tbuckley/cabot-search huggingface dataset:
Protein expression and clinical features of ovarian cancer in the elderly
Authors: J. Liu, M. S. Hirsch, H. Lee, U. A. Matulonis
Journal: Journal of Clinical Oncology (2007)

5574 Background: Ovarian carcinoma is the leading cause of death due to gynecologic malignancies, and age at the time of diagnosis has been suggested to predict for a poorer prognosis. However, few studies have determined if specific biomarkers can predict a difference in prognosis between younger and older patients. We have constructed a tissue microarray (TMA) with correlative clinical data comprised of cases of advanced papillary serous (PS) ovarian cancer to evaluate the features of ovarian cancer in the elderly. Methods: Two cohorts (patient’s age =65 and =55 at diagnosis) were identified by retrospective review of PS ovarian carcinoma pathology cases seen between 1999 and 2005. Patients with stage III or IV were included; those with BRCA mutations were excluded. A high density TMA (with 4 cores per primary tumor) was constructed, and sections were immunostained with ER, PR, and ErbB2. Clinical data were obtained by chart and database review; age, stage, and protein expression were then correlated with overall survival. Correlation of protein expression and age was also examined. Results: 154 cases were examined, with 74 cases in the =55 group and 80 cases in =65 group. There was no difference in survival between the 2 cohorts (p=0.42), but overall survival differed significantly between those patients diagnosed at =70 and &gt;70 years of age (p=0.004). Tumors from the =65 cohort were more likely to express ER (66.7% ≥65, 44.1% ≤55; p=0.009) and less likely to express PR (34.7% ≥65, 57.1% ≤55; p=0.009). Only 3 cases in the older cohort, and none in the younger cohort, expressed ErbB2; these findings were not significant. Protein expression did not correlate with overall survival. However, multivariate analysis revealed that stage IIIc or IV disease (HR 2.38, p=0.04) and age&gt;70 (HR 1.93, p=0.008) were independent risk factors for poorer outcome. Conclusions: This study suggests that patients with advanced PS ovarian carcinoma diagnosed at age &gt;70 have poorer overall survival. PS ovarian cancer in older patients is more likely to express ER and less likely to express PR, but this does not correlate statistically with clinical outcome. Other characteristics of ovarian cancer in the elderly may account for their poorer prognosis, and this TMA will be a valuable tool to assess additional biomarkers. No significant financial relationships to disclose.
First-line, long-term treatment of multiple myeloma with thalidomide, dexamethasone, and zoledronate in combination (TDZ)
Authors: U. Klueppelberg, L. Chen, C. M. Aloba, J. Shapira, E. Smith, N. Palanisamy, J. Schmidt, M. Moezi, O. Batuman
Journal: Journal of Clinical Oncology (2004)

6702 Background. Thalidomide + dexamethasone is a rescue regimen for multiple myeloma (MM) in relapse, and for pretransplant in newly diagnosed patients. The bisphosphonate zoledronate mitigates bone resorption and possibly tumor growth and angiogenesis. The long-term utility of this combination in newly diagnosed MM is addressed in this Phase II trial. Methods: Of 26 consecutive enrollees, 19 (15F/4M) were evaluable. Mean age was 59 years (range = 43–76); all had skeletal lesions, 32% (n = 6) were HIV+ (mean age = 46, range 46–50, all female). Patients received thalidomide 100 mg QD, dexamethasone 10–40 mg PO on Days 1–4, 9–12, and 17–20 monthly for six months, then on Days 1–4 monthly; and zoledronate 4 mg IV monthly, until progression or relapse. Baseline β2-microglobulin indicated high risk for all patients (mean = 6.2 μg/ml, SD = 3.8). Results: Overall response rate (> 50% decrease in M protein) is 68 % (n = 13). In 32% (n = 6) M protein levels were < 0.3 g/dL. In 30 % (n = 5) M protein was reduced by < 50%. Median time to response was 2 months, and mean time on TDZ was 11 months. TDZ treatment decreased serum β2-microglobulin (P < .001). One patient did not respond, and two relapsed; all three eventually died. Response to treatment was unaffected by HIV status. Side effects of treatment were reversible by anticoagulant therapy or dexamethasone reduction. Conclusions: TDZ had significant activity against newly diagnosed MM, suggesting that zoledronate may facilitate response with lower doses of thalidomide. HIV status did not affect response. These findings underscore the potential effectiveness of this combination of anti-myeloma agents as a long-term alternative to previously described protocols. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis
Gene expression profiling predicts nonresponders to chemoradiation in HPV16-positive head and neck squamous cell carcinoma.
Authors: B. J. Thibodeau, T. J. Geddes, S. Ahmed, B. L. Pruetz, P. Y. Chen, G. D. Wilson, J. A. Akervall
Journal: Journal of Clinical Oncology (2011)

5589 Background: Human papillomavirus (HPV) has been shown to have a causal role in the development of Head and Neck Squamous Cell Carcinoma (HNSCC). In one study, 22% of tumors were HPV+, with 87% being of the HPV16 subtype. HPV-related HNSCC represents a distinct and well-defined pathology. HPV+ HNSCC is associated with a better response to radiation and prognosis. However, approximately 15% of the patients do not respond favorably to radiation or chemoradiation, thus suffering unnecessary morbidity and delay to receive effective therapy. Methods: 11 patients with laryngeal and oropharyngeal HPV+ HNSCC were selected for the study, 5 of which had a complete response to treatment and 6 who were non-responders. RNA from prospectively collected, pre-treatment tumor specimens were subjected to gene expression analysis using Affymetrix Human Exon 1.0ST arrays. HPV-status was confirmed by detection of HPV16 E7 with RT-PCR. Results: ANOVA (p≤0.05) and a 2-fold cutoff were used to identify 118 altered genes, including 112 genes over-expressed in the complete responders compared to the non-responders. Genes over-expressed in the complete responders included genes associated with T cell proliferation (PTPRC, ITGAL, IL6ST, CD3E, CORO1A) and antigen processing/presentation (HLA-F, HLA-DRA, HLA-DQA2, PSMB9, ERAP1, CD74). Utilizing Ariadne Pathway Studio to characterize the data, changes in gene expression were enriched in genes encoding proteins involved in regulating cell processes such as presentation of endogenous peptide antigen, lymphocyte adhesion, and T-cell related processes. Further, genes associated with the Gene Ontology group “response to virus” are up-regulated in complete responders. Conclusions: Our gene expression analysis suggests that differences in response to chemoradiation therapy are related to immune response prior to treatment. These data can potentially lead to an assay that can be used clinically to predict HPV+ HNSCC patients that will not benefit from chemoradiation, thus helping clinicians to lower morbidity and get selected patients to surgery faster.
Family information service (FIS) in a <i>BRCA1</i> extended family
Authors: H. T. Lynch, C. Snyder, J. Lynch, S. Ghate, S. Thome
Journal: Journal of Clinical Oncology (2006)

1028 Background: Considering that 10% of breast cancer is hereditary, it is essential to effectively educate hereditary cancer family members regarding the syndrome, cancer risk, genetic testing and cancer control options. Researchers at Creighton University (CU) have for many years provided family (group-oriented) information services (FISs) for hereditary cancer families. Methods: Such a session was held in collaboration with a genetic counselor in a community where many members of an extended hereditary breast-ovarian cancer family with a known BRCA1 mutation reside. Family members helped contact relatives and invited them to attend the full-day FIS at a local hospital. Informal presentations were provided by a CU geneticist/oncologist, a CU nurse counselor, and a local genetic counselor. Questions and comments were encouraged. An opportunity to provide a blood sample for genetic testing was offered. Results: Contacting relatives for the FIS identified more than 400 family members from previously unknown branches. Many attendees indicated this was their first opportunity to learn about this hereditary cancer syndrome, their risk, and recommended cancer control options. Patient-stated benefits of the FIS included increased communication of cancer risk among family members as well as with their physicians, motivation to become more vigilant with screening and health management and receipt of initial cancer risk education in a non-threatening venue. Conclusions: The FIS is a relatively simple, cost-effective educational cancer control program that increases communication among family members and their physicians, educates high-risk individuals and provides an opportunity for genetic testing which will ultimately provide an accurate cancer risk status and thereby alter health management and cancer control strategies. No significant financial relationships to disclose.
A phase I study of decitabine (DCT) in combination with doxorubicin (DOX) and cyclophosphamide (CTX) in the treatment of relapsed or refractory solid tumors: A Children’s Oncology Group Study
Authors: R. E. George, C. Medeiros-Nancarrow, P. C. Adamson, S. M. Blaney, V. Kidd, J. M. Lahti, M. Krailo, A. T. Look, L. Diller
Journal: Journal of Clinical Oncology (2005)

8530 Background: In vitro treatment of neuroblastoma and rhabdomyosarcoma cells with the demethylating agent DCT results in increases in caspase-8 expression and enhanced apoptosis after secondary exposure to DOX. Purpose: To determine the maximum-tolerated dose (MTD), dose limiting toxicity (DLT) and pharmacokinetic profile of DCT when combined with DOX and CTX in children with relapsed or refractory solid tumors. Patients and Methods: Patients received a 1-hour infusion of DCT daily for 7 days, followed by 45 mg/m2 of DOX (with dexrazoxane) and 1 g/m2 of CTX (with mesna) on day 7. G-CSF was started 24 hours after completion of DOX and CTX. Cycles were repeated every 28 days. Cohorts of 3 to 6 patients were studied at 5 and 10 mg/m2 of DCT. Pharmacokinetic profiles were also characterized. Results: Eleven patients (1 female) were entered onto the study, of whom 9 were fully evaluable for toxicity. Prolonged neutropenia in 3 of 3 patients and prolonged thrombocytopenia in 1 of 3 patients were dose limiting at the 10 mg/m2 dose level. Other non-dose limiting toxicities were infection, mild nausea, vomiting, elevated transaminases and headache. An increase in hemoglobin F, an indicator of demethylation of a marker promoter, was observed in 4 of 9 patients. Conclusions: The MTD of DCT given for 7 days prior to DOX (45 mg/m2) and CTX (1 g/m2) is 5 mg/m2/d. Neutropenia and thrombocytopenia were the dose-limiting toxicities. Studies to determine whether this dose of DCT is capable of inducing caspase-8 expression and apoptosis are being done in patients with neuroblastoma. No significant financial relationships to disclose.
Ketoconazole activates chloride and fluid secretion by Necturus gallbladder at low pH.
Authors: U Kersting, K R Spring
Journal: Journal of the American Society of Nephrology (1996)

Necturus gallbladder epithelium, normally a reabsorptive epithelium, was stimulated to secrete chloride and fluid by the combined effects of ketoconazole and a reduction in perfusate pH to 7.0. The reversal in the direction of net fluid transport was accompanied by inhibition of the conductance of the apical cell membrane to sodium, potassium, and a striking stimulation of the conductance to chloride. The results are consistent with a previously unidentified mechanism for regulation of the apical cell membrane transport properties of reabsorptive epithelia.
Phase II trial of iboctadekin (rhIL-18) on a daily X 5 schedule in metastatic melanoma (MM)
Authors: J. M. Kirkwood, R. Kefford, T. Logan, P. N. Mainwaring, M. Millward, A. C. Pavlick, M. M. Dar, S. Kathman, K. Laubscher, W. Bell
Journal: Journal of Clinical Oncology (2006)

10043 Background: Interleukin-18 (IL-18) is an immunostimulatory cytokine with potent antitumor activity in preclinical models. Two phase I studies of recombinant human (rh) IL-18 explored a wide dose range (0.03–1.0 mg/kg) without reaching a maximum tolerated dose (MTD) on the daily × 5 schedule. Pharmacodynamic data including inflammatory cytokine production and activation of lymphocyte subsets revealed optimal biologic activity at the lower end of the dose range (0.01–0.2 mg/kg) as did 2 unconfirmed partial responses (PRs) in a MM and a renal cancer patient (pt) at 0.1 mg/kg. Methods: An open-label, randomized, phase II trial in 60 adult pts with previously untreated MM was conducted to evaluate the efficacy and safety of rhIL-18 administered as a 2-hour IV infusion daily × 5 every 28 days for 6 cycles. Pts with PS ≤ 1, without known CNS involvement, and with adequate end organ function were randomized in stage 1 to 3 dose levels of IL-18 stratified according to AJCC M stage 1a/b vs. 1c. Two confirmed responses for a given dose level in Stage 1 were required to enroll 20 additional pts/level in Stage 2. The 1° objective was determination of overall response rate (ORR) for each dose level. Progression-free survival (PFS), tolerability, and immunogenicity were 2° endpoints. Results: 64 pts were treated at 3 dose levels. Nine pts remain on study. One pt experienced a confirmed PR. Based on preliminary data, the difference in PFS 6 months (mos) was significant (p=0.03) for 0.01 vs 0.1 mg/kg. Most common toxicities were mild to moderate fever, rigors, chills, n/v, and headache. Anti-IL18 antibody (Ab) development correlated with dose level. No clinically significant adverse events were associated with Ab development. Conclusion: Iboctadekin has an acceptable tolerability profile and has activity in MM but insufficient confirmed responses have been observed at this time to initiate Stage 2. Preliminary PFS 6 months indicates an advantage for pts treated at the lowest dose. [Table: see text] [Table: see text]
High frequency of human leucocyte antigen (HLA) A2 and HLA-B7, -B44, -B15 and -DRB1–4 haplotypes in Swedish prostate cancer patients
Authors: G. V. Masucci, E. Andersson, L. Egevad, K. Kälkner, U. Harmenberg, M. Ryberg, S. Nilsson, P. Pisa
Journal: Journal of Clinical Oncology (2006)

14543 Background: Immune escape mechanisms depend on alterations in the expression of major histocompatibility complex (MHC) molecules and are known to play a crucial part in tumour development. We have previously presented high prevalence of the A2 allele in Scandinavia, which decreases with latitude in Europe and we noticed that prostate cancer mortality decreases among European countries in a similar way. We have furthermore characterized a group of prostate cancer patients with high frequency of HLA-A2 phenotype. Here we present prospectively the incidence of HLA-A2, homozygotes and haplotypes related to clinical parameters. Methods: Unbiased selected patients (n = 35) with localized prostate cancer, stage T1–3, NX-0, M0, eligible for curative full-dose radiotherapy, were analyzed for the genotypes HLA-A, -B, -C, and -DRB1 loci, by PCR/sequence-specific oligonucleotide hybridisation. Furthermore they have been compared to the frequencies of HLA alleles of healthy bone marrow donors in Sweden (based on 43 000 individuals). Results: The HLA-A2* phenotype frequency was 69% compared to the healthy Swedish population 58% (genotype frequency 39% vs. 35%). We also observed an increase in haplotypes compared to A2-B7 (14% vs 6%), A2-B44 (13% vs 6%), A2-B15 (14% vs 6%), A2-DRB1*04 (24% vs 8%). The ancestral haplotype HLA-A2, -B44, -DRB1*04 and HLA-A2, -B15, -DRB1*04 were expressed in 6% and 13% respectively in the patients group compared to the healthy Swedish population (2% and 3%). Conclusions: Our findings indicate that there is an unusual overrepresentation of the HLA-A2 allele and related haplotypes in prostate cancer patients. Further investigations are mandatory to establish if the negative prognostic correlation with HLA-A2 and the high frequent haplotypes is related to histological and clinical parameters as a result of disfunction of the immune system. No significant financial relationships to disclose.
Abstract 006: An Advance toward Making A Heart: Engineering Functional Human Heart Constructs with Induced Pluripotent Stem Cells and Decellularized Mouse Hearts
Authors: Lei Yang, Tung-Ying Lu, Bo Lin, Jong Kim, Kimimasa Tobita, Guy Salama
Journal: Circulation Research (2013)

Background: Heart disease is the leading cause of death in the world, requiring the development of novel and personalized therapeutic strategies for disease treatment. Heart tissue engineering holds a great promise for those therapies based on the reconstruction of patient-specific cardiac muscle. A bioartificial heart was reported by reseeding rat cardiomyocytes ( CMs ) into decellularized rat heart. Whether such method could be used to make human heart constructs remained unknown. Objectives: We sought to rebuild functional heart constructs using human induced pluripotent stem ( iPS) cells and decellularized whole mouse hearts. Methods: We repopulated decellularized mouse hearts with human iPS cell derived multipotential cardiovascular progenitors ( MCPs ). MCPs represent the earliest heart progenitors during human cardiogenesis and can give rise to multiple cardiovascular lineage cells. Results: The seeded MCPs differentiated in situ into CMs, smooth muscle and endothelial cells, which reconstructed the decellularized mouse hearts. The engineered constructs exhibited myocardium and vessel-like structures, contracted spontaneously with a rate of 40~50 beats/min, exhibited intracellular Ca2+ transients and responded as expected to various drug interventions. In addition, we found heart ECM could promote proliferation and myofilament formation of CMs from the repopulated human MCPs. Therefore this study established a novel strategy of human heart tissue engineering, which could be beneficial to study heart development, and future preclinical applications.
The CD40 agonistic monoclonal antibody APX005M has potent immune stimulatory capabilities
Authors: Pia Bjorck, Erin Filbert, Yongke Zhang, Xiaodong Yang, Ovid Trifan
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts The co-stimulatory receptor CD40 is a member of the tumor necrosis factor receptor (TNFR) superfamily and plays an important role in the control and regulation of immune activation, especially in crosstalk between T cells and antigen presenting cells (APCs). The natural ligand for
The impact of non-compliance with imatinib (IM) therapy on health care costs
Authors: H. J. Henk, S. K. Thomas, W. Feng, B. Jean-Francois, G. A. Goldberg, A. Hatfield
Journal: Journal of Clinical Oncology (2006)

6083 Background: While compliance to drug therapy is vital to receive optimal patient benefits, the costs of delivering adequate medical care for cancer patients remain an important consideration for society and payers. This study examined the relationship between compliance with IM therapy and health care costs for patients with CML and GIST. Methods: Claims data from 6/1/01–3/31/04 from a US health plan were used to identify non-Medicare IM-treated patients with a CML or GIST diagnosis who had continuous pharmacy and medical benefits in the 3 months prior and 12 months following initiation of IM therapy. Compliance was defined by medication possession ratio (MPR=total days IM supply in the first year ÷365) and patients were stratified into three segments by MPR (&lt;50%, 50–90%, 90–100%). Total health care costs include hospital, laboratory testing, office, ER, and pharmacy charges. Disease-related health care costs were also analyzed. Multivariate analyses were used to examine the relationship between MPR and first-year health care costs, controlling for age, sex, number of medications, initial starting dose, diagnosis (CML or GIST), year of initial IM fill, and complications due to underlying disease. Results: Total 878 IM-treated patients were identified of whom 413 had at least 15 months of continuous eligibility. Of these, 307 were non-Medicare CML or GIST patients. Total health care costs per patient in the first year of therapy in MPR &lt; 50%, 50–90%, and 90–100% groups were $163,828, $53,924, and $40,924 respectively (p &lt; 0.001). The corresponding numbers for disease-related health care costs were $103,118, $36,436, and $34,086 (p&lt;0.001). Controlling for the variables listed above, a 10% increase in MPR is associated with a 5% decrease in total health care costs (p=0.021). Similar association was found between MPR and disease-related health care costs. Conclusions: Improved compliance with imatinib therapy is associated with decreased total health care costs and disease-related health care costs. Improving compliance to imatinib therapy may not only optimize clinical outcomes but may also reduce the overall societal burden of health care costs associated with cancer. [Table: see text]
Phase I study (twice weekly schedule) of 17-allylamino-17 demethoxygeldanamycin (17AAG, NSC-704057) in patients with advanced refractory tumors
Authors: R. K. Ramanathan, C. P. Belani, D. Friedland, S. Ramalingam, S. S. Agarwala, P. Ivy, D. Potter, G. Chatta, E. Zuhowski, M. J. Egorin
Journal: Journal of Clinical Oncology (2005)

3050 Background: 17AAG is a benzoquinone antibiotic known to down-regulate oncoproteins by binding to heat shock protein 90. Previous studies have evaluated weekly, daily x 3 or daily x 5 schedules. In-vitrodata show increased activity of 17AAG when dosed at short intervals. We performed a phase I study of 17AAG given twice a week (wk) x 3 wks (6 doses/ cycle, schedule A) or twice a wk x 2 wks (4 doses/cycle, schedule B). Cycles were repeated after a 1-week rest. The objectives were to establish the maximal tolerated dose and dose-limiting toxicity (DLT). Methods: Escalating doses of 17AAG, were given IV over 1–2 h to cohorts of 3–6 patients (pts) each, using a modified Fibonacci schema. The dose levels for Schedule A were 100, 125, 150, 175 and 200 mg/m2 and for schedule B were 150, 200 and 250 mg/m2. Peripheral blood mononucleocytes were collected for assessment of biomarkers. Results: 44 pts were enrolled (Schedule A, 32 pts; Schedule B, 12 pts). Pt characteristics: Male 26; Age 34–78 (median 63); ECOG performance status 0 (n=16), 1 (n=28). The most common tumor types were colorectal (n=15), lung (n=7), head & neck (n=4) and genito-urinary (n=4). On schedule A at 200 mg/m2, DLT's were seen in 2 of 6 pts (grade 3 thrombocytopenia and grade 3 abdominal pain). On schedule B at 250 mg/m2, DLT's were seen in 2 of 2 pts (grade 3 headache with vomiting). Grade 3/4 toxicities attributed to drug administration (possible, probable or definite) were reversible elevations of liver enzymes (n=11), nausea and vomiting (n=7), headache (n=2) and abdominal pain, diarrhea, hypokalemia, fatigue (1 pt each). No objective tumor responses were observed. Conclusions: Overall, 17 AAG is well tolerated when given twice weekly. The recommended phase II dose of 17AAG on schedule A is 150 mg/m2 and on schedule B is 200 mg/m2. These schedules are now undergoing evaluation in combination with other antineoplastic drugs. (Support: 1UO1-CA099168–01 and NIH/NCCR/GCRC #5M01 RR 00056 to Univ Pittsburgh) No significant financial relationships to disclose.