tbuckley/cabot-search huggingface dataset:
A randomized study of lenalidomide (LEN) with or without EPO in RBC transfusion dependent (TD) IPSS low and int-1 (lower risk) myelodysplastic syndromes (MDS) without del 5q resistant to EPO.
Authors: Andrea Toma, Sylvie Chevret, Olivier Kosmider, Jacques Delaunay, Aspasia Stamatoullas, Christian Rose, Odile Beyne-Rauzy, Anne Banos, Agnes Guercy-Bresler, Eric Jourdan, Veronique Sardnal, Denis Caillot, Kamel Laribi, Benoit De Renzis, Dominique Bordessoule, Borhane Slama, Laurence Sanhes, Michaela Fontenay, Pierre Fenaux, Francois Dreyfus
Journal: Journal of Clinical Oncology (2013)

7002 Background: ESAs, the first line treatments of anemia in non del 5q lower risk MDS, yield only 40-50% responses. LEN gives RBC transfusion independence (TI) in about 25% of ESA resistant (or relapsing) TD lower risk MDS without del 5q (Raza, Blood, 2008), and a gene expression signature can predict response (Ebert, Plos Med 2008). We randomized in this patient population LEN alone and LEN+EPO. Methods: In this prospective multicenter open-label phase II study (NCT01718379), lower risk MDS patients without del 5q, with TD (≥4 RBC units during the previous 8 weeks (w)) with ESA resistance or relapse after a response were randomized between LEN alone, 10mg/d x 21 d/4 w (L arm) or LEN (same schedule) + EPO beta, 60 000 U/w (LE arm). The primary endpoint was erythroid response (HI-E, IWG 2006 criteria) after 4 treatment cycles. Secondary objectives included identification of biomarkers of response. Results: Between July 2010 and June 2012, 132 patients (pts, 66 / arm), median age 73 (range 46-88), M/F: 88/44 were enrolled. Median TD was 6 RBC units/8w (range 2-18). IPSS was Low in 45% and Int-1 in 55% pts. Pretreatment characteristics did not differ between the 2 groups. All but 3 pts, who withdrew consent (2L+1LE), were evaluable for response. In this ITT population, HI-E was obtained in 15 pts (23.4%) in L arm and 26 (40.0%) in LE arm (RR= 1.7, p= 0.043, chi2 test), and TI in 9 (14.1%) versus 16 (24.6%) pts (RR=1.7, p= 0.13). In the 99 pts who completed 4 treatment cycles, 41 achieved HI-E, including 15/49 (30.6%) in L arm versus 26/50 (52.0%) in LE arm (p= 0.03), and TI in 9 (18.4%) versus 16 (32.0%) pts (RR= 1.7, p=0.12). Side effects (cytopenias and 1 DVT/arm) were similar in the 2 arms. A 29-gene expression profile signature predicting HI-E to L or LE, different from that previously published, was identified and a polymorphism in the CRBN gene (Kosmider, submitted) was significantly associated with HI-E in the entire cohort (p=0.034). Conclusions: LEN + EPO yielded a significantly better erythroid response than LEN alone in lower risk MDS patients with anemia resistant to ESA alone. A gene expression signature and a CRBN gene polymorphism correlated with the erythroid response. Clinical trial information: NCT01718379.
A phase II study of erlotinib (E) and bevacizumab (B) in patients (pts) with previously untreated stage IIIB/IV non-small cell lung cancer (NSCLC)
Authors: H. J. Groen, E. F. Smit, A. Dingemans
Journal: Journal of Clinical Oncology (2007)

7625 Background: In advanced NSCLC, E and B either as a single agent (E) or in combination with chemotherapy (B) show improved survival. Combinations of targeted agents may prove to be effective and better tolerated than chemotherapy. Methods: This is a multi-center 2-stage phase II study (Simon's optimal design; p0=40%, p1=60%, a=0.05, β=0.20). Primary endpoint is non-progression (NPR) at 6 weeks defined by CT and FDG-PET. If 7 or less of the first 16 pts had NPR, the study would close. If 24/46 pts had NPR at 6 wks treatment would be declared to have sufficient activity for further testing. Pts (PS 0–2) with advanced non- squamous NSCLC who had received no prior chemotherapy were treated with E (150 mg/day) plus B (15 mg/kg every 21 days) until PD or unacceptable toxicity. Results: Between 30/01/06 and 08/12/06, 38 pts were included; 33 pts are evaluable for safety, 32 for efficacy. M/F 17/16; median age 59 (range 34–80); stage IIIB/IV 8/25; PS 0/1/2: 16/13/4; smoking status: current/former/never 12/17/4. Treatment-related adverse events (all grades) were: rash (32%); diarrhea (18%); hemorrhage (2.6%); hypertension (2.7%); and thrombosis (2.7%). Grade 3/4 events were rash (9.9%); thrombosis (1.8%); diarrhea (0.9%); and hypertension (0.9%). Six pts withdrew early from the study: 2 due to toxicity (trombosis and mucositis); 2 due to death (1 death for unknown reason, 1 due to pneumonia); 2 for treatment unrelated reasons. Six pts had E dose reductions due to toxicity. Five pts had delays of less than 2 wks before receiving B. Percentage of NPR at 6 weeks is 75% (24/32). The median follow-up: 6.3 months (95% CI 3.5–9.2). Median TTP: 5.5 months (95% CI 1.9 - 9.2), At time of analysis 22/33 patients are alive, 17 patients are without PD. Conclusions: E + B regimen is well tolerated, with a low rate of grade 3/4 adverse events and no unexpected toxicities. The primary endpoint has already been met. Updated results including correlative imaging studies will be presented. No significant financial relationships to disclose.
Correlation of cytogenetic changes and tumor-specific differential gene expression in colorectal cancer.
Authors: Muhammad Ghulam Kibriya, Farzana Jasmine, Mohammed Kamal, Rezwan Islam, Shantanu Roy, Zahidul Haq, Maruf Raza, Rupash Paul, Habibul Ahsan
Journal: Journal of Clinical Oncology (2014)

e14598 Background: Studies have consistently reported frequent gross cytogenetic changes in tumor genome in colorectal cancer (CRC) – mainly copy number (CN) loss of 8p, 17p, 18q, and gain of 8q, 9p, 13q, 20p, 20q harboring a large number of genes. In this study we tried to identify the genomic regions which show amplification/ deletion in cytogenetic data (structural change at DNA level) and also correlate to tumor-specific differential gene expression (functional consequences at transcriptome level) in CRC tissue. Methods: We studied a set of consecutive 43 left sided microsatellite stable (MSS) adenocarcinoma cases from a series of 86 CRC patients for which we had DNA from fresh frozen sample and RNA from RNA Later preserved sample available from tumor tissue and corresponding healthy colonic tissue for genome-wide assays. Cytogenomic changes were detected using Illumina Human Cyto12 SNP chip. Gene expression data was obtained from Illumina HT12 v4 chips and mutation by sequencing. Results: Using genomic segmentation algorithm implemented within Partek Genomic suite, the total genome was divided into 84,147 genomic segments. We detected a total of 15,121 segments of various sizes which showed amplification (CN >=2.3) in at least 5% samples. Similarly, a total of 43,593 genomic regions showed deletion (CN =<1.7) in at least 5% samples. Gene expression data showed a total of 1,647 genes differentially expressed in CRC tissue compared to corresponding surrounding healthy tissue at least by 1.5 fold at FDR 0.01. CN of 122 genomic segments strongly correlated (r>=0.5, p<8.2x10-7) with 96 differentially expressed genes (at least by 1.5 fold) in CRC. Among these, 38 genomic regions cover a total of 32 genes which are at least 2-fold differentially expressed in CRC: 21 down- and 11 up-regulated including a few drug- targetable genes. We also identified that amplification of EGFR was specifically found only in tumors with wild type KRAS confirmed by sequencing. This may explain the efficacy of Cetuximab in wild type only. Conclusions: We identified few regions in tumor genome, cytogenetic changes of which perhaps exert functional effect in CRC pathogenesis that may be explored for prognostic significance in future study.
Development of an immunoglobin variable region specific DNA microarray: Analysis of B-Cell clonality
Authors: D. Baunoch, M. Opel, M. Giordano, M. Cabeen, K. Bloom, M. Moore
Journal: Journal of Clinical Oncology (2004)

6608 Introduction: B-Cell Lymphoproliferative disorders arise from the proliferation of a single B lymphocyte. Currently, these disorders are diagnosed using morphological, immunohistochemical, and molecular methods such as Southern blot, or PCR analysis. Clinically, both molecular techniques are limited in utility. Southern blots exhibit high sensitivity (>90%), but require fresh frozen tissue for analysis, while PCR based analysis is applicable to both fresh and formalin fixed tissues (FFPE) but suffers from low sensitivity (∼60%). Therefore we investigated an alternative assay that is both sensitive and applicable to standard FFPE sections. Presented is a method for the identification of variable region usage by DNA microarray for the detection of B-cell clonality. Methods: Briefly, DNA was extracted, and the rearranged IgH locus amplified using a Cy5-labeled primer set. PCR products were heat denatured, and hybridized to a DNA oligonucleotide microarray with loci specific for IgH variable gene segments. Arrays were washed and hybridization assessed by Cy5 fluorescence. Results: A high degree of correlation was observed between the microarray analysis and a reference set of over 50 known lymphomas (diagnosed by morphology, IHC and molecular analysis) (>90% concordance), and 50 normal controls (100% concordance). Conclusions: Presented is a method for the detection of B-Cell Lymphoproliferative disorders by identification of specific variable genes, where hybridization to a single gene member is diagnostic of a clonal population and hybridization to multiple gene members is diagnostic of a polyclonal (normal) population. Unlike the current method of PCR amplification / fragment sizing, which implies clonality through determination of gene length, this assay directly identifies the specific variable region present in a clonal population. As individual gene segments have been associated with specific disorders, for example mucosa-associated lymphoid tissue (MALT) (V1–69), mantle cell lymphoma (MCL) (V4–34), and chronic lymphocytic leukemia (CLL) (V3–21), we believe this assay will have significant clinical utility. No significant financial relationships to disclose.
Molecular characterization of the PI3/Akt pathway in head and neck squamous cell cancer (HNSCC)
Authors: S. I. Angelaki, A. K. El-Naggar, E. N. Brown, S. Lnu, G. D. Ayers, J. J. Lee, V. A. Papadimitrakopoulou
Journal: Journal of Clinical Oncology (2004)

9643 Background: Molecular cancer therapeutics are based on the concept that key molecular abnormalities or pathways drive cancer cell growth. The PI3/Akt pathway, is a regulator of cell growth, proliferation and survival. Akt is overexpressed or constitutively activated in many human tumors including HNSCC in which Akt activation has been associated with increased local treatment failure. The goal of the present study was to dissect the PI3K/Akt pathway in vivo in HNSCC in order to recognize patterns that could be used as the basis for molecularly-targeted therapeutics. Methods:Biopsies obtained from primary, recurrent or second primary tumor of HNSCC patients were placed on a tissue micro-array and subjected to immunohistochemistry with activation state-specific (phospho-) antibodies for multiple components of the PI3K/Akt pathway. We estimated correlations among Akt activation and its downstream effectors FHKR, mTOR, pGSK3β and p70S6 kinase and 4EBP1 operating downstream from mTOR and evaluated differences in expression between patients with primary versus recurrent tumor. Results: Tumor specimens from 38 patients (27 males, 11 females), median age 55 (range, 27–53 yrs), 23 from primary, 12 from recurrent and 3 from second primary tumor, 2 (5%) stage I, 5 (13%) stage II, 2 (5%) stage III and 27 (71%) (2 not available) at initial diagnosis, were analysed. Akt activation was detected in 30 (79%) of cases. Statistically significant Spearman correlations of activity between Akt and FKHR (p=0.03), mTOR (p=0.04) and GSK3β (p=0.01) and between FKHR and GSK3β (p<0.01) were detected. Only GSK3β showed significantly higher activity in recurrent tumors (p=0.02) Conclusions: PI3/Akt pathway activation is frequent in HNSCC and Akt activation correlates positively with known downstream signaling molecules, establishing the relevance of the pathway in head and neck tumorigenesis. The impact of pathway activation on treatment outcome and survival remains to be determined but molecular PI3K/Akt pathway targeting should be of particular importance for the treatment of the disease (supported by the ASCO CDA to VP). No significant financial relationships to disclose.
Post-treatment paternity in testicular cancer survivors
Authors: M. Brydoy, S. Fossa, O. Klepp, E. Wist, R. Bremnes, O. Dahl
Journal: Journal of Clinical Oncology (2004)

4527 Background: Previous studies on fertility following treatment of testicular cancer (TC) mainly address s-FSH values and sperm parameters. The aim of this study was to analyse post-treatment fatherhood according to treatment. Methods: An unselected population of 1814 patients treated for unilateral TC in Norway in 1980–1994 was invited to participate in the survey with a questionnaire enquiring data on the attempt and achievement of pre- and post-treatment children, as well as the use of medical assistance and cryopreserved semen. Results: 1433 patients were evaluable (compliance 79 %, mean observation time 11.3y). Of these, 826 (58 %) had own children at diagnosis. A total of 556 patients attempted post-treatment paternity. They were grouped according to treatment: Surveillance (N= 53), retroperitoneal surgery (RPLND, N=81), radiotherapy (RT, N=202) and two chemotherapy ± RPLND/RT groups according to cisplatin dose (≤ or > 850 mg; N=183 and 37). Of these, 361 (65 %) fathered 1–7 children by semen produced after treatment. Factors influencing the ability to father children (multivariate cox regression analysis) were treatment group (table), ejaculation function (table), pre-treatment fatherhood (p<0,001) and period of treatment (1989–1994 more favourable, p=0,001). The overall median actuarial time from diagnosis to 1. born child was 6,7 y (table). The actuarial paternity rate at 15 years in patients treated with 3–4 courses of cisplatin based chemotherapy ± RPLND was 82 % if they retained antegrade ejaculation and 14 % with
Value of PSA measured in middle age in predicting diagnosis of advanced prostate cancer in an unscreened population
Authors: D. Ulmert, A. Serio, A. Vickers, J. Eastham, P. Scardino, G. Berglund, T. Björk, H. Lilja
Journal: Journal of Clinical Oncology (2007)

5006 Background: The association between PSA-levels in blood and prostate cancer (PCa) is currently under intense debate as many benign conditions also affect blood levels. We recently reported that PSA-levels in blood predicted very strongly later PC-diagnosis at any stage in a large representative population-based cohort in Malmö, Sweden (MPM) where the rate of PSA-testing is very low. Now, we studied predictors of stages =T3 or metastatic (M+) PCa at the time of cancer diagnosis. Material: Among archived bloods from 22,439 men (aged =50 or 60) during 1974–86, 192/549 men diagnosed with PCa until Dec 31, 1999, were eligible cases with =T3 or M+ at time of diagnosis. Median delay from baseline to diagnosis was 17 years among cases aged =50 (n=161) and 10 years among men aged 60 (n=31). Conditional logistic regression between cases and controls nested within our study cohort determined association and interaction between analyte levels, time to diagnosis, and age. Results: There was strong evidence that plasma levels of all PSA-forms and kallikrein 2 (hK2) associate with case status (p&lt;0.01), and even a small elevation in total PSA (tPSA) markedly increased the risk of subsequent event. A tPSA of 2.1 - 3.0 ng/ml raised the odds of subsequent event 22-fold compared to a tPSA =0.5 ng/ml and men with tPSA =2 ng/ml had a predicted probability of advanced prostate cancer of 12% - three times the population mean. AUC for a model with tPSA alone, compared to tPSA+cPSA+%fPSA+hK2 were higher in men aged 60 (AUC increase of 0.054) compared to men aged =50 (AUC increase of 0.030). This is consistent with the results of interaction analysis showing that the association between hK2-level and cases status grows stronger as the interval between date of venipuncture and diagnosis decreases. Similarly, the effect of %fPSA on case status was dependent on age suggesting that the association between %fPSA and case status is stronger in older compared to younger men. Conclusion: Very strong associations exist between levels of all PSA-forms and hK2 measured at middle age and decade(s) before diagnosis of advanced stages of prostate cancer. There is an urgent need to validate these data in independent study cohorts as they could contribute important arguments in the revision of current PC- screening guidelines. No significant financial relationships to disclose.
Brain metastases in esophageal carcinoma.
Authors: K. Saadah, A. Miller, D. Prasad, G. Yang, T. Bellavia, R. V. Iyer, N. I. Khushalani
Journal: Journal of Clinical Oncology (2010)

e14609 Background: Brain metastases (BM) are uncommon (< 2%) in esophageal carcinoma (EC). With our anecdotal experience suggesting this occurrence to be more frequent, a retrospective review was undertaken to investigate this pattern of spread in EC. Methods: Patients (pts) with EC or gastroesophageal junction (GEJ) cancer, and BM were identified from the RPCI tumor registry from Jan, 1998 to July, 2009. Demographic, clinical, and treatment (Rx) data were retrieved. Results: Of 1167 pts with EC/GEJ cancer, 60 pts (5.1%) with BM were included (2 pts excluded due to concomitant lung cancer and vertebral metastases). Median age 65 yrs (range 26-83); male (n = 55); white (n = 57), black (n = 3). Most EC/GEJC were adenocarcinomas (n = 56). Site of the primary was distal in 90% and mid-esophagus in 10%. Clinical stage at presentation was I (n = 2), IIa (n = 3), IIb (n = 5), III (n = 10), IV (n = 38). 46 pts (78%) developed BM only, 8 pts (14%) had leptomeningeal spread only and 5 pts had both. Seven pts (12%) had BM concurrent with original cancer diagnosis. Venous thromboembolism (VTE) developed in 14 pts (23%). Of 11 pts who underwent an esophagectomy, only 1 achieved a pathologic complete response. 45 pts received platinum-based chemotherapy. Notably 40 pts with BM were diagnosed from 2004-09, and 20 from 1998-2003 (p = 0.18). Treatment modalities included whole brain radiation only (RT, n = 26), surgery (S) + RT (n = 6), stereotactic radiosurgery (SR, n = 5), R + SR (n = 6), S + SR (n = 3), S + RT + SR (n = 3). Overall survival (OS) was 14.4 m (95% CI, 12, 20.8); median OS from BM diagnosis was 2.5 m (95% CI, 1.5, 4.7). Median OS from BM diagnosis was significantly better in pts receiving multimodal Rx; RT only (1.5 m), S + RT (4.7 m), RT + SR (12.9 m), S + RT + SR (27 m). The primary tumor location, prior esophagectomy, presence of VTE, or period of diagnosis (dichotomized) had no effect on survival. Conclusions: The incidence of BM in EC may be higher than previously believed; this should be confirmed in a larger cohort. Aggressive regional therapy for BM including surgery and SR is warranted for appropriate pts as our experience suggests superior survival for these pts. No significant financial relationships to disclose.
Identifying the surgical cavity following oncoplastic breast surgery.
Authors: Michael Cross, Gail Lebovic, James Stubbs, Joe Ross, Scott Jones, Thad Beck
Journal: Journal of Clinical Oncology (2014)

81 Background: Oncoplastic surgery (OPS) has improved outcomes for partial mastectomy. However, tissue rearrangement poses challenges in the post-operative management of these patients. In most cases, these patients will require post-operative radiotherapy. Accurately visualizing the surgical cavity can be particularly troublesome in patients who have oncoplastic closure of the resection cavity. Recent advances have made it feasible to perform external beam radiation using advanced methods, but these are not commonly used for breast cancer. This is due to the difficulty in identifying the exact area of the surgical site. In this series of patients, a novel method for marking the surgical site when using oncoplastic techniques was evaluated. Methods: 65 patients had a 3-D tissue marker implanted at the time of lumpectomy. All patients were candidates for partial mastectomy and local breast reconstruction using OPS. Post-operative treatment plans for radiation and/or adjuvant chemotherapy were completed. Patients were evaluated with standard breast imaging methods for treatment planning. Results: The marker was easily identified and clearly delineated within the lumpectomy cavity. It provided 3-D characterization of the borders surrounding the cavity, and was easily distinguished from seroma and other tissue changes. Respiratory motion was easily tracked using the device making it possible to use IMRT and accelerated protocols. Use of the marker resulted in treatment volumes that were reduced by an average of 50% when compared to standard methods. In appropriate patients when the marker facilitated an accelerated protocol, total treatment time was decreased to 5-7 days. No complications were reported, and overall patient outcomes were excellent. Conclusions: This novel 3-D marker was consistently visualized without difficulty, was readily incorporated into standard practices and had appreciable benefits when designing optimal treatment plans. Its unique features were helpful in all cases, but particularly useful when using oncoplastic techniques to reconstruct the breast with local tissue flaps.
CA125 as a predictive marker for optimal interval debulking surgery in advanced ovarian cancer.
Authors: N. Furukawa, H. Shigetomi, S. Yoshida, R. Kawaguchi, S. Komeda, Y. Tanase, Y. Yamada, H. Kobayashi
Journal: Journal of Clinical Oncology (2011)

e15543 Background: Neoadjuvant chemotherapy (NAC) followed by interval debulking surgery (IDS) is an accepted treatment for patients with advanced ovarian cancer. It is unclear, however, whether achieving optimal IDS can be predicted by preoperative analysis using imaging (CT and MRI) or by measuring cancer antigen (CA) 125 levels. The aim of the present study was to assess whether CA125 values can be used to identify patients who are candidates for optimal IDS following NAC for advanced ovarian cancer. Methods: Eighty-one women diagnosed with ovarian cancer (6 FIGO IIIA and 75 IIIC) between 1995 and 2010, with serum CA125 levels greater than 40 IU/mL prior to NAC that underwent NAC followed by IDS, were retrospectively evaluated. After each NAC, CA 125 levels were measured and CA125 regression rates ([pre first NAC CA125 – pre each NAC CA125]/pre first NAC CA125) were calculated. Optimal IDS was defined as the largest volume of residual disease less than 1 cm in the maximal dimension. The ability of CA125 values and patient and disease characteristics to predict optimal IDS was determined by univariate and multivariate analyses. Results: On univariate analysis, CA125 regression rates from pre first NAC to pre second NAC and from pre first NAC to pre third NAC, and CA125 levels before IDS were statistically significant (p<0.01). On multivariate analysis, CA125 level before IDS was an independent predictor of optimal IDS (p<0.01). The CA125 level cut-off point before IDS for optimal IDS calculated using a receiver operating characteristic curve was 9 IU/mL. Conclusions: In this retrospective study, a pre-IDS CA125 level of 9 IU/mL or less predicted optimal IDS.