tbuckley/cabot-search huggingface dataset:
Clinically Relevant Diagnostic Criteria for a Persistent Impairing Grief Disorder
Authors: Charles F. Reynolds, Stephen J. Cozza, M. Katherine Shear
Journal: JAMA Psychiatry (2017)

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A genome-wide association study (GWAS) of overall survival (OS) in 609 metastatic colorectal cancer (mCRC) patients treated with chemotherapy and biologics in CALGB 80405.
Authors: Federico Innocenti, Kouros Owzar, Chen Jiang, Alexander Sibley, Donna Niedzwiecki, Heinz-Josef Lenz, Monica M. Bertagnolli, Paula N. Friedman, Yoichi Furukawa, Michiaki Kubo, Mark J. Ratain, Charles David Blanke, Alan P. Venook, Howard L. McLeod
Journal: Journal of Clinical Oncology (2015)

3599 Support: U10CA180821, U10CA180882, CA31946, Bristol-Myers Squibb, Genentech, Pfizer Background: Irinotecan/5-FU (FOLFIRI) or oxaliplatin/5-FU (FOLFOX), combined with bevacizumab or cetuximab, are first-line treatments for mCRC. We aimed to identify germline variants associated with survival in mCRC patients treated with these regimens. Methods: In CALGB 80405, patients with wild-type KRAS (codons 12 and 13) mCRC received either FOLFOX ( > 80% of patients) or FOLFIRI and were randomized to either cetuximab or bevacizumab. The primary endpoint of the study was OS.DNA was extracted from peripheral blood and genotyped for ~700,000 single-nucleotide polymorphisms (SNPs). The association between SNPs and OS in 609 patients (both arms combined) of European genetic ancestry was tested by a Cox proportional hazards model. Results: Median OS in genotyped patients was 29.6 months, and was comparable to that of the parent study (Venook et al., ASCO 2014). The three most significant SNPs associated with OS were in the genes RDH14 (hazard ratio, HR 1.63, p < 1.12x10-6), TMEM16J (HR 1.52, p < 2.03x10-6), and AXIN1 (HR 1.40, p < 4.26x10-6). Among these genes, the most compelling evidence for a link to the biology of CRC is for AXIN1. The AXIN1 protein functions as a negative regulator of WNT signaling by interacting with APC in CRC (Li et al., Cell 2012). In the present GWAS, rs11644916 (G to A) in AXIN1 is a common germline intronic variant (30% allele frequency). Median OS for patients with the AA, AG or GG genotypes of rs11644916 was 18.4 (95% CI 14.2-27.6), 25.6 (23.6-30.4) or 36.6 (32.9-41.1) months, respectively. Testing of arm and extended RAS analysis as covariates did not alter the association with the rs11644916 in AXIN1. Conclusions: This is the first, large GWAS ever conducted in mCRC patients treated with standard of care in a randomized phase III trial. A common SNP in the AXIN1 gene confers worse OS. This study selects AXIN1 as a new putative determinant of CRC progression. Further replication in additional patient cohorts and functional studies in CRC experimental models are required. Clinical trial information: NCT00265850.
Do children, adolescents, and young adults with soft tissue sarcoma benefit from early detection of recurrences? Results of a population-based study.
Authors: Tobias M. Dantonello, Peter Winkler, Stefanie Kube, Thekla von Kalle, Daniel Kosztyla, Rupert Handgretinger, Iris Veit-Friedrich, Peter Kaatsch, Ruediger Fengler, Stefan S. Bielack, Ivo Leuschner, Felix Niggli, Gustaf Ljungman, Thomas Klingebiel, Ewa Koscielniak
Journal: Journal of Clinical Oncology (2012)

9573 Background: Most patients with pediatric soft tissue sarcoma (PSTS) achieve a 1 st remission with primary therapy, but recurrences are frequent and drive mortality. Relapse detection (RD) is the foundation of post-treatment surveillance. The rationale for frequent follow-up investigations is RD in an early stage with better salvage options. There is however little evidence regarding the value of early asymptomatic RD and it was not investigated by any larger or population-based study in PSTS. We determined whether early radiographic RD in asymptomatic patients improves post-relapse outcome. Methods: Patients aged &lt; 18 years at first reference-reviewed PSTS-diagnosis registered with CWS were enrolled if a 1 st relapse occurred between 1/2003 and 7/2010. The methods of RD and their impact on outcome were evaluated. The data were correlated with the German Childhood Cancer Registry (GCCR), which receives all information about cancer patients &lt; 18 years. Results: 235 patients from Germany (n = 212) and Sweden/Switzerland (n = 23) were eligible. In 2010 all German PSTS-patients were registered both with the GCCR and CWS. The most common PSTS-histiotypes were embryonal (n = 76) and alveolar (n = 74) rhabdomyosarcoma. 156 patients had primary nonmetastatic PSTS. The median time to relapse diagnosis (TTRD) was 1.4 years. 118 recurrences were locoregional, 38 combined and 79 metastatic. In 229 patients, the methods leading to RD could be evaluated. 139 recurrences were detected because of clinical signs and symptoms, primarily observed by patients and/or parents in 72%. 90 RDs were radiographic in asymptomatic patients. TTRD did not differ between symptomatic and asymptomatic patients. As of 12/2011, 77/235 patients are currently alive with a median follow-up of 5.4 years. Overall survival from primary surgery at 3-, 5-, and 10-years for all 235 patients was 49%, 34% and 22%. It was 43%, 29% and 23% for the symptomatic and 59%, 40% and 21% for the asymptomatic group (p = 0.05). Conclusions: In this series, early radiographic RD in asymptomatic PSTS-patients had no significant impact on TTRD or post-relapse survival, although asymptomatic patients tended to survive longer.
Racial disparities in the incidence and survival trends in women with squamous cell carcinoma of the oral tongue based on the Surveillance, Epidemiology, and End Results (SEER) analysis.
Authors: Lindsay Joseph, Michael Goodman, Kristin A. Higgins, Rathi Pilai, Suresh S. Ramalingam, Taofeek Kunle Owonikoko, Jonathan Jay Beitler, Dong Moon Shin, Fadlo Raja Khuri, Nabil F. Saba
Journal: Journal of Clinical Oncology (2014)

6085 Background: The incidence of oral tongue cancer (OTC) in the United States is increasing in women. To better understand this phenomenon, we examined thetime trends and racial disparities in incidence and survival in this population. Methods: We identified 6,199 women diagnosed with OTC that were reported to the Surveillance, Epidemiology and End Results (SEER) Program from 1973 to 2010. Cases were categorized by age, race, and year of diagnosis. The incidence and survival rates were compared across metropolitan, urban and rural residential settings and several other demographic categories by calculating rate ratios (RRs) with the corresponding 95% confidence intervals (CIs). We examined temporal variations in incidence of OTC across racial groups using joinpoint analyses to evaluate changes since 1973. Results: Cases were predominantly white (85.5%), and 60-64 years of age. OTC incidence in white females demonstrated a statistically significant increase with 0.53 annual percentage change (APC) between 1973 and 2010. For African American (AA) females, on the other hand, the incidence has decreased by -2.79 APC since 1973. Overall incidence was higher among white women (1.30 cases per 100,000/year) compared to AA women (0.67 cases per 100,000/year). Comparisons across residential settings produced similar results wherein incidence rates among women living in metropolitan areas were significantly lower for AA females compared to white females (RR=0.51; 95% CI: 0.43-0.60). The 1-, 5- and 10-year relative survival estimates (RS: defined as observed survival among cancer patients divided by the expected survival in the general population) for all women with OTC were 85%, 63% and 53%, respectively. When stratified on race, the corresponding 1-, 5- and 10-year race specific RS estimates were 86%, 63% and 54% for white women, and 76%, 46% and 33% for AA women. Conclusions: The racial disparity in survival of women with oral tongue cancer is pronounced. Identifying the demographic characteristics of white women with OTC may lead to a better understanding of the causes behind the increased incidence in this group.
Open-label study to assess effect of omeprazole (O) on pharmacokinetics of bortezomib (B) in subjects with advanced solid tumors, NHL, or multiple myeloma
Authors: D. I. Quinn, J. Nemunaitis, J. Fuloria, C. D. Britten, N. Y. Gabrail, L. Yee, M. Acharya, K. C. Chan, P. Bishop, A. P. Dudov
Journal: Journal of Clinical Oncology (2007)

13000 Background: Omeprazole (O), an over-the-counter proton pump inhibitor, is also a potent inhibitor of cytochrome P450 (CYP) 2C19, an enzyme responsible for the metabolism of many drugs including bortezomib (B; VELCADE®). This study sought to evaluate potential drug interactions between omeprazole and bortezomib. Methods: Between January 2005 and August 2006, 18 men and 9 women were randomized to receive B 1.3 mg/m 2 iv alone on Days 1, 4, 8, and 11 of a 21-day cycle or B + O 40 mg (2 x 20 mg capsules) on the mornings of Days 6–10 and the evening of Day 8 in Cycle 1, crossing over to receive the other treatment in Cycle 2. Baseline plasma samples were collected before B administration on Day 1 Cycle 1 and Day 8. Results: 17 patients completed both cycles and were evaluable for pharmacokinetics (PK) analysis. The PK of bortezomib with and without omeprazole overlapped and the peak concentrations and time to reach peak concentrations were similar (Table). As observed in other studies of B, there was a high degree of inter-subject variability (B alone, %CV = 64.7; B + O %CV = 60.3); however, differences in mean exposure values between treatments were within the degree of inter- subject variation. There was no increase in adverse events related to bortezomib as a result of treatment with O. In both groups over 95% of patients had over 80% 20S proteasome inhibition. No meaningful relationships were apparent among CYP gene polymorphisms (2C19, 2D6, 3A4, 3A5) and PK endpoints (AUC 8 and C max ) or pharmacodynamic (PD) endpoints (AUE 72 and E max ) in either group or both groups combined. Conclusion: Addition of O to B did not alter PK, PD or safety parameters. Clinically significant drug interaction is unlikely when B is co-administered with O or other CYP2C19 inhibitors. [Table: see text] No significant financial relationships to disclose.
Molecular analysis in breast cancer subtypes and correlation with pathologic complete response (pCR) to neoadjuvant chemotherapy.
Authors: Maria Gonzalez Cao, Carlota Costa, Miguel Angel Molina-Vila, Maria Teresa Cusido, Santiago Viteri Ramirez, Sonia Baulies, Alejandro Martinez-Bueno, Rafael Fabregas, Francesc Tresserra, Irene Sansano, Carmen Ara, David Amselen, Belen Ubeda, Marc Simo-Perdigo, Amaya Gasco, Ignacio Rodriguez, Rafael Rosell
Journal: Journal of Clinical Oncology (2013)

e22119 Background: Although it is know that pCR following neoadjuvant chemotherapy is more frequent in some subtypes of breast cancer such as Triple Negative (TN) or erb2 tumors, the predictive role of gene expression and mutation status is not well defined in this setting. Methods: We analyzed samples from 41 patients (p) prospectively treated with neoadjuvant chemotherapy (sequential AC followed by weekly TXL, or inverse sequence, plus trastuzumab for erb2 positive p). Pathologic response (PR) was classified according to Miller-Payne and RCB criteria. Radiologic evaluation was performed by ultrasonography, dynamic MR and PET-TAC after each chemotherapy sequence. We performed expression analysis of AXL, BRCA1, RAP80, BIM, EZH2, ROR1, FGFR1, PTPN12, YAP, GAS6, beta-TRCP, HIF1 alpha and ZNF217 by RT-PCR, and mutational status of p53 and PI3K genes in pretreatment biopsies. Statistical analysis was performed using Mann-Whitney U and Pearson’s chi-squared tests. Results: pCR was detected in 5 p (3TN, 2 erb2) of 25 p (9 luminal A, 5 luminal B, 6 erb2 and 5 TN) evaluated for PR at time of submitting this abstract. TN tumors had lower levels of RAP80 (p=.0013), PTPN12 (p=.003), beta TRCP (p=.001), ZNF217 (p=.014) and YAP (p=.097). Luminal B tumors had low levels of YAP and the highest levels of FGFR1 (p=.09) and ZNF217 (p=.014). Luminal A tumors had high levels of beta-TRCP (p=.003). We found no differences in BRCA1, AXL, BIM, EZH2, ROR1, GAS6 and HIF1 levels by breast cancer subtype. P with low levels of FGFR1 (p=.087), HIF1alpha (p=.07) or EZH2 (p=.005) had higher probability of pCR. No pCR was observed in p with higher levels of AXL, EZH2, RAP80, GAS6, beta TRCP, HIF alpha. Four p had p53 mutations (1 luminal B, 1 erb2 and 2 TN) and 4 p had PI3K mutations (2 luminal A, 1 erb2, 1 luminal B). There was no correlation between p53 status and PR. P with PI3K mutations did not achieve pCR vs 46% of p with wild type PI3K (p=.23). Conclusions: Gene expression profile varies by breast cancer subtype. Chemosensitivity could be higher in tumors with lower levels of FGFR1, HIF1alpha or EZH2. Further results will be presented.
Allogeneic hematopoietic stem cell transplantation to improve survival in acute myeloid leukemia patients with FLT3 internal tandem duplication.
Authors: Po-Han Lin, Hwai-I Yang, Li-Yuan Bai, Su-Peng Yeh, Chang-Fang Chiu
Journal: Journal of Clinical Oncology (2012)

e17014 Background: Fms-like tyrosine kinase (FLT3) gene with internal tandem duplication (ITD) is a poor prognostic factor in patients with acute myeloid leukemia (AML). Allogeneic hematopoietic stem cell transplantation (HSCT) is considered as an effective treatment for AML patients with poor risk. However, the efficacy of allogenic HSCT in the treatment of AML patients with FLT3-ITD was not clear. Methods: A total of 122 patients, who were newly diagnosed as de novo AML and received intensive chemotherapy at China Medical University Hospital between 2003 January and 2010 December, were retrospectively analyzed. At diagnosis, all patients received French-American-British (FAB) classification, cytogenetic analyses and immunophenotyping. The HSCT was performed on the basis of the consensus of the hematologists in this institute, mainly according to the two factors: unfavorable karyotype and suitable donor availability. The FLT3-ITD was detected by polymerase chain reaction and confirmed by direct sequencing. The Cox proportional hazards regression analysis was used to estimate the hazards ratios of the overall survival and corresponding 95% confidence interval (CI) for various combinations of FLT3-ITD and HSCT status. Results: An FLT3-ITD was detected in 34 patients (27.9%). The allogeneic HSCT was performed in 39 patients; 29 patients with wild type (wt)-FLT3 and 10 patients with FLT3-ITD. The number of death/number of patients (medium overall survival) of wt-FLT3/HSCT(+), wt-FLT3/HSCT(-), FLT3-ITD/HSCT(+) and FLT3-ITD/HSCT(-) was 12/29 (53.4 months), 25/59 (40.7 months), 3/10 (medium not reached) and 17/24 (12.0 months), respectively (p=0.014). Comparing with wt-FLT3/HSCT(-) patients, the hazard ratio (95% CI) of overall survival for wt-FLT3/HSCT(+), FLT3-ITD/HSCT(+) and FLT3-ITD/HSCT(-) was 1.39 (0.61-3.18), 0.40 (0.11-1.49), and 3.57 (1.58-8.09), respectively, after adjustment of age, sex, WBC, LDH, karyotype and FAB classification. Conclusions: AML patients without FLT3-ITD had better survival than those with FLT3-ITD regardless of the allogeneic-HSCT. The allogeneic HSCT may improve overall survival in AML patients with FLT3-ITD.
Utility of microsieve device for enumeration and miRNA expression profiling of CTCs for personalized cancer management.
Authors: Steven Tucker, Karen Mei Ling Tan, Sai Mun Leong, Chua Hui Wen, Delly Fareda Jumaat, Doreen Chek Yee Tan, Mo-Huang Li, Evelyn S. C. Koay
Journal: Journal of Clinical Oncology (2013)

e22107 Background: Although a rare peripheral cell population, circulating tumor cells (CTCs) represent a potential alternative to serial invasive biopsies as a source of tissue in monitoring clinical states of non-hematological malignancies. CTCs harvested from a single patient are a heterogeneous mixture of cells differing in their transcriptome expressional profiles, metastatic potential and drug resistance properties. Mere identification and enumeration of CTCs are unable to provide qualitative information about individual CTC biology. The presence of a few highly malignant, metastasis-capable CTCs and cancer stem cells among the other less aggressive CTCs in the circulating population will not be apparent from CTC counts alone. Methods: We developed a high-throughput size-exclusion microsieve device (CellSievo, Singapore) to isolate CTCs (defined as DAPI-positive, CD45-negative cells), regardless of the cell surface receptors expressed, from 74 breast cancer patients. Using CTCs eluted from the microsieve post-capture, we performed microRNA expression profiling to further characterize breast cancer CTCs. Results: Using CellSievo’s microsieve device, we obtained an average mean CTC count of 21.2 (+/- 31.8; range=0-112.5) per 7.5ml peripheral blood, for breast cancer patients, as opposed to 1.3 (+/-1.6, range 0-5.0) for healthy subjects. Viable CTCs from breast cancer patients were successfully harvested for downstream microRNA profiling. CTCs from breast cancer patients were routinely found to express microRNA profiles mediating epithelial-to-mesenchymal transition, tumor invasion, and regulation of chemotherapeutic drug resistance to tamoxifen, anthracyclines, taxanes, and trastuzumab. Serial monitoring of microRNA expression pattern of CTCs could identify emergence of novel tumor populations with distinct microRNA expression patterns during or after anticancer therapy (detailed microRNA expression data to be presented). Conclusions: Our results suggest that microRNA biomarkers derived from peripheral CTCs can yield highly useful information and offer prognostic and predictive applications for therapeutics and companion diagnostic development.
Analysis of genomic DNA copy number alterations in chromosome arm 18q demonstrates distinct molecular categories of colorectal carcinoma
Authors: H. Ji, M. Zhang, K. Farnam, K. Salari, R. Davis, J. M. Ford
Journal: Journal of Clinical Oncology (2006)

10005 Background: Genomic instability is a major feature of neoplastic development in colorectal carcinoma and other cancers. Specific genomic instability events such as genomic deletions have potential utility as biologically relevant prognostic biomarkers. Loss of heterozygosity (LOH) on chromosome arm 18q is an indicator of colorectal carcinoma behavior and potentially, prognosis. For stage II and III colorectal cancer, a number of retrospective studies have shown strong correlations between deletions in 18q and reduced survival. However, other studies have failed to identify this correlation. This discrepancy is likely the result of different sets of genetic markers and their widely disparate locations along chromosome arm 18q, often separated by megabases. New technologies are needed to overcome these issues. Methods: Using a novel genomic technology called molecular inversion probes (MIPs), we analyzed genomic deletions at exon-level resolution in primary colorectal carcinoma. Unlike microsatellite genetic markers, MIPs are not dependent on having informative alleles to discern a LOH event. This enables querying microsatellite genetic markers used in any clinical study. We designed a set of probes to interrogate several hundred individual exons of over two hundred cancer genes with an overall distribution covering all chromosome arms. Also represented were a series of over 100 probes along chromosome arm 18q representing genetic markers used in clinical studies. An analysis was carried out on primary tumor samples from patients with stage II and III disease. Results: We discovered several distinct categories of colorectal carcinomas based upon their profile of 18q genomic deletions and other allelic imbalances. Colorectal carcinoma extent of invasion showed an association with cluster designation which suggests that the multiple genomic instability events influence the invasive behavior of colorectal carcinoma. Conclusions: Colorectal cancer has distinct patterns of 18q genomic deletions, representing a potential molecular classifier. This finding has potential clinical ramifications given the application of 18q LOH events as an indicator for adjuvant treatment in stage II colorectal carcinoma. No significant financial relationships to disclose.
Sunitinib dose escalation after disease progression in metastatic renal cell carcinoma.
Authors: Jacques Raphael, Alia Thawer, Georg A. Bjarnason
Journal: Journal of Clinical Oncology (2017)

458 Background: Previous pharmacologic studies demonstrated that higher sunitinib ( S) exposure is associated with improved clinical outcomes in metastatic renal cell carcinoma (mRCC) patients. We aimed to assess the efficacy and toxicity of S dose escalation in mRCC patients progressing on the standard 50mg dose. Methods: A single institution retrospective review was conducted on mRCC patients, treated outside trials with a 50 mg S dose given on an individualized schedule between October 2009 and January 2016, who subsequently progressed on imaging. At progression, patients were dose escalated to 62.5 and 75mg on an individualized schedule if toxicity permitted. Median Progression and Overall Survival (PFS, OS) were analyzed using the Kaplan Meier method. PFS1 and 2 were defined as the time between the start of sunitinib and first progression and the time between dose escalation and second progression respectively. Results: Twenty-five eligible patients were identified, with a median follow-up of 40.3 months (11.1-66.6) and a mean age of 54 years (12.4). The majority of patients underwent cytoreductive surgery (92%) and were men (88%). Thirty two percent, 44%, and 24% had a good, intermediate, and poor prognostic Heng score respectively. At the 50 mg doses, 60% and 16% of patients had a partial response (PR) and stable disease (SD) respectively with a median time to progression (TTP) of 11.4 months (95% CI, 3-20.7). After progression, 36% and 28% had PR and SD on higher doses of S respectively with a TTP of 7.8 months (95% CI, 6.3-12.4). Three patients with progressive disease as best response on a 50 mg S dose achieved SD (2/3) or PR (1/3) after dose escalation. The median PFS1, PFS2, and OS were 6.1 months (95% CI, 2.3-19.4), 6.7 months (95% CI, 3.1-8.4), and 63.7 months (95% CI, 26-not reached) respectively. The most common adverse events after dose escalation were fatigue (56%), diarrhea (40%), and skin toxicity (28%). Conclusions: Patients with mRCC who progress on a 50 mg S dose, may derive a clinical benefit and prolonged survival from dose escalation with acceptable toxicity profiles. These results need to be confirmed in well-designed prospective studies with the aim to optimize the duration of benefit from S therapy.