tbuckley/cabot-search huggingface dataset:
Retrospective analysis of prognostic factors in non-small cell lung cancer with <i>EGFR </i>mutations.
Authors: Shingo Nishikawa, Takashi Sone, Taro Yoneda, Kazuhiko Shibata, Koji Kurokawa, Toshiyuki Kita, Hiroki Shirasaki, Kazuyoshi Watanabe, Hideharu Kimura, Kazuo Kasahara
Journal: Journal of Clinical Oncology (2014)

e19103 Background: Prognostic factors in non-small cell lung cancer (NCSLC) with EGFR mutations have not been evaluated in detail. Methods: We retrospectively examined NSCLC pts with EGFR mutations treated with EGFR-TKIs, and evaluated patient characteristics and serum tumor markers from the perspective of prognosis. Survival time was analyzed using Kaplan-Meier methods and Cox regression modeling. Results: Participants comprised 159 pts, among whom 106 were women, 115 were never- or light smokers, and 155 had with adenocarcinoma. Deletions in exon 19 were seen in 76 pts, the L858R mutation in 67, and other EGFRmutations in 16. All pts were treated with EGFR-TKIs (gefitinib, n=110; erlotinib, n=28; both sequentially, n=17; other, n=4). No significant relationship was observed between response rate and patient characteristics; however, progression-free survival (PFS) with EGFR-TKI treatment was significantly associated with ECOG PS at start of treatment with EGFR-TKI (good PS [0,1] vs. poor PS [2-4], MST 10.9 m vs. 7.0 m; p<0.001), serum albumin level (low [<3.5 mg/dl] vs. high, 8.9 m vs. 10.9 m; p=0.003), LDH level (low [<250 IU/l] vs. high, 10.8 m vs. 7.2 m; p=0.01), CEA level (normal [<5 ng/ml] vs. high, 13.2 m vs. 9.5 m; p=0.007) and CYFRA 21-1 level (normal [<3.5 ng/ml] vs. high, 11.4 m vs. 8.9 m; p=0.002). Multivariate analysis revealed that good PS was independently associated with PFS (hazard ratio [HR], 0.56; p=0.04). Overall survival (OS) from starting treatment with EGFR-TKI was significantly associated with PS (good vs. poor, 25.5 m vs.17.1 m; p<0.001), albumin level (low vs. high, 14.3 m vs. 25.5 m; p<.001), LDH (25.5 m vs. 17.8 m; p<0.001), CEA (normal vs high, 63.1 m vs. 21.5 m; p<0.001), CYFRA 21-1 (32.2 m vs. 16.0 m; p<0.001) and smoking status (never- or light smoker vs. heavy smoker, 24.8 m vs. 19.4 m; p=0.03). Multivariate analysis revealed high CEA level (HR, 3.01; p=0.002), high CYFRA 21-1 level (HR, 2.24; p=0.01) and low albumin level (HR, 2.04; p=0.04) as independently associated with poor prognosis. Conclusions: Serum CEA and CYFRA 21-1 levels represent independent prognostic factors not related to anti-tumor effect or PFS of EGFR-TKI treatment in NSCLC pts with EGFR mutations.
Abstract 1504: Quantification of dedifferentiation rates in breast cancer using fluorescent reporter constructs and lineage tracing
Authors: Michael D. Brooks, Max S. Wicha
Journal: Cancer Research (2015)

Abstract Breast cancer is the second most common cancer in women and despite significant advances in treatment, once metastatic it is almost universally fatal. One explanation for this is that current treatments don't target the true driver of tumor growth, cancer stem cells (CSCs). It has been shown that many cancers, including breast cancer, are hierarchically organized with CSCs driving tumor growth. It is also well known that a hallmark of tumor biology is an increased phenotypic plasticity, which helps tumor cells to evade treatment. It has been hypothesized that one consequence of this is an increased rate of dedifferentiation of bulk tumor cells back to CSCs. While a good deal of research has shown that this can sometimes occur, recent work showing the existence of multiple CSC states in breast cancer combined with a lack of direct lineage tracing experiments merits further investigation into the rate, and biological significance, of dedifferentiation in breast cancer. In order to monitor movement between cell states, we have developed a number of fluorescent reporter constructs for genes important in breast cancer including stemness genes (CD44, ALDH1A1, ALDH1A3, Sox2, Oct4), luminal genes (ESR1, Gata3, KRT19, E-Cadherin), myoepithelial/basal genes (CD10, p63, KRT7, Vimentin), and proliferation genes (Ki67, PCNA). These genes will be used in combination with each other in Cre-Recombinase mediated LoxP-STOP-LoxP lineage tracing constructs to track movement between luminal or basal bulk tumor cells and cancer stem cells. Validation of ALDH1A1 and ALDH1A3 reporters by immunofluorescent staining and the AldeFluor Assay has shown good concordance between the reporters and native expression of the genes. These reporters will help to quantify the rate of dedifferentiation and cell state flux in breast cancer. Citation Format: Michael D. Brooks, Max S. Wicha. Quantification of dedifferentiation rates in breast cancer using fluorescent reporter constructs and lineage tracing. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1504. doi:10.1158/1538-7445.AM2015-1504
Reduced intensity conditioned allograft yields favorable survival for older adults with B‐cell acute lymphoblastic leukemia
Authors: Ashley E. Rosko, Hai‐Lin Wang, Marcos de Lima, Brenda Sandmaier, H. Jean Khoury, Andrew Artz, Johnathan Brammer, Christopher Bredeson, Sherif Farag, Mohamed Kharfan‐Dabaja, Hillard M. Lazarus, David I. Marks, Rodrigo Martino Bufarull, Joseph McGuirk, Mohamed Mohty, Taiga Nishihori, Ian Nivison‐Smith, Armin Rashidi, Olle Ringden, Matthew Seftel, Daniel Weisdorf, Veronika Bachanova, Wael Saber
Journal: American Journal of Hematology (2016)

Older adults with B-cell acute lymphoblastic leukemia (B-ALL) have poor survival. We examined the effectiveness of reduced intensity conditioning (RIC) hematopoietic cell transplant (HCT) in adults with B-ALL age 55 years and older and explored prognostic factors associated with long-term outcomes. Using CIBMTR registry data, we evaluated 273 patients (median age 61, range 55-72) with B-ALL with disease status in CR1 (71%), >CR2 (17%) and Primary Induction Failure (PIF)/Relapse (11%), who underwent RIC HCT between 2001 and 2012 using mostly unrelated donor (59%) or HLA-matched sibling (32%). Among patients with available cytogenetic data, the Philadelphia chromosome (Ph+) was present in 50%. The 3-year cumulative incidences of nonrelapse mortality (NRM) and relapse were 25% (95% confidence intervals (CI): 20-31%) and 47% (95% CI: 41-53%), respectively. Three-year overall survival (OS) was 38% (95% CI: 33-44%). Relapse remained the leading cause of death accounting for 49% of all deaths. In univariate analysis, 3 year risk of NRM was significantly higher with reduced Karnofsky performance status (KPS <90: 34% (95% CI: 25-43%) versus KPS ≥90 (18%; 95% CI: 12-24%, P = 0.006). Mortality was increased in older adults (66+ vs. 55-60: Relative Risk [RR] 1.51 95% CI: 1.00-2.29, P = 0.05) and those with advanced disease (RR 2.13; 95% CI: 1.36-3.34, P = 0.001). Survival of patients in CR1 yields 45% (95% CI: 38-52%) at 3 years and no relapse occurred after 2 years. We report promising OS and acceptable NRM using RIC HCT in older patients with B-ALL. Disease status in CR1 and good performance status are associated with improved outcomes. Am. J. Hematol. 92:42-49, 2017. © 2016 Wiley Periodicals, Inc.
Rising incidence of glioblastoma and meningioma in the United States: Projections through 2050.
Authors: Derek Richard Johnson
Journal: Journal of Clinical Oncology (2012)

2065 Background: In the absence of proven environmental or behavioral risk factors, patient age and sex remain the most important predictors of primary brain tumor risk. In coming years, an increasing incidence of brain tumors in the United States can be anticipated based on shifts in the demographic structure of the population. This study provides estimates of glioblastoma and meningioma incidence through 2050. Methods: Group-specific glioblastoma and meningioma incidence rates based on age (eleven categories) and sex were calculated from National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) data for the period 2004-2008. United States Census projections based on data from the 2000 census were used to compute the size of the twenty-two demographic subpopulations of interest in 2010, 2020, 2030, 2040, and 2050. The estimated number of new glioblastoma and meningioma diagnoses for each of these years was calculated from the defined incidence rates and population size. Results: Crude annual tumor incidence rates were 3.13 per 100,000 persons for glioblastoma and 6.81 per 100,000 persons for meningioma. While the overall size of the population is expected to increase only 42% between 2010 and 2050, the number of Americans over 65 years of age, the group at highest risk of glioblastoma and meningioma, is expected to increase by 120%. We estimate that the number of new glioblastoma diagnoses will rise from 10,688 in 2010 to 18,466 in 2050, a 72% increase. Likewise, the number of new meningioma diagnoses will rise from 22,946 to 40,680 over the same period, a 77% increase. Conclusions: The number of new glioblastoma and meningioma diagnoses will increase substantially in the future. This analysis, which assumes a fixed incidence rate, may underestimate the true magnitude of the coming change given reports suggesting that incidence rates of glioblastoma and meningioma are rising over time.
cDNA screening to identify genes correlated with <i>SCCRO</i>-associated angiogenesis and metastasis in squamous cell carcinoma of the lung
Authors: S. G. Talbot, I. S. Sarkaria, N. D. Socci, E. Maghami, M. Dudas, R. A. Ghossein, A. Viale, C. G. Azzoli, V. W. Rusch, B. Singh
Journal: Journal of Clinical Oncology (2004)

9549 Background: Lung cancer remains the leading cause of cancer deaths in the United States. We have cloned a novel oncogene - squamous cell carcinoma related oncogene (SCCRO) and established the importance of SCCRO in these tumors. Angiogenesis and metastasis play key roles in the aggressive behavior of SCCRO over-expressing tumors. To investigate these pathways we have developed a novel targeted angiogenesis/metastasis cDNA microarray and corresponding tissue microarray. Methods: Thirty-four previously-untreated patients undergoing resection of primary lung squamous cell carcinomas were selected. SCCRO expression was analyzed using real-time RT-PCR. We identified 277 genes associated with angiogenesis and metastasis based on a comprehensive literature search and constructed a multi-replicate cDNA microarray. RNA was extracted from patient tissue, reverse-transcribed, hybridized, scanned, and normalized. Spotted genes were correlated with SCCRO over-expression. A tissue microarray was constructed using paraffin-embedded blocks from the same patients and immunohistochemistry was used to validate cDNA microarray results. Results: SCCRO over-expression was present in 53% of cases. Of the 277 genes in our array, 13 were highly correlated with SCCRO over-expression (p<0.001, R>0.67). These genes represent putative pathways activated by SCCRO and include genes correlated with aggressive behavior including members of the transforming growth factor family, ephrin A1, Id3, small inducible cytokine A2, and CD44 antigen. Immunohistochemistry for several genes including SCCRO has confirmed their importance. Conclusions: We have constructed high-density cDNA and tissue microarrays and used them to identify genes implicated in SCCRO-driven angiogenic and metastatic pathways. Candidate genes may serve as therapeutic targets in lung cancer. No significant financial relationships to disclose.
Investing in the foundation of sustainable development: pathways to scale up for early childhood development
Authors: Linda M Richter, Bernadette Daelmans, Joan Lombardi, Jody Heymann, Florencia Lopez Boo, Jere R Behrman, Chunling Lu, Jane E Lucas, Rafael Perez-Escamilla, Tarun Dua, Zulfiqar A Bhutta, Karin Stenberg, Paul Gertler, Gary L Darmstadt
Journal: The Lancet (2016)
Self-evaluation subjective toxicity according to the Common Toxicity Criteria in breast cancer patients undergoing adjuvant chemotherapy: final results of an Italian prospective study
Authors: F. Montemurro, G. Mittica, C. Cagnazzo, M. Foresto, V. Longo, P. Berchialla, G. Solinas, P. Culotta, R. Martinella, A. Calori, B. Grasso, C. Volpone, G. Bertola, G. Parola, M. Del Torre, P.L. Giuliano, M. Aglietta, A.M. Ballari
Journal: Annals of Oncology (2015)
Prospective Cohort Study with Risk-Adapted Central Nervous System (CNS) Evaluation in Diffuse Large B-Cell Lymphoma Patients Treated with Rituximab-CHOP: Analysis of Incidence and Risk Factors for Secondary CNS Involvement.
Authors: Seok Jin Kim, Yong Park, Soon Il Lee, Hyeon Seok Eom, Jin Seok Kim, Min Kyoung Kim, Young Rok Do, Dok Hyun Yoon, Jong-Ho Won, Yeung-Chul Mun, Won Sik Lee, Hye Jin Kang, Hyo Jung Kim, Jung Hye Kwon, Jeong-A Kim, Jae-Yong Kwak, Jae Hoon Lee, Jee Hyun Kong, Sung Yong Oh, Sun Ah Lee, Eun Kyung Park, Sung Hwa Bae, Je-Jung Lee, Yang Soo Kim, Myung Hee Chang, Hyun Jung Jun, Won Seog Kim, Cheolwon Suh
Journal: Blood (2012)
Topoisomerases: Resistance versus Sensitivity, How Far We Can Go?
Authors: Sandhya Bansal, Priyanka Bajaj, Stuti Pandey, Vibha Tandon
Journal: Medicinal Research Reviews (2016)

Abstract DNA topoisomerases are ubiquitously present remarkable molecular machines that help in altering topology of DNA in living cells. The crucial role played by these nucleases during DNA replication, transcription, and recombination vis‐à‐vis less sequence similarity among different species makes topoisomerases unique and attractive targets for different anticancer and antibacterial drugs. However, druggability of topoisomerases by the existing class of molecules is increasingly becoming questationable due to resistance development predominated by mutations in the corresponding genes. The current scenario facing a decline in the development of new molecules further comprises an important factor that may challenge topoisomerase‐targeting therapy. Thus, it is imperative to wisely use the existing inhibitors lest with this rapid rate of losing grip over the target we may not go too far. Furthermore, it is important not only to design new molecules but also to develop new approaches that may avoid obstacles in therapies due to multiple resistance mechanisms. This review provides a succinct account of different classes of topoisomerase inhibitors, focuses on resistance acquired by mutations in topoisomerases, and discusses the various approaches to increase the efficacy of topoisomerase inhibitors. In a later section, we also suggest the possibility of using bisbenzimidazoles along with efflux pump inhibitors for synergistic bactericidal effects.
The association of D<sup>4</sup>, 3-keto-abi (D4A) and response to abiraterone in castration-resistant prostate cancer (CRPC).
Authors: Hamid Emamekhoo, Mohammad Alyamani, Zhenfei Li, Paul Elson, Petros Grivas, Brian I. Rini, Marianne Petro, Sylvia Stybor, Anthony Salatino, Jorge A. Garcia, Nima Sharifi
Journal: Journal of Clinical Oncology (2016)

245 Background: Abiraterone (Abi), a potent inhibitor of 17α-hydroxylase/17,20-lyase (CYP17A1), is a standard treatment for men with metastatic CRPC. Abi is converted to D4A by 3β-hydroxysteroid dehydrogenase (3βHSD). D4A inhibits CYP17A1, 3βHSD, and steroid-5α-reductase (SRD5A) and has direct androgen receptor antagonist activity, which together make it a more potent agent than Abi in xenograft models. It is not known if conversion to D4A in patients (pts) correlates with response or resistance to Abi. Methods: Blood was collected (single time point on Abi) from CRPC pts who started Abi during 2011-2015. Abi and D4A were extracted from serum and analyzed by mass spectrometry. The purpose of this ongoing study is to assess the potential correlation between D4A and response to treatment. Results: 32 patients with CRPC had blood collected. 4 pts (12.5%) received ketoconazole and 6 (18.8%) chemotherapy prior to Abi. Median pre-Abi prostate-specific antigen (PSA) was 14.3 ng/ml (0.6-646.1). Median time from initiation of androgen deprivation therapy (ADT) to CRPC was 34.3 months (m) (6-129.6) and median time from CRPC to Abi initiation was 4.8 m (0-14.9). PSA decline &gt; 50% (PSA50) on Abi was seen in 68% (12/31) and 73% (19/26) of pts at 3 and 6 m, respectively. Treatment with Abi was ongoing in 23/32 pts (74%), and discontinued in 8 pts (26%) due to disease progression (no follow up data on 1 pt) with median duration of Abi treatment 14.6 m (2.9-44.4 m) at last follow up. As the absolute concentration of detected levels of Abi and D4A varied significantly among pts, the percentage of the total extracted metabolites was used to assess correlation with response. Abi and D4A comprised 94.3% (73.8-97.4%) and 5.7% (2.6-26.2%), respectively, of total levels. Conclusions: Abi absorption and metabolism significantly vary among pts. Most of these pts had prolonged duration of response to Abi (74% ongoing treatment and median treatment duration 13.3 m in 8 pts that came off treatment). Longer follow up, accrual of pts with shorter duration of response, and sampling at multiple time points on Abi and at progression is ongoing to further evaluate the impact of D4A on treatment response.
Platinum re-treatment as a second-line option for clinically and molecularly defined platinum-sensitive metastatic non-small cell lung cancer (NSCLC).
Authors: L. H. de Lima Araujo, S. B. S. P. Terra, A. R. C. Pires, I. A. Small, A. C. D. Melo, C. Sternberg, C. G. M. Ferreira
Journal: Journal of Clinical Oncology (2011)

e18032 Background: Despite significant advances in NSCLC therapy during the past decade, platinum (Pl) compounds remain the most important drug class in the metastatic setting. Notably, a subgroup of patients (pts) is particularly sensitive to first-line (FL) Pl-based chemotherapy. For these pts, platinum re-challenge might be an interesting approach in the second-line (SL). Identifying those patients beforehand could be crucial. Methods: We describe a unique cohort of pts that upon FL Pl-based chemotherapy show significantly high disease control rate (DCR) and progression-free interval (PFI) – generally > 6 ms (Pl-sensitive). These pts were re-treated with a Pl-doublet in the SL, mostly comprising the same regimen used in the FL. We also evaluated ERCC1 and XIAP expression as potential biomarkers. Clinical and molecular characteristics were compared to a Pl-non-sensitive group (N=65), with < 6 ms PFI after FL-Pl therapy. Results: 28 pts were re-treated with a Pl-doublet in the SL between 2000 and 2007. This Pl-sensitive group was older than the Pl-non-sensitive group (median age 64 vs 58; P=.004), presented a higher proportion of females (46% vs 28%; P=.08), never-smokers (36% vs 18%; P=.07), and squamous histology (39% vs 19%; P=.04). The DCR (100% vs 27%; P<.0001), and PFI (median 10.7 vs 0.9 ms; P<.0001) were clearly superior in the Pl-sensitive group. Accordingly, the progression-free (median, 12.6 vs 3.3 ms; P<.0001) and overall survival (27.4 vs 6.1 ms; P<.0001) were considerably longer in the Pl-sensitive group. For pts with available tumor samples, the expression of ERCC1 and XIAP in Pl-non-sensitive group was 30% (14/46) and 45% (21/47). In contrast, no expression of ERCC1 or XIAP was observed in the Pl-sensitive - 0/3 (P=.25) and 0/4 (P=.08). Conclusions: A group of clinically selected pts - with high DCR and long PFI after FL - derived great benefit from Pl-therapy also in the SL. The outcomes are in line with SL FDA-approved options, which support further prospective evaluation. ERCC1 and XIAP are evolving biomarkers in this field, and coupled to clinical features here identified may add to patient selection and enhance the benefits from Pl re-treatment strategy.
An open-label randomized controlled phase II study of clarithromycin (CL) plus CVP in patients (pts) with previously untreated stage III/IV indolent non Hodgkin lymphoma (NHL).
Authors: Amr S Saad, Sara M Shaheen, Manal H Elhamamsy, Osama A Badary
Journal: Journal of Clinical Oncology (2014)

e19510 Background: Clarithromycin an oral active antibiotic used for H Pylori (HP) eradication, an effect that leads to regression of HP induced gastric MALT NHL. Angiogenesis is associated with NHL tumor growth (Ribatti et al, Neoplaisa 2013). Reports show that CL has direct anti neoplastic activity that can be partly attributed to an anti angiogeneic effect (Aoki et al, Anticancer Res 2005) (Ohe and Hashino, KJIN 2013). This study was designed to evaluate the efficacy and safety of CL plus CVP in indolent NHL pts and to understand the association between NHL response to CL therapy and serum(s)VEGF level. Methods: Pts (aged ≥18 yrs, histological proven indolent NHL, HP negative in case of MALToma, stage III/IV & chemo naive) were randomized to receive either CVP (cyclophosphamide 750mg/m2 IV D1, vincristine 1.4mg/m2 IV D1 and prednisone 40mg/m2 oral (D1- D5) (arm A) or CVP plus CL 500 mg bid (D5-D18) (arm B) every 21 days. Response was evaluated every 2 cycles; toxicity was assessed using NCI CTCAE v4. Baseline and after 2 cycles, sVEGF levels were measured by ELISA. The primary endpoint was progression free survival (PFS), and secondary endpoints included overall response rate (ORR), overall survival (OS), safety and differential changes in sVEGF levels between the 2 arms of the study. Results: Overall, 60 pts with FL (45%), MZL (16.7%) and SLL (38.3%) were enrolled and 55 pts were eligible for evaluation. CR and ORR % in arms A and B were 18.5% (95%CI [CI]; 8, 37) vs 32.1% (CI; 18, 51) and 70.4% (CI; 52, 84) vs 92.8% (CI; 77, 98), respectively; P=0.04. Two years, PFS and OS rates were (46.2% vs 75%) P=0.02 and (85.4% vs 89.5%) P=0.636, respectively. The most common Grade ≥3 toxicities were anemia (14.9%, 3.6%), neutropenia (15.6 % 10.7%), thrombocytopenia (3.8%, 0%), mucositis (14.9 vs. 17.9%), respectively. Differential reduction in sVEGF level after 2 cycles was (20.5% vs 38.4%), P<0.001 respectively. Conclusions: CL plus CVP is active and safe in pts with previously untreated stage III/IV indolent NHL. Increased differential reduction in sVEGF level with CL suggests that anti angiogenesis may contribute to its anti neoplastic activity.