tbuckley/cabot-search huggingface dataset:
Support services of head and neck cancer survivors at 3 months post-treatment.
Authors: Jean Marie Quispe, Kellie Martens, Jessica Geller, David Raben, Kristin Kilbourn
Journal: Journal of Clinical Oncology (2014)

244 Background: Support services offer a multi-disciplinary approach to improve quality of life (QOL) in head and neck cancer (HNC) survivors. This study assessed support services of HNC survivors treated at a University-based cancer center. Methods: HNC survivors (N=115) who completed three-month post-treatment self-report questionnaires were recruited from three radiation oncology clinics. Questionnaires assessed emotional and physical symptoms, QOL, and use and interest in support services. Symptoms were assessed individually on a 5-point Likert scale. Utilization and interest of support services were assessed with yes/no scales while helpfulness of utilization was assessed on a 5-point Likert scale. Spearman correlation analyses were conducted in SPSS v22. Results: Participants’ were mostly male (77%) and Caucasian (79%), with a mean age of 58.71 years (SD=11.05), and 36% had stage III/IV cancer. The majority of participants (93.7%) agreed they received adequate support, yet, interest in classes/education (7.8%), integrative medicine (7.0%) and support groups (6.1%) were endorsed. Surprisingly, interest in these support services was associated with lower ratings of total symptoms: classes/education (r = -.48), integrative medicine (r = -.41) and support groups (r = -.55). More than half of participants utilized at least one support service (67.83%) with the most frequent including: nutritionist/dietitian (55.7%), social worker/navigator (21.0%) and cancer information line (15.7%). Utilization of some services was associated with lower ratings of individual symptoms: social worker/navigator and problems swallowing (r = -.31), fatigue (r = -.27) and pain (r = -.24); and cancer information line and weight loss (r = -.30). Meanwhile, overall helpfulness of support services (M = 2.37, SD = 1.51) was rated between “somewhat” and “quite a bit” helpful. Conclusions: This study suggests a relationship between utilization and interest in support services and symptom ratings. Notably, those who report more physical and emotional symptoms may be less likely to report interest in support services. This may be due to an inability to access support services because of lack of transportation, poor social living conditions, etc.
Five years survival and risk of death in a phase III study of intermmittent monotherapy versus continuous combined androgen deprivation
Authors: F. M. Calais da Silva, F. E. Calais da Silva, F. Gonçalves, A. Santos, J. Kliment, P. Whelan, R. T. Oliver, N. Antoniou, S. Pastidis, C. Robertson, M. Queimadelos
Journal: Journal of Clinical Oncology (2008)

16034 Background: Intermittent androgen deprivation therapy can only be appropriately evaluated in a randomized fashion, we propose this Phase III study comparing the intermittent monotherapy with continuous combined androgen deprivation using an LHRH analogue and ciproterone acetate and associated components of quality of life. Methods: 1,045 men with a median PSA of 15.9ng/ml were registered between October 1999 and September 2007.914 patients (mean age 72) have been randomized 460 to Intermittent therapy and 454 to Continuous. The median PSA at randomisation is 1.0 ng/ml ranging from 0.1 to 4. 48 % of patients have a PSA less than 1 ng/ml at randomisation. Results: The maximum follow up is 7 years with a median of 2 years.83 patients have gone off study for progression (21% of which for subjective progression, 39% for objective and 39% for both subjective and objective). The estimated five year survival is 72% (95% CI 65%, 80%) though only 72 patients have been followed up after five years. Metastatic status and age at randomization are both prognostic factors for survival. M1 patients have an increased risk of dying (HR=1.56, 95% CI 0.91, 2.66) and there is a trend for an increasing hazard of death with increasing age so that men aged 75+ have a hazard ratio of 2.74 (95% CI 0.85, 8.82) compared to men aged under 60. There was no evidence that T Stage (p=0.90) or PSA at randomization (p=0.93) were prognostic factors for survival. Gleason score of 8 or more is associated with an increased risk of death HR= 1.51 (95% CI 0.99, 2.29). Registration PSA ranges from 4 to 104 with a median of 15 ng/ml. Registration PSA in excess of 15 is associated with an increased risk of dying HR=1.4 (95% CI 0.98, 2.01) Conclusions: The early results from this trial are promising and are in line with previous studies of intermittent therapy. It is too early in the study to report any treatment comparisons on progressions and survival as 658 deaths are required to give adequate power in this equivalence study nevertheless the estimated five is 72% (95% CI 65%, 80%) though only 72 patients have been followed up after five years. Metastatic status and age at randomization are both prognostic factors for survival. No significant financial relationships to disclose.
Do the published toxicity data from clinical trials in oncology give the full picture? An example using pemetrexed and docetaxel
Authors: G. Stynes, U. Gatzemeier, N. Thatcher, S. Bhalla, M. Aristides, M. Leschinger, D. Tilden
Journal: Journal of Clinical Oncology (2005)

8188 Background: Current toxicity reporting from clinical trials in oncology tends to focus on Grade (G) 3 & 4 toxicities or report only the overall incidence of certain adverse events (AEs). Published data generally do not report the duration of toxicities. Reassessment of clinical trial data to determine toxicity profiles over time could help to communicate the full burden of toxicity. Methods: A phase III trial comparing pemetrexed, Alimta (A), with docetaxel, Taxotere (D), in pts with advanced, previously treated non-small cell lung cancer (NSCLC) was analyzed to determine the time that pts being treated with A or D would expect to spend enduring drug-related AE episodes of varying severity (G1–4). The median number of cycles for both treatment arms was 4 cycles, making the duration of treatment comparable. The length of time receiving study drug (TRSD), during which each pt experienced AEs and the relative proportions of time spent with AEs of different severity were calculated. The multiplicity of toxicities were not accounted for, the maximum toxicity grade was analyzed. Results: see Table 1. Conclusions: The incidence, severity and persistence of AEs can be a relevant consideration for both physicians and pts when selecting a treatment. The impact of AE profiles is not fully disclosed in current toxicity reporting practices. This type of analysis on toxicity data should be considered when publishing results from clinical trials. Analyzing the data by hematological and non-hematological toxicities would provide further insight. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly Eli Lilly, Lilly Oncology Pfizer
External validation of the International Metastatic Renal Cell Carcinoma (mRCC) Database Consortium prognostic model and comparison to four other models in the era of targeted therapy.
Authors: D. Y. C. Heng, W. Xie, L. C. Harshman, G. A. Bjarnason, U. N. Vaishampayan, J. Lebert, L. Wood, F. Donskov, M. Tan, S. Y. Rha, C. Wells, Y. Wang, C. K. Kollmannsberger, B. I. Rini, T. K. Choueiri
Journal: Journal of Clinical Oncology (2011)

4560 Background: The Heng et al JCO 2009 prognostic model was developed in the age of VEGF-targeted therapy and this study serves as an external validation while comparing its performance to other models. Methods: 1,028 previously unanalyzed patients were used to externally validate the prognostic criteria for overall survival (OS). The model's discriminatory value was compared to four other prognostic models using C-indices and Net Reclassification Improvement (NRI) (Pencina et al 2008). NRI indicates how the Heng et al model improves upon other models by reclassifying a percentage of patients (pts) into the more correct risk group based on the observed OS at 2 years. Results: The median OS of all pts was 18.8 mons. On multivariable analysis, the pre-identified Heng's risk factors (anemia, thrombocytosis, neutrophilia, hypercalcemia, Karnofsky performance status <80% and time from diagnosis to treatment < 1 year) continue to be independent predictors of poor OS (p<0.05). When pts were segregated into 3 risk categories, the median OS was 44, 21 and 8 mons in the favorable (17% of pts), intermediate (52%) and poor (31%) risk groups, respectively (p<0.0001, C-index=0.664). The NRI demonstrated that the Heng model was able to more accurately reclassify pts by a net of 23% and 9.7% of pts compared to the French and MSKCC models and was less accurate in reclassifying 13% of pts when compared to the CCF model (but lower c-index) based on observed 2-year OS (see table). Sensitivity analyses with 5 imputation datasets for missing data produced similar results. Conclusions: The Heng et al model was derived in the targeted therapy era and is now externally validated. The c-index is similar to other models primarily derived in the era of immunotherapy or early VEGF-targeted therapy. Median OS in mons (% of pts) Favorable Intermediate Poor C-index NRI* Heng et al JCO 2009 44 (17%) 21 (52%) 8 (31%) 0.664 CCF (Choueiri Cancer 2007) 33 (34%) 18 (37%) 9 (29%) 0.662 -13% French (Escudier ASCO 2008) 49 (5%) 21 (67%) 7 (28%) 0.638 23% IKCWG (Royston ASCO 2007) 35 (14%) 24 (50%) 8 (36%) 0.668 3.2% Motzer JCO 2002 44 (19%) 18 (59%) 7 (22%) 0.657 9.7% *Comparing the Heng model with others.
Survey of the sociodemographic and motivational profile of volunteers in oncology
Authors: O. Nanni, P. Serra, C. Tison, M. De Castro, R. Ridolfi, F. Falcini, D. Amadori, V. Erroi, E. Meggiolaro
Journal: Journal of Clinical Oncology (2006)

16011 Background: The volunteer sector developed rapidly in Italy throughout the 1980s, especially in the areas of cancer and palliative care. Istituto Oncologico Romagnolo (IOR), a non profit organization based in Forlì, actively supports the public health sector in the fight against cancer by funding scientific research, organizing voluntary work, promoting education campaigns, and setting up prevention and screening programs. The aim of the present work is to trace a sociodemographic and motivational profile of IOR volunteers. Methods: In May 2005, all IOR volunteers were invited to complete an anonymous questionnaire composed of 12 structured questions designed to collect sociodemographic data, information on type of voluntary work done and the reasoning behind such a choice. Results: Of IOR’s 1043 volunteers, 471 completed the questionnaire, of whom 70% were female and about one-third over 65 years of age. The majority of professions were represented, even though about two-thirds of men and half of the female volunteers were retired. About 40% of the group had been doing voluntary work for more than 10 years. Although fund-raising proved to be the most frequent activity (80%), there is a growing number of volunteers, especially those of a younger age group, involved in home- and hospital-based care. Various reasons were given for becoming a IOR volunteer: ethical considerations (35 % males and 28% females), personal experiences (24% and 38%, respectively), high regard held for IOR and its work (31 and 26%, respectively), and involvement directly through other volunteers (29 and 36%, respectively). Conclusions: The major involvement in fund-raising and perseverance over time of volunteers indicate a favorable social perception of medical research. It also emerged that the decision to start voluntary work was often closely linked to a previous personal experience of loss or disease, especially in female volunteers, who tend to react more constructively and develop a more active and concrete solidarity than men. We can therefore conclude that volunteers in the area of cancer act out of a sense of responsibility and awareness rather than out of pity or a desire for self-gratification. No significant financial relationships to disclose.
Abstract 97: High mobility group box-1 Promotes Restenosis Via Toll like receptor-4 Signal Pathway
Authors: Jingjing Cai, Hong Yuan, Qingde Wang, Timothy R. Billiar, Alex F. Chen
Journal: Circulation Research (2014)

Background: High-mobility group box 1 (HMGB1) is an endogenous molecule released during cell stress and death termed damage-associated molecular patterns (DAMPs). HMGB1 activates the pattern recognition receptor, toll-like receptor 4 (TLR4), and induces sterile inflammation. However, how HMGB1 and TLR4 affect restenosis, the major complication following balloon and stent intervention clinically, remains unknown. We tested the hypothesis that HMGB1 released following acute arterial injury promotes intimal hyperplasia (IH), a hallmark of restenosis, via TLR4 signaling pathway. Methods and Results: Wire injury of the carotid artery in C57BL/6 wild-type (WT) mice significantly increased intima-to-media ratio in 4 weeks. Global deletion of HMGB1 using an inducible knockout mouse strain prevented IH and vessel remodeling. IH decreased by over 50% in WT mice treated with a HMGB1 neutralizing antibody. Of the mouse strains deficient in putative receptors and co-regulator for HMGB1 (TLR4-/-, TLR2-/-, RAGE-/- and CD14-/-), TLR4-/- mice showed the greatest inhibition of IH after injury. Both TLR4 adaptors MYD88 and TRIF synergistically participated in the inflammatory response to vascular injury. HMGB1 antibody-treated mice and TLR4-/- mice showed a marked decrease in monocytic recruitment following injury. Mice with selective depletion of TLR4 from macrophages (TLR4-/--Mø) exhibited similar level of IH inhibition and macrophage infiltration, compared to the global TLR4-/- mice. In vitro, disulfide HMGB1 concentration-dependently promoted smooth muscle cell (SMC) migration and MCP-1/CCR2 expression, which were abolished by treatment with TLR4 inhibitory peptide. Moreover, conditioned media from HMGB1-treated macrophage induced SMC proliferation, which was blunted by blocking TLR4 on macrophage, but not SMCs. Finally, HMGB1 increased cytokine (TNF-α and IL-6), chemokine (MCP-1) and mitogen (PDGF-A) levels in macrophage in a TLR4-dependent manner. Conclusion: These findings demonstrate, for the first time, that HMGB1 released following acute arterial injury promotes restenosis via SMC migration and MCP-1/CCR2 production as well as macrophage-released TNF-α, IL-6, MCP-1 and PDGF-A in SMC through the TLR4-MyD88/TRIF signal cascade.
An update of pharmacogenetic analysis of adjuvant rectal cancer patients treated with 5-fluorouracil and pelvic radiation in a phase III intergroup trial (INT-0144, SWOG 9304)
Authors: W. Zhang, C. J. Rankin, K. D. Danenberg, J. K. Benedetti, P. V. Danenberg, C. M. Ulrich, R. S. Holmes, K. W. Makar, C. D. Blanke, S. R. Smalley, H. J. Lenz
Journal: Journal of Clinical Oncology (2008)

4115 Background: Clinical trials have shown postoperative chemoradiotherapy for adjuvant rectal cancer has improved overall survival and pelvic control. However, the efficacy of chemoradiation therapy may be significantly compromised as a result of individual variations in clinical response and host toxicity. In GI symposium 2008, we have reported our preliminary data suggesting COX-2, IL-8 and TS- 3’UTR gene polymorphisms may help to identify adjuvant rectal cancer patients who are more likely to experience longer survival. Here we explore whether gene-expression levels of genes involved in the critical pathways of cancer progression (i.e., drug metabolism (TS,TP,DPD,GSTP), tumor growth (COX-2, EGFR), angiogenesis (VEGF,IL-8), cell cycle regulation (CyclinD1,P53), and DNA repair (ERCC1,XPD)) may predict the clinical outcome in the same group of rectal cancer patients treated with 5-fluororacil and pelvic radiation. Methods: A total of 105 stage II/III rectal patients from a phase III trial (INT-0144, S9304) of three regimens of 5-fluorouracil and radiation were available for gene-expression assays. mRNA was extracted from laser-capture-microdissected tumor tissue. After cDNA was prepared by reverse transcription, quantitation of the candidate genes and an internal reference gene (ß-actin) was performed using a fluorescence-based real-time detection method (TaqMan). Results: In univariate analysis, we found TS gene expression levels to be significantly associated with overall survival (p=0.04) and progression-free survival (p=0.02). Patients with low TS expression levels showed better overall survival and progression-free survival compared to those with medium or high TS gene expression levels. All other genes we tested did not show significant association with either overall survival or progression free survival. Conclusions: Future analyses will be expanded to additional patients enrolled in this trial to validate our preliminary data, and to assess whether these markers may identify patients who might selectively benefit from one of the study regimens. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Response Genetics, Inc Bristol-Myers Squibb, Genentech, ImClone, Merck, Pfizer, Response Genetics, Inc Response Genetics, Inc Genentech, Merck, Pfizer, Roche, sanofi-aventis Dhont Family Foundation, NCI, NIH
Phase II trials of clofarabine in pediatric acute leukemia
Authors: S. Jeha, B. Razzouk, P. Gaynon, R. Kadota, S. Rheingold, L. Luchtman-Jones, R. Arceci, M. Fernandez, S. Weitman, P. Steinherz
Journal: Journal of Clinical Oncology (2005)

6588 Background: Clofarabine, a next-generation nucleoside analogue, has shown clinical activity when used as a single agent in heavily pretreated patients with relapsed or refractory acute leukemias. The results of two Phase 2 multicenter, open-label studies with clofarabine in children with refractory or relapsed ALL or AML are presented here. Methods: Clofarabine was administered at 52 mg/m2 given by intravenous infusion over 2 hours daily over 5 consecutive days. Cycles were repeated every 2 to 6 weeks based on response and toxicity. Results: 103 patients (61 ALL, 42 AML) have been treated. Patients on the ALL trial had received a median of 3 prior regimens (range 2–6). Thirty percent had received prior transplant. As determined by independent review, preliminary data indicate overall response rates of 30% in ALL (7 CR, 5 CRp, and 6 PR). Median duration of CR/CRp is 29 weeks. On the AML trial, median age was 12 years (range 2–22). Median number of prior regimens was 2 (range 1–5). Forty three percent had received prior transplant. Overall response in AML was 26% (1CRp and 10PR). Most responders on the AML trial proceeded to transplant with an M1 marrow (0–5% blasts) without awaiting peripheral counts recovery. Median duration of remission for AML patients is 12.4 weeks (range 1.1 - 73.4+). Toxicity profile was expected and acceptable for this patient population. Conclusions: Clofarabine is active in heterogenous subtypes of multiply relapsed or refractory pediatric leukemia. Ongoing plans are to evaluate clofarabine combinations in children with ALL and AML. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Ilex Products Ilex Products Ilex Products Ilex Products
Molecular profiling of malignant peritoneal mesothelioma identifies the ubiquitin-proteasome pathway as a therapeutic target in poor prognosis tumors
Authors: G. Antonini Cappellini, A. Borczuk, H. Kim, M. Hesdorffer, R. Taub, C. Powell
Journal: Journal of Clinical Oncology (2006)

9549 Background: Malignant peritoneal mesothelioma (MPM) is an aggressive neoplasm derived from cells lining serosal membranes. The characteristics of the epithelial (E) type MPM are distinct from those of the biphasic and sarcomatous (BS) type tumors. The goal of our study was to examine the molecular basis for this distinction. Methods: We used global molecular profiling with DNA microarrays to identify pathways associated with histologic subtype of 16 MPM tumor specimens acquired from patients entered into pilot multimodality protocols at our Institution. We performed immunohistochemistry on a tissue microarray and quantitative-real time PCR to validate the microarray results. Results: We performed average linkage agglomerative hierarchical clustering using microdissected MPM specimens and normal peritoneal tissue. The tumors segregated into two clades associated with histological subtype, which were distinct from the controls. 476 genes were differentially expressed between E and BS histologic classes (P &lt; .001, with permutation test P value of .001). To identify biologically important differentially expressed genes and pathways, we examined the functional annotation of mesothelioma histologic subtype classifiers using the Pathway Comparison tool of BRB-Array. Among the differentially expressed categories was the ubiquitin-proteasome (UP) pathway, which was upregulated in BS tumors. Cytoxicity experiments by MTS assay indicated that, by the computation of combination indexes of activity, cells derived from BS tumors were exquisitely sensitive to sequential combination regimens containing the proteasome inhibitor (PI) bortezomib and oxaliplatin. The mechanism of this synergistic response, which was not detected in cells of E tumor origin, was apoptosis. Conclusions: Together, our results identify the ubiquitin-proteasome pathway as a biomarker of poor prognosis biphasic and sarcomatous malignant peritoneal mesothelioma tumors and suggest that proteasome inhibitors could increase the effectiveness of cytotoxic chemotherapy in this subset of patients. No significant financial relationships to disclose.
Orphaned mitochondria in heart failure
Authors: Christoph Maack
Journal: Cardiovascular Research (2015)

This editorial refers to ‘Impaired mitochondrial network excitability in failing guinea-pig cardiomyocytes’ by K.Y. Goh et al. , pp. 79–89. 

The heart is a highly efficient engine that relies on perfect tuning of all processes that support excitation–contraction (EC) coupling to pump blood to the body's organs. Since this engine must adapt its pumping capacity to any evolving variations in the metabolic demand of the organism, it possesses efficient control mechanisms on the cellular level to match ATP supply to the constantly varying cellular demand.1 In the heart, ATP is produced primarily in mitochondria, and the ATP pool is turned over in less than a minute. Due to this high energetic demand, 30% of the cellular volume is partitioned to mitochondria, which are aligned in a highly organized fashion in areas with the highest energetic demand, i.e. underneath the plasma membrane with its ATP-consuming ion transporters, and along the myofilaments, where myosin ATPase is the dominant consumer of cellular ATP.

Two major factors that control mitochondrial respiration during workload transitions are Ca2+ and ADP. While ADP accelerates respiration and oxidizes the redox state of the energetic precursor NADH, Ca2+ activates the Krebs cycle to regenerate oxidized NAD+ to NADH.1 The close spatial alignment of mitochondria along the myofilaments and the sarcoplasmic reticulum (SR), the major cellular Ca2+ store, constitutes so-called microdomains in which privileged transfer of ADP and Ca2+ between myofilaments, the SR, and mitochondria is facilitated.1–3

An important role for the spatial organization of mitochondria in this three-dimensional lattice within cardiac …