This study aimed to evaluate the impact of hemoglobin level on clinical outcome (local response, ... more This study aimed to evaluate the impact of hemoglobin level on clinical outcome (local response, progression-free survival, and overall survival) in patients with carcinoma of the anal canal treated with definitive chemoradiotherapy. This is a retrospective study of patients with anal cancer treated between 1992 and 2005 with definitive chemoradiotherapy at Tom Baker Cancer Centre. Patient treatment, laboratory, and outcome data were extracted from the chart. Seventy-two patients treated with definitive chemoradiotherapy were identified. The median age was 56 years, the male-to-female ratio was 1:2, and the median tumor size was 3.5 cm. At 6 weeks after the completion of chemoradiotherapy, 62% of patients (38/61) had complete clinical response, and 34% (21/61) had achieved a partial clinical response. At 3 months after treatment, complete clinical response was observed in 78% (49/63) and a partial response in 16% (10/63). The median pretreatment hemoglobin level was 138.5 g/L, and the median on-treatment hemoglobin level was 129 g/L. Distant relapse was associated with hemoglobin levels in the lowest quartiles, pretreatment and on-treatment (P = .007 and P = .008, respectively). Hemoglobin levels were not associated with response at 6 weeks or 3 months. A pretreatment hemoglobin level of <130 g/L was associated with worse progression-free and overall survival (P < .0001, both). A hemoglobin on-treatment level of <121 g/L was associated with progression-free and overall survival (P < .0001 and P = .019, respectively), when stratified by gender. Hemoglobin status was correlated with progression-free and overall survival, and distant relapse, but not clinical response, in patients with carcinoma of the anal canal treated with chemoradiotherapy. The clinically relevant cut point, and the value of correcting hemoglobin levels before or during treatment, remains to be elucidated.
The treatment of breast cancer has benefitted tremendously from the generation of estrogen recept... more The treatment of breast cancer has benefitted tremendously from the generation of estrogen receptor alpha (ERα)-targeted therapies, but disease relapse continues to pose a challenge due to intrinsic or acquired drug resistance. In an effort to delineate potential predictive biomarkers of therapy responsiveness, multiple groups have identified several uncharacterized cofactors and interacting partners of ERα, including Split Ends (SPEN), a transcriptional co-repressor. Here we demonstrate a role for SPEN in ERα-expressing breast cancers. SPEN nonsense mutations were detectable in the ERα-expressing breast cancer cell line T47D, and corresponded to undetectable protein levels. Further analysis of 101 primary breast tumors revealed that 23% displayed loss of heterozygosity at the SPEN locus and that 3-4% harbored somatically acquired mutations. A combination of in vitro and in vivo functional assays with microarray-based pathway analyses showed that SPEN functions as a tumor suppressor...
The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques
Chemoradiotherapy followed by monthly temozolomide (TMZ) is the standard of care for patients wit... more Chemoradiotherapy followed by monthly temozolomide (TMZ) is the standard of care for patients with glioblastoma multiforme (GBM). Case reports have identified GBM patients who experienced transient radiological deterioration after concurrent chemoradiotherapy which stabilized or resolved after additional cycles of adjuvant TMZ, a phenomenon known as radiographic pseudoprogression. Little is known about the natural history of radiographic pseudoprogression. We retrospectively evaluated the incidence of radiographic pseudoprogression in a population-based cohort of GBM patients and determined its relationship with outcome and MGMT promoter methylation status. Out of 43 evaluable patients, 25 (58%) exhibited radiographic progression on the first MRI after concurrent treatment. Twenty of these went on to receive adjuvant TMZ, and subsequent investigation demonstrated radiographic pseudoprogression in 10 cases (50%). Median survival (MS) was better in patients with pseudoprogression (MS ...
Bone is the most common site of breast cancer distant metastasis, affecting 50-70 % of patients w... more Bone is the most common site of breast cancer distant metastasis, affecting 50-70 % of patients who develop metastatic disease. Despite decades of informative research, the effective prevention, prediction and treatment of these lesions remains elusive. The Breast Cancer to Bone (B2B) Metastases Research Program consists of a prospective cohort of incident breast cancer patients and four sub-projects that are investigating priority areas in breast cancer bone metastases. These include the impact of lifestyle factors and inflammation on risk of bone metastases, the gene expression features of the primary tumour, the potential role for metabolomics in early detection of bone metastatic disease and the signalling pathways that drive the metastatic lesions in the bone. The B2B Research Program is enrolling a prospective cohort of 600 newly diagnosed, incident, stage I-IIIc breast cancer survivors in Alberta, Canada over a five year period. At baseline, pre-treatment/surgery blood sample...
Atypical proliferations of immature cervical squamous metaplasia were reviewed and correlated wit... more Atypical proliferations of immature cervical squamous metaplasia were reviewed and correlated with p16 and Ki-67 expression to determine whether immunoprofiling could enable more conventional classification. The longitudinal outcome of atypical immature metaplasia (AIM) and predictive role of biomarker expression were also investigated. All atypias of immature squamous metaplasia in the year 2000 were reviewed and stained with p16 and Ki-67. Biomarker features were evaluated and the Ki-67 index calculated. Diagnoses were correlated with the immunoprofile of each antibody, both separately and combined. The progression to squamous intraepithelial lesion (SIL) of lesions reclassified as AIM was determined, and biomarker immunoprofiles were correlated with outcome. The 172 atypias were reviewed as 3 (1.7%) negative, 54 (31.4%) benign, 60 (34.9%) AIM, 43 (25%) low-grade SIL (LSIL), and 12 (6.9%) high-grade SIL (HSIL). HSIL correlated significantly with a combined high index (>15%) and p16 diffusely positive profile (P = .01). Benign diagnoses correlated significantly with a low index (1%-15%) and p16 negative or focal profile (P = .01). AIM and LSIL correlations were not significant, but their profiles were very variable and nearly identical. AIM was the only pathology in 43 cases, and follow-up was available for 32 (74.4%). SIL developed in 66% (50% LSIL and 16% HSIL) and p16 positivity correlated (P = .02). p16 and Ki-67 immunoprofiling are reliable in reclassifying some atypical proliferations of immature squamous metaplasia as HSIL and some as benign. The similarity between AIM and LSIL in regard to their immunoprofile as well as outcome suggests AIM is a morphological type of LSIL.
2007 IEEE Antennas and Propagation International Symposium, 2007
Mariya Lazebnik(1)*, Cynthia B. Watkins(1), Susan C. Hagness(1), and John H. Booske(1) (1) Depart... more Mariya Lazebnik(1)*, Cynthia B. Watkins(1), Susan C. Hagness(1), and John H. Booske(1) (1) Department of Electrical and Computer Engineering, University of Wisconsin 1415 Engineering Dr., Madison, WI 53706 (hagness@engr.wisc.edu) ... Dijana Popovic(2), Leah ...
INhibitor of Growth 1 (ING1) expression is repressed in breast carcinomas, but its role in breast... more INhibitor of Growth 1 (ING1) expression is repressed in breast carcinomas, but its role in breast cancer development and metastasis is unknown. ING1 levels were quantified in >500 patient samples using automated quantitative fluorescence immunohistochemistry, and data were analysed for correlations to patient outcome. Effects of altering ING levels were examined in microarrays and metastasis assays in vitro, and in a mouse metastasis model in vivo. ING1 levels were lower in tumors compared to adjacent normal breast tissue and correlated with tumor size (p=0.019) and distant recurrence (p=0.001) in ER- or Her2+ patients. In these patients ING1 predicted disease-specific and distant metastasis-free survival. Transcriptome analysis showed that the pathway most affected by ING1 was breast cancer (p = 0.0008). Decreasing levels of ING1 increased, and increasing levels decreased, migration and invasion of MDA-MB231 cells in vitro. ING1 overexpression also blocked cancer cell metastasis...
ABSTRACT Background Anal cancer accounts for 4% of all lower gastrointestinal tract malignancies ... more ABSTRACT Background Anal cancer accounts for 4% of all lower gastrointestinal tract malignancies in the US. One of the most important predictors of prognosis among anal cancer patients is the size of the primary tumour. Tumours with diameters >5cm have poorer disease-free survival than those with smaller tumours. Understanding the biological changes associated with tumour growth may provide information to guide therapy and improve patient outcomes. DNA methylation changes are critical epigenetic events in cancer development. Methods: In this study we sought to characterise the epigenomic signatures associated with anal cancer tumour size (≤5cm vs >5cm) in FFPE tissues from 121 patients (≤5cm=88; >5cm=33) who participated in the RTOG 98-11 cooperative group anal cancer clinical trial. Differential methylation, examined at >450000 CpG loci using the Illumina Human Methylation 450 Array, were compared between the two groups using Mann-Whitney test (significance=P<0.001 and difference in methylation β-value >0.1). Results: This study included 74 women and 47 men with a median age of 54 years. A total of 86 CpG loci were differentially methylated (78 increased and 8 decreased) in large vs small tumours. Genes harbouring CpG sites that were among the most highly differentially methylated included those associated with WNT signalling (FZD10, WNT9A), microRNAs (MIR200A) and novel methylated targets (PON3). Conclusions: These data provide evidence that epigenetic events likely play a significant role in the progression of anal SCC and may serve as biomarkers of prognosis. Similar epigenomic approaches may be useful at earlier stages of anal neoplastic progression for application in screening and early detection.
No data on mortality for Crohn's disease are available from southern Europe. Five hundred... more No data on mortality for Crohn's disease are available from southern Europe. Five hundred and thirty-one patients with Crohn's disease were observed in our unit between 1973 and 1993. In 325 patients the first diagnosis was made in our hospital. In this consecutive incidence series, in which the follow-up was 99% complete, the standardized mortality rate (SMR) was calculated. Nine deaths were observed, against 9.25 expected. The SMR was 0.97 (95% confidence interval (CI), 0.4-1.8). The relative risk of dying was significantly higher in the female group in the first 5 years after diagnosis (SMR, 10.3; 95% CI, 2.30-30.2). There was an excess of deaths from tumors of the digestive organs (1 observed, 0.37 expected). These results show that in our geographic area the mortality from Crohn's disease was not increased as shown in other community studies.
This study aimed to evaluate the impact of hemoglobin level on clinical outcome (local response, ... more This study aimed to evaluate the impact of hemoglobin level on clinical outcome (local response, progression-free survival, and overall survival) in patients with carcinoma of the anal canal treated with definitive chemoradiotherapy. This is a retrospective study of patients with anal cancer treated between 1992 and 2005 with definitive chemoradiotherapy at Tom Baker Cancer Centre. Patient treatment, laboratory, and outcome data were extracted from the chart. Seventy-two patients treated with definitive chemoradiotherapy were identified. The median age was 56 years, the male-to-female ratio was 1:2, and the median tumor size was 3.5 cm. At 6 weeks after the completion of chemoradiotherapy, 62% of patients (38/61) had complete clinical response, and 34% (21/61) had achieved a partial clinical response. At 3 months after treatment, complete clinical response was observed in 78% (49/63) and a partial response in 16% (10/63). The median pretreatment hemoglobin level was 138.5 g/L, and the median on-treatment hemoglobin level was 129 g/L. Distant relapse was associated with hemoglobin levels in the lowest quartiles, pretreatment and on-treatment (P = .007 and P = .008, respectively). Hemoglobin levels were not associated with response at 6 weeks or 3 months. A pretreatment hemoglobin level of <130 g/L was associated with worse progression-free and overall survival (P < .0001, both). A hemoglobin on-treatment level of <121 g/L was associated with progression-free and overall survival (P < .0001 and P = .019, respectively), when stratified by gender. Hemoglobin status was correlated with progression-free and overall survival, and distant relapse, but not clinical response, in patients with carcinoma of the anal canal treated with chemoradiotherapy. The clinically relevant cut point, and the value of correcting hemoglobin levels before or during treatment, remains to be elucidated.
The treatment of breast cancer has benefitted tremendously from the generation of estrogen recept... more The treatment of breast cancer has benefitted tremendously from the generation of estrogen receptor alpha (ERα)-targeted therapies, but disease relapse continues to pose a challenge due to intrinsic or acquired drug resistance. In an effort to delineate potential predictive biomarkers of therapy responsiveness, multiple groups have identified several uncharacterized cofactors and interacting partners of ERα, including Split Ends (SPEN), a transcriptional co-repressor. Here we demonstrate a role for SPEN in ERα-expressing breast cancers. SPEN nonsense mutations were detectable in the ERα-expressing breast cancer cell line T47D, and corresponded to undetectable protein levels. Further analysis of 101 primary breast tumors revealed that 23% displayed loss of heterozygosity at the SPEN locus and that 3-4% harbored somatically acquired mutations. A combination of in vitro and in vivo functional assays with microarray-based pathway analyses showed that SPEN functions as a tumor suppressor...
The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques
Chemoradiotherapy followed by monthly temozolomide (TMZ) is the standard of care for patients wit... more Chemoradiotherapy followed by monthly temozolomide (TMZ) is the standard of care for patients with glioblastoma multiforme (GBM). Case reports have identified GBM patients who experienced transient radiological deterioration after concurrent chemoradiotherapy which stabilized or resolved after additional cycles of adjuvant TMZ, a phenomenon known as radiographic pseudoprogression. Little is known about the natural history of radiographic pseudoprogression. We retrospectively evaluated the incidence of radiographic pseudoprogression in a population-based cohort of GBM patients and determined its relationship with outcome and MGMT promoter methylation status. Out of 43 evaluable patients, 25 (58%) exhibited radiographic progression on the first MRI after concurrent treatment. Twenty of these went on to receive adjuvant TMZ, and subsequent investigation demonstrated radiographic pseudoprogression in 10 cases (50%). Median survival (MS) was better in patients with pseudoprogression (MS ...
Bone is the most common site of breast cancer distant metastasis, affecting 50-70 % of patients w... more Bone is the most common site of breast cancer distant metastasis, affecting 50-70 % of patients who develop metastatic disease. Despite decades of informative research, the effective prevention, prediction and treatment of these lesions remains elusive. The Breast Cancer to Bone (B2B) Metastases Research Program consists of a prospective cohort of incident breast cancer patients and four sub-projects that are investigating priority areas in breast cancer bone metastases. These include the impact of lifestyle factors and inflammation on risk of bone metastases, the gene expression features of the primary tumour, the potential role for metabolomics in early detection of bone metastatic disease and the signalling pathways that drive the metastatic lesions in the bone. The B2B Research Program is enrolling a prospective cohort of 600 newly diagnosed, incident, stage I-IIIc breast cancer survivors in Alberta, Canada over a five year period. At baseline, pre-treatment/surgery blood sample...
Atypical proliferations of immature cervical squamous metaplasia were reviewed and correlated wit... more Atypical proliferations of immature cervical squamous metaplasia were reviewed and correlated with p16 and Ki-67 expression to determine whether immunoprofiling could enable more conventional classification. The longitudinal outcome of atypical immature metaplasia (AIM) and predictive role of biomarker expression were also investigated. All atypias of immature squamous metaplasia in the year 2000 were reviewed and stained with p16 and Ki-67. Biomarker features were evaluated and the Ki-67 index calculated. Diagnoses were correlated with the immunoprofile of each antibody, both separately and combined. The progression to squamous intraepithelial lesion (SIL) of lesions reclassified as AIM was determined, and biomarker immunoprofiles were correlated with outcome. The 172 atypias were reviewed as 3 (1.7%) negative, 54 (31.4%) benign, 60 (34.9%) AIM, 43 (25%) low-grade SIL (LSIL), and 12 (6.9%) high-grade SIL (HSIL). HSIL correlated significantly with a combined high index (>15%) and p16 diffusely positive profile (P = .01). Benign diagnoses correlated significantly with a low index (1%-15%) and p16 negative or focal profile (P = .01). AIM and LSIL correlations were not significant, but their profiles were very variable and nearly identical. AIM was the only pathology in 43 cases, and follow-up was available for 32 (74.4%). SIL developed in 66% (50% LSIL and 16% HSIL) and p16 positivity correlated (P = .02). p16 and Ki-67 immunoprofiling are reliable in reclassifying some atypical proliferations of immature squamous metaplasia as HSIL and some as benign. The similarity between AIM and LSIL in regard to their immunoprofile as well as outcome suggests AIM is a morphological type of LSIL.
2007 IEEE Antennas and Propagation International Symposium, 2007
Mariya Lazebnik(1)*, Cynthia B. Watkins(1), Susan C. Hagness(1), and John H. Booske(1) (1) Depart... more Mariya Lazebnik(1)*, Cynthia B. Watkins(1), Susan C. Hagness(1), and John H. Booske(1) (1) Department of Electrical and Computer Engineering, University of Wisconsin 1415 Engineering Dr., Madison, WI 53706 (hagness@engr.wisc.edu) ... Dijana Popovic(2), Leah ...
INhibitor of Growth 1 (ING1) expression is repressed in breast carcinomas, but its role in breast... more INhibitor of Growth 1 (ING1) expression is repressed in breast carcinomas, but its role in breast cancer development and metastasis is unknown. ING1 levels were quantified in >500 patient samples using automated quantitative fluorescence immunohistochemistry, and data were analysed for correlations to patient outcome. Effects of altering ING levels were examined in microarrays and metastasis assays in vitro, and in a mouse metastasis model in vivo. ING1 levels were lower in tumors compared to adjacent normal breast tissue and correlated with tumor size (p=0.019) and distant recurrence (p=0.001) in ER- or Her2+ patients. In these patients ING1 predicted disease-specific and distant metastasis-free survival. Transcriptome analysis showed that the pathway most affected by ING1 was breast cancer (p = 0.0008). Decreasing levels of ING1 increased, and increasing levels decreased, migration and invasion of MDA-MB231 cells in vitro. ING1 overexpression also blocked cancer cell metastasis...
ABSTRACT Background Anal cancer accounts for 4% of all lower gastrointestinal tract malignancies ... more ABSTRACT Background Anal cancer accounts for 4% of all lower gastrointestinal tract malignancies in the US. One of the most important predictors of prognosis among anal cancer patients is the size of the primary tumour. Tumours with diameters >5cm have poorer disease-free survival than those with smaller tumours. Understanding the biological changes associated with tumour growth may provide information to guide therapy and improve patient outcomes. DNA methylation changes are critical epigenetic events in cancer development. Methods: In this study we sought to characterise the epigenomic signatures associated with anal cancer tumour size (≤5cm vs >5cm) in FFPE tissues from 121 patients (≤5cm=88; >5cm=33) who participated in the RTOG 98-11 cooperative group anal cancer clinical trial. Differential methylation, examined at >450000 CpG loci using the Illumina Human Methylation 450 Array, were compared between the two groups using Mann-Whitney test (significance=P<0.001 and difference in methylation β-value >0.1). Results: This study included 74 women and 47 men with a median age of 54 years. A total of 86 CpG loci were differentially methylated (78 increased and 8 decreased) in large vs small tumours. Genes harbouring CpG sites that were among the most highly differentially methylated included those associated with WNT signalling (FZD10, WNT9A), microRNAs (MIR200A) and novel methylated targets (PON3). Conclusions: These data provide evidence that epigenetic events likely play a significant role in the progression of anal SCC and may serve as biomarkers of prognosis. Similar epigenomic approaches may be useful at earlier stages of anal neoplastic progression for application in screening and early detection.
No data on mortality for Crohn's disease are available from southern Europe. Five hundred... more No data on mortality for Crohn's disease are available from southern Europe. Five hundred and thirty-one patients with Crohn's disease were observed in our unit between 1973 and 1993. In 325 patients the first diagnosis was made in our hospital. In this consecutive incidence series, in which the follow-up was 99% complete, the standardized mortality rate (SMR) was calculated. Nine deaths were observed, against 9.25 expected. The SMR was 0.97 (95% confidence interval (CI), 0.4-1.8). The relative risk of dying was significantly higher in the female group in the first 5 years after diagnosis (SMR, 10.3; 95% CI, 2.30-30.2). There was an excess of deaths from tumors of the digestive organs (1 observed, 0.37 expected). These results show that in our geographic area the mortality from Crohn's disease was not increased as shown in other community studies.
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Papers by Anthony Magliocco