for articles by this author Show More The University of Texas, M.D. Anderson Cancer Center, Houston, TX https://doi.org/10.1200/JCO.2002.20.7.1714 Full Text PDF Figures and Tables "Pathologic Evaluation of Total Mesorectal Excision: Big Brother Is Watching." Journal of Clinical Oncology, 20(7), pp. 1714–1715© 2002 by American Society of Clinical Oncology
Prostate specific antigen doubling time (PSADT) predicts for distant failure and prostate cancer specific survival (PCSS) in men with biochemical relapse after radical prostatectomy (RP)
Authors: A. W. Partin, M. A. Eisenberger, V. J. Sinibaldi, E. Humphreys, L. A. Mangold, P. C. Walsh
Journal: Journal of Clinical Oncology (2004)

4555 Background: Patients (pts) with biochemical (PSA) relapse after RP represent a rapidly rising population in whom appropriate standards of care remain undefined. Over the past several years we have focused on studying the natural history of these pts. Our previous report (Pound et al; JAMA 1999) suggests that the Gleason score, time of PSA relapse (>0.2 ng/ml) and PSADT are the strongest predictors of the probability of distant metastasis (DM) (Cox model). A recent update (Partin; AUA 2003, Eisenberger; ASCO 2003) suggests that PSADT overrides the other parameters in the prediction of DM. Our experience has been expanded (> 1000 additional pts and longer follow-up). We evaluate the relationship between PSADT and PCSS. Methods: 4,415 pts underwent a RP from 1982–2003 and 825 demonstrated evidence of PSA relapse. All pts were followed with yearly PSAs with no androgen deprivation given until development of DM. Cox-proportional hazards and Kaplan-Meier survival analyses were completed with time from PSA relapse to censoring (last follow-up) or death used as endpoint. Results: 825/4,415 demonstrated PSA relapse (mean time 8.4yrs), 170/825(20.6%) developed DM and 109/825(13%) have died of prostate cancer (PCa). PSADT was calculated on 411 pts (mean 9 PSAs /pt, range 2–33), ROC-AUC for PSADT prediction of PCSS was 0.77. Conclusions: PSADT is a potent predictor of the probability of DM and PCSS. Pts with PSADT ≤10 mos. are at significant risk for developing DM and dying of PCa. In this group, clinical trials should evaluate progression-free and overall survival with aggressive approaches. Pts with PSADT of >10 mos. may be observed or treated to delay onset of DM. (Supported by CAPCURE). No significant financial relationships to disclose.
Immunohistochemical staining for XRCC1, XRCC3 and Ku70/80 proteins and their correlation with clinical outcome in locally advanced cervical cancer
Authors: J. E. O’Hagan, A. Dodson, C. S. Foster
Journal: Journal of Clinical Oncology (2006)

15011 Background: Locally advanced cervical cancer can be successfully treated with radiotherapy but the toxicity of this treatment is at the limit of tolerability (5–15% serious late complications). A test of the cancer’s likely response to radiotherapy would be invaluable to clinically individualize treatment. Protein XRCC1 is involved in DNA single strand break repair and sister chromatid exchanges. Protein XRCC3 is involved in homologous recombinational repair forming a heterodimer with RAD51L2. XRCC5 codes for the Ku70/80 heterodimer and is involved in double strand break repair and V(D)J recombination. The objective of this study was to correlate protein expression with the clinical response to treatment, disease free survival (DFS) and overall survival (OS). Methods: The archived paraffin embedded tissue blocks from 122 women with locally advanced cervical cancer previously treated with either radiotherapy or chemoradiotherapy were stained for XRCC1, XRCC3 and Ku70/80 proteins. The slides were reviewed and the intensity of the staining graded from 0 to 3 (none - strong). Clinical data from the patients’ case notes included baseline characteristics, response at the time of brachytherapy, response at 3months, dates of diagnosis, relapse, last clinic visit and death. The χ2 test, log rank test and Kaplan-Meier methods were used for statistical analysis. Results: The median follow up was 31 months (range 1–76 months). Clinical response at 3 months (RECIST criteria) was strongly correlated with both OS and DFS, patients who progressed had a mean OS of 9.5months (CI 4.2–14.7) compared to patients who had a partial response, mean OS 45.2months (32.6–57.8), and patients who had a complete response had 60% OS at 4years. However, no significant relationships were found between staining for XRCC1, XRCC3 or Ku70/80, OS, DFS or clinical response. Conclusions: This study did not find an association between expression of XRCC1, XRCC3 and Ku70/80 proteins and clinical response, OS or DFS in locally advanced cervical cancer. No significant financial relationships to disclose.
Outcomes of sunitinib therapy in patients (pts) with metastatic renal cell carcinoma (mRCC) with poor risk features.
Authors: Romualdo Barroso-Sousa, Rodrigo Ramella Munhoz, Leonardo Gomes Fonseca, Angelo Bezerra de Sousa Fede, Rudinei Diogo Marques Linck, Camila Motta Venchiarutti Moniz, Milena Perez Mak, Ciro Eduardo Souza, Paulo M. Hoff, Carlos Dzik
Journal: Journal of Clinical Oncology (2013)

476 Background: Temsirolimus is perceived as the standard of care in pts with mRCC with poor risk features. However, sunitinib (Su) is commonly used in this setting. In this study, we assessed the use of Su in an unselected mRCC population. Methods: Retrospective analysis of 51 pts with mRCC and ≥ 3 poor prognosis features, as determined in the Advanced Renal Cell Carcinoma (ARCC) trial, treated with Su between January 2006 and July 2012. Primary outcome was overall survival (OS). Clinical and laboratory parameters were evaluated, as well as Su-related adverse events (AE). Median time to treatment failure (mTTF) and OS were estimated by Kaplan–Meier methods. On exploratory grounds, univariate, and multivariate analysis using Cox regression model was performed to determine possible prognostic variables. Results: Median age was 60 years (26-89). Most had clear cell histology (98%), 19% prior systemic treatment, and 51% prior nephrectomy. 64%, 15%, and 4% had 4, 5, and 6 adverse prognosis factors respectively. 88% had diagnosis to treatment intervals &lt; 1 year and 45% had KPS scores of &lt; 80. A median of 2 cycles (0–12) were administered. 63% received standard regimen of Su (50 mg/d 4 wk on/2 wk off). Reasons for discontinuation were disease progression (63%) and adverse events (21%). Most grade ≥ 3 AE were fatigue (14%), neutropenia (8%), and stomatitis (8%). 17%, 25%, and 14% developed hypothyroidism, hand-foot syndrome (HFS), and hypertension, respectively. Two therapy-related deaths were observed (one febrile neutropenia and one intracranial hemorrhage). Estimated mTTF and mOS of this cohort were 2.4 and 6.6 months, respectively. Multivariate analysis revealed that in a model adjusted for type of Su regimen, KPS, presence of brain metastasis, and occurrence of HFS, only Su-associated hypothyroidism was significantly associated with survival (respectively, odds ratio [OR] = 0.23; 95% CI = 0.07-0.68). Conclusions: Pts with mRCC with poor risk features treated with Su have an OS, TTF and rates of therapy discontinuation due to AE comparable to clinical trial subsets of similar pts. Our data suggest that the development of hypothyroidism in this setting might be useful as a predictor of OS, and this finding should be further investigated.
Temperature- and volume-dependent dissolution of amifostine 500 mg reconstituted for subcutaneous injection in normal saline or sterile water for injection
Authors: C. Allan, R. V. Boccia
Journal: Journal of Clinical Oncology (2005)

3207 Background: Because the dissolution of amifostine (Ethyol) 500 mg in 0.9% normal saline (NaCl) or sterile water for injection (SWI) for subcutaneous administration is temperature- and volume-dependent, studies were performed to evaluate amifostine dissolution using three different volumes of the two diluents at four temperatures. Methods: Amifostine 500 mg was reconstituted in 2.0, 2.5, or 2.9 mL NaCl or SWI at 15, 20, 25, and 30°C with gentle rotation in controlled water bath. Dissolution times were determined visually. Reconstituted vials were subsequently held in a water bath at 22°C for 5 hr or 4°C for 8 hr. The stability of the amifostine solution was assessed by HPLC analysis of WR-1065, the primary hydrolysis product. Results: The final volume after reconstitution of amifostine 500 mg in 2.5 mL NaCl was 2.88 ± 0.04 mL, and in 2.9 mL NaCl the final volume was 3.34 ± 0.05 mL. Mean levels of WR-1065 in 2.9 mL NaCl were 0.6% ± 0.1% after 5 hr at 22°C and 0.4% ± 0.1% after 8 hr at 4°C, well below the lot-release specification of 1.3%. Dissolution times are summarized in Table 1. Conclusions: Dissolution of amifostine for subcutaneous injection is volume- and temperature-dependent. Reconstitution of lyophilized amifostine powder (500 mg) with 2.9 mL NaCl or SWI (final volume, 3.3–3.4 mL) at 20–25° C, (68–77° F) results in complete dissolution within minutes. Reconstitution in smaller volumes such as 2.0 mL or 2.5 mL is feasible, but requires more time, and/or warmer temperature. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration MedImmune MedImmune MedImmune MedImmune
Modulation of integrin α5 in head and neck cancer cells by epidermal growth factor and its contribution to the malignant phenotype
Authors: J. Kertsman, E. Cohen, M. Abdellatif, R. Wieder
Journal: Journal of Clinical Oncology (2006)

15512 Background: The primary therapy for head and neck cancer consists of combination treatment with radiation and chemotherapy. While this combined modality approach is often curative, a significant fraction of patients have residual viable tumor cells after treatment that can result in progressive disease or relapse. We hypothesize that a significant contribution of cell survival results from interaction of cancer cells with the tumor microenvironment that includes soluble ligands of growth factor receptors and structural ligands of cell surface adhesion molecules. One of the growth factors with reported tumor survival effects is epidermal growth factor (EGF). We investigated the contribution of EGF to the relationship of 1483 head and neck cancer cells with their microenvironment. Methods: We treated 1483 head and neck cancer cells with variable concentrations of EGF from 0.1 to 20 nM and carried out western blots and flow cytometry to determine the expression of relevant integrins. Effects of interventions were evaluated by soft agar colony assays, proliferation and survival in tissue culture and adhesion to culture plates coated with integrin ligands. Results: Western blots demonstrated an EGF-induced increase in the expression of intgerin α5 but no change in the expression of integrins α2 or β1. The presence of dissolved fibronectin, a ligand of integrin α5β1, but not of collagen I, a ligand of integrin α2β1, provided a survival advantage to colonies in soft agar in EGF-treated cells. Experiments are determining whether this survival advantage translates to a shift in the dose-response curve to paclitaxel and ionizing radiation, on activation of caspases 3 and 8 and cleavage of poly (ADP- ribose) polymerase (PARP). These data are being correlated with EGF-induced modulation of adhesion to fibronectin, collagen and control plates. We have constructed adenoviral vectors expressing short hairpin RNA (shRNA) sequences to integrins α5 and α2 to confirm the role of integrin α5 expression in the EGF-induced modulation of survival. Conclusions: These data support a potential contribution to survival of head and neck cancer cells by modulation of integrins by EGF through interaction with their ligands in the microenvironment. No significant financial relationships to disclose.
The value of concurrent symptoms in predicting clinical outcomes in lung cancer survivors.
Authors: A. L. Cheville, P. J. Novotny, J. A. Sloan, J. R. Basford, J. A. Wampfler, Y. I. Garces, A. Jatoi, P. Yang
Journal: Journal of Clinical Oncology (2010)

6110 Background: Aggregates of concurrent symptoms, known as symptom clusters (SxCl), are reported to have prognostic capabilities beyond that of single symptoms. The objectives of this study are to delineate symptom clusters in lung cancer survivors, investigate their stability over time, and characterize their predictive value relative to isolated symptoms for important outcomes. Methods: Analysis of a 9-year prospective cohort study that annually assessed 2,405 patients with lung cancer for employment status, medical comorbidities, degree of physical activity, and symptom burden assessed with 11-point numerical rating scales. Results: A single symptom SxCl of fatigue, cough, and dyspnea was identified in 14.6%, 12.9%, 14.1%, 14.6%, and 15.4% of participants at years 1-5 after diagnosis, respectively. Participants with the SxCl were more likely to die than those without it but this tendency diminished over time. SxCl persistence varied, with ≥ 40% of surviving patients annually transitioning to or from the SxCl(+) state, until year 4 after which it became increasingly stable. Presence of the SxCl was negatively associated with survival in Cox models of years 1-3 following diagnosis. Relative to individual symptoms in the cluster or symptom pairs, the SxCl offered little additional prognostic capacity for survival and was not predictive of participants' employment status or engagement in regular physical activity. Fatigue and dyspnea levels were strongly inversely associated with these latter two outcomes. Conclusions: Fatigue and dyspnea are strongly associated with poor clinical outcomes in lung cancer survivors; however their combination as part of a SxCl does not significantly improve predictive capability. No significant financial relationships to disclose.
Long-term utilities after localized prostate cancer treatment: Is treatment-related dysfunction important?
Authors: R. C. Chen, J. A. Talcott
Journal: Journal of Clinical Oncology (2008)

6546 Background: While sexual, bowel, and urinary dysfunction caused by localized prostate cancer (CaP) treatments is well described, it is unclear if and/or how this dysfunction affects patients' valuation of their global health. This is the largest report of long- term utilities after CaP treatment, which reflect not only patient symptoms, but also the value or preference a patient places on his health state. Methods: Using validated symptom indices and the Short Form 36 (SF-36), we prospectively collected data from 409 patients at baseline and at fixed intervals after surgical or radiation treatment. Numerical index scores were translated into good, intermediate, and poor levels of function as described previously, and SF-6D utilities were derived from 11 items of the SF-36. Univariable and multivariable regression models were used to assess whether long-term functional outcomes, patient age, and comorbid disease were significantly associated with 36-month utilities. Results: Mean 36-month SF-6D is 0.80 (range 0.50–1.0, standard deviation 0.10). Patients with different long- term sexual, bowel, and urinary functional outcomes had significantly different 36-month utilities (Table). Age (p=.006) and baseline index of comorbid disease (ICED, p<.001) were also significant on univariable analysis. Multivariable analysis showed that urinary incontinence (p<.001) and bowel dysfunction (p=.01) were significantly correlated with 36-month utilities. Baseline ICED was of borderline significance (p=.07). Conclusions: Prostate cancer patients after localized treatment rate their health states highly, but treatment-related dysfunction, especially urinary incontinence and bowel dysfunction, are associated with utility decrements comparable to those from cataracts or heart disease. Our study provides further evidence that dysfunction from early prostate cancer treatment can meaningfully affect patients' long-term health. Mean Utilities for Patients with Different Levels of Function Sexual Function Bowel Function Urinary Incontinence Urinary Obstruction/Irritation Good 0.85 0.83 0.82 0.83 Intermediate 0.82 0.79 0.77 0.79 Poor 0.79 0.75 0.67 0.75 p=.003 (ANOVA) p<.001 p<.001 p<.001 No significant financial relationships to disclose.
C-MYC and C-MYC-Regulated Micrornas Increase The Activity Of The Error-Prone ALT NHEJ Pathway Through Upregulation Of LIG3 and PARP1 In Tyrosine Kinase-Activated Leukemias
Authors: Nidal E. Muvarak, Shannon M. Kelley, Mario Tarasco, Maria R. Baer, Kara A. Scheibner, Feyruz Rassool
Journal: Blood (2013)
Effects of moderate aerobic exercise trainning in acute and late phase of lung infection induced by streptococcus pneumoniae
Authors: Clarice Rosa Olivo, Eliane Miyaji, Maria Leonor Oliveira, Juliana Dias Lourenço, Francine Maria Almeida, Petra M. Arantes, Fernanda Dtqs Lopes, Milton A. Martins
Journal: European Respiratory Journal (2013)

Despite of use of agressive antibiotics and support, the fatality rate associated with  Streptococcus pneumonia (SP)  remained higher. Moderate aerobic exercise training (AE) have been somewhat recognise as responsible for increase resistance to infection even if mechanism involved remain unclear. Our aim is to evaluate if AE prior to  SP  infection alter the inflammatory profile and lung mechanics in an acute and late phase of the infection. 56 BALB/C mice were divided in 8 groups: sedentary (S); exercise training (T);  Streptococcus pneumonia  (SP);  Streptococcus pneumonia +exercise training (TP). Animals were submitted to AE during 4wk (5x/wk/1h).72hs after last session, animals received nasal drop of  SP  and 12hs (acute phase) or 10days (late phase) after instillation, they were anesthetized and euthanized to evaluate respiratory mechanics and inflammatory profile. At acute phase, we found an increase in resistance and elastance of respiratory system in SP group as well as number of total cells, characterized by neutrophils, lymphocytes and macrophages in bronchoalveolar lavage (BAL) and polymorphonuclear cells in lung parenchyma compared to others. AE were effective in reduce these parameters in TP group. At late phase, we did not find differences in lung mechanics.We found an increase in number of total cells in BAL and polymorphonuclear cells in lung parenchyma in SP group compared to others. Although AE were effective to reduce these parameters in TP group, in BAL it to reduces only macrophages. In conclusion, AE were effective in reduce the inflammatory process of infection even of profile of this process were changed.Supported by FAPESP, LIMHC-FMUSP.
Bortezomib ± irinotecan in relapsed/refractory colorectal cancer (CRC): Interim analysis results from phase (ph) 2b study
Authors: T. Dragovich, H. J. Lenz, C. M. S. Rocha Lima, P. Kozuch, H. Hochster, B. O'Neil, O. Atiq, J. M. Pipas, O. Kashala, D. P. Schenkein
Journal: Journal of Clinical Oncology (2004)

3591 Background: Irinotecan (Camptosar, CPT), a topoisomerase I inhibitor, is active against CRC. Bortezomib (VELCADE, Vc), a reversible proteasome inhibitor, overcomes CPT resistance in vitro and in vivo. Vc + CPT combination was synergistic in colon tumor models, and was well tolerated without additive toxicities in a ph 1 study. Methods: The primary objective of this randomized, multicenter, open-label, ph 2b study was to determine objective tumor response to Vc ± CPT in patients (pts) with refractory CRC. Secondary objectives were safety and tolerability, survival, and quality of life. Pts were randomized to Vc alone (Arm A) or Vc + CPT (Arm B). Eligibility criteria: age ≥18 yr, relapsed or refractory, inoperable, locally advanced or metastatic CRC, KPS ≥70, 1 or 2 prior chemotherapy regimens for metastatic disease. Most pts had previously received CPT. Arm A pts received Vc 1.5 mg/m2 IV on d 1, 4, 8, and 11 q21d. Arm B pts received CPT 125 mg/m2 IV on d 1 and 8, and Vc 1.3 mg/m2 d 1, 4, 8, and 11 q21d. Results: Toxicity and safety data are available for 68 (of 175 planned) pts enrolled from 12/02–9/03 (Arm A: n=30 pts; Arm B, n=38 pts). >60% pts received ≥2 cycles. AE were generally similar in both arms. Grade (G) 3/4 AE occurred in 24/68 (35%) pts, mainly gastrointestinal (22%), fatigue (10%), neuropathy (7%), and hematologic (neutropenia: 9%; thrombocytopenia: 6%). 51% had drug-related AE (all grades), including nausea (34%), fatigue (32%), diarrhea (32%), vomiting (22%), and constipation (16%). Accrual, interim analyses, and efficacy assessments are ongoing. Conclusions: Vc and Vc + CPT was generally safe and well tolerated in pts with advanced/refractory CRC. Efficacy results will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Millennium Pharmaceuticals, Inc.; MPI Millennium Pharmaceuticals, Inc.; MPI; Pfizer; Responsegenetics Millennium Pharmaceuticals, Inc.; MPI Genetech; Pfizer; Pharmacia Millennium Pharmaceuticals, Inc.