tbuckley/cabot-search huggingface dataset:
Prognostic and predictive effect of microsatellite instability (MSI) in MAGIC.
Authors: Elizabeth Catherine Smyth, Sanna Hulkki Wilson, Matthew Guy Nankivell, David Gonzalez de Castro, Andrew Wotherspoon, Alicia Frances Clare Okines, Ruth E Langley, Sally Patricia Stenning, David Cunningham
Journal: Journal of Clinical Oncology (2015)

62 Background: MSI is prognostic for survival in diverse cancers and predicts resistance to fluoropyrimidine chemotherapy in colon cancer. We examined the interaction between MSI and patient (pt) characteristics and survival for pts randomised to surgery alone or perioperative ECF chemotherapy in the MRC MAGIC trial. Methods: Tumor and normal control DNA was extracted from resection FFPE. MSI status was determined using the Promega MSI Analysis System (NR-21, BAT-26, BAT-25, NR-24, MONO-27). Tumors were classified as MSS when all markers were stable, MSI-L when only one marker was unstable and MSI-H with minimum of instability in two markers. MSI status was correlated with pt characteristics and survival. Results: MSI results were available for 303 pts (66% resected pts). Twenty (6.6%) and 2 (0.6%) pts were MSI-H and MSI-L. All pts with MSI-H had stomach tumors (vs.GEJ/esophagus). KRAS mutation was more common in MSI-H tumours (30% vs. 4%, p-value &lt;0.001); rates of BRAF, PIK3CA and TP53 mutations were comparable. Median overall survival (OS) from surgery was greater for pts with MSI-H tumours treated with surgery alone (1.69y for MSS vs. not reached for MSI-H) (Table 1), whereas patients with MSI-H tumors treated with chemotherapy plus surgery had inferior outcomes compared to MSS stable pts (median OS 0.8y vs. 1.89y respectively). An interaction test for MSI-H vs. MSS status and treatment arm was positive (p=0.007). Conclusions: In MAGIC, MSI-H status is associated with a positive prognostic effect in pts treated with surgery alone, and a negative predictive effect in pts treated with chemotherapy. As pt selection biomarkers for perioperative chemotherapy are lacking, validation of this finding in an independent dataset is warranted. [Table: see text]
Prostate cancer management: Racial disparities in the United States.
Authors: Omar Al Dhaybi, Peter T. Silberstein
Journal: Journal of Clinical Oncology (2013)

e16012 Background: Racial disparities in prostate cancer management have been reported. Black patients with well–differentiated disease were less likely to receive definitive therapy than whites with similar disease according to Underwood et. al., who included 142,340 patients from the Surveillance, Epidemiology and End Result (SEER) registry (J Urol, Vol. 171, 1504 – 1507, April 2004). Our objective was to identify racial disparities in the management of prostate cancer patients from the National Cancer Database. Methods: Prostate cancer treatment according to race in the USA, obtained from the National Cancer Database, was retrospectively reviewed. 1,497,540 patients with prostate cancer in 1397 US teaching and community hospitals between 2000 and 2010 were included. Chi square and Fisher tests were used for statistical analysis. Results: Black patients with stage II disease underwent radical prostatectomy significantly less than white patients (34.3% versus 43%, p&lt;0.05). 10.9% of blacks with stage II disease did not receive any therapy, versus 6.7% of whites (p&lt;0.05). 0.9% of whites with stage III disease didn’t receive any therapy versus 2% of blacks (p&lt;0.05). The disparity was even more accentuated for stage IV disease, where 13.4% of blacks did not receive any form of treatment versus 10.3% of whites (p&lt;0.05). 44% of blacks with localized disease (stage I and II) received radiation therapy, 34% received surgery. Blacks were less likely to receive radical prostatectomy for stage I and II disease compared to whites (34% versus 43%, p&lt;0.05). Stage IV disease at presentation was more common in blacks (7.2%) than in whites (4.7%, p&lt;0.05). Conclusions: This is the largest study which has analyzed ethnicity and prostate cancer management. Significant racial disparities exist in prostate cancer management between whites and blacks in the USA. Our study reveals that blacks are more likely to receive radiation therapy and less likely to get radical prostatectomy for stage I and II disease. A higher percentage of black patients with stage II, III or IV disease do not undergo any treatment as compared to whites. Blacks are also more likely to present with stage IV disease.
Association of germ-line genetic variation in the NK3 homeobox 1 gene with overall survival in advanced-stage castrate-resistant prostate cancer (CRPC).
Authors: Manish Kohli, Shannon McDonnell, Graham Bevan, Shaun M. Riska, Brian Addis Costello, Sherri Longenbach, Roxana Stefania Dronca, Timothy Jerome Moynihan, Henry Clement Pitot, Fernando Quevedo, James Robert Cerhan
Journal: Journal of Clinical Oncology (2013)

75 Background: We investigated the association of germline variation in ten candidate genes important in prostate cancer biology (NKX3-1, JAK2, SLCO2B1, STAT3, CYP19A1, HSD17B4, TRMT11, PRMT3, HSD17B12, NCOA4) with overall survival (OS) in a cohort of metastatic CRPC stage patients. Methods: Patients (N=497) were enrolled at the time of androgen deprivation therapy failure for D2 stage prostate cancer. Candidate genes were selected from the literature and pilot studies. Genes were tagged using SNPs from HapMap with minor allele frequency (MAF) of &gt;5% and r 2 ≥0.8. DNA was extracted from peripheral blood and genotyped using Illumina Veracode platform. The primary endpoint was OS, defined as time from development of CRPC to death. Principle components analysis was used for gene-levels tests. To account for multiple testing we calculated the false discovery rate (FDR). For SNP level results we estimated per allele (ordinal model) hazard ratios (HR) and 95% confidence intervals (CI) using Cox regression and adjusted for age and Gleason score (GS). Results: We successfully genotyped 60 SNPs (from 10 genes) in 497 Caucasian subjects. The median age of the CRPC cohort was 71 years (range 43,93). The GS distribution was 51% subjects with GS≥8; 32% with GS7 and 17% with GS&lt;7. After a median follow up of 2.1 years (IQ range: 1.2-3.6), 297 subjects had died. In unadjusted gene level analyses, NKX3-1 (p=0.04; FDR=0.03) was associated with OS. After adjusting for age and GS the result remained significant (p=0.03). Two of the 5 genotyped SNPs in this gene were associated with OS after adjustment for age and GS: rs10503733 (dominant model p=0.03, HR=0.77; 95 CI=0.60-0.98; A&gt;C; MAF = 0.22) and rs7005368 (dominant model p=0.05, HR=1.38, 95CI=1.0-1.92; G&gt;A; MAF=0.07). Both SNPs are in Hardy Weinberg Equilibrium and in complete LD (D ' =1), although r 2 is low (r 2 =0.025) due to different allele frequencies. Conclusions: Variation in the homeobox NKX-1 gene, a prostate specific tumor suppressor gene involved in prostate development and carcinogenesis is significantly associated with OS in CRPC after accounting for age and GS. Further validation is needed to develop these as prognostic biomarkers.
Genomic characterization of metastatic urothelial carcinoma.
Authors: Richard M. Bambury, Markus Riester, Joaquim Bellmunt, Edward C. Stack, Lillian Werner, Rachel Park, Gopa Iyer, Massimo Loda, Philip W. Kantoff, Franziska Michor, Jonathan E. Rosenberg
Journal: Journal of Clinical Oncology (2013)

247 Background: The genetic profile of primary urothelial carcinoma (UC) has been well documented but no reports analyze specific chromosomal alterations in metastatic disease. We performed molecular inversion probe array (MIP) analysis to compare chromosomal gains or losses in metastatic and primary UC samples. Methods: 33 samples of metastatic UC and 30 primary samples were analyzed from 48 patients (pts), of which paired primary and metastatic tissue was available for 14 pts. DNA from all samples was subjected to molecular inversion probe array analysis to identify focal areas of copy number gain (CNG) or loss (CNL). We focused this analysis on 21 genes from signaling pathways known to be of interest in UC (Table). CNG or CNL was defined as a log2 copy number ratio ≥ 0.8 or ≤ -0.8. GISTIC 2.0 was used to identify significantly altered regions. Results: In the loci analyzed, there were significantly more alterations in metastases than primary samples (8.4% vs 4.3% p=0.002). In particular, there was a significantly higher frequency of E2F3CNG in metastases (27% vs 7% p=0.046). There was frequent discordance in alterations when comparing primary and metastatic tissue from the same patients: 7 of 14 pts harbored potentially oncogenic CNG/CNL in their metastases that were not present in the primary. Conclusions: More alterations in UC-relevant genes were identified in metastases compared with primary tumors, in keeping with the multistep model of cumulative genetic change in cancer progression. More frequent CNG of the E2F3 gene was noted and may represent a mechanism of UC progression. Frequent discordance in alterations between primaries and metastases may be of significant clinical relevance in the future when selecting patients for appropriate molecularly targeted therapy. [Table: see text]
The role of pharmacokinetic (PK) modeling and simulations in selecting anti-SEMA4D antibody dose for phase I study in patients with advanced malignancies.
Authors: A. F. Nasser, B. Budda, C. A. Cornelius, T. Fisher, L. A. Winter, J. E. Leonard
Journal: Journal of Clinical Oncology (2011)

e13072 Background: VX15/2503 is a humanized IgG4 monoclonal antibody that binds specifically to the SEMA4D antigen, an important mediator of angiogenesis. PK in rats and primates followed nonlinear kinetics with half life increasing with dose. A phase I clinical study, sponsored by Vaccinex, Inc. will determine the MTD after single and multiple doses in patients with advanced malignancies. Exploratory modeling and simulations were completed using single-dose primate PK data to support that the predicted human exposures for the selected doses remain under the maximum primate exposures. Methods: Compartmental PK modeling using Phoenix (V6.1, Pharsight) software was performed with primate VX15/2503 PK data obtained from animals administered single IV doses of 0.01-100 mg/kg. The derived parameters from the model were escalated to human using allometric scaling. The model was used to predict VX15/2503 human levels from the planned doses (2-hours IV infusion of 0.3-15 mg/kg/week) in the phase I study. Results: Several PK models (1, 2, and 3 compartmental model) were developed; however, the 2-compartment model with target mediated disposition best described the data as determined by the goodness of fit criteria (e.g. Akaike Information Criterion). Model predictions showed that the VX15/2503 human total exposures (AUC0-τ) following the planned multiple doses ranging from 0.3 to 15 mg/kg/week were 627 to 83559 mcg*hr/mL. The maximum total exposure observed in primate was 702740 mcg*hr/mL. Conclusions: A two compartment model with target mediated disposition best described the primate single dose PK data. The predicted human exposure from the model simulation of the highest planned phase I dose (15 mg/kg/week) was below maximum primate exposure levels. Observed phase I PK data will be compared to the model predictions.
An evaluation of phosphorylated EGFR expression in predicting outcome of EGFR-TKI therapy for the advanced NSCLC patients with EGFR wild type.
Authors: F. Wang, J. Wang, H. Bai, J. Zhao, Z. Wang, M. Zhuo, T. An, J. Duan, L. Yang, M. Wu, Y. Wang, S. Wang, X. Liu
Journal: Journal of Clinical Oncology (2011)

7532 Background: EGFR mutation is a strong predict factor of response and PFS to EGFR-TKI. However,at least 18% of patients with EGFR wild type are susceptible to TKIs, suggesting that might exist other mechanisms besides EGFR mutation. Here,we hypothesize that the activation (phosphorylation) of EGFR could be a potential predictive biomarkers to EGFR-TKI treatment among patients in absence of EGFR mutations. Methods: Total of 244 stage IIIb and IV NSCLC pts who had the tissue samples available for the molecular analysis were included in this study. 208 out of 244 patients received EGFR-TKI as first-or second-line therapy. the phosphorylated EGFR at tyrosine 1068 (pTyr1068) and 1173 (pTyr1173) were assessed by immunohistochemistry, and EGFR mutation were detected by denaturing high performance liquid chromatograph (DHPLC). Results: The median follow-up time of the patients was 9.4 months (range 0.4 to 77.2 months). Of the 242 patients assessable for mutation and phosphorylated EGFR expression detection, 102 (42%) were positive for EGFR mutation, and 80.2% and 57.1% of patients had pTyr1068 and pTyr1173 expressions, respectively. No significant relationship between expressions of pTyr1173 or pTyr1068 and EGFR mutation was observed. The patients with EGFR mutation had prolonged PFS than those without EGFR mutation (median PFS 9.1 ms vs 3.1 ms; P=0.024). Superior PFS for EGFR TKIs in patients with pTyr1068 expression positive was seen (median PFS 7.4 ms vs 1.3 ms; P<0.001 ). There appeared a negative correlation between pTyr1173 expression and clinical outcomes of EGFR-TKI (median PFS 4.7 ms vs 7.8 ms; P=0.009). Interestingly, in the subgroup patients with EGFR wild type, phosphorylated pTyr1068 expression predicted prolonged PFS (median PFS 5.2 ms vs 1.2 ms; P<0.001) and elevated DCR (71.6% vs 37.5%; P=0.001). Conclusions: This study provides strong evidences to suggest that phosphorylated Tyr1068 of EGFR may be an promising pridictive biomarker for screening superior population in EGFR TKIs treatment, especially in EGFR mutation negative NSCLC. A prospective, multicenter study should be performed to validate the ﬁndings.
Comparison of Outcomes of Bone Marrow and Umbilical Cord Blood Transplants from Unrelated Donors in Adult Patients with Acute Myeloid Leukemia/Myelodysplastic Syndrome.
Authors: Kazuhiro Masuoka, Shigesaburo Miyakoshi, Kazuya Ishiwata, Masanori Tsuji, Shinsuke Takagi, Hisashi Yamamoto, Daisuke Kato, Keiko Matsuhashi, Sachiko Seo, Naofumi Matsuno, Naoyuki Uchida, Atsushi Wake, Akiko Yoneyama, Shuichi Taniguchi
Journal: Blood (2007)
A completed phase I trial of 13-cis retinoic acid, alpha interferon, docetaxel, and estramustine (R.I.T.E.) for the treatment of hormone refractory prostate cancer (HRPC) and other advanced malignancies and effect on BCL-2 expression
Authors: M. N. Stein, M. B. Todd, R. A. Morton, S. Doyle-Lindrud, S. Goodin, A. Shah, W. Shih, V. Garikapaty, D. Dvorzhinski, R. S. Dipaola
Journal: Journal of Clinical Oncology (2005)

4740 Background: To test the hypothesis that 13-cis retinoic acid (R) and interferon alpha (I), which have been shown to decrease the expression of Bcl-2, are capable of improving the results of standard chemotherapy with docetaxel (T) and estramustine (E), we conducted a phase I study in patients (pts) with HRPC and other advanced malignancies. Methods: Pts received retinoic acid 1 mg/kg and interferon 6 million units/m2 on days 1–4, estramustine 280mg, orally tid on days 1–5, with escalating doses of docetaxel (0, 40, 50, 60 mg/m2) on day 2. Ttreatment was repeated every 21 days. Each pt had peripheral blood mononuclear cells (PBMCs) obtained prior to therapy and on days 1–4 of cycle 1 to assess the effect of therapy on Bcl-2 by immunoblot. Results: Sixteen pts (HRPC-13, larynx-1, colon-1, ovarian-1) with mean age of 67 were enrolled. Of the 13 pts with HRPC, nine had prior chemotherapy (seven pts had ≥ 2 prior chemotherapy regimens and eight pts had prior docetaxel). Of the 3 pts with non-prostate solid tumors, 2 had received prior paclitaxel. The mean number of cycles administered was 5.2 (range 2–10), with 2 pts in cohort 2 continuing to receive treatment. Therapy was well tolerated on this study. Grade 3 fatigue occurred during the first cycle in two pts in cohort 3 and one pt in cohort 4, defining a DLT, and occurred in 3 pts after cycle 1. Fatigue resolved with interferon dose reduction per protocol. Of 13 pts with HRPC, 4 pts had a response of a >50% reduction in PSA. Five additional pts had confirmed stable disease over a median of 5 cycles and 2 pts continue on therapy. All pts with non-prostate solid tumors progressed on therapy. In 11 evaluable pts, the ratio of BCL-2 to actin in PBMCs was significantly decreased on days 2–4 of therapy, compared to baseline (p<0.05 via signed rank test). Conclusions: R.I.T.E. therapy was well tolerated and active in HRPC. The MTD of taxotere is 40mg/2. The R.I.T.E. regimen significantly downregulates PBMC Bcl-2 expression. These data support further studies to determine the activity of this regimen and to determine the validity of PBMC BCL-2 as a marker of drug effect. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Aventis
Changes in HER2 status after neoadjuvant treatment of breast cancer.
Authors: H. Skalova, P. Dundr, C. Povysil, O. Pribylova, L. B. Petruzelka, D. Tvrdik
Journal: Journal of Clinical Oncology (2011)

e11110 Background: Her2/neu proto-oncogene amplification and protein overexpression is observed in 20 - 40% of patients with breast cancer and play a crucial role in invasive breast cancer disease and its treatment. Number of studies have postulated the stability of Her2/neu gene expression, showing that in most patients the status of expression was not significantly changed after neoadjuvant treatment. Methods: In the present study, we investigated samples from 20 patients with invasive breast carcinoma, who underwent neoadjuvant chemotherapy and subsequent surgery. In all cases, the expression level of Her2/neu was evaluated both in pre- therapeutically obtained tumor tissue by core needle biopsy and in speciemen removed by final surgery, using immunohistochemistry (IHC). Fluorescence in situ hybridization (FISH) and quantitative reverse transcription polymerase chain reaction (qRT-PCR) methods were used for verification of the results obtained by IHC. Results: In the present study, Her2/neu status determined by immunohistochemistry remained unchanged in 12 of 20 (60%) patients after neoadjuvant treatment. In six cases (30%) minor changes was observed due to the treatment. However, in two cases (10%) we found Her2/neu expression alteration from strongly positive in pre-treatment biopsy to negative in post-treatment surgery specimen. Conclusions: This is the first report which describes the changes in Her2/neu status on all protein, RNA and DNA levels by using immunohistochemistry (IHC), quantitative reverse transcription polymerase chain reaction (qRT-PCR) and fluorescence in situ hybridization (FISH), respectively. This work was supported by Grant IGA MZ CR NS/10575-3.
Clinical relevance of pulmonary amyloidosis: an analysis of 76 autopsy-derived cases
Authors: Kamonpun Ussavarungsi, Eunhee S. Yi, Joseph J. Maleszewski, Paul J. Kurtin, Surenda Dasari, Jason D. Theis, Angela Dispenzieri, Jay H. Ryu
Journal: European Respiratory Journal (2017)

Amyloidosis refers to a group of diseases characterised by the extracellular tissue deposition of insoluble misfolded proteins that disrupt the function of the involved organs [1]. The principal types of systemic amyloidosis include immunoglobulin light-chain amyloidosis (AL) due to an underlying monoclonal B-lymphocyte/plasma cell disorder, serum amyloid A amyloidosis (AA) due to chronic inflammatory diseases, and transthyretin amyloidosis (ATTR) from variations (mutations) in the transthyretin gene (mut-ATTR) or acquired form, i.e. wild-type ATTR (wt-ATTR) [1]. Pulmonary involvement was common in amyloidosis but was not the immediate cause of death in most of these patients <http://ow.ly/WK3N307cbE6>
Long-term survival (S) of induction chemotherapy (CTx) with three cycles cisplatin (cis)/paclitaxel (pac) followed by concurrent (cc) chemoradiation (CTx/RTx) cis/etoposide (eto) and 45 Gy (1.5 Gy bid) plus surgery (SURG): Phase II results (CISTAXOL).
Authors: W. E. E. Eberhardt, T. C. Gauler, C. Le Pechoux, R. Hepp, S. Welter, B. Fischer, S. Bildat, D. Grunenwald, G. Stamatis, M. Stuschke, C. Poettgen
Journal: Journal of Clinical Oncology (2011)

7047 Background: CTx/RTx followed by SURG remains possible treatment (Tx) for pts with stage IIIA(N2) NSCLC (Albain, Lancet 2009) and selected IIIB (Eberhardt, JCO 1998; Stupp, Lancet Oncol 2009). Here we report long-term S from a prospective phase-II with trimodality Tx (CISTAXOL) that served as predecessor/baseline dataset for our ongoing randomized phase-III (ESPATÜ) (Poettgen, Int J Radiat Oncol Biol Phys 2010). Methods: Pts with histopathologically (mediastinoscopy) proven IIIA(N2) and selected IIIB NSCLC received three CTx cycles cis (50 mg/m2 d 1+8) and pac (175 mg/m2 d 1) qd 22. This was followed by cc CTx/RTx including cis 50 mg/m2 d 2 + 9 and eto 100 mg/m2 d 4-6 cc with 45 Gy (1.5 Gy bid). Three to five weeks after end of RTx pts received SURG if possible. In pts determined inoperable at end of RTx, a definitive CTx/RTx-boost (20 Gy; 2 Gy qd) was added. Here we report ten-year (overall) OS for this cohort and look for exploratory subgroups. Results: Pts accrual from 3/1999 to 2/2002. Pts characteristics: 64 (IIIA(N2) 24; IIIB 40); gender m 48; f 16; PS 0-1; histo: adeno (ADC) 17; squamous cell (SCC) 28; large cell (LCC) 17; NOS 2; age: median 52.5 (range 28-69). 36 pts taken to SURG: R0 32; R1/R2 3; exploratory 1; pCR 16. Long-term exploratory OS analysis (5-y-OS %, 10-y-OS %): med S of all pts still alive on f-up: 8 y 10 mo; all pts 30.1 27.8; IIIA(N2) 34.3 34.3; IIIB 27.7 23.8 (ns log rank); groups defined by pre-Tx factors: histo SCC 46.2 41.0 LCC 23.5 23.5 ADC 11.8 11.8 p = 0.0075 log rank; age < 50 45.9 45.9 age ≥ 50 23.1 20.3 p = 0.035 log rank; groups defined by Tx-dependent factors: R0 46.4 46.4 no R0 14.6 9.7 p = 0.0013 log rank ; R0/pCR 66.0 66.0 R0/vital TU 27.0 27.0 p = 0.03 log rank. Conclusions: long-term S of CISTAXOL defines the rationale for our ongoing randomized trial with SURG after induction Tx in selected pts with stage IIIA/IIIB. Interestingly, histo and age turn out to be important factors in exploratory analysis. ADC and older pts demonstrate poor prognosis even with trimodality. We will prospectively validate these findings in ESPATÜ and perform competing risk analysis.