tbuckley/cabot-search huggingface dataset:
Modulation of NK receptors by budesonide and/or formoterol in healthy volunteers and COPD patients
Authors: Chiara Folli, Alessandra Chiappori, Michele Pellegrini, Valentina Garelli, Anna Maria Riccio, Laura De Ferrari, Fulvio Braido, Giorgio Walter Canonica
Journal: European Respiratory Journal (2011)

Rationale: Natural killer (NK) cells function is regulated by multiple cell-surface receptors. Nowadays little is known about the involvement and function of NK cells in COPD. Recently a role in pulmonary immunity has been ascribed to NK cells and several in vitro studies have shown corticosteroid-induced inhibition of NK cell-mediated cytotoxicity.

Methods: NK cells were isolated from peripheral blood of healthy volunteers and COPD patients. Cells were cultured for 20 hours in 96-well plates with IL-2 (100 I.U./ml)+IL-12 (2,5 ng/ml), in the absence or in the presence of budesonide (B) (1μM and 10nM) and formoterol (F) (30 and 0,3nM) alone or in combination. Cells were analyzed by flow cytometry and supernatants were used to investigate the production of IFN-γ by ELISA technique.

Results: We found no difference in expression of NK cell receptors analyzed in resting conditions both in healthy volunteers and patients. When cells were stimulated over night with cytokines and treated with drugs, only NKG2D receptor resulted modulated. Its expression was significantly reduced by budesonide alone and in combination, irrespectively of the dose, in COPD patients (p<0.05 and p<0.01, respectively). IFN-γ production induced by stimulation with IL2+IL12 was higher in healthy volunteers than in patients (p<0.05), but it was decreased in a highly significant way (p<0.01) by all treatments in both groups.

Conclusion: Our results show that NKG2D expression and IFN-γ secretion are modulated by treatment with budesonide, both alone and in combination with formoterol, in COPD patients. This might be of relevance in the treatment of diseases such as COPD.

This work was supported by ARMIA and AstraZeneca.
Adjuvant bortezomib and dexamethasone following risk-adapted melphalan and stem cell transplant in patients with light-chain amyloidosis (AL)
Authors: H. J. Landau, J. Hoffman, H. Hassoun, H. Elizabeth, E. Riedel, S. D. Nimer, A. Cohen, R. L. Comenzo
Journal: Journal of Clinical Oncology (2009)

8540 Background: Melphalan (MEL) and autologous stem cell transplant (SCT) induces both hematologic and clinical remissions in AL, and prolongs overall survival (OS) when complete hematologic remissions (CR) are achieved. We have reported improved responses (including 39% CR) at 12 mos post-SCT using risk-adapted MEL followed by adjuvant dexamethasone (Dex) and thalidomide (Thal) (BJH 2007;139:224). In this phase II trial we use bortezomib (Bort) in place of Thal in an effort to further improve frequency and depth of response. Methods: Pts with newly diagnosed AL involving ≤2 organs were assigned to MEL 100, 140 or 200mg/m2 with SCT, based on age, renal function and cardiac involvement. Response was assessed at 2–3 months (mos) and 12 mos following SCT. Pts who did not achieve hematologic CR at 2–3 mos post-SCT received adjuvant therapy with Bort and Dex for up to 6 cycles (26 weeks). The impact of heart disease on OS was determined using the log-rank test; BNP and Trop-I were correlated with OS using the Cox proportional hazards model. Results: Of 27 pts enrolled, organ involvement was kidney (63%), heart (44%), liver/GI (15%) and peripheral nervous system (7%); 33% have 2 organs involved. Two pts were removed from study prior to SCT (1 due to 3 organ involvement and 1 for comorbid illness that resulted in ineligibility for SCT). Transplant related mortality was 12% (3/25) and was restricted to pts with cardiac AL. Of 21 pts evaluable post-SCT, 5 achieved CR and 16&lt;CR, 15 receiving adjuvant therapy. At 12 mos post-SCT, 12 pts are evaluable. In these 12 pts, the ORR was 92% (11/12) with 67% (8/12) achieving CR. Fifty percent of pts had organ improvement. Adjuvant therapy resulted in improved responses in 7/8 (88%) of pts. Cardiac involvement, BNP and trop-I were all significantly associated with OS. As either BNP or Trop-I increases, the risk of death increased (p=0.006 and p=0.007, respectively). Conclusions: Adjuvant Bort and Dex effectively eradicates clonal plasma cell disease in pts with AL following SCT and results in an unprecedented CR rate at 12 mos post-SCT. Pts with cardiac AL continue to do poorly. Baseline BNP and Trop-I both predict survival. A revised risk-adapted treatment approach incorporating these cardiac biomarkers may be warranted. [Table: see text]
Multiple mechanisms of apoptosis induction by the histone deacetylase inhibitor PCI-24781 lead to predictive efficacy biomarkers
Authors: Sriram Balasubramanian, Mint Sirisawad, Jason Ramos, Shanthi Adimoolam, Joseph Buggy
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

3613 

PCI-24781 is a novel orally bioavailable broad-spectrum HDAC inhibitor that is currently in clinical trials in patients with solid and hematologic malignancies. PCI-24781 inhibits growth and induces apoptosis in most tumor cell lines tested, but, as with other broad-spectrum HDAC inhibitors, there are multiple mechanisms of action for this compound, that are cell- and tumor- type dependent. We have previously shown that PCI-24781 can upregulate tumor suppressor genes including the CDK inhibitors p21 and p19, induce cell cycle arrest in G1 or G2/M, upregulate death receptors including TRAIL and LIGHT, and inhibit homologous recombination by downregulation of RAD51 and BRCA1 (Adimoolam S. et al, 2007, PNAS, epub Nov 27). In this work, we identify clinically useful biomarkers based on early events in the mechanism of caspase-dependent induction of apoptosis by PCI-24781 in tumor cell lines. In HCT-116, OVCAR-3, PC-3, CEM, and Jurkat cells, the pan-caspase inhibitor qVD-OPh blocked 70-90% of PCI-24781-induced apoptosis, whereas inhibitors of individual caspases reduced it by only 20-30%, with caspase-9 inhibitor LEHD-fmk showing the most activity. Caspase activation assays show that while caspases 2, 3, 6 and 9 are activated at 48 hours, only caspase-9 activation is observed at 16 hours, indicating an early activation of the intrinsic apoptosis pathway. Accordingly, mitochondrial outer-membrane permeability (MOMP) and cytochrome c release from mitochondria are observed at 12 hours in all the cell lines sensitive to PCI-24781. However, events preceding this, including death receptor activation, Bid cleavage, calcium efflux and ROS production, vary in importance for apoptotic sensitivity to PCI-24781 in different lines. Interestingly, while Bid cleavage is observed in most cell lines, PCI-24781 does not activate caspase-8 nor is apoptosis inhibited by the caspase-8 inhibitor IETD-fmk. Some of these early events appear are found to be conserved in multiple sensitive cell lines as well as in primary human tumors treated ex vivo , and could be broadly useful as predictors of PCI-24781 sensitivity in the clinic.
A Gynecologic Oncology Group study of frequent copy number aberrations in DNA repair genes and other genomic regions in stage I serous ovarian cancers
Authors: T. Pejovic, D. P. Gaile, K. M. Darcy, S. Liu, L. Shepherd, W. H. Rodgers, E. Kohn, R. Mannel, M. J. Birrer, N. Nowak
Journal: Journal of Clinical Oncology (2009)

e16504 Background: A proof of principle array-based comparative genomic hybridization (aCGH) analysis was performed in archival formalin-fixed and paraffin-embedded (FFPE) stage I ovarian cancers (EOC) to determine if frequent (&gt;40%) copy number aberrations (CNAs) can be detected in DNA repair genes including the Fanconi anemia complementation group (FANC) and RAD51 families compared with the rest of the genome. Methods: Tumor DNA was isolated from 22 serous cancers from the GOG-175 virtual tissue bank. RPCI 19K BAC arrays were hybridized (GeneTAC HybStation) and scanned (Gene Pix 4200AL Laser Scanner). Spot fluorescence values were quantified using ImaGene, vetted for quality and loess corrected with adjustments for chip-specific spatial effects. The genome was segmented to identify regions with common copy number means (DNAcopy software). Posterior aberration probabilities for the regions were obtained using CGHcall and data was visualized and annotated using iGenomicViewer in R. Results: Several genes associated with the Fanconi DNA-damage response pathway were frequently altered in stage I serous ovarian carcinomas. A RAD51 homology DMC1 was amplified in 55% of the specimens. Genomic losses were observed in FANC-D1 (BRCA2), and RAD51L3 in 41%, and 27% of specimens, respectively. In contrast, frequent genomic losses or gains involved 13q33.1; 13 q21.31; 17p12; 17q22; 18q12.3; 9p11.2; 9p22.2–22.3; 9q33.1; 8p23.2; 21q21.3; and 5q14.2; or 8q24.3; 3q29; 12p11.1; 17q25.1; 17q25.3; 20q13.33; 20q11.21; 20q11.23; 19p13.13; and 19p13.2, respectively. Conclusions: The GOG-0175 virtual tissue bank yielded high quality DNA for detecting and mapping CNAs in archival FFPE specimens with high resolution. Frequent genomic losses and gains were observed in DNA repair genes and other genomic regions in stage I serous ovarian cancer which may promote genomic instability, resistance, metastasis and aggressiveness of this disease. No significant financial relationships to disclose.
Subsequent Maltreatment in Children With Disabilities After an Unsubstantiated Report for Neglect
Authors: Caroline J. Kistin, Martha C. Tompson, Howard J. Cabral, Robert D. Sege, Michael R. Winter, Michael Silverstein
Journal: JAMA (2016)

This cohort study uses data from the US National Child Abuse and Neglect Data System to examine the incidence and timing of re-referral of children with disabilities to child protective services after an initial referral for neglect in fiscal years 2008 through 2012.
Molecular analysis of NSCLC patients with acquired resistance to gefitinib or erlotinib
Authors: W. Pao, M. N. Balak, G. J. Riely, A. R. Li, M. F. Zakowski, M. Ladanyi, V. A. Miller
Journal: Journal of Clinical Oncology (2006)

7078 Background: We previously reported that in 2 of 5 non-small cell lung cancer (NSCLC) patients with acquired resistance to the tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, tumors biopsied after disease progression contained a second site mutation (T790M) in the epidermal growth factor receptor (EGFR) kinase domain, in addition to a primary drug-sensitive mutation (exon 19 deletion (del) or exon 21 point mutation (L858R)) (Pao et al, PLoS Med ‘05). No patients had KRAS mutations, which are associated with primary resistance to these TKIs. We sought to determine the frequency of second site EGFR kinase domain and KRAS mutations in tumors from patients with acquired resistance to TKIs, administered either as monotherapy or with chemotherapy. Methods: 18 patients with NSCLC who responded to either TKI alone (n = 14) or TKI plus chemotherapy (n = 4) and then progressed were re-biopsied. Genomic DNA samples from tumors were examined for EGFR (exons 18–24) and KRAS (exon 2) mutations. Results: Sequence analysis was successfully performed on tumors from 17 patients. The T790M EGFR mutation was detected in 6 of 13 (46%, 95% CI 19–75%) on TKI monotherapy, and in 0 of 4 (0%, 95% CI 0–53%) on TKI plus chemotherapy. In one autopsy case, the T790M mutation was detected in 5 of 5 sites, which all harbored the same exon 19 del. No other EGFR or KRAS mutations were detected. Conclusions: Secondary EGFR T790M but not KRAS mutations are commonly associated with acquired resistance to TKI monotherapy. More patients are being studied, and we are trying to elucidate determinants of acquired resistance in the absence of T790M mutations. New therapies are needed to treat and/or suppress the development of acquired resistance to gefitinib or erlotinib. Support: Joan’s Legacy, DDCF, K08-CA097980, R21-CA115051. [Table: see text]
A phase I trial of targeted COX-2 and EGFR TK inhibition in advanced NSCLC
Authors: K. L. Reckamp, S. M. Dubinett, K. Krysan, R. A. Figlin
Journal: Journal of Clinical Oncology (2005)

7112 Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibition (TKI) is a novel targeted therapy for selected pts with NSCLC. Cyclooxygenase-2 (COX-2) is overexpressed in lung cancer and acts through PGE2 to promote tumor proliferation, invasion, angiogenesis, decreased anti-tumor immunity and resistance to apoptosis. Cross talk between EGFR and COX-2 signaling pathways results in regulation of tumorigenesis. Previously, we have described a mechanism in which signaling through the COX-2 pathway activates the Erk/MAPK pathway in an EGFR TKI-resistant manner. These findings have led to evaluations of the combination of COX-2 and EGFR inhibition in NSCLC. Methods: A phase I, dose escalation trial to investigate the optimal biologic dose of the combination of COX-2 inhibition (celecoxib-C) and EGFR inhibition (erlotinib-E) in pts with refractory stage IIIB/IV NSCLC. Pts receive increasing doses of C (200mg, 300mg, 400mg, 600mg and 800mg BID) and a fixed dose of E (150mg QD). Primary endpoints include evaluation of toxicity and determination of the biologically active dose of the combination. Secondary endpoints investigate exploratory biological markers and clinical response rates. Results: All 5 cohorts have been enrolled to date, n=15. Average age is 66 yrs, 3 female and 12 male pts, and smoking history is 27 pack yrs. 13 subjects have stage IV disease and 2 have stage IIIB. The combination has been generally well tolerated without unanticipated toxicities. Of 12 evaluable subjects to date, we have seen 4 partial responses and three patients with stable disease in pts both with and without EGFR activating mutations. The duration of partial response has been 16+-48+ wks. TTP is 62+ weeks in one patient with stable disease. A significant decline in urinary PGE-M was demonstrated after 8 wks of treatment with C at 400mg BID compared with doses of 200mg and 300mg BID. Conclusions: This study defines the optimal biologic dose of celecoxib when combined with an EGFR TKI and may enhance efficacy with an acceptable toxicity profile. A randomized Phase II trial is planned comparing erlotinib and celecoxib with erlotinib plus placebo in advanced NSCLC. Supported by UCLA Lung Cancer SPORE NCI P50 CA 90388, GLAVAHS CDA and STOP Cancer Memorial Award. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech
Continuous ambulatory ECG monitoring during fluorouracil therapy: a prospective study.
Authors: S Rezkalla, R A Kloner, J Ensley, M al-Sarraf, S Revels, A Olivenstein, S Bhasin, S Kerpel-Fronious, Z G Turi
Journal: Journal of Clinical Oncology (1989)

Although there have been anecdotal reports of cardiac toxicity associated with fluorouracil (5-FU) therapy, this phenomenon has not been studied in a systematic fashion. We prospectively performed continuous ambulatory ECG monitoring on 25 patients undergoing 5-FU infusion for treatment of solid tumors in order to assess the incidence of ischemic ST changes. Patients were monitored for 23 +/- 4 hours before 5-FU infusion, and 98 +/- 9 hours during 5-FU infusion. Anginal episodes were rare: only one patient had angina (during 5-FU infusion). However, asymptomatic ST changes (greater than or equal to 1 mm ST deviation) were common: six of 25 patients (24%) had ST changes before 5-FU infusion v 17 (68%) during 5-FU infusion (P less than .002). The incidence of ischemic episodes per patient per hour was 0.05 +/- 0.02 prior to 5-FU infusion v 0.13 +/- 0.03 during 5-FU infusion (P less than .001); the duration of ECG changes was 0.6 +/- 0.3 minutes per patient per hour before 5-FU v 1.9 +/- 0.5 minutes per patient per hour during 5-FU (P less than .01). ECG changes were more common among patients with known coronary artery disease. There were two cases of sudden death, both of which occurred at the end of the chemotherapy course. We conclude that 5-FU infusion is associated with a significant increase in silent ST segment deviation suggestive of ischemia, particularly among patients with coronary artery disease. The mechanism and clinical significance of these ECG changes remain to be determined.
Effects of glucocorticoid treatment on the functional capacity of stem cell transplant recipients entering a rehabilitation program
Authors: J. S. Scheetz, G. S. Morris, K. E. Brueilly, E. A. Brannan, E. Del Fabbro
Journal: Journal of Clinical Oncology (2009)

7104 Background: Emerging data strongly supports the concept that stem cell transplant (SCT) recipients derive psychological and physiological benefit from participation in exercise training programs. Many SCT recipients receive glucocorticoids (GC) for prolonged periods, increasing their risk for proximal muscle damage and raising the possibility that SCT recipients on GC may differ from those SCT recipients not receiving GC in terms of their exercise/functional capacity. This becomes an important reconditioning issue because exercise prescription and progression is predicated on initial exercise capacity. Therefore the purpose of this study was to compare the initial functional capacity of outpatient STC recipients receiving GC to STC recipients not receiving GC. Methods: The medical records of 163 successive SCT recipients referred to Rehabilitation Services for reconditioning were retrospectively reviewed for demographic information and measures of exercise/functional capacity (6-min walk test, 50-ft fast walk, and repeated sit-to-stand times) collected at the initial physical therapy visit. Data from SCT recipients on GC (ON) were compared with that of SCT recipients not on GC (OFF) by means of an unpaired t-test (α=0.05). Data are presented as mean + standard deviation. Results: Demographic and functional measures are presented in the following tables. Significant differences between group means are denoted by an asterisk. Conclusions: STC recipients on steroids have comparable endurance capacity to those STC recipients not on steroids, but are less capable of performing lower extremity activities requiring rapid movement and receive rehabilitation services later in the post transplant recovery course. These results suggest rehabilitation strategies are 1) needed for STC patients, 2) should be individualized according to the patient's drug regime, and 3) should be initiated soon after the stem cell transplant. [Table: see text] No significant financial relationships to disclose.
Diagnostic imaging and biopsy use among elderly medicare beneficiaries with hepatocellular carcinoma: Evaluating community guideline adherence.
Authors: N. N. Massarweh, J. O. Park, R. S. Yeung, J. Bruix, R. B. Etzioni, R. G. Symons, L. Baldwin, D. R. Flum
Journal: Journal of Clinical Oncology (2010)

6019 Background: Consensus guidelines regarding appropriate use of diagnostic biopsy for hepatocellular carcinoma (HCC) have been available since 2000 (tumors 1-2 cm in which a radiologic diagnosis cannot be established), and reflect the high level of perceived accuracy of modern imaging. These guidelines were intended to decrease the use of biopsy in cases when a diagnosis might be established using less invasive or more efficient approaches. The use of biopsy and diagnostic imaging for HCC has not been evaluated in the general community. Methods: Cohort study using Surveillance, Epidemiology, and End Results (SEER)-Medicare data (2000-2005) evaluating biopsy, imaging modalities (Ultrasound, CT scan, and/or MRI), and HCC risk factors. Logistic regression was used to evaluate trends and factors associated with biopsy and imaging. Results: Of 5,221 patients (mean age 76.2 ± 6.3 years, 66.2% male), 1,688 (32.3%) underwent ≥ 1 biopsy (mean 1.1 biopsies, 9.8% ≥ 2 biopsies), with no change in yearly biopsy rate (trend test, p = 0.55). Patients with tumors > 5 cm were most commonly biopsied (61.9%), with increasing biopsy use for larger tumors (p < 0.001). Biopsied patients underwent more nonultrasound (1.5 vs 0.9, p < 0.001) and total imaging procedures (2.4 vs. 1.6, p < 0.001) than nonbiopsied patients. In 20.6% of patients (33.5% biopsied vs. 14.5% nonbiopsied; p < 0.001) the sequence of imaging procedures did not conform to guidelines. Biopsied patients were more likely to have an HCC risk factor (56.3% vs. 48.9% with ≥ 1 risk factor; p < 0.001)—in particular patients with tumors > 5 cm (50.9 vs. 38.2%, p < 0.001). Patients with tumors > 5 cm in the setting of a concurrent HCC risk factor were at increased odds of biopsy (OR 2.45, 95% CI 2.04-2.95 compared to patients with lesions ≤ 2 cm without a risk factor). Conclusions: Despite widespread availability and a high reported accuracy of CT scan and MRI, one third of patients with HCC undergo biopsy in real world practice. This suggests either limited impact of the guidelines and/or a widespread problem with the quality of imaging. Understanding the factors driving biopsy use should help improve the care provided to patients with HCC. No significant financial relationships to disclose.
The Quality Oncology Practice Initiative (QOPI): Understanding and improving “Best Practices” by a community of oncologists
Authors: K. K. McNiff, M. Neuss, C. Desch, J. Guo, J. V. Simone
Journal: Journal of Clinical Oncology (2005)

6023 Background: One goal of the QOPI project is to provide tools for practitioners to implement “best practices.” In an effort to provide comparative data regarding best practices, QOPI has developed a set of evidence and consensus-based measures. Concordance is assessed through a structured chart review that allows numeric scoring and generation of practice reports. Results can be compared over time and among practices. Methods: 23 practices of various sizes from across the U.S. were invited to participate. Measures relate to ASCO practice guidelines, national standards, or expert consensus. 2,410 charts have been abstracted to date. Observations and comparisons among groups are analyzed by construction of 95% confidence intervals (CI). Conclusions: We observed a clinically meaningful and statistically significant variation in achieving quality measures in oncology practices. The QOPI process provides a mechanism for documenting concordance with quality measures, testing interventions and documenting improvement. Measure N Mean %Yes 95% CI Lowest Ob- served Value Highest Ob- served Value Was pain addressed on the visit prior to death? 394 65.0% 55–75% 15.0% 92.9% Were granulocytic growth factors given per guideline? 203 30.6% 34–50% 0% 100% Were serotonin antagonist antiemetics given per guideline? 1160 97.0% 96–98% 84.1% 100% Were corticosteroids added per guideline? 1102 97.9% 97–99% 90.3% 100% Were erythroid growth factors given per guideline? 824 72.7% 68–77% 36.7% 94.7% Was a pathology report available in the chart? 2410 97.1% 96–98% 88.2 % 100% Was staging completed prior to definitive therapy? 2159 96.1% 94–98% 70.2% 100% Were flow sheets used when chemotherapy was given? 1997 99.8% 99–100% 97.3% 100% Was a signed consent for non-protocol chemotherapy in the chart? 1997 39.5% 28–51% 0% 100% Was verbal consent for chemotherapy documented? 692 88.7% 80–96% 73.6% 100% Was adjuvant chemotherapy given to breast cancer patients per NICCQ specifications? 131 100% N/A N/A N/A Was adjuvant chemotherapy given to colorectal cancer patients per NICCQ specifications? 270 99.2% 99–100% 91.7% 100% No significant financial relationships to disclose.