Objectives QT prolongation is an independent risk factor for cardiovascular mortality. Because QT... more Objectives QT prolongation is an independent risk factor for cardiovascular mortality. Because QT prolonging medications and conditions cross all disciplines of medicine, an institution wide computer-based clinical decision support system was designed and implemented at the Mayo Clinic, Rochester, MN. This QT alert system automatically screens all ECGs and alerts the providers if the QTc is > 500ms. Here, we analyzed the frequency of QTc alerts and outcome of patients with an alerted QTc. Methods During 7 months, 86,107 ECGs were performed in 53,286 patients. Alerts were sent for 1145 patients (2%). All alerted ECGs were reviewed manually. QT-influencing clinical diagnoses, laboratory abnormalities, and medications were collected from the electronic medical records and summarized in a Pro-QTc score with each QT prolonging factor receiving one point. Survival was compared to 52,141 Mayo Clinic patients with QTc < 500 ms during the same time period. Results Of the 1145 patients with a QTc alert, 470 (41%) p...
4270 Background: Few effective options are available for the treatment of unresectable HCC. Chemo... more 4270 Background: Few effective options are available for the treatment of unresectable HCC. Chemotherapy, in particular, has been of limited benefit. Several phase I trials suggest promising activity of a combination of gemcitabine and docetaxel. METHODS Patients with unresectable or metastatic HCC were treated with docetaxel 40 mg/m2 (later reduced to 30 mg/m2) and gemcitabine 800 mg/m2 on days 1, 8 every 3 weeks. A Simon study design called for accrual of 40 patients, with an interim analysis after 22, requiring at least 2 responses, with acceptable toxicity, to continue accrual. RESULTS 25 patients were enrolled in 26 months. Median age was 67 (range 27-78), 17 were male,15 had liver-only disease and10 had extrahepatic disease. 9 patients had cirrhosis, 6 viral hepatitis, and 1 hemachromatosis. Response -Of 21 patients evaluable for the primary endpoint (response), 2 (10%) have a confirmed response. TTP and Survival -The median TTP is 2.3 months (95% CI 1.3-5.6 months). Median survival is not yet reached with a median followup of 5.3 months (range 0-24 months). Toxicity -Two patients died on-study due to adverse events (1 hepatic and 1 renal failure), neither of which were attributed to the study medications. 17 patients (81%) have experienced grade 3+ adverse events, including 8 with grade 4+ adverse events. Hematologic toxicity and associated hemorrhage resulted in a reduction of the docetaxel dose. CONCLUSIONS A response rate of 10% was observed in patients with HCC receiving gemcitabine and docetaxel. Patients experienced a high rate of grade 3+ toxicity including neutropenia and thrombocytopenia. Based on these results, accrual to the trial will not continue. The combination of gemcitabine and docetaxel at the dose and schedule used is not recommended for HCC. [Table: see text].
Nearly 10% of human gliomas are oligodendrogliomas. Deletion of chromosome arm 19q, often in conj... more Nearly 10% of human gliomas are oligodendrogliomas. Deletion of chromosome arm 19q, often in conjunction with deletion of 1p, has been observed in 65-80% of these tumors. This has suggested the presence of a tumor suppressor gene located on the 19q arm. Chromosome 19 deletion is also of interest due to the better prognosis of patients with deletion, including longer survival and better response to chemotherapy, compared with patients without deletion. Two glioma cell lines with deletion of 19q were used for chromosome 19 microcell-mediated transfer, to assess the effect of replacing the deleted segment. Complementation with chromosome 19 significantly reduced the growth rate of the hybrid cells compared with the parental cell lines. Affymetrix U133 Plus 2.0 Gene Chip analysis was performed to measure and compare the expression of the chromosome 19 genes in the chromosome 19 hybrid cell lines to the parental cell line. Probes were considered significantly different when a P value <0.01 was seen in all of the cell line comparisons. Of 345 probes within the commonly deleted 19q region, seven genes (APOE, RCN3, FLJ10781, SAE1, STRN4, CCDC8, and BCL2L12) were identified as potential candidate genes. RT-PCR analysis of primary tumor specimens showed that several genes had significant differences when stratified by tumor morphology or deletion status. This suggests that one or more of these candidates may play a role in glioma formation or progression.
e14063 Background: Surrogate biomarkers are lacking for predicting or monitoring anti-angiogenesi... more e14063 Background: Surrogate biomarkers are lacking for predicting or monitoring anti-angiogenesis therapies. We investigated if CECs were correlated to treatment efficacy in mCRC pts treated with BEV and sorafenib. METHODS Peripheral blood samples were obtained for CEC analysis from mCRC pts enrolled in the NCCTG phase II study N054C [Grothey, ASCO 2010]. Blood collection time points were: baseline (BL), cycle 1 day 3, prior to treatment cycles 2, 3, 5, 7, 9, 11, 13, and after the pt went off study. CECs, defined as CD146(+), CD3(-), and CD31(+), were enumerated by flow cytometry. Unequal variance two-sample and paired t-tests were performed to compare values between pt outcome groups and serial measurements within a pt, respectively. RESULTS 78/79 eligible N054C pts went off study and had their CECs analyzed. 76 pts had BL blood evaluable for CEC analysis. Median BL CECs were 80.0 (mean: 177.5; range: 1.02-1718) cells/mL. We found no correlation between BL CECs and 3 month progression-free survival for mCRC pts treated with BEV/sorafenib (p=0.56). The absolute change and log2-fold change (FC) from BL CECs were decreasing at all time points, with the exception of cycle 1 day 3. The percent change in CEC from BL was significantly decreased in cycles 2, 3, 5, and 7 (p-values: 0.01, 0.008, 0.04, and 0.018, respectively). This remained consistent when examining the CEC log2-FC at cycles 3, 5, and 7 (p = 0.008, 0.014, and 0.0004, resp.). The CEC log2-FC was significantly decreased from BL to end of treatment draws (≤14 days) for pts off study for progression (p=0.0007), but not for pts off study for other reasons (p=0.96). CONCLUSIONS Baseline CECs do not appear to be prognostic in mCRC pts treated with a salvage protocol of BEV/sorafenib. CECs, however, decrease on this anti-angiogenic therapy. The significance of decreasing CECs is unclear and further evaluation of serial CECs to determine their predictive value is warranted.
Journal of the American Medical Informatics Association, 2021
Objective We aimed to develop a model for accurate prediction of general care inpatient deteriora... more Objective We aimed to develop a model for accurate prediction of general care inpatient deterioration. Materials and Methods Training and internal validation datasets were built using 2-year data from a quaternary hospital in the Midwest. Model training used gradient boosting and feature engineering (clinically relevant interactions, time-series information) to predict general care inpatient deterioration (resuscitation call, intensive care unit transfer, or rapid response team call) in 24 hours. Data from a tertiary care hospital in the Southwest were used for external validation. C-statistic, sensitivity, positive predictive value, and alert rate were calculated for different cutoffs and compared with the National Early Warning Score. Sensitivity analysis evaluated prediction of intensive care unit transfer or resuscitation call. Results Training, internal validation, and external validation datasets included 24 500, 25 784 and 53 956 hospitalizations, respectively. The Mayo Clini...
Despite studies that show the antitumor activity of Hsp90 inhibitors, such as geldanamycin (GA) a... more Despite studies that show the antitumor activity of Hsp90 inhibitors, such as geldanamycin (GA) and its derivative 17-allylamino-demethoxygeldanamycin (17-AAG), recent reports indicate that these inhibitors lack significant single-agent clinical activity. Resistance to Hsp90 inhibitors has been previously linked to expression of P-glycoprotein (P-gp) and the multidrug resistant (MDR) phenotype. However, the stress response induced by GA treatment can also cause resistance to Hsp90-targeted therapy. Therefore, we chose to further investigate the relative importance of P-gp and the stress response in 17-AAG resistance. Colony-forming assays revealed that high expression of P-gp could increase the 17-AAG IC50 6-fold in cells transfected with P-gp compared with parent cells. A549 cells selected for resistance to GA overexpressed P-gp, but verapamil did not reverse the resistance. These cells also overexpressed Hsp27, and Hsp70 was induced with 17-AAG treatment. When the GA and 17-AAG resistant cells were transfected with Hsp27 and/or Hsp70 small interfering RNA (siRNA), the 17-AAG IC50 decreased 10-fold compared with control transfected cells. Transfection with siRNA directed against Hsp27, Hsp70, or Hsp27 and Hsp70 also increased sensitivity to EC78, a purine scaffold-based Hsp90 inhibitor that is not a P-gp substrate. We conclude that P-gp may contribute, in part, to resistance to 17-AAG, but induction of stress response proteins, such as Hsp27 and Hsp70, by Hsp90-targeted therapy plays a larger role. Taken together, our results indicate that targeting of Hsp27 and Hsp70 should be exploited to increase the clinical efficacy of Hsp90-directed therapy. [Cancer Res 2008;68(18):7419–27]
Background: Bevacizumab (BEV), a monoclonal antibody against vascular endothelial growth factor-A... more Background: Bevacizumab (BEV), a monoclonal antibody against vascular endothelial growth factor-A (VEGF-A), is a standard component of medical therapy of metastatic colorectal cancer (mCRC). Activation of alternative angiogenesis pathways has been implicated in resistance to BEV. This phase II study examines the activity of combined vertical blockade of VEGF signaling with sorafenib and BEV as salvage therapy in patients with progressive disease (PD) on all standard therapy in mCRC. Methods: mCRC patients with documented PD on standard therapy, received sorafenib (200 mg orally twice daily, days 1-5 and 8-12) and BEV (5 mg/kg intravenously, day 1) every 2 weeks. Primary endpoint was 3-month progression-free survival (PFS) rate and secondary endpoints were overall survival (OS), response rate (RR), safety, and feasibility. Results: Of the 83 patients enrolled, 79 were evaluable. Of these, 42 (53%) were progressionfree at 3 months. Median PFS was 3.5 months and median OS was 8.3 months. One patient had a partial response and 50 patients (63.3%) had at least one stable tumor assessment. Of 79 evaluable patients, 54 (68%) experienced grade 3/4 adverse events (AEs) at least possibly related to treatment. Most frequent grade 3/4 AEs were: fatigue (24.1%), hypertension (16.5%), elevated lipase (8.9%), hand-foot skin reaction (8.9%), diarrhea (7.6%), and proteinuria (7.6%). Reasons for treatment discontinuation were PD (72%), AEs (18%), patient refusal (8%), physician decision (1%), and death (1%). Conclusions: The combination of BEV and sorafenib as salvage therapy in heavily pretreated mCRC patients is tolerable and manageable, with evidence of promising activity.
Background: MicroRNAs (miRNAs) are a class of approximately 22 nucleotide long, widely expressed ... more Background: MicroRNAs (miRNAs) are a class of approximately 22 nucleotide long, widely expressed RNA molecules that play important regulatory roles in eukaryotes. To investigate miRNA function, it is essential that methods to quantify their expression levels be available. Methods: We evaluated a new miRNA profiling platform that utilizes Illumina's existing robust DASL chemistry as the basis for the assay. Using total RNA from five colon cancer patients and four cell lines, we evaluated the reproducibility of miRNA expression levels across replicates and with varying amounts of input RNA. The beta test version was comprised of 735 miRNA targets of Illumina's miRNA profiling application. Results: Reproducibility between sample replicates within a plate was good (Spearman's correlation 0.91 to 0.98) as was the plate-to-plate reproducibility replicates run on different days (Spearman's correlation 0.84 to 0.98). To determine whether quality data could be obtained from a broad range of input RNA, data obtained from amounts ranging from 25 ng to 800 ng were compared to those obtained at 200 ng. No effect across the range of RNA input was observed. Conclusion: These results indicate that very small amounts of starting material are sufficient to allow sensitive miRNA profiling using the Illumina miRNA high-dimensional platform. Nonlinear biases were observed between replicates, indicating the need for abundance-dependent normalization. Overall, the performance characteristics of the Illumina miRNA profiling system were excellent.
Objectives-Few effective options are available for the treatment of unresectable hepatocellular c... more Objectives-Few effective options are available for the treatment of unresectable hepatocellular carcinoma (HCC). Several phase I trials suggest promising activity of a combination of gemcitabine and docetaxel. Methods-Patients with unresectable or metastatic HCC were treated with docetaxel 40 mg/m 2 (later reduced to 30 mg/m 2) and gemcitabine 800 mg/m 2 on days 1, 8 every 3 weeks. Twenty-five patients were enrolled in 26 months. Median age was 64 (range 27-78), 17 were male, 14 had liver-only disease and, 11 had extrahepatic disease. Results-Of 25 patients evaluable for the primary endpoint (response), 2 (8%) have a confirmed partial response. The median TTP is 2.76 months (95% CI 1.84-6.64 months). Median survival was 12.8 months (95% CI: 5.26-28.00). Two patients died on-study due to adverse events (1 hepatic and 1 renal failure), neither of which were attributed to the study medications. Twenty patients (81%) have experienced grade 3+ adverse events, including 11 with grade 4+ adverse events, primarily neutropenia, thrombocytopenia, diarrhea, and fatigue. 1 This study was conducted as a trial of the North Central Cancer Treatment Group and Mayo Clinic and was supported in part by
Objectives: Vascular endothelial growth factor has been shown to be overexpressed in several stud... more Objectives: Vascular endothelial growth factor has been shown to be overexpressed in several studies of hepatocellular carcinoma (HCC). Cediranib is a potent inhibitor of vascular endothelial growth factor signaling. We assessed the efficacy and toxicity of cediranib in patients with HCC. Methods: Twenty-eight patients with unresectable or metastatic HCC were enrolled in this study. Patients received 45 mg of cediranib orally, once daily, for 28-day cycles. The primary objective of this phase II study was to assess 6-month survival. Secondary objectives were to assess tumor response, time to progression, and toxicity. Results: All 28 patients were evaluable for efficacy outcomes. Twelve patients (42.9%) survived 6 months, 15 (53.6%) died within 6 months, and 1 (3.6%) was lost to follow-up before 6 months. The median overall survival was 5.8 months (95% confidence interval, 3.4-7.3 mo). No patients experienced confirmed response. The median time to progression was 2.8 months (95% confidence interval, 2.3-4.4 mo). Twenty-six patients (93%) experienced a grade 3+ adverse event with the most common adverse event s being fatigue (46%), anorexia (25%), hypertension (21%), and elevated alanine aminotransferase (18%). Conclusions: Owing to the toxicity, cediranib at this dose and schedule is not an effective treatment in patients with unresectable or metastatic HCC.
5017 Background: The majority of men with prostate cancer are diagnosed with cancers with low mor... more 5017 Background: The majority of men with prostate cancer are diagnosed with cancers with low mortality. Such men are treated with radical prostatectomy, external beam radiotherapy, or brachytherapy and followed by serum PSA evaluations. Some men with a rising PSA therapy will have local recurrence or metastasis, but many will have no other evidence of recurrent disease other than a rising PSA. The PSA doubling time has been used to determine which of these men deserve adjuvant hormonal ablation, radiation therapy, or observation. We hypothesize that additional biomarkers will predict which men with a rising PSA post-definitive therapy would benefit from additional therapy. Methods: We designed a custom array containing 526 RNA targets whose expression has been reported to be altered in association with prostate cancer progression. We included targets from Mayo Clinic prostate cancer research. Together with a second commercial array, 530 genes implicated in prostate cancer progressi...
Within the past five years studies published from this laboratory and others have identified or c... more Within the past five years studies published from this laboratory and others have identified or confirmed CD38 as a marker for aggressive disease in B cell chronic lymphocytic leukemia (B-CLL). To learn more about the possible role of CD38 in this disease, we performed gene expression profiling (GEP; Affymetrix U133A platform) on primary leukemic B cells isolated from CD38 positive and negative patients. We and others have previously shown that the leukemic compartment within some patients consists of both CD38neg and CD38pos CLL B cells. To optimize identification of differentially expressed genes associated with CD38 expression or lack thereof, we restricted our gene profiling to patient cells that were unimodally negative for CD38 and those that expressed unimodally high levels of CD38. In both groups of patients, CD19 positive cells were purified using magnetic bead cell sorting on a Miltenyi AutoMacs prior to isolation of total RNA. To determine genes that appear to be differen...
Objectives QT prolongation is an independent risk factor for cardiovascular mortality. Because QT... more Objectives QT prolongation is an independent risk factor for cardiovascular mortality. Because QT prolonging medications and conditions cross all disciplines of medicine, an institution wide computer-based clinical decision support system was designed and implemented at the Mayo Clinic, Rochester, MN. This QT alert system automatically screens all ECGs and alerts the providers if the QTc is > 500ms. Here, we analyzed the frequency of QTc alerts and outcome of patients with an alerted QTc. Methods During 7 months, 86,107 ECGs were performed in 53,286 patients. Alerts were sent for 1145 patients (2%). All alerted ECGs were reviewed manually. QT-influencing clinical diagnoses, laboratory abnormalities, and medications were collected from the electronic medical records and summarized in a Pro-QTc score with each QT prolonging factor receiving one point. Survival was compared to 52,141 Mayo Clinic patients with QTc < 500 ms during the same time period. Results Of the 1145 patients with a QTc alert, 470 (41%) p...
4270 Background: Few effective options are available for the treatment of unresectable HCC. Chemo... more 4270 Background: Few effective options are available for the treatment of unresectable HCC. Chemotherapy, in particular, has been of limited benefit. Several phase I trials suggest promising activity of a combination of gemcitabine and docetaxel. METHODS Patients with unresectable or metastatic HCC were treated with docetaxel 40 mg/m2 (later reduced to 30 mg/m2) and gemcitabine 800 mg/m2 on days 1, 8 every 3 weeks. A Simon study design called for accrual of 40 patients, with an interim analysis after 22, requiring at least 2 responses, with acceptable toxicity, to continue accrual. RESULTS 25 patients were enrolled in 26 months. Median age was 67 (range 27-78), 17 were male,15 had liver-only disease and10 had extrahepatic disease. 9 patients had cirrhosis, 6 viral hepatitis, and 1 hemachromatosis. Response -Of 21 patients evaluable for the primary endpoint (response), 2 (10%) have a confirmed response. TTP and Survival -The median TTP is 2.3 months (95% CI 1.3-5.6 months). Median survival is not yet reached with a median followup of 5.3 months (range 0-24 months). Toxicity -Two patients died on-study due to adverse events (1 hepatic and 1 renal failure), neither of which were attributed to the study medications. 17 patients (81%) have experienced grade 3+ adverse events, including 8 with grade 4+ adverse events. Hematologic toxicity and associated hemorrhage resulted in a reduction of the docetaxel dose. CONCLUSIONS A response rate of 10% was observed in patients with HCC receiving gemcitabine and docetaxel. Patients experienced a high rate of grade 3+ toxicity including neutropenia and thrombocytopenia. Based on these results, accrual to the trial will not continue. The combination of gemcitabine and docetaxel at the dose and schedule used is not recommended for HCC. [Table: see text].
Nearly 10% of human gliomas are oligodendrogliomas. Deletion of chromosome arm 19q, often in conj... more Nearly 10% of human gliomas are oligodendrogliomas. Deletion of chromosome arm 19q, often in conjunction with deletion of 1p, has been observed in 65-80% of these tumors. This has suggested the presence of a tumor suppressor gene located on the 19q arm. Chromosome 19 deletion is also of interest due to the better prognosis of patients with deletion, including longer survival and better response to chemotherapy, compared with patients without deletion. Two glioma cell lines with deletion of 19q were used for chromosome 19 microcell-mediated transfer, to assess the effect of replacing the deleted segment. Complementation with chromosome 19 significantly reduced the growth rate of the hybrid cells compared with the parental cell lines. Affymetrix U133 Plus 2.0 Gene Chip analysis was performed to measure and compare the expression of the chromosome 19 genes in the chromosome 19 hybrid cell lines to the parental cell line. Probes were considered significantly different when a P value <0.01 was seen in all of the cell line comparisons. Of 345 probes within the commonly deleted 19q region, seven genes (APOE, RCN3, FLJ10781, SAE1, STRN4, CCDC8, and BCL2L12) were identified as potential candidate genes. RT-PCR analysis of primary tumor specimens showed that several genes had significant differences when stratified by tumor morphology or deletion status. This suggests that one or more of these candidates may play a role in glioma formation or progression.
e14063 Background: Surrogate biomarkers are lacking for predicting or monitoring anti-angiogenesi... more e14063 Background: Surrogate biomarkers are lacking for predicting or monitoring anti-angiogenesis therapies. We investigated if CECs were correlated to treatment efficacy in mCRC pts treated with BEV and sorafenib. METHODS Peripheral blood samples were obtained for CEC analysis from mCRC pts enrolled in the NCCTG phase II study N054C [Grothey, ASCO 2010]. Blood collection time points were: baseline (BL), cycle 1 day 3, prior to treatment cycles 2, 3, 5, 7, 9, 11, 13, and after the pt went off study. CECs, defined as CD146(+), CD3(-), and CD31(+), were enumerated by flow cytometry. Unequal variance two-sample and paired t-tests were performed to compare values between pt outcome groups and serial measurements within a pt, respectively. RESULTS 78/79 eligible N054C pts went off study and had their CECs analyzed. 76 pts had BL blood evaluable for CEC analysis. Median BL CECs were 80.0 (mean: 177.5; range: 1.02-1718) cells/mL. We found no correlation between BL CECs and 3 month progression-free survival for mCRC pts treated with BEV/sorafenib (p=0.56). The absolute change and log2-fold change (FC) from BL CECs were decreasing at all time points, with the exception of cycle 1 day 3. The percent change in CEC from BL was significantly decreased in cycles 2, 3, 5, and 7 (p-values: 0.01, 0.008, 0.04, and 0.018, respectively). This remained consistent when examining the CEC log2-FC at cycles 3, 5, and 7 (p = 0.008, 0.014, and 0.0004, resp.). The CEC log2-FC was significantly decreased from BL to end of treatment draws (≤14 days) for pts off study for progression (p=0.0007), but not for pts off study for other reasons (p=0.96). CONCLUSIONS Baseline CECs do not appear to be prognostic in mCRC pts treated with a salvage protocol of BEV/sorafenib. CECs, however, decrease on this anti-angiogenic therapy. The significance of decreasing CECs is unclear and further evaluation of serial CECs to determine their predictive value is warranted.
Journal of the American Medical Informatics Association, 2021
Objective We aimed to develop a model for accurate prediction of general care inpatient deteriora... more Objective We aimed to develop a model for accurate prediction of general care inpatient deterioration. Materials and Methods Training and internal validation datasets were built using 2-year data from a quaternary hospital in the Midwest. Model training used gradient boosting and feature engineering (clinically relevant interactions, time-series information) to predict general care inpatient deterioration (resuscitation call, intensive care unit transfer, or rapid response team call) in 24 hours. Data from a tertiary care hospital in the Southwest were used for external validation. C-statistic, sensitivity, positive predictive value, and alert rate were calculated for different cutoffs and compared with the National Early Warning Score. Sensitivity analysis evaluated prediction of intensive care unit transfer or resuscitation call. Results Training, internal validation, and external validation datasets included 24 500, 25 784 and 53 956 hospitalizations, respectively. The Mayo Clini...
Despite studies that show the antitumor activity of Hsp90 inhibitors, such as geldanamycin (GA) a... more Despite studies that show the antitumor activity of Hsp90 inhibitors, such as geldanamycin (GA) and its derivative 17-allylamino-demethoxygeldanamycin (17-AAG), recent reports indicate that these inhibitors lack significant single-agent clinical activity. Resistance to Hsp90 inhibitors has been previously linked to expression of P-glycoprotein (P-gp) and the multidrug resistant (MDR) phenotype. However, the stress response induced by GA treatment can also cause resistance to Hsp90-targeted therapy. Therefore, we chose to further investigate the relative importance of P-gp and the stress response in 17-AAG resistance. Colony-forming assays revealed that high expression of P-gp could increase the 17-AAG IC50 6-fold in cells transfected with P-gp compared with parent cells. A549 cells selected for resistance to GA overexpressed P-gp, but verapamil did not reverse the resistance. These cells also overexpressed Hsp27, and Hsp70 was induced with 17-AAG treatment. When the GA and 17-AAG resistant cells were transfected with Hsp27 and/or Hsp70 small interfering RNA (siRNA), the 17-AAG IC50 decreased 10-fold compared with control transfected cells. Transfection with siRNA directed against Hsp27, Hsp70, or Hsp27 and Hsp70 also increased sensitivity to EC78, a purine scaffold-based Hsp90 inhibitor that is not a P-gp substrate. We conclude that P-gp may contribute, in part, to resistance to 17-AAG, but induction of stress response proteins, such as Hsp27 and Hsp70, by Hsp90-targeted therapy plays a larger role. Taken together, our results indicate that targeting of Hsp27 and Hsp70 should be exploited to increase the clinical efficacy of Hsp90-directed therapy. [Cancer Res 2008;68(18):7419–27]
Background: Bevacizumab (BEV), a monoclonal antibody against vascular endothelial growth factor-A... more Background: Bevacizumab (BEV), a monoclonal antibody against vascular endothelial growth factor-A (VEGF-A), is a standard component of medical therapy of metastatic colorectal cancer (mCRC). Activation of alternative angiogenesis pathways has been implicated in resistance to BEV. This phase II study examines the activity of combined vertical blockade of VEGF signaling with sorafenib and BEV as salvage therapy in patients with progressive disease (PD) on all standard therapy in mCRC. Methods: mCRC patients with documented PD on standard therapy, received sorafenib (200 mg orally twice daily, days 1-5 and 8-12) and BEV (5 mg/kg intravenously, day 1) every 2 weeks. Primary endpoint was 3-month progression-free survival (PFS) rate and secondary endpoints were overall survival (OS), response rate (RR), safety, and feasibility. Results: Of the 83 patients enrolled, 79 were evaluable. Of these, 42 (53%) were progressionfree at 3 months. Median PFS was 3.5 months and median OS was 8.3 months. One patient had a partial response and 50 patients (63.3%) had at least one stable tumor assessment. Of 79 evaluable patients, 54 (68%) experienced grade 3/4 adverse events (AEs) at least possibly related to treatment. Most frequent grade 3/4 AEs were: fatigue (24.1%), hypertension (16.5%), elevated lipase (8.9%), hand-foot skin reaction (8.9%), diarrhea (7.6%), and proteinuria (7.6%). Reasons for treatment discontinuation were PD (72%), AEs (18%), patient refusal (8%), physician decision (1%), and death (1%). Conclusions: The combination of BEV and sorafenib as salvage therapy in heavily pretreated mCRC patients is tolerable and manageable, with evidence of promising activity.
Background: MicroRNAs (miRNAs) are a class of approximately 22 nucleotide long, widely expressed ... more Background: MicroRNAs (miRNAs) are a class of approximately 22 nucleotide long, widely expressed RNA molecules that play important regulatory roles in eukaryotes. To investigate miRNA function, it is essential that methods to quantify their expression levels be available. Methods: We evaluated a new miRNA profiling platform that utilizes Illumina's existing robust DASL chemistry as the basis for the assay. Using total RNA from five colon cancer patients and four cell lines, we evaluated the reproducibility of miRNA expression levels across replicates and with varying amounts of input RNA. The beta test version was comprised of 735 miRNA targets of Illumina's miRNA profiling application. Results: Reproducibility between sample replicates within a plate was good (Spearman's correlation 0.91 to 0.98) as was the plate-to-plate reproducibility replicates run on different days (Spearman's correlation 0.84 to 0.98). To determine whether quality data could be obtained from a broad range of input RNA, data obtained from amounts ranging from 25 ng to 800 ng were compared to those obtained at 200 ng. No effect across the range of RNA input was observed. Conclusion: These results indicate that very small amounts of starting material are sufficient to allow sensitive miRNA profiling using the Illumina miRNA high-dimensional platform. Nonlinear biases were observed between replicates, indicating the need for abundance-dependent normalization. Overall, the performance characteristics of the Illumina miRNA profiling system were excellent.
Objectives-Few effective options are available for the treatment of unresectable hepatocellular c... more Objectives-Few effective options are available for the treatment of unresectable hepatocellular carcinoma (HCC). Several phase I trials suggest promising activity of a combination of gemcitabine and docetaxel. Methods-Patients with unresectable or metastatic HCC were treated with docetaxel 40 mg/m 2 (later reduced to 30 mg/m 2) and gemcitabine 800 mg/m 2 on days 1, 8 every 3 weeks. Twenty-five patients were enrolled in 26 months. Median age was 64 (range 27-78), 17 were male, 14 had liver-only disease and, 11 had extrahepatic disease. Results-Of 25 patients evaluable for the primary endpoint (response), 2 (8%) have a confirmed partial response. The median TTP is 2.76 months (95% CI 1.84-6.64 months). Median survival was 12.8 months (95% CI: 5.26-28.00). Two patients died on-study due to adverse events (1 hepatic and 1 renal failure), neither of which were attributed to the study medications. Twenty patients (81%) have experienced grade 3+ adverse events, including 11 with grade 4+ adverse events, primarily neutropenia, thrombocytopenia, diarrhea, and fatigue. 1 This study was conducted as a trial of the North Central Cancer Treatment Group and Mayo Clinic and was supported in part by
Objectives: Vascular endothelial growth factor has been shown to be overexpressed in several stud... more Objectives: Vascular endothelial growth factor has been shown to be overexpressed in several studies of hepatocellular carcinoma (HCC). Cediranib is a potent inhibitor of vascular endothelial growth factor signaling. We assessed the efficacy and toxicity of cediranib in patients with HCC. Methods: Twenty-eight patients with unresectable or metastatic HCC were enrolled in this study. Patients received 45 mg of cediranib orally, once daily, for 28-day cycles. The primary objective of this phase II study was to assess 6-month survival. Secondary objectives were to assess tumor response, time to progression, and toxicity. Results: All 28 patients were evaluable for efficacy outcomes. Twelve patients (42.9%) survived 6 months, 15 (53.6%) died within 6 months, and 1 (3.6%) was lost to follow-up before 6 months. The median overall survival was 5.8 months (95% confidence interval, 3.4-7.3 mo). No patients experienced confirmed response. The median time to progression was 2.8 months (95% confidence interval, 2.3-4.4 mo). Twenty-six patients (93%) experienced a grade 3+ adverse event with the most common adverse event s being fatigue (46%), anorexia (25%), hypertension (21%), and elevated alanine aminotransferase (18%). Conclusions: Owing to the toxicity, cediranib at this dose and schedule is not an effective treatment in patients with unresectable or metastatic HCC.
5017 Background: The majority of men with prostate cancer are diagnosed with cancers with low mor... more 5017 Background: The majority of men with prostate cancer are diagnosed with cancers with low mortality. Such men are treated with radical prostatectomy, external beam radiotherapy, or brachytherapy and followed by serum PSA evaluations. Some men with a rising PSA therapy will have local recurrence or metastasis, but many will have no other evidence of recurrent disease other than a rising PSA. The PSA doubling time has been used to determine which of these men deserve adjuvant hormonal ablation, radiation therapy, or observation. We hypothesize that additional biomarkers will predict which men with a rising PSA post-definitive therapy would benefit from additional therapy. Methods: We designed a custom array containing 526 RNA targets whose expression has been reported to be altered in association with prostate cancer progression. We included targets from Mayo Clinic prostate cancer research. Together with a second commercial array, 530 genes implicated in prostate cancer progressi...
Within the past five years studies published from this laboratory and others have identified or c... more Within the past five years studies published from this laboratory and others have identified or confirmed CD38 as a marker for aggressive disease in B cell chronic lymphocytic leukemia (B-CLL). To learn more about the possible role of CD38 in this disease, we performed gene expression profiling (GEP; Affymetrix U133A platform) on primary leukemic B cells isolated from CD38 positive and negative patients. We and others have previously shown that the leukemic compartment within some patients consists of both CD38neg and CD38pos CLL B cells. To optimize identification of differentially expressed genes associated with CD38 expression or lack thereof, we restricted our gene profiling to patient cells that were unimodally negative for CD38 and those that expressed unimodally high levels of CD38. In both groups of patients, CD19 positive cells were purified using magnetic bead cell sorting on a Miltenyi AutoMacs prior to isolation of total RNA. To determine genes that appear to be differen...
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Papers by Bruce Morlan