tbuckley/cabot-search huggingface dataset:
CRCAPRO: A statistical model to evalute the risk of MMR mutations
Authors: F. Bianchi, R. Bracci, S. Rosati, E. Galizia, L. Belvederesi, C. Loretelli, G. Giorgetti, F. Giorgi, R. Cellerino
Journal: Journal of Clinical Oncology (2005)

9693 Background: Hereditary Non Polyposis Colorectal Cancer (HNPCC) is linked to MisMatch Repair (MMR) genes mutations. MMR mutation carriers show a high susceptibility to colon and some extracolonic tumours, in particular endometrial tumours. Amsterdam and Bethesda guidelines are usually used to select patients which should undergo testing for HNPCC mutations. For hereditary breast and ovarian cancer, the choice of subjets to be tested for gene mutations may be done with BRCAPRO, a statistical model developed by Johns Hopkins University. The same group has developed a CRCAPRO software to assess the probability that an individual carries a germline mutation of the hMLH1 or hMSH2 genes, (the most frequently mutated genes of the MMR system) based on family history of colorectal and endometrial cancer. Age-dependent penetrance and prevalence are based on a systematic review of the literature. Aim of this study was to evalute the reliability of CRCAPRO in identifying mutation carriers in our data-base. Methods: We used CRCAPRO to evaluate carrier probability risk in a group of 85 patients which were selected for HNPCC based on Amsterdam and Bethesda guidelines criteria. Germline analysis for hMLH1 and hMSH2 mutations was performed using direct sequencing of the entire open reading frame of both genes in all the 85 patients. Results: Fifteen patients, harbouring respectively 5 hMLH1 and 10 hMSH2 germline mutations, were identified. Six of them carried a risk of 25% or more, 6 of then patients from 5% to 16% and 3 patients about 1%. Conversely, of the 6 patients with a risk higher then 35%, no one harboured a mutation and of the 15 patients with a risk 20 to 35%, 6 presented with hMSH2 or hMLH1 mutations. No significant financial relationships to disclose.
Second-line therapy with irinotecan or gefitinib in docetaxel pretreated patients with non-small cell lung cancer: A new treatment strategy according to clinical predictors for response
Authors: S. Park, J. Park, E. Cho, D. Shin
Journal: Journal of Clinical Oncology (2007)

18026 Background: Retrospective analyses of previous trials have shown the clinical advantage of gefitinib in advanced non-small cell lung cancer (NSCLC) patients with certain favorable baseline factors (Asian ethnicity, female, adenocarcinoma, or no smoking history). This prospective phase II study was designed to test the hypothesis that higher response rates might be achieved if patients are selected according to these clinical predictors for response. Methods: Korean NSCLC patients who have failed after docetaxel-based first-line chemotherapy were consecutively accrued. Patients without any of the favorable clinical predictors (i.e., male smoker with non-adenocarcinoma) received irinotecan 100 mg/m 2 on days 1, 8 and 15 every 4 weeks (irinotecan arm). Patients who had at least one of the predictors for response received gefitinib 250 mg/d orally from day 1 (gefitinib arm). Primary endpoint was response rate. With a two-stage phase II design, the required number of patients was at least 25 per each arm. Results: Of 68 patients accrued, 25 were treated with irinotecan and 43 with gefitinib. In the gefitinib arm, 22 patients were female, 20 were never-smoker, and 33 had adenocarcinoma. Treatment duration was significantly longer in the gefitinib arm (2.0 months for irinotecan arm v 4.4 months for gefitinib arm; p&lt;0.01). Median number of chemotherapy cycles was 2 (range, 1–4) for irinotecan arm. Fewer drug-related toxicities were observed with gefitinib compared with irinotecan. In the irinotecan and gefitinib arm, 28% and 13% of patients, respectively, discontinued treatment because of toxicity. The objective responses of irinotecan and gefitinib arm were 16% (95% CI, 2–30) and 37% (95% CI, 21–51), respectively (p=0.07). Patients in the gefitinib arm had a longer, although statistically insignificant (p=0.11), progression-free survival (6.5 months; 95% CI, 3.8–9.2) than those in the irinotecan arm (3.2 months; 95% CI, 2.0–4.4). Conclusions: Gefitinib could be a reasonable second-line option in Korean NSCLC patients who had at least one favorable clinical predictor. Updated results, including an exploratory analysis of molecular characterization, will be presented. No significant financial relationships to disclose.
Regional differences in characteristics of patients referred to European sleep centers. Results from the European Sleep Apnea Database (ESADA)
Authors: Tarja Saaresranta, Marisa Bonsignore, Ludger Grote, Jan Hedner, Walter McNicholas, Josep Montserrat, Thomas Penzel, Martin Pretl, Renata Riha, Pawel Sliwinski, Jan Zielinski
Journal: European Respiratory Journal (2012)

The ESADA contains multiple information from patients with suspected OSA at 22 European sleep centers. We analyzed regional differences in characteristics of 5,103 patients. Centers were grouped into the following regions: NORTH (Forde, NOR – Gothenburg, SWE – Turku, FIN), SOUTH (Barcelona, Caceres, Lleida, ESP – Milan, Palermo, ITA – Haifa, ISR), EAST (Klaipeda, LTU – Kosice, SVK – Prague, CZE – Riga, LVA – Warsaw, POL), WEST (Dublin, IRL – Edinburgh, GBR) and CENTRAL (Antwerp, Brussels, BEL – Berlin, Giessen, GER – Paris, FRA).  Mean age was 51.8 (12.6) years in the cohort and females were slightly older than males. The highest and lowest prevalence of obesity (BMI>30) was found in the WEST and NORTH regions, respectively. The sleep study technique varied between regions, with the NORTH reporting more than 99% cardiorespiratory polygraphy compared with only 34% in the EAST. Sleep apnea severity varied between regions and the proportion of male patients with severe sleep apnea (AHI>30) was 23% in the NORTH compared with >40% in all other regions. Less than 50% of all patients reported severe daytime sleepiness (ESS>10); the highest ESS was found in patients in the WEST, the lowest scores in men in NORTH and women from EAST centers. Sleep length was 7.0 (1.8) hrs in women and 6.8 (1.6) hrs in men, and was shorter in the SOUTH compared with all other regions. No systematic regional differences were detected in frequency of comorbidities.  The data shows considerable regional differences between patients referred to European sleep centers, suggesting an influence of local referral patterns and/or phenotypic traits in Europe.
Survival study of RTA 744 (currently a single agent phase I study) alone and in combination with temozolomide in orthotopic model of glioma
Authors: C. A. Conrad, C. Meyer, T. Madden, W. Priebe, F. F. Lang
Journal: Journal of Clinical Oncology (2006)

1577 Background: Treatment for high-grade gliomas represents an area of significant unmet medical need, largely because few agents cross the blood-brain barrier (BBB). RTA 744744 (WP744, 4’-O-benzyldoxorubicin hydrochloride) is a potent topoisomerase II poison and novel anthracycline screened for its ability to circumvent P-gp and MRP1allowing it to cross the BBB. To assess the drug’s potential in gliomas, RTA 744 was tested alone or in combination with temozolomide in an intracranial xenograft model of glioblastoma multiforme (GBM). It was hypothesized that a DNA repair inhibitor such as RTA 744 would enhance the effects of temozolomide. In vitro cell based assays confirmed this hypothesis and led to in vivo testing of this novel combination. Methods: U87MG cells were implanted into the right basal ganglia of nu/nu mice via an implantable screw system. In all studies, groups of 5 or 6 mice received PBS, temozolomide, RTA 744, or the combination of RTA 744 and temozolomide administered IP. PBS and temozolomide were given on a QDx5 schedule, and several schedules were tested for RTA 744. The primary endpoint in these studies was survival. Results: In the single agent study, by day 33, all 5 of the control animals had died compared with just one of the RTA 744-treated animals. Median survival for control animals was 28 days versus 37 for RTA 744-treated animals (T/C=132%). In the combination study, median survival was 30 days for controls, 40 days for temozolomide alone (T/C=133%), and 48 days for animals receiving the optimal combination of RTA 744 and temozolomide (T/C=160%). One animal in the combination group survived to day 78, whereas no control or Temodar treated animals survived past days 32 and 45, respectively. Conclusions: RTA 744 demonstrated potent single agent activity in a rigorous preclinical model of GBM. The combination of RTA 744 and temozolomide produced survival results significantly better than those from any chemotherapeutics tested in this model. This data supports the current Phase 1 trial of RTA 744 in patients with brain tumors as well as future trials testing the combination of RTA 744 and temozolomide. [Table: see text]
A phase II study of pemetrexed (P) plus gemcitabine (G) in patients with recurrent or metastatic (R/M) head and neck squamous cell cancer (HNSCC).
Authors: D. G. Pfister, S. Haque, H. Stambuk, D. M. Lisa, R. Shen, D. Carlson, M. G. Fury
Journal: Journal of Clinical Oncology (2010)

5554 Background: Pemetrexed yielded an objective response rate of 26.5% in a phase II study for patients (pts) with locally advanced or metastatic HNSCC (Br J Ca 2001;85:649). Pemetrexed plus gemcitabine has demonstrated evidence of additive or synergistic antitumor effects in preclinical models, and encouraging efficacy against HNSCC (CCR 2008;14:6310) in a phase I study that evaluated an every two week schedule of these agents Methods: This was a single-institution, single-arm, open-label phase II study. Eligible pts had R/M HNSCC, Karnofsky score ≥70, and adequate hematologic, metabolic and renal function. No more than 2 prior cytotoxic regimens for R/M HNSCC were allowed. The study regimen was pemetrexed 500 mg/m2 intravenously (IV) plus gemcitabine 1,250 mg/m2 IV every two weeks, with vitamin B12 and folate support. Objective response rate by RECIST criteria was the primary endpoint (target response rate ≥30%); secondary endpoints were overall survival and safety/tolerability Results: 26 pts were enrolled: all had received prior radiotherapy; half prior cytotoxic chemotherapy for R/M disease. Among 25 pts who received therapy, there were no grade 5 events; ≥grade 3 toxicities occurring in >20% of pts included neutropenia (24%), lymphopenia (84% [64% grade 3]), and anemia (24%). The RECIST partial response (PR) rate was 16% (4/25); there were no complete responses. Five additional patients (20%) experienced objective tumor reductions of >20% but <30% (but <RECIST PR). Median overall survival was 8.8 months Conclusions: The outlined regimen of pemetrexed plus gemcitabine is feasible and has an acceptable side effect profile in pts with R/M HNSCC, but the observed response rate was less than our desired target. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Lilly
Invasive penile carcinoma: Are p16, p53 and HPV ISH prognostically significant?
Authors: Jasreman Dhillon, Anders E. Berglund, Julio Pow-Sang, Philippe E. Spiess, Anthony M. Magliocco
Journal: Journal of Clinical Oncology (2015)

394 Background: Penile carcinoma accounts for 0.4% to 0.6% of all malignancies in men. Due to its low incidence the prognostic role of clinicopathological characteristics, p16, p53 and HPV infection remains unclear. We report our experience with p16, p53 and HPV ISH (types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58 and 66) in determining the aggressive nature of this carcinoma. Methods: A tissue microarray (TMA) of 57 cases of invasive penile squamous cell carcinomas was immunohistochemically stained with immunohistochemical stains p16 and p53. HPV ISH was performed as well. The TMA slides were scored semi quantitatively by a specialized genitourinary surgical pathologist. The H score was calculated for p53 using a combination of staining intensity and extent according to the following formula: H score = 1 x % of tumor cells with weak staining + 2 x % of tumor cells with moderate staining + 3 x % of tumor cells with strong staining, resulting in a total score of 0 – 300. Calculations for p53 were done considering values above 0 as positive. For p16 and HPV ISH, the results were recorded as negative or positive. The overall survival curves for up to 60 months were estimated by Kaplan-Meier (KM) method. Results: HPV ISH was positive in 23 cases and p16 was positive in 23 cases as well. However, there were 9 discordant cases between the two (p16+/HPV ISH- = 5; p16-/HPV ISH+ = 4). p53 was positive in 39 cases. Tumors positive for HPV ISH had a better survival as compared to HPV ISH negative tumors (p = 0.0040; Hazard ratio 4.991). Whereas p16 (p = 0.206; Hazard ratio 1.838) and p53 (p = 0.1582; Hazard ratio 0.5198) were not significantly associated with survival at 60 months. Conclusions: Overall HPV positive penile carcinomas appear to have a distinct biology with better prognosis. There is no significant difference in survival for tumors with different p16 and p53 expression.
Gamma-Secretase, ErbB4 nuclear localization and neuregulin expression correlates with prostate cancer patient clinical outcome
Authors: I. Koumakpayi, C. Le Page, P. I. Karakiewicz, J. Diallo, L. Lessard, A. Mes-Masson, F. Saad
Journal: Journal of Clinical Oncology (2007)

10587 Background: Membrane protein ErbB4 is a member of ErbB growth factor receptor family, which can be activated by neuregulins (NRG). Upon neuregulin activation, ErbB4 is cleaved within its transmembrane domain by presenilin γ-secratase (PSN) to release an intracellular domain that translocates into the nucleus. Although, ErbB4 ligand-dependant translocation of ErbB4 to the nucleus and its nuclear activity has been reported in breast cancer cell lines, there are few reports concerning ErbB4 nuclear localization and its clinical relevance. Here, we report for the first time the clinical relevance of ErbB4 nuclear localization, NRG, and PSN expression in prostate cancer tissues. Methods: Immunostaining using anti-ErbB4, anti-PSN2 and anti-neuregulin antibodies was done on a set of tissue microarrays (TMA) from 140 patients. The TMAs contained, 92 cores of normal prostate tissue obtained from 46 autopsy specimens from young males, 373 tumor and normal adjacent cores from 63 hormone sensitive PCa (HSPCa) patients, and 146 cores from 31 hormone refractory PCa (HRPCa) patients. Results: We found a statistically significant increase (p&lt;0.01) in the percentage of ErbB4 nuclear localization (68.7% vs 53.2%), NRG expression (2.06 vs 1.41) and PSN2 expression (2.14 vs 1.53) when comparing cancerous tissues to normal tissue adjacent to cancer. Interestingly, a similar statistically significant increase in nuclear ErbB4 and NRG expression was observed when comparing HRPCa to HSPCa (p&lt;0.001). In cancerous tissues, a strong correlation was found between nuclear ErbB4 and NRG expression (r=0.672), between nuclear ErbB4 and PSN2 expression (r=0.51), and between PSN2 and NRG expression (r=0.71). Nuclear ErbB4 and PSN2 inversely correlated with tumor stage and lymph node invasion. Kaplan Meier analysis of nuclear ErbB4 (p=0.030) and PSN2 expression (p=0.018) showed an inverse association with biochemical recurrence (BCR) of PCa. In multivariate analyses including these three markers and clinical parameters, only nuclear ErbB4 retained an independent prognosis value. Conclusion: Our results suggest that high nuclear ErbB4 along with increased PSN2 expression have a protective effect against prostate cancer progression and BCR. No significant financial relationships to disclose.
Thymic malignancies (TM) in the United States: A population-based study of incidence and survival trends.
Authors: M. A. Gubens, C. Clément-Duchêne, H. A. Wakelee
Journal: Journal of Clinical Oncology (2010)

1606 Background: TM are rare, and there has been limited epidemiologic literature analyzing large population-based cohorts. Methods: We used data from the Surveillance, Epidemiology and End Results program, a large population-based registry, to examine TM incidence and survival trends in the United States from 1973-2006. We specified cases by site (thymus), histology (thymic carcinoma and thymoma), and behavior (malignant). Age-adjusted incidence rates were calculated. Survival was modeled by the Kaplan-Meier (K-M) method. We also developed a Cox proportional hazard model controlling for age, gender, race, date of diagnosis, stage, and histologic subtype. Results: The incidence of TM was 0.18 cases per 100,000 person-years and was higher in males (0.21 vs. 0.16, p < 0.001). Compared to whites, blacks and other races had higher incidence (0.15 vs. 0.27 and 0.38, p < 0.001). There was a trend toward increased incidence over time, with an annual increase of 2.5% (95% CI 1.9-3.1%). Females showed a trend toward superior survival on univariate analysis (90 vs. 79 mo, p = 0.104), and a significantly lower hazard ratio (HR) of death on multivariate analysis (0.82, p = 0.001). There was no significant difference in survival among whites, blacks, and other races (p = 0.242 by K-M, p = 0.246 by Cox). Stage correlated with survival (median 156, 90, and 34 mo for local, regional and distant disease respectively, p < 0.001). Thymic carcinoma showed a trend for higher mortality compared to thymoma with median survival 73 vs. 86 mo on univariate analysis (p = 0.124), and a significant difference on multivariate analysis (HR 1.51, p = 0.016). Over time there has been improvement in median survival by date of diagnosis (49, 80 and 99 mo for those diagnosed 1973-82, 1983-92 and 1993-2002 respectively, p < 0.001). Conclusions: This is the first population-based analysis of survival in US patients with TM of all stages over the duration of SEER follow-up, and updates an earlier seminal study of trends in incidence. Male gender, advanced stage disease, and thymic carcinoma histology portend significantly poorer survival. Plans underway for international collaboration in data collection should further refine our understanding of the epidemiology of this rare disease. No significant financial relationships to disclose.
Spatial distribution of veliparib measured by matrix-assisted laser desorption ionization mass spectrometry in triple-negative breast cancer tumors.
Authors: Imke Heleen Bartelink, Brendan Prideaux, Byron Hann, Gregor Krings, Jean-Philippe Coppe, Lamorna Brown Swigart, Evelyn Pei Rong Lee, Laura Esserman, Douglas Yee, Denise Wolf, Rada M. Savic
Journal: Journal of Clinical Oncology (2014)

161 Background: Veliparib is a potent inhibitor of the protein Poly(ADP-ribose) polymerase (PARP). Although effective, in the first clinical trials some TNBC patients fail to respond. We hypothesize that heterogeneous or insufficient drug concentrations in the solid tumor lead to inadequate response to PARPi in some TNBC patients. First we performed a mouse xenograft study to determine the penetration and distribution of veliparib in TNBC tumors in mice. Methods: MDA.MB.231 cells were injected bilaterally into mamamary fat pad of 10 Beige SCID mice. Veliparib (20mg/kg or 60mg/kg) or placebo was orally administered 3 times daily for 3 days. These doses and dosing schedules were estimated to result in equivalent plasma and tumor concentrations in mice compared to the doses currently used in clinical trials. Mice were euthanized 3 hours after the last dose of veliparib and tumors, liver and muscle tissues were obtained. In addition, control tissues were spiked with a broad range of concentrations of veliparib. The spatial distribution of the drugs in the tumor tissue was measured using Matrix-assisted laser desorption/ionization mass spectrometric imaging (MALDI). The protonated molecular ion at m/z245.1 was used to construct 2D ion maps of the tissue showing relative quantitation of drug levels. HE staining was performed to characterize the tumors. Results: Veliparib in control tissues was detected at very low concentrations with a range of detection between 100 fmol-1nmol. After dosing, veliparib penetrates into the tumors and was detectable at both dose levels. However, drug distribution within the tumors was observed to be inhomogeneous. In spots where the drug accumulated, necrosis was observed. Conclusions: Veliparib can be measured using MALDI with good specificity and sensitivity and using concentrations equivalent to patients. TNBC tumors show largely heterogeneous distribution of PARPi. Future analyses will determine whether this heterogeneity in drug distribution explains variability in response to PARPi therapies.
C-src: A potential target for the treatment of triple-negative breast cancer.
Authors: S. Walsh, D. Tryfonopoulos, C. Quinn, L. Flanagan, A. Pierce, E. McDermott, D. Evoy, N. O'Donovan, J. Crown, M. J. Duffy
Journal: Journal of Clinical Oncology (2010)

10617 Background: Triple-negative (TN) breast cancers are so-called as they lack expression ER and PR and overexpression of HER-2. Unlike other subgroups of patients with breast cancer, targeted therapy is currently unavailable for these patients. Consequently, the only systemic therapy for TN patients is chemotherapy. The aim of this study was to investigate the use of c-src as a potential target for the treatment of patients with TN breast cancer. Methods: Src immunoreactivity was determined using TMAs in 87 randomly-selected TN and 93 non-TN breast cancers diagnosed at St Vincent's Univ Hospital over the period 2002-2006. In vitro proliferation assays were performed to test combinations of dasatinib and cytotoxic drugs in breast cancer cell lines. Synergy analysis was performed using the Tchou and Talalay equation on CalcuSyn software. Results: 83/87 (95%) of TN cancers were positive for src compared to 78/93 (84%) of non-TN samples (p = 0.012, chi square test). Similarly, membrane staining for src was found more frequently in TN than in non-TN samples (74% vs 38%, p < 0.0001, chi square test). Using 9 different breast cancer cell lines in culture, dasatinib (an inhibitor of c-src) blocked growth in 3 out of 5 TN cell lines with IC50 < 1 μM (i.e, in MDA-MB-231, HCC-1143, HCC-1937) but in only 1 out of 4 HER2 amplified cell lines. Dasatinib combined with docetaxel displayed moderate synergy in MDA-MB-231 and HCC-1937 cells (CI < 0.9), but was antagonistic in HCC-1143 cells (CI > 1.1). Combined treatment with dasatinib and cisplatin was synergistic in the three dasatinib sensitive cell lines (CI < 0.9). In MDA-MB-231 and HCC-1143 cells, combined treatment with dasatinib and 5′-DFUR displayed synergy (CI < 0.9), whereas the combination was additive in HCC-1937 cells (CI = 0.98). Conclusions: We conclude that a combination of dasatinib and cisplatin is a potential new treatment for patients with TN-negative breast cancer. Acknowledgements: The authors wish to thank Science Foundation Ireland (08/SRC/B1410) and the Health Research Board (CSA/2007/1) for funding this work. No significant financial relationships to disclose.