tbuckley/cabot-search huggingface dataset:
Distribution of promoter hypermethylation in epithelial cells collected by endobronchial brushes of patients (pts) with non- small cell lung cancer (NSCLC) and controls
Authors: W. K. De Jong, J. Louwagie, A. Meunier, G. F. Verpooten, H. J. Groen
Journal: Journal of Clinical Oncology (2007)

18078 Background: Epigenetic gene silencing by promoter hypermethylation is an early event in NSCLC development. Exposure to tobacco smoke may explain random occurrence of hypermethylation events throughout the bronchial epithelium of pts with NSCLC. We assessed the methylation status of 11 genes in brushes sampled in 3 well-defined endobronchial locations in pts with NSCLC and in brushes of controls. Methods: In pts with NSCLC we collected bronchial brushes of 1) tumor, 2) normal appearing bronchus 2–3 cm proximally of tumor, and 3) main bronchus of contralateral lung. Also, we collected a brush of the normal appearing main bronchus of controls. Methylation status of RASSF1A, GATA4, GATA5, SFRP1, RARβ2, DAPK, MGMT, p16(INK4A), p14, CHFR, and APC was determined in all samples using quantitative methylation specific PCR. Genes were considered hypermethylated if the gene/actin ratio was higher than gene-specific cut-off values previously defined in NSCLC tissue (A). Alternatively, cut-off values were defined by ratios for which no hypermethylation was observed in controls (B). Results: Ten pts with NSCLC (5 adeno, 4 large cell, 1 neuro-endocrine carcinoma) and 24 controls (20 asthma, 4 COPD) were included. Median packyears of pts 32 (range 20–60), of controls 6 (0–70). Six pts had one or more hypermethylated genes in their tumor brush using cut-off A and eight pts using B. Hypermethylation of genes in proximal or contralateral locations was only observed if the same gene was also hypermethylated in tumor brush. No hypermethylation was observed controls. Total sensitivity was 60% (A) and increased to 80% in B, while specificity remained 100%. RASSF1A showed the highest single gene sensitivity (40%). Presence of hypermethylation in pts was not associated with number of packyears (p=0.61/0.53) or histological subtype (p=0.39/0.28) for cut-off A or B, respectively. Conclusions: Hypermethylation events were observed in up to 80% of bronchial tumor brushes of NSCLC pts. Hypermethylation comes from tumor cells and not from normal bronchial epithelium near or distant to the primary tumor. No significant financial relationships to disclose.
Dose-dependent pharmacokinetic (PK) interaction of pegylated liposomal doxorubicin (PLD) with escalating doses of veliparib in a phase I study.
Authors: Bhavana Pothuri, Franco Muggia, Joseph A. Sparano, Stephanie V. Blank, John Patrick Curtin, Ellen Chuang, Dawn L. Hershman, Alice Chen, Leonard Liebes
Journal: Journal of Clinical Oncology (2013)

2591 Background: PARP1 inhibition enhances the effects of DNA-damaging agents such as doxorubicin. We sought to investigate PK of PLD in a phase I study of veliparib (ABT-888, V) and PLD in patients (pts) with recurrent ovarian, fallopian tube, and primary peritoneal, and triple negative breast cancers. No prior PK interactions have been described in V clinical trials. Methods: Complete blood samples on day (D) 1 (pre-PLD and 1 hr post PLD), D 8, D 22 on cycle 1 and 2 of treatment in pts receiving PLD 40 mg/m2, day (D) 1 and V D1-14 at varying dose levels of 50,100,150, 200, 300, 350 mg twice daily, were collected in 25 of 31 pts enrolled to a previously reported dose finding phase I study of V and PLD (SGO2012). Plasma PLD levels were measured by HPLC methodology detailed by Gabizon et al Cancer Chemo Pharmacol 2008, 61:695. PK parameter estimates were obtained using non-linear modeling programs available in Winnonlin Ver 5.3. Affect of V dose on PK parameters was estimated with linear regression analysis. Due to a higher degree of GI toxicity with V dosages &gt; 200 mg, we utilized a cut-off of 200 mg for V. PK parameters in the group with dosages greater than or equal to 200 mg (high V, n=18) and those less than 200 mg (low V, n=7) were compared, utilizing an unpaired, 2 sided t-test. Results: PLD clearance (CL) was reduced, half-life (hL) was increased, and AUC/mg was increased with higher dosages of V when compared to historical published data. We noted a positive correlation of the auc/mg dose, p=0.001 and a negative correlation with the CL, p=0.001 and increasing V dose. When analyzed as low and high V groups, the mean ± SEM hL (hrs) was significantly lower in the low V when compared to the high V group, 83.2 ± 11.7 vs 108.6 ± 6.0(p =0.042) , and the mean PLD clearance (ml/h)was greater in the low V versus the high V group 35.9 ± 5.6 vs 14.2 + 1.0, P&lt;.0001. Similarly the AUC/mg dose (mg x h/L) was significantly lower in the low vs high V groups, 35.0 ±5.2 vs 74.9 ± 4.4, P&lt;0.0001. Conclusions: Higher exposure of PLD is noted with V at doses greater than or equal to 200 mg twice daily. An expansion cohort with patients receiving PLD alone in cycle 1, and PLD + V 200 mg twice daily in subsequent cycles, will validate the presence of a PK interaction. Clinical trial information: NCT01145430.
Is pancreaticoduodenectomy performed at a comprehensive community cancer center comparable to tertiary centers' results?
Authors: C. Cheng, D. Duppler, B. Koczon-Jaremko
Journal: Journal of Clinical Oncology (2011)

334 Background: We maintained a prospective database covering the period from 2001 to 2010. Outcome data are analyzed. We believe that the outcome achieved at a small cancer center is comparable to a tertiary cancer center. Methods: Our study measures the outcome of pancreaticoduodenectomy. Data were compared to the published literature. Results: There are 62 patients with histology-proven pancreatic cancer; ampullary adenocarcinoma and other histology types were included in the study. PPPD was performed in 41 patients. Twenty patients had classic PD. Three patients had portal venorrhaphy. Fifty patients had malignancy, whereas 11 had a benign histology. One case had dual histology (ductal carcinoma and neuroendocrine). The average age of patients was 63. Mean preoperative CA19-9 for exocrine pancreatic malignancies was 638, whereas for benign lesions and endocrine tumors it was 122. Average operative time is 6 hours 25 minutes for surgeries before 2005 and 5 hrs 48 minutes for surgeries performed after 2005. Blood transfusion was rare with 15 patients received blood product. There was one perioperative death due to ischemic bowel (4.3%). Average length of stay in the hospital was 15 days (range 0-87 days). There was no pancreatic leak among any of the patients. Two bile leaks were identified, one controlled with the drainage tube and the other one required repeat surgery. 30 days mortality rate was calculated at 10%. To date, 27 patients have died, with two from causes unrelated to carcinoma. Mean survival during our study period is 30.6 months. In comparison to published literature, the mortality, morbidity, and survival are similar. In the literature five year survival for pancreatic cancer patients treated with pancreaticoduodenectomy ranges from 10% to 29%. Conclusions: In our study 5-yr survival was 45%. Despite overall poor outcome for patients with pancreatic and biliary malignancies, surgery can be performed in community hospitals with special interest in treating pancreatic disorder, offering patients prolonged survival and quality of life. Pancreaticoduodenectomy is effective and safe with low hospital mortality and with acceptable complication rates. No significant financial relationships to disclose.
Primary tumor and patient characteristics in breast cancer as predictors of adjuvant chemotherapy regimen: A regression model
Authors: V. Francescutti, F. Farrokhyar, R. Tozer, B. Heller, P. Lovrics, G. Jansz, K. Kahnamoui
Journal: Journal of Clinical Oncology (2009)

e11632 Background: Adjuvant chemotherapy is used to reduce the risk of recurrence of breast cancer. This study was undertaken to determine which patient and tumor characteristics are important in guiding the choice of adjuvant chemotherapy. Methods: A retrospective review was undertaken of patients diagnosed with breast cancer (stages I-III) at a regional cancer center from 2004–7. Patient and tumor characteristics were identified and chemotherapy regimens compared. Binary logistic regression analysis was performed to the choice of FEC/D, CEF, AC/T, or ddAC/T against AC or CMF, or the choice of chemotherapy to hormonal therapy only. Univariate analysis was used to select factors (p&lt;0.1) for entry into a multivariate stepwise logistic regression model using the forward method. Odds ratios with 95% CI were calculated. A p-value of &lt; 0.05 was significant and comparisons were two tailed. Results: Model 1 (n=871) included regimen (AC or CMF vs. aggressive regimen) as the dependant variable. Indicators of choice of aggressive regimen were higher stage [OR 4.7 (CI 3.3, 6.8)], positive nodes [2.5 (1.6, 3.8)], negative PR [2.1 (1.4, 3.1)], higher grade [1.4 (1.0, 1.8)], and age [0.91 (0.88, 0.92)]. Model 2 (n=640) involved choice of any regimen (chemotherapy vs. hormonal therapy only) as the dependant variable. Indicators of choice of chemotherapy were higher stage [7.19 (2.8, 18.4)], higher grade [7.02 (3.3, 14.8)], positive nodes [3.25 (0.98, 10.77)], age [0.85 (0.81, 0.90)], and ER negativity [0.04 (0.004, 0.37)]. Factors not significant in both models were: family history, comorbidities (renal/hepatic dysfunction, diabetes, cardiac history, or neuropathy), treating medical oncologist, histology, Her2/neu, &gt; 3 positive nodes, ratio of positive to total nodes, multicentricity, multifocality, and positive margin status. Conclusions: This study verifies known important factors for choice of chemotherapy regimen as found in current guidelines, quantifies their effects at our center, and excludes others thought to be important. Further studies are required to confirm these results both nationally and internationally, where risk stratification may be different, and if variables predicting adjuvant radiation therapy are similar. No significant financial relationships to disclose.
Breast cancer survival in carriers of BRCA1 and BRCA2 mutations
Authors: G. Rennert, S. Bisland, N. Bar Joseph, S. Zhang, H. S. Rennert, O. Barnett-Griness, S. A. Narod
Journal: Journal of Clinical Oncology (2007)

10552 Background: The characteristic pathologic features of breast cancers in women with a BRCA1 mutation suggest that women with hereditary breast cancer might have a worse than expected prognosis, but the results of clinical studies have been inconsistent. The current study is a national population-based study of Israeli women aimed at evaluating the impact of the inheritance of a BRCA1 or a BRCA2 mutation on breast cancer prognosis. Methods: All incident cases of invasive breast cancer diagnosed in Israel from January 1, 1987 to December 31, 1988 were identified. Paraffin-embedded tumor blocks or unstained slides and pathology and oncology records were requested for all patients. DNA was extracted from each paraffin block and was analyzed for three founder Jewish mutations in BRCA1 and BRCA2. Of 2,514 diagnosed cases, a pathology sample was retrieved from 1,794 (71.4%) and the medical record was retrieved for 1,545 of these (86.1%). Results: A BRCA1 or BRCA2 mutation was identified in 10% of Ashkenazi women with breast cancer, including 18% of women diagnosed below the age of 50. The adjusted hazard ratio for breast cancer-specific survival was not different for non-carriers and carriers of a BRCA1 (HR = 0.8, 95% CI: 0.5 - 1.3, p = 0.3) or BRCA2 (HR = 1.3, 95% CI: 0.8 - 2.2, p = 0.3) mutation. Among women who were treated with CMF/CAF chemotherapy, BRCA1 carriers experienced better survival than non-carriers (HR = 0.5; 95% CI 0.2–1.2) but the difference did not reach statistical significance (p = 0.1). Tumor size (&gt;2 cm) was a significant predictor of breast cancer specific mortality in non-carriers (HR = 2.8; 95%CI: 2.2 to 3.5) but not in BRCA1 carriers (HR = 1.1; 95% CI 0.5 to 2.8). ER status also did not play a significant predictive role in survival of carriers. Conclusions: Compared to non-carriers, women with breast cancer who carry a founder Jewish mutation in one of the BRCA genes experience similar or possibly even lower breast cancer-specific mortality rate, in spite of a bad profile of prognostic factors. No significant financial relationships to disclose.
bcl-2 protein expression in primary cutaneous large B-cell lymphoma is site-related.
Authors: F A Geelen, M H Vermeer, C J Meijer, S C Van der Putte, E Kerkhof, P M Kluin, R Willemze
Journal: Journal of Clinical Oncology (1998)

Primary cutaneous large B-cell lymphoma (PCLBCL) that presents on the leg has recently been recognized as a distinct disease entity. These lymphomas have a reduced disease-free survival and a worse prognosis as compared with the more common, morphologically similar PCLBCL that present on the head or trunk. Studies in noncutaneous diffuse large B-cell lymphomas suggest a relationship between the expression of bcl-2 protein and clinical behavior. In the present study, we investigated whether these two groups of PCLBCL differ in the expression of bcl-2 protein and the presence of t(4;18), known as one of the causes of bcl-2 overexpression.Paraffin sections from pretreatment biopsies of 14 PCLBCLs of the head or trunk and nine PCLBCLs of the legs were investigated for expression of bcl-2 protein using immunohistochemistry, and for the presence of the 14;18 translocation using polymerase chain reaction (PCR) amplification with primers against both the major breakpoint region (mbr) and the minor cluster region (mcr) of bcl-2. For reasons of comparison, nine secondary cutaneous large B-cell lymphomas (SCLBCLs) were also studied.Expression of bcl-2 protein was found in all nine PCLBCLs of the leg and in all nine SCLBCLs, but not in any of the 14 PCLBCLs on the head and trunk. The t(14;18) was only detected in two of seven SCLBCLs, but not in the five PCLBCLs of the leg or the eight PCLBCLs on the head or trunk studied.The striking differences in bcl-2 expression between PCLBCL of the head or trunk and PCLBCL on the leg suggest that bcl-2 expression is site-related and may contribute to the different clinical behavior between these two groups of lymphomas. In addition, they underscore that PCLBCL on the head and trunk and PCLBCL on the leg are distinct disease entities, as recently recognized in the European Organization for Research and Treatment of Cancer (EORTC) classification for primary cutaneous lymphomas.
Response of relapsed/refractory diffuse large B-cell lymphoma (DLBCL) with nongerminal center B-cell phenotype to lenalidomide (L) alone or in combination with rituximab (R).
Authors: F. J. Hernandez-Ilizaliturri, G. Deeb, P. L. Zinzani, S. A. Pileri, F. Malik, W. R. Macon, T. E. Witzig, A. Goy, M. S. Czuczman
Journal: Journal of Clinical Oncology (2010)

8038 Background: Novel salvage therapies for relapsed/refractory (r/r) DLBCL and the identification of specific biomarkers predictive of response to a specific therapy are needed. L has an overall response rate (ORR) of 28% in r/r DLBCL. Methods: We retrospectively evaluated differences in clinical outcomes for germinal center B-cell (GCB)-like vs non-GCB-like DLBCL patients treated with salvage L alone (RPCI) or L+R (DHOS-S). We are augmenting the current database with pathology specimens from r/r DLBCL patients treated with L monotherapy at the Mayo Clinic and Hackensack Cancer Center. The initial data set from RPCI included 18 patients with r/r large cell lymphoma: 8M/10F; median age: 64 yrs; median 4 prior treatments. Patients were classified as GCB (n=9) or non-GCB (n=9) using the Hans criteria. Differences in overall response rate (ORR), CR or PR rates, progression-free survival (PFS), and overall survival (OS) were compared between GCB and non-GCB DLBCL. Results: No differences in stage, international prognostic index (IPI) score, prior number of treatments, were noted between the two groups. A significant difference in clinical response to L was observed: ORR was 77% for non-GCB patients vs 11% for GCB patients (P=0.011); and 44% of non- GCB patients achieved a CR vs 11% of patients with the GCB phenotype. PFS for patients with the non-GCB subtype was 336 days vs 72 days for patients with the GCB subtype (P=0.008). Although, median OS for the non-GCB subgroup was 420+ days compared with 73 days for GCB patients, it did not reach statistical significance (P=0.4). In a separate analysis, an additional 8 patients with r/r DLBCL (all non-GCB subtype), treated at the DHOS-S with L+R, achieved an ORR of 50%. This appears to be favorable relative to historical controls. Conclusions: Our data suggests that these two subgroups of patients with DLBCL (i.e. GCB vs non-GCB) appear to have a significantly different response to L in the r/r setting. Results from the analysis of the expanded data set are anticipated in time for the congress, and a large international trial is in development in an attempt to prospectively validate our findings. No significant financial relationships to disclose.
Press: Doctors as gods
Authors: C. Dyer
Journal: BMJ (1999)

The BMA is the envy of other professional trade unions for its headline grabbing powers. The Law Society, the solicitors' professional body, produces worthy tracts—what's wrong with the law in this subject, ethics guides for solicitors in that subject—but its strike rate in the media comes nowhere near the BMA's. Perhaps lawyers are thought to have their own interests too much at heart. With doctors, there's no obvious link with money so they must be motivated by their patients' interests, mustn't they?

But wait a minute, what about that other corrupting motivator—power? Power, in this case, over life and death. Maybe doctors want to be God. That seemed to be the thought behind much of the media coverage of last week's guidance from the BMA ethics committee on withholding and withdrawing life-prolonging medical treatment. The BMA was giving doctors new powers to take life or death decisions, proclaimed the headlines, or doctors were taking the powers for themselves. “More life and death powers for doctors,” said the Daily Mail 's headline, over a news story which began: “Doctors were effectively given greater powers yesterday to end the …
A phase II trial of gemcitabine and carboplatin (GC) in patients with transitional cell carcinoma of the urinary tract (TCC)
Authors: J. Olivares, W. Hyman, N. Senzer
Journal: Journal of Clinical Oncology (2004)

4590 Background: Recent studies have demonstrated the effectiveness of cisplatin (CP) based combinations in patients with TCC. Concern over CP toxicity instigated a search for alternative regimens. This study assesses the activity and tolerability of the GC combination in patients with advanced and metastatic TCC. Methods: Chemonaive patients with locally advanced/metastatic TCC not amenable to curative surgery or radiotherapy with adequate organ function (including creatinine <1.5 mg/dL and calculated creatine clearance of >40 mL/min) and Karnofsky performance status (KPS) 70 or greater received G 1200 mg/m2 day 1 and 8 plus C AUC 5 on day 1 every 21 days for 6 cycles or 6 cycles beyond SD, PR, or CR to maximum of 10 cycles. Results: 50 patients have been enrolled into the study and evaluable for response and toxicity. Patient characteristics include: median age 69 years (range 39–79); 34 men:16 women; stage II in 3, stage III in 19, stage IV in 28; KPS 60–70 in 9 and 80–100 in 41 (72%); high risk group (KPS <80 or bone/visceral metastases) in 9 and standard risk in 41. Grades 3/4 toxicity was predominantly hematologic; of 296 cycles 21 episodes (7%) of neutropenia, 10 (3.4%) of thrombocytopenia, and 9 (3%) of anemia. Grades 3/4 non-hematologic toxicity included 3 episodes each of asthenia, hematuria, dyspnea, and superficial thrombophlebitis. There were 8 CR (16%) and 20 PR (40%) for an overall response rate of 56%. Nine patients (18%) achieved SD. Time to progression was 344 days (404 days standard vs. 316 days high-risk group, p=0.1). Median survival was 343 days (range 295–465), 377 days standard risk vs. 205 days high-risk group (p=0.02). Conclusions: Combination GC in patients with TCC exhibits an acceptable toxicity profile and produces response rates at least comparable to CP based combinations. On the basis of this and other studies, comparative trials with other regimens stratifying for risk factors are warranted. No significant financial relationships to disclose.
Abstract 20267: Bipotency of Late Cardiac Progenitors; a Possible Role of the Plasticity of Isl1/SLN Atrial Progenitors in Boundary Formation in Cardiac Inflow Tract via Myocardin-dependent Pathway
Authors: Haruko Nakano, Estrelaia S Williams, Masahiko Hoshijima, Susumu Minamisawa, Kenneth R Chien, Gary K Owens, Atsushi Nakano
Journal: Circulation (2010)

The cardiac chambers and great vessels form smooth transition at the arterial and venous pole of the heart tube and establish a functional syncytium to facilitate the dynamism of circulatory system...
Retrospective analysis of cutaneous T-cell lymphoma (CTCL) biopsy samples for interleukin-2 receptor (IL2-R) subunit expression by immunohistochemistry (IHC) and real-time quantitative PCR (RT-PCR): Correlation to response to denileukin diftitox
Authors: V. J. Alexander, R. P. Bissonnette, J. I. Rosen, T. Cooke, F. M. Foss
Journal: Journal of Clinical Oncology (2006)

20080 Background: Denileukin diftitox, a chimeric diphtheria toxin-IL2 protein, exerts its cytotoxic effect on cells expressing high or intermediate affinity IL2-R. IL2-R is a complex of 3 distinct polypeptide chains: IL2-Rα (CD25), IL2-Rβ (CD122), and IL2-Rγ (CD132). IL2-R α/β/γ heterotrimer binds with high affinity, IL2-R β/γ with intermediate affinity, and IL2-R α/γ with low affinity. Denileukin diftitox is indicated for patients with persistent or recurrent CTCL whose malignant cells express IL2-Rα protein. There is no currently available methodology to measure expression of the high affinity receptor in patient samples. This study was initiated to discover a correlation between expression of IL2-R components (at the mRNA and protein levels) and clinical response to denileukin diftitox. Methods: Of 33 available frozen clinical CTCL biopsy samples, 27 (10 responders) were sufficient for IHC. IL2-Rβ staining intensity was assigned a value of 0 (no staining relative to background), 1+ (weak), 2+ (moderate), or 3+ (strong). 22 samples (8 responders) were sufficient for RT-PCR. mRNA levels of the 3 IL2-R chains were normalized to 36B4 mRNA or 18S rRNA. Correlation between clinical response and IL2-R chain expression was assessed using Spotfire Decision Site. Results: The population of samples tested was representative of the study population. 26 of 27 samples exhibited 2+, all exhibited 1+, and none 3+ IL2-Rβ staining. The percentage of cells stained varied from 20%–90% for 1+ and 10%–80% for 2+ with no correlation to response. Correlation of levels of individual IL2-R subunit mRNA expression with response could not be established. Conclusions: Neither the IL2-Rβ IHC nor the RT-PCR assay, at current sensitivity levels, appear to identify denileukin diftitox responders. Larger sample datasets from current studies, and further assay refinement, are ongoing to define the merits of these approaches. [Table: see text]