Motomi Mori - Academia.edu (original) (raw)

Papers by Motomi Mori

Immunotherapies targeting aspects of T cell functionality are efficacious in many solid tumors, b... more Immunotherapies targeting aspects of T cell functionality are efficacious in many solid tumors, but pancreatic ductal adenocarcinoma (PDAC) remains refractory to these treatments. Deeper understanding of the PDAC immune ecosystem is needed to identify additional therapeutic targets and predictive biomarkers for therapeutic response and resistance monitoring. To address these needs, we quantitatively evaluated leukocyte contexture in 135 human PDACs at single-cell resolution by profiling density and spatial distribution of myeloid and lymphoid cells within histopathologically defined regions of surgical resections from treatment-naive and presurgically (neoadjuvant)-treated patients and biopsy specimens from metastatic PDAC. Resultant data establish an immune atlas of PDAC heterogeneity, identify leukocyte features correlating with clinical outcomes, and, through an in silico study, provide guidance for use of PDAC tissue microarrays to optimally measure intratumoral immune heterogeneity. Atlas data have direct applicability as a reference for evaluating immune responses to investigational neoadjuvant PDAC therapeutics where pretherapy baseline specimens are not available. SigniFiCAnCe: We provide a phenotypic and spatial immune atlas of human PDAC identifying leukocyte composition at steady state and following standard neoadjuvant therapies. These data have broad utility as a resource that can inform on leukocyte responses to emerging therapies where baseline tissues were not acquired.

American journal of clinical oncology, Jan 18, 2018

Colorectal cancer (CRC) is the second leading cause of cancer death in the United States. Cycloox... more Colorectal cancer (CRC) is the second leading cause of cancer death in the United States. Cyclooxygenase-2 (COX-2) overexpression is associated with increased tumor invasiveness and proliferation in CRC, and COX-2 inhibition has demonstrated chemopreventive activity. This study investigated the addition of celecoxib, a selective COX-2 inhibitor, to the irinotecan, 5-fluorouracil, and leucovorin (IFL) regimen for patients with previously untreated metastatic CRC. Forty-seven patients enrolled in this single-arm phase II study received celecoxib at 400 mg orally twice daily in combination with weekly irinotecan (125 mg/m), 5-fluorouracil (500 mg/m), and leucovorin (20 mg/m) for 4 weeks every 6 weeks. The primary endpoint was response rate (RR) as measured by Response Evaluation Criteria in Solid Tumors. The protocol was amended midway to additionally exclude patients with Eastern Cooperative Oncology Group performance status 2 and require all patients with specific cardiovascular risk...

PLoS ONE, 2013

Following transplantation of hematopoietic lineage cells, genetic markers unique to the transplan... more Following transplantation of hematopoietic lineage cells, genetic markers unique to the transplanted cells have been detected in non-hematopoietic recipient cells of human liver, vascular endothelium, intestinal epithelium and brain. The underlying mechanisms by which this occurs are unclear. Evidence from mice suggests it is due in part to fusion between cells of hematopoietic and non-hematopoietic origins; however, direct evidence for this in humans is scant. Here, by quantitative and statistical analysis of X-and Y-chromosome numbers in epithelial and non-epithelial intestinal cells from gender-mismatched hematopoietic cell transplant patients, we provide evidence that transplanted cells of the hematopoietic lineage incorporate into human intestinal epithelium through cell fusion. This is the first definitive identification of cell fusion between hematopoietic cells and any epithelial cell type in humans, and provides the basis for further understanding the physiological and potential pathological consequences of cell fusion in humans.

Journal of Virology, 2011

A major goal of human immunodeficiency virus type 1 (HIV-1) vaccine efforts is the design of Enve... more A major goal of human immunodeficiency virus type 1 (HIV-1) vaccine efforts is the design of Envelope (Env)-based immunogens effective at eliciting heterologous or broad neutralizing antibodies (NAbs). We hypothesized that programming the B-cell response could be achieved by sequentially exposing the host to a collection of env variants representing the viral quasispecies members isolated from an individual that developed broad NAbs over time. This ordered vaccine approach (sequential) was compared to exposure to a cocktail of env clones (mixture) and to a single env variant (clonal). The three strategies induced comparable levels of the autologous and heterologous neutralization of tier 1 pseudoviruses. Sequential and mixture exposure to quasispecies led to epitope targeting similar to that observed in the simian-human immunodeficiency virus (SHIV)-infected animal from which the env variants were cloned, while clonal and sequential exposure led to greater antibody maturation than t...

The Journal of Immunology, 2010

The second and sixteenth authors' names were published incorrectly. The correct names are Susan S... more The second and sixteenth authors' names were published incorrectly. The correct names are Susan Smyk-Pearson and Michael K. Axthelm.

Journal of Clinical Oncology, 2004

Purpose Neuroblastoma (NB) is a common childhood malignancy characterized by heterogeneous clinic... more Purpose Neuroblastoma (NB) is a common childhood malignancy characterized by heterogeneous clinical behavior. The purpose of this study was to identify potential NB biomarkers that may improve outcome prediction. Patients and Methods The suppression subtractive hybridization (SSH) technique was used to identify the genes differentially expressed between NB and control tissue. RNA isolated from 235 primary NB tumor samples obtained from the Children's Cancer Group was evaluated for expression of the candidate markers using quantitative reverse transcriptase polymerase chain reaction (Taqman assays). The association between the mRNA expression levels in the identified candidate genes and clinical outcome was evaluated. Results SSH analysis identified differential expression of members of the GABAergic gene family in NB. Lower levels of gamma-aminobutyric acid (GABA) receptor–associated protein (GABARAP) gene expression predict decreased survival among all patients. GABAA δ recepto...

Cancer, Jan 16, 2016

Prior research has identified unrealistic optimism as a bias that might impair informed consent a... more Prior research has identified unrealistic optimism as a bias that might impair informed consent among patient-subjects in early-phase oncology trials. However, optimism is not a unitary construct; it also can be defined as a general disposition, or what is called dispositional optimism. The authors assessed whether dispositional optimism would be related to high expectations for personal therapeutic benefit reported by patient-subjects in these trials but not to the therapeutic misconception. The authors also assessed how dispositional optimism related to unrealistic optimism. Patient-subjects completed questionnaires designed to measure expectations for therapeutic benefit, dispositional optimism, unrealistic optimism, and the therapeutic misconception. Dispositional optimism was found to be significantly associated with higher expectations for personal therapeutic benefit (Spearman rank correlation coefficient [r], 0.333; P<.0001), but was not associated with the therapeutic mi...

Nutrition and cancer

Animal and human studies suggest fish oil and green tea may have protective effect on prostate ca... more Animal and human studies suggest fish oil and green tea may have protective effect on prostate cancer. Fatty acid synthase (FAS) has been hypothesized to be linked to chemoprotective effects of both compounds. This study evaluated the independent and joint effects of fish oil (FO) and green tea supplement (epigallocatechin-3-gallate, EGCG) on FAS and Ki-67 levels in prostate tissue. Through a double-blinded, randomized controlled trial with 2 × 2 factorial design, 89 men scheduled for repeat prostate biopsy following an initial negative prostate biopsy were randomized into either FO alone (1.9 g DHA + EPA/day), EGCG alone (600 mg/day), a combination of FO and EGCG, or placebo. We used linear mixed-effects models to test the differences of prostate tissue FAS and Ki-67 by immunohistochemistry between pre- and post-intervention within each group, as well as between treatment groups. Results did not show significant difference among treatment groups in pre-to-post-intervention changes ...

Prostaglandins, Leukotrienes and Essential Fatty Acids, 2010

The role of fatty acids (FA) in prostate carcinogenesis is unclear. Interest in the interrelation... more The role of fatty acids (FA) in prostate carcinogenesis is unclear. Interest in the interrelationship among different types of FA has resulted in new analytic approaches to FA and their role in cancer development. We evaluated the association between erythrocyte FA and prostate cancer in 127 prostate cancer patients and 183 screen negative controls. We present three approaches to analyses of the FA and prostate cancer association; 1) individual or common groups of FA, 2) biologically meaningful FA ratios and 3) principal components analysis. Monounsaturated FA and the alpha-linolenic:eicosapentaenoic ratio were associated with reduced risk of prostate cancer. However, Factor 1, which was strongly correlated with some long chain saturated FA, was associated with an increased risk of prostate cancer. We provide an example of modeling FA and their interrelationships on the risk of prostate cancer. Comparing three approaches suggests the importance of considering the impact of the entire fatty acid profile in disease prevention.

Journal of Clinical Oncology, 2011

178 Background: Agent Orange (AO), a defoliate contaminated with the known carcinogen dioxin, has... more 178 Background: Agent Orange (AO), a defoliate contaminated with the known carcinogen dioxin, has become a prominent concern as veterans of the Vietnam War who were exposed to AO are now reaching the age at which prostate cancer is most prevalent. While sufficient evidence has linked AO exposure to many diseases, only limited but suggestive evidence exists to support a positive association between AO and prostate cancer. Despite mixed findings, recent studies have found that the risk of prostate cancer in those exposed to AO was as high as twice the risk in those not exposed. The goal of this study was to examine this association between AO exposure and prostate cancer in a cohort of men referred for a prostate biopsy. Methods: In this retrospective cohort-design, risk factors were identified using historical clinical data from a population of veterans referred to the Portland VA Hospital for a prostate biopsy between 1993 and 2010. In addition to AO exposure, covariates included pr...

Journal of Clinical Oncology, 2004

Purpose Adverse events in chemotherapy clinical trials are assessed and reported by clinicians, y... more Purpose Adverse events in chemotherapy clinical trials are assessed and reported by clinicians, yet clinician accuracy in assessing symptoms has been questioned. We compared patient reporting of eight symptoms using a validated instrument, the European Organization for the Research and Treatment of Cancer Quality-of-Life Questionnaire C30 (QLQ-C30 or QLQ) with physicians' reporting of the same symptoms in the study's adverse events log. Patients and Methods Thirty-seven men with metastatic, androgen-independent prostate cancer enrolled onto a phase II trial of weekly calcitriol and docetaxel completed the QLQ every 4 weeks for up to 28 weeks. A patient-reported symptom was defined as an increase in a QLQ symptom score by at least 10 points (0 to 100 scale), sustained for at least 4 weeks. A physician-reported symptom was considered present if it was ever documented in the adverse event log. Results Forty-nine (new or worsened) symptoms were detected by both physician and QLQ...

Blood, 2004

We followed 141 patients treated with imatinib mesylate (> 300 mg) for chronicphase chronic my... more We followed 141 patients treated with imatinib mesylate (> 300 mg) for chronicphase chronic myelogenous leukemia (CML) following failure of treatment with interferon. During 12 months from the start of imatinib mesylate treatment, 96.5% achieved a complete hematologic response, 47.0% achieved a major cytogenetic response, and 32.4% achieved a complete cytogenetic response. The proportion of patients with hematologic relapse was 10.9% at 12 months and 14.6% at 18 months. In a univariate Cox regression analysis, the only pretreatment characteristics that correlated with an increased risk of hematologic relapse were hemoglobin level less than 120 g/L (12 g/dL) (P = .02), increased bands in the peripheral blood (P = .01), and clonal evolution (P < .0001). In a multivariate analysis, an elevated platelet count (P = .03) and clonal evolution (P < .0001) were the only significant factors for hematologic relapse. During treatment, the absence of a major cytogenetic response within ...

Cancer, 2012

Purpose-To determine, in rural settings, the relationship between the type and status of insuranc... more Purpose-To determine, in rural settings, the relationship between the type and status of insurance coverage and being up-to-date for breast, cervical, and colorectal cancer screening. Methods-Four primary care practices in two rural Oregon communities participated. Medical chart reviews conducted between October 2008 and August 2009 assessed insurance coverage and up-to-date status for breast, cervical, and colorectal cancer screening. Inclusion criteria involved having at least one healthcare visit in the past five years, and being age 55 or older for eligibility of study services. Results-Most patients were female aged 55-70, employed or retired, had private health insurance and an average of 2.5 co-morbid conditions. The overall proportion of eligible women up-to-date for cervical cancer screening was 30%: 27% of women were up-to-date for clinical breast exam, 37% for mammography and 19% for both mammography and clinical breast exam. Thirty-eight percent of men and 35% of women were up-to-date for colorectal cancer screening using any test at appropriate screening intervals. In general, having any insurance versus being

Pediatric Blood & Cancer, 2009

Background-Residual disease or rapidity of response to induction therapy is among the most powerf... more Background-Residual disease or rapidity of response to induction therapy is among the most powerful predictors of outcome in pediatric Acute Lymphoblastic Leukemia (ALL). Method-Utilizing a multiparameter flow cytometric chemosensitivity assay (FCCA), we studied the relationship between in vitro drug sensitivity of diagnostic leukemic blasts from 30 children with ALL and rapidity of response to induction therapy. We also analyzed the in vitro drug sensitivity of de novo leukemic blasts among various clinical subsets. Results-Compared to rapid early responders (RER), slow early responders (SER) had a significantly greater in vitro drug resistance to Dexamethasone (DEX) (P = 0.04) and Prednisone (P = 0.05). The studies with all other drugs showed a non-significant trend with the SER having a higher in vitro drug resistance compared to the RER. Risk group stratified analyses indicated that in vitro resistance to Asparaginase (ASP), DEX, and Vincristine (VCR) were each significantly related to having very high risk ALL. Additionally, a significantly higher in vitro drug resistance to ASP and VCR was associated with unfavorable lymphoblast genetics and ultimate relapse. Conclusion-Our data indicate that this FCCA is a potentially simple and rapid method to detect inherent resistance to initial ALL therapy very early in induction, thus allowing for treatment modification shortly thereafter.

Blood, 2002

In chronic myelogenous leukemia (CML), the development of chromosomal abnormalities in addition t... more In chronic myelogenous leukemia (CML), the development of chromosomal abnormalities in addition to the Philadelphia chromosome (clonal evolution) is considered by many to be a feature of accelerated phase (AP). Imatinib mesylate (STI571), a selective inhibitor of the Bcr-Abl tyrosine kinase, has significant activity in AP CML. As clonal evolution could allow Bcr-Abl independent proliferation, we analyzed its impact on the outcome of 71 AP patients treated with 600 mg of imatinib mesylate. Fifteen patients had clonal evolution alone (AP-CE), 32 had AP features but no evidence of clonal evolution (HEM-AP), and 24 had AP features plus clonal evolution (HEM-AP + CE). Of the AP-CE patients, 73% had a major cytogenetic response, compared with 31% of the HEM-AP patients (P = .043) and 12.5% of the HEM-AP + CE patients (P = .007). Complete cytogenetic responses were seen in 60% of AP-CE patients, compared with 31% of HEM-AP patients (P = .19) and 8% of HEM-AP + CE patients (P < .001). Wi...

Blood, 2006

Although most patients with chronic myeloid leukemia (CML) treated with imatinib mesylate achieve... more Although most patients with chronic myeloid leukemia (CML) treated with imatinib mesylate achieve a complete cytogenetic response (CCR), some patients will relapse. To determine the potential of real-time quantitative BCR-ABL reverse transcriptase–polymerase chain reaction (RT-PCR) to predict the duration of continued CCR, we monitored 85 patients treated with imatinib mesylate who achieved a CCR. With a median follow-up of 13 months after CCR (29 months after imatinib mesylate; median 6 RQ-PCR assays), 23 patients (27%) had disease progression (predominantly loss of CCR). Compared with the median baseline level of BCR-ABL mRNA, 42% of patients achieved at least a 2-log molecular response at the time of first reaching CCR. Failure to achieve a 2-log response at the time of CCR was an independent predictive marker of subsequent progression-free survival (hazard ratio = 5.8; 95% CI, 1.7-20; P = .005). After CCR, BCR-ABL mRNA levels progressively declined for at least the next 15 month...

Aging Cell, 2008

We have recently shown in non-human primates that caloric restriction (CR) initiated during adult... more We have recently shown in non-human primates that caloric restriction (CR) initiated during adulthood can delay T-cell aging and preserve naïve CD8 and CD4 T cells into advanced age. An important question is whether CR can be initiated at any time in life, and whether age at the time of onset would modulate beneficial effects of CR. In the current study we evaluated the impact of CR started before puberty or during advanced age on T cell senescence and compared it to the effects of CR started in early adulthood. Our data demonstrate that the beneficial effects of adult onset CR upon T-cell aging were lost by both early and late CR onset. In fact, some of our results suggest that inappropriate initiation of CR may be harmful to the maintenance of T cell function. This suggests that there may be an optimal window during adulthood where CR can delay immune senescence and improve correlates of immunity in primates.

Proceedings of the National Academy of Sciences of the United States of America, Sep 7, 2017

Translating the genetic and epigenetic heterogeneity underlying human cancers into therapeutic st... more Translating the genetic and epigenetic heterogeneity underlying human cancers into therapeutic strategies is an ongoing challenge. Large-scale sequencing efforts have uncovered a spectrum of mutations in many hematologic malignancies, including acute myeloid leukemia (AML), suggesting that combinations of agents will be required to treat these diseases effectively. Combinatorial approaches will also be critical for combating the emergence of genetically heterogeneous subclones, rescue signals in the microenvironment, and tumor-intrinsic feedback pathways that all contribute to disease relapse. To identify novel and effective drug combinations, we performed ex vivo sensitivity profiling of 122 primary patient samples from a variety of hematologic malignancies against a panel of 48 drug combinations. The combinations were designed as drug pairs that target nonoverlapping biological pathways and comprise drugs from different classes, preferably with Food and Drug Administration approva...

Experimental Hematology, 2016

Recent large cohort studies revealed that healthy older individuals harbor somatic mutations that... more Recent large cohort studies revealed that healthy older individuals harbor somatic mutations that increase their risk for hematologic malignancy and all-cause cardiovascular deaths. The majority of these mutations are in chromatin and epigenetic regulatory genes (CERGs). CERGs play a key role in regulating DNA methylation (DNMT3A and TET2) or histone function (ASXL1) and in clonal proliferation of hematopoietic stem cells. We hypothesize that older women demonstrating

Diseases of the Colon & Rectum, 2018

BACKGROUND: microRNAs are dysregulated in colorectal cancer and subsets correlated with advanced ... more BACKGROUND: microRNAs are dysregulated in colorectal cancer and subsets correlated with advanced tumor stage and metastasis. Data are lacking on microRNA dysregulation from early to late stage disease. OBJECTIVE: Identify a microRNA signature associated with the primary tumor and metastatic site in stage IV disease. Examine whether the signature is evident in earlier stages. DESIGN: A microRNA profile was generated, then explored in normal colon tissue (N = 5), early stage (stage I & II, N = 10), and late stage (stage III & IV, N = 14) colorectal primary tumors via polymerase chain reaction to delineate molecular events that may promote colorectal carcinogenesis. SETTINGS: Genome-wide microRNA expression profiling was performed on fourteen patientmatched stage IV primary colorectal cancer tumors and corresponding liver metastases.

Immunotherapies targeting aspects of T cell functionality are efficacious in many solid tumors, b... more Immunotherapies targeting aspects of T cell functionality are efficacious in many solid tumors, but pancreatic ductal adenocarcinoma (PDAC) remains refractory to these treatments. Deeper understanding of the PDAC immune ecosystem is needed to identify additional therapeutic targets and predictive biomarkers for therapeutic response and resistance monitoring. To address these needs, we quantitatively evaluated leukocyte contexture in 135 human PDACs at single-cell resolution by profiling density and spatial distribution of myeloid and lymphoid cells within histopathologically defined regions of surgical resections from treatment-naive and presurgically (neoadjuvant)-treated patients and biopsy specimens from metastatic PDAC. Resultant data establish an immune atlas of PDAC heterogeneity, identify leukocyte features correlating with clinical outcomes, and, through an in silico study, provide guidance for use of PDAC tissue microarrays to optimally measure intratumoral immune heterogeneity. Atlas data have direct applicability as a reference for evaluating immune responses to investigational neoadjuvant PDAC therapeutics where pretherapy baseline specimens are not available. SigniFiCAnCe: We provide a phenotypic and spatial immune atlas of human PDAC identifying leukocyte composition at steady state and following standard neoadjuvant therapies. These data have broad utility as a resource that can inform on leukocyte responses to emerging therapies where baseline tissues were not acquired.

American journal of clinical oncology, Jan 18, 2018

Colorectal cancer (CRC) is the second leading cause of cancer death in the United States. Cycloox... more Colorectal cancer (CRC) is the second leading cause of cancer death in the United States. Cyclooxygenase-2 (COX-2) overexpression is associated with increased tumor invasiveness and proliferation in CRC, and COX-2 inhibition has demonstrated chemopreventive activity. This study investigated the addition of celecoxib, a selective COX-2 inhibitor, to the irinotecan, 5-fluorouracil, and leucovorin (IFL) regimen for patients with previously untreated metastatic CRC. Forty-seven patients enrolled in this single-arm phase II study received celecoxib at 400 mg orally twice daily in combination with weekly irinotecan (125 mg/m), 5-fluorouracil (500 mg/m), and leucovorin (20 mg/m) for 4 weeks every 6 weeks. The primary endpoint was response rate (RR) as measured by Response Evaluation Criteria in Solid Tumors. The protocol was amended midway to additionally exclude patients with Eastern Cooperative Oncology Group performance status 2 and require all patients with specific cardiovascular risk...

PLoS ONE, 2013

Following transplantation of hematopoietic lineage cells, genetic markers unique to the transplan... more Following transplantation of hematopoietic lineage cells, genetic markers unique to the transplanted cells have been detected in non-hematopoietic recipient cells of human liver, vascular endothelium, intestinal epithelium and brain. The underlying mechanisms by which this occurs are unclear. Evidence from mice suggests it is due in part to fusion between cells of hematopoietic and non-hematopoietic origins; however, direct evidence for this in humans is scant. Here, by quantitative and statistical analysis of X-and Y-chromosome numbers in epithelial and non-epithelial intestinal cells from gender-mismatched hematopoietic cell transplant patients, we provide evidence that transplanted cells of the hematopoietic lineage incorporate into human intestinal epithelium through cell fusion. This is the first definitive identification of cell fusion between hematopoietic cells and any epithelial cell type in humans, and provides the basis for further understanding the physiological and potential pathological consequences of cell fusion in humans.

Journal of Virology, 2011

A major goal of human immunodeficiency virus type 1 (HIV-1) vaccine efforts is the design of Enve... more A major goal of human immunodeficiency virus type 1 (HIV-1) vaccine efforts is the design of Envelope (Env)-based immunogens effective at eliciting heterologous or broad neutralizing antibodies (NAbs). We hypothesized that programming the B-cell response could be achieved by sequentially exposing the host to a collection of env variants representing the viral quasispecies members isolated from an individual that developed broad NAbs over time. This ordered vaccine approach (sequential) was compared to exposure to a cocktail of env clones (mixture) and to a single env variant (clonal). The three strategies induced comparable levels of the autologous and heterologous neutralization of tier 1 pseudoviruses. Sequential and mixture exposure to quasispecies led to epitope targeting similar to that observed in the simian-human immunodeficiency virus (SHIV)-infected animal from which the env variants were cloned, while clonal and sequential exposure led to greater antibody maturation than t...

The Journal of Immunology, 2010

The second and sixteenth authors' names were published incorrectly. The correct names are Susan S... more The second and sixteenth authors' names were published incorrectly. The correct names are Susan Smyk-Pearson and Michael K. Axthelm.

Journal of Clinical Oncology, 2004

Purpose Neuroblastoma (NB) is a common childhood malignancy characterized by heterogeneous clinic... more Purpose Neuroblastoma (NB) is a common childhood malignancy characterized by heterogeneous clinical behavior. The purpose of this study was to identify potential NB biomarkers that may improve outcome prediction. Patients and Methods The suppression subtractive hybridization (SSH) technique was used to identify the genes differentially expressed between NB and control tissue. RNA isolated from 235 primary NB tumor samples obtained from the Children's Cancer Group was evaluated for expression of the candidate markers using quantitative reverse transcriptase polymerase chain reaction (Taqman assays). The association between the mRNA expression levels in the identified candidate genes and clinical outcome was evaluated. Results SSH analysis identified differential expression of members of the GABAergic gene family in NB. Lower levels of gamma-aminobutyric acid (GABA) receptor–associated protein (GABARAP) gene expression predict decreased survival among all patients. GABAA δ recepto...

Cancer, Jan 16, 2016

Prior research has identified unrealistic optimism as a bias that might impair informed consent a... more Prior research has identified unrealistic optimism as a bias that might impair informed consent among patient-subjects in early-phase oncology trials. However, optimism is not a unitary construct; it also can be defined as a general disposition, or what is called dispositional optimism. The authors assessed whether dispositional optimism would be related to high expectations for personal therapeutic benefit reported by patient-subjects in these trials but not to the therapeutic misconception. The authors also assessed how dispositional optimism related to unrealistic optimism. Patient-subjects completed questionnaires designed to measure expectations for therapeutic benefit, dispositional optimism, unrealistic optimism, and the therapeutic misconception. Dispositional optimism was found to be significantly associated with higher expectations for personal therapeutic benefit (Spearman rank correlation coefficient [r], 0.333; P<.0001), but was not associated with the therapeutic mi...

Nutrition and cancer

Animal and human studies suggest fish oil and green tea may have protective effect on prostate ca... more Animal and human studies suggest fish oil and green tea may have protective effect on prostate cancer. Fatty acid synthase (FAS) has been hypothesized to be linked to chemoprotective effects of both compounds. This study evaluated the independent and joint effects of fish oil (FO) and green tea supplement (epigallocatechin-3-gallate, EGCG) on FAS and Ki-67 levels in prostate tissue. Through a double-blinded, randomized controlled trial with 2 × 2 factorial design, 89 men scheduled for repeat prostate biopsy following an initial negative prostate biopsy were randomized into either FO alone (1.9 g DHA + EPA/day), EGCG alone (600 mg/day), a combination of FO and EGCG, or placebo. We used linear mixed-effects models to test the differences of prostate tissue FAS and Ki-67 by immunohistochemistry between pre- and post-intervention within each group, as well as between treatment groups. Results did not show significant difference among treatment groups in pre-to-post-intervention changes ...

Prostaglandins, Leukotrienes and Essential Fatty Acids, 2010

The role of fatty acids (FA) in prostate carcinogenesis is unclear. Interest in the interrelation... more The role of fatty acids (FA) in prostate carcinogenesis is unclear. Interest in the interrelationship among different types of FA has resulted in new analytic approaches to FA and their role in cancer development. We evaluated the association between erythrocyte FA and prostate cancer in 127 prostate cancer patients and 183 screen negative controls. We present three approaches to analyses of the FA and prostate cancer association; 1) individual or common groups of FA, 2) biologically meaningful FA ratios and 3) principal components analysis. Monounsaturated FA and the alpha-linolenic:eicosapentaenoic ratio were associated with reduced risk of prostate cancer. However, Factor 1, which was strongly correlated with some long chain saturated FA, was associated with an increased risk of prostate cancer. We provide an example of modeling FA and their interrelationships on the risk of prostate cancer. Comparing three approaches suggests the importance of considering the impact of the entire fatty acid profile in disease prevention.

Journal of Clinical Oncology, 2011

178 Background: Agent Orange (AO), a defoliate contaminated with the known carcinogen dioxin, has... more 178 Background: Agent Orange (AO), a defoliate contaminated with the known carcinogen dioxin, has become a prominent concern as veterans of the Vietnam War who were exposed to AO are now reaching the age at which prostate cancer is most prevalent. While sufficient evidence has linked AO exposure to many diseases, only limited but suggestive evidence exists to support a positive association between AO and prostate cancer. Despite mixed findings, recent studies have found that the risk of prostate cancer in those exposed to AO was as high as twice the risk in those not exposed. The goal of this study was to examine this association between AO exposure and prostate cancer in a cohort of men referred for a prostate biopsy. Methods: In this retrospective cohort-design, risk factors were identified using historical clinical data from a population of veterans referred to the Portland VA Hospital for a prostate biopsy between 1993 and 2010. In addition to AO exposure, covariates included pr...

Journal of Clinical Oncology, 2004

Purpose Adverse events in chemotherapy clinical trials are assessed and reported by clinicians, y... more Purpose Adverse events in chemotherapy clinical trials are assessed and reported by clinicians, yet clinician accuracy in assessing symptoms has been questioned. We compared patient reporting of eight symptoms using a validated instrument, the European Organization for the Research and Treatment of Cancer Quality-of-Life Questionnaire C30 (QLQ-C30 or QLQ) with physicians' reporting of the same symptoms in the study's adverse events log. Patients and Methods Thirty-seven men with metastatic, androgen-independent prostate cancer enrolled onto a phase II trial of weekly calcitriol and docetaxel completed the QLQ every 4 weeks for up to 28 weeks. A patient-reported symptom was defined as an increase in a QLQ symptom score by at least 10 points (0 to 100 scale), sustained for at least 4 weeks. A physician-reported symptom was considered present if it was ever documented in the adverse event log. Results Forty-nine (new or worsened) symptoms were detected by both physician and QLQ...

Blood, 2004

We followed 141 patients treated with imatinib mesylate (> 300 mg) for chronicphase chronic my... more We followed 141 patients treated with imatinib mesylate (> 300 mg) for chronicphase chronic myelogenous leukemia (CML) following failure of treatment with interferon. During 12 months from the start of imatinib mesylate treatment, 96.5% achieved a complete hematologic response, 47.0% achieved a major cytogenetic response, and 32.4% achieved a complete cytogenetic response. The proportion of patients with hematologic relapse was 10.9% at 12 months and 14.6% at 18 months. In a univariate Cox regression analysis, the only pretreatment characteristics that correlated with an increased risk of hematologic relapse were hemoglobin level less than 120 g/L (12 g/dL) (P = .02), increased bands in the peripheral blood (P = .01), and clonal evolution (P < .0001). In a multivariate analysis, an elevated platelet count (P = .03) and clonal evolution (P < .0001) were the only significant factors for hematologic relapse. During treatment, the absence of a major cytogenetic response within ...

Cancer, 2012

Purpose-To determine, in rural settings, the relationship between the type and status of insuranc... more Purpose-To determine, in rural settings, the relationship between the type and status of insurance coverage and being up-to-date for breast, cervical, and colorectal cancer screening. Methods-Four primary care practices in two rural Oregon communities participated. Medical chart reviews conducted between October 2008 and August 2009 assessed insurance coverage and up-to-date status for breast, cervical, and colorectal cancer screening. Inclusion criteria involved having at least one healthcare visit in the past five years, and being age 55 or older for eligibility of study services. Results-Most patients were female aged 55-70, employed or retired, had private health insurance and an average of 2.5 co-morbid conditions. The overall proportion of eligible women up-to-date for cervical cancer screening was 30%: 27% of women were up-to-date for clinical breast exam, 37% for mammography and 19% for both mammography and clinical breast exam. Thirty-eight percent of men and 35% of women were up-to-date for colorectal cancer screening using any test at appropriate screening intervals. In general, having any insurance versus being

Pediatric Blood & Cancer, 2009

Background-Residual disease or rapidity of response to induction therapy is among the most powerf... more Background-Residual disease or rapidity of response to induction therapy is among the most powerful predictors of outcome in pediatric Acute Lymphoblastic Leukemia (ALL). Method-Utilizing a multiparameter flow cytometric chemosensitivity assay (FCCA), we studied the relationship between in vitro drug sensitivity of diagnostic leukemic blasts from 30 children with ALL and rapidity of response to induction therapy. We also analyzed the in vitro drug sensitivity of de novo leukemic blasts among various clinical subsets. Results-Compared to rapid early responders (RER), slow early responders (SER) had a significantly greater in vitro drug resistance to Dexamethasone (DEX) (P = 0.04) and Prednisone (P = 0.05). The studies with all other drugs showed a non-significant trend with the SER having a higher in vitro drug resistance compared to the RER. Risk group stratified analyses indicated that in vitro resistance to Asparaginase (ASP), DEX, and Vincristine (VCR) were each significantly related to having very high risk ALL. Additionally, a significantly higher in vitro drug resistance to ASP and VCR was associated with unfavorable lymphoblast genetics and ultimate relapse. Conclusion-Our data indicate that this FCCA is a potentially simple and rapid method to detect inherent resistance to initial ALL therapy very early in induction, thus allowing for treatment modification shortly thereafter.

Blood, 2002

In chronic myelogenous leukemia (CML), the development of chromosomal abnormalities in addition t... more In chronic myelogenous leukemia (CML), the development of chromosomal abnormalities in addition to the Philadelphia chromosome (clonal evolution) is considered by many to be a feature of accelerated phase (AP). Imatinib mesylate (STI571), a selective inhibitor of the Bcr-Abl tyrosine kinase, has significant activity in AP CML. As clonal evolution could allow Bcr-Abl independent proliferation, we analyzed its impact on the outcome of 71 AP patients treated with 600 mg of imatinib mesylate. Fifteen patients had clonal evolution alone (AP-CE), 32 had AP features but no evidence of clonal evolution (HEM-AP), and 24 had AP features plus clonal evolution (HEM-AP + CE). Of the AP-CE patients, 73% had a major cytogenetic response, compared with 31% of the HEM-AP patients (P = .043) and 12.5% of the HEM-AP + CE patients (P = .007). Complete cytogenetic responses were seen in 60% of AP-CE patients, compared with 31% of HEM-AP patients (P = .19) and 8% of HEM-AP + CE patients (P < .001). Wi...

Blood, 2006

Although most patients with chronic myeloid leukemia (CML) treated with imatinib mesylate achieve... more Although most patients with chronic myeloid leukemia (CML) treated with imatinib mesylate achieve a complete cytogenetic response (CCR), some patients will relapse. To determine the potential of real-time quantitative BCR-ABL reverse transcriptase–polymerase chain reaction (RT-PCR) to predict the duration of continued CCR, we monitored 85 patients treated with imatinib mesylate who achieved a CCR. With a median follow-up of 13 months after CCR (29 months after imatinib mesylate; median 6 RQ-PCR assays), 23 patients (27%) had disease progression (predominantly loss of CCR). Compared with the median baseline level of BCR-ABL mRNA, 42% of patients achieved at least a 2-log molecular response at the time of first reaching CCR. Failure to achieve a 2-log response at the time of CCR was an independent predictive marker of subsequent progression-free survival (hazard ratio = 5.8; 95% CI, 1.7-20; P = .005). After CCR, BCR-ABL mRNA levels progressively declined for at least the next 15 month...

Aging Cell, 2008

We have recently shown in non-human primates that caloric restriction (CR) initiated during adult... more We have recently shown in non-human primates that caloric restriction (CR) initiated during adulthood can delay T-cell aging and preserve naïve CD8 and CD4 T cells into advanced age. An important question is whether CR can be initiated at any time in life, and whether age at the time of onset would modulate beneficial effects of CR. In the current study we evaluated the impact of CR started before puberty or during advanced age on T cell senescence and compared it to the effects of CR started in early adulthood. Our data demonstrate that the beneficial effects of adult onset CR upon T-cell aging were lost by both early and late CR onset. In fact, some of our results suggest that inappropriate initiation of CR may be harmful to the maintenance of T cell function. This suggests that there may be an optimal window during adulthood where CR can delay immune senescence and improve correlates of immunity in primates.

Proceedings of the National Academy of Sciences of the United States of America, Sep 7, 2017

Translating the genetic and epigenetic heterogeneity underlying human cancers into therapeutic st... more Translating the genetic and epigenetic heterogeneity underlying human cancers into therapeutic strategies is an ongoing challenge. Large-scale sequencing efforts have uncovered a spectrum of mutations in many hematologic malignancies, including acute myeloid leukemia (AML), suggesting that combinations of agents will be required to treat these diseases effectively. Combinatorial approaches will also be critical for combating the emergence of genetically heterogeneous subclones, rescue signals in the microenvironment, and tumor-intrinsic feedback pathways that all contribute to disease relapse. To identify novel and effective drug combinations, we performed ex vivo sensitivity profiling of 122 primary patient samples from a variety of hematologic malignancies against a panel of 48 drug combinations. The combinations were designed as drug pairs that target nonoverlapping biological pathways and comprise drugs from different classes, preferably with Food and Drug Administration approva...

Experimental Hematology, 2016

Recent large cohort studies revealed that healthy older individuals harbor somatic mutations that... more Recent large cohort studies revealed that healthy older individuals harbor somatic mutations that increase their risk for hematologic malignancy and all-cause cardiovascular deaths. The majority of these mutations are in chromatin and epigenetic regulatory genes (CERGs). CERGs play a key role in regulating DNA methylation (DNMT3A and TET2) or histone function (ASXL1) and in clonal proliferation of hematopoietic stem cells. We hypothesize that older women demonstrating

Diseases of the Colon & Rectum, 2018

BACKGROUND: microRNAs are dysregulated in colorectal cancer and subsets correlated with advanced ... more BACKGROUND: microRNAs are dysregulated in colorectal cancer and subsets correlated with advanced tumor stage and metastasis. Data are lacking on microRNA dysregulation from early to late stage disease. OBJECTIVE: Identify a microRNA signature associated with the primary tumor and metastatic site in stage IV disease. Examine whether the signature is evident in earlier stages. DESIGN: A microRNA profile was generated, then explored in normal colon tissue (N = 5), early stage (stage I & II, N = 10), and late stage (stage III & IV, N = 14) colorectal primary tumors via polymerase chain reaction to delineate molecular events that may promote colorectal carcinogenesis. SETTINGS: Genome-wide microRNA expression profiling was performed on fourteen patientmatched stage IV primary colorectal cancer tumors and corresponding liver metastases.