Publications by authors named "Valerie Lee"

55 Publications

Steroid-refractory PD-(L)1 pneumonitis: incidence, clinical features, treatment, and outcomes.

J Immunother Cancer 2021 Jan;9(1)

Oncology, Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA

Background: Immune-checkpoint inhibitor (ICI)-pneumonitis that does not improve or resolve with corticosteroids and requires additional immunosuppression is termed steroid-refractory ICI-pneumonitis. Herein, we report the clinical features, management and outcomes for patients treated with intravenous immunoglobulin (IVIG), infliximab, or the combination of IVIG and infliximab for steroid-refractory ICI-pneumonitis.

Methods: Patients with steroid-refractory ICI-pneumonitis were identified between January 2011 and January 2020 at a tertiary academic center. ICI-pneumonitis was defined as clinical or radiographic lung inflammation without an alternative diagnosis, confirmed by a multidisciplinary team. Steroid-refractory ICI-pneumonitis was defined as lack of clinical improvement after high-dose corticosteroids for 48 hours, necessitating additional immunosuppression. Serial clinical, radiologic (CT imaging), and functional features (level-of-care, oxygen requirement) were collected preadditional and postadditional immunosuppression.

Results: Of 65 patients with ICI-pneumonitis, 18.5% (12/65) had steroid-refractory ICI-pneumonitis. Mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35-85), 50% patients were male, and the majority had lung carcinoma (75%). Steroid-refractory ICI-pneumonitis occurred after a mean of 5 ICI doses from PD-(L)1 start (range: 3-12 doses). The most common radiologic pattern was diffuse alveolar damage (DAD: 50%, 6/12). After corticosteroid failure, patients were treated with: IVIG (n=7), infliximab (n=2), or combination IVIG and infliximab (n=3); 11/12 (91.7%) required ICU-level care and 8/12 (75%) died of steroid-refractory ICI-pneumonitis or infectious complications (IVIG alone=3/7, 42.9%; infliximab alone=2/2, 100%; IVIG + infliximab=3/3, 100%). All five patients treated with infliximab (5/5; 100%) died from steroid-refractory ICI-pneumonitis or infectious complications. Mechanical ventilation was required in 53% of patients treated with infliximab alone, 80% of those treated with IVIG + infliximab, and 25.5% of those treated with IVIG alone.

Conclusions: Steroid-refractory ICI-pneumonitis constituted 18.5% of referrals for multidisciplinary irAE care. Steroid-refractory ICI-pnuemonitis occurred early in patients' treatment courses, and most commonly exhibited a DAD radiographic pattern. Patients treated with IVIG alone demonstrated an improvement in both level-of-care and oxygenation requirements and had fewer fatalities (43%) from steroid-refractory ICI-pneumonitis when compared to treatment with infliximab (100% mortality).
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http://dx.doi.org/10.1136/jitc-2020-001731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797270PMC
January 2021

Use of virtual reality in the supportive care management of paediatric patients with cancer.

Lancet Child Adolesc Health 2020 12;4(12):899-908

Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore.

Paediatric patients with cancer undergo multiple treatments and procedures that can be invasive and painful. Virtual reality technologies could support the management of paediatric cancer. This Review focuses on the physiological and psychological efficacy of virtual reality in supportive care management. Virtual reality has shown potential in reducing pain scores, pulse rates, and distress scores, but has no significant effect on other indicators, such as anxiety, fear, and depression. Several virtual reality characteristics might affect its effectiveness when used in the paediatric cancer setting. Virtual reality games with high fidelity (eg, fully-isolating head-mounted display, stereo sound, and controllers) components provide a higher level of immersion, presence, and narrative engagement, which could better manage pain. Personalising the virtual reality experience to the patient and procedure would also improve accessibility and comfort. Clinicians should work closely with virtual reality developers to ensure that the virtual reality applications used are appropriate for their patients.
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http://dx.doi.org/10.1016/S2352-4642(20)30240-6DOI Listing
December 2020

Challenges of the current precision medicine approach for pancreatic cancer: A single institution experience between 2013 and 2017.

Cancer Lett 2021 Jan 28;497:221-228. Epub 2020 Oct 28.

The Pancreatic Cancer "Precision Medicine" Program, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA. Electronic address:

Recent research on genomic profiling of pancreatic ductal adenocarcinoma (PDAC) has identified many potentially actionable alterations. However, the feasibility of using genomic profiling to guide routine clinical decision making for PDAC patients remains unclear. We retrospectively reviewed PDAC patients between October 2013 and December 2017, who underwent treatment at the Johns Hopkins Hospital and had clinical tumor next-generation sequencing (NGS) through commercial resources. Ninety-two patients with 93 tumors tested were included. Forty-eight (52%) patients had potentially curative surgeries. The median time from the tissue available to the NGS testing ordered was 229 days (interquartile range 62-415). A total of three (3%) patients had matched targeted therapies based on genomic profiling results. Genomic profiling guided personalized treatment for PDAC patients is feasible, but the percentage of patients who receive targeted therapy is low. The main challenges are ordering NGS testing early in the clinical course of the disease and the limited evidence of using a targeted approach in these patients. A real-time department level genomic testing ordering system in combination with an evidence-based flagging system for potentially actionable alterations could help address these shortcomings.
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http://dx.doi.org/10.1016/j.canlet.2020.10.039DOI Listing
January 2021

Association of Low Muscle Mass and Low Muscle Radiodensity With Morbidity and Mortality for Colon Cancer Surgery.

JAMA Surg 2020 10;155(10):942-949

Human Nutrition Research Unit, Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada.

Importance: Given the risks of postoperative morbidity and its consequent economic burden and impairment to patients undergoing colon resection, evaluating risk factors associated with complications will allow risk stratification and the targeting of supportive interventions. Evaluation of muscle characteristics is an emerging area for improving preoperative risk stratification.

Objective: To examine the associations of muscle characteristics with postoperative complications, length of hospital stay (LOS), readmission, and mortality in patients with colon cancer.

Design, Setting, And Participants: This population-based retrospective cohort study was conducted among 1630 patients who received a diagnosis of stage I to III colon cancer from January 2006 to December 2011 at Kaiser Permanente Northern California, an integrated health care system. Preliminary data analysis started in 2017. Because major complication data were collected between 2018 and 2019, the final analysis using the current cohort was conducted between 2019 and 2020.

Exposures: Low skeletal muscle index (SMI) and/or low skeletal muscle radiodensity (SMD) levels were assessed using preoperative computerized tomography images.

Main Outcomes And Measures: Length of stay, any complication (≥1 predefined complications) or major complications (Clavien-Dindo classification score ≥3), 30-day mortality and readmission up to 30 days postdischarge, and overall mortality.

Results: The mean (SD) age at diagnosis was 64.0 (11.3) years and 906 (55.6%) were women. Patients with low SMI or low SMD were more likely to remain hospitalized 7 days or longer after surgery (odds ratio [OR], 1.33; 95% CI, 1.05-1.68; OR, 1.39; 95% CI, 1.05-1.84, respectively) and had higher risks of overall mortality (hazard ratio, 1.40; 95% CI, 1.13-1.74; hazard ratio, 1.44; 95% CI, 1.12-1.85, respectively). Additionally, patients with low SMI were more likely to have 1 or more postsurgical complications (OR, 1.31; 95% CI, 1.04-1.65) and had higher risk of 30-day mortality (OR, 4.85; 95% CI, 1.23-19.15). Low SMD was associated with higher odds of having major complications (OR, 2.41; 95% CI, 1.44-4.04).

Conclusions And Relevance: Low SMI and low SMD were associated with longer LOS, higher risk of postsurgical complications, and short-term and long-term mortality. Research should evaluate whether targeting potentially modifiable factors preoperatively, such as preserving muscle mass, could reverse the observed negative associations with postoperative outcomes.
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http://dx.doi.org/10.1001/jamasurg.2020.2497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7424546PMC
October 2020

Body Composition, Adherence to Anthracycline and Taxane-Based Chemotherapy, and Survival After Nonmetastatic Breast Cancer.

JAMA Oncol 2020 02;6(2):264-270

Division of Research, Kaiser Permanente Northern California, Oakland.

Importance: Although most chemotherapies are dosed on body surface area or weight, body composition (ie, the amount and distribution of muscle and adipose tissues) is thought to be associated with chemotherapy tolerance and adherence.

Objectives: To evaluate whether body composition is associated with relative dose intensity (RDI) on anthracycline and taxane-based chemotherapy or hematologic toxic effects and whether lower RDI mediates the association of adiposity with mortality.

Design, Setting, And Participants: An observational cohort study with prospectively collected electronic medical record data was conducted at Kaiser Permanente Northern California, a multicenter, community oncology setting within an integrated health care delivery system. Participants included 1395 patients with nonmetastatic breast cancer diagnosed between January 1, 2005, and December 31, 2013, and treated with anthracycline and taxane-based chemotherapy. Data analysis was performed between February 25 and September 4, 2019.

Exposures: Intramuscular, visceral, and subcutaneous adiposity as well as skeletal muscle were evaluated from clinically acquired computed tomographic scans at diagnosis.

Main Outcomes And Measures: The primary outcome was low RDI (<0.85), which is the ratio of delivered to planned chemotherapy dose, derived from infusion records; in addition, hematologic toxic effects were defined based on laboratory test values. To evaluate associations with overall and breast cancer-specific mortality, logistic regression models adjusted for age and body surface area were fit as well as Cox proportional hazards models adjusted for age, race/ethnicity, adiposity, Charlson comorbidity index score, and tumor stage and subtype. The mediation proportion was computed using the difference method.

Results: The mean (SD) age at diagnosis of the 1395 women included in the study was 52.8 (10.2) years. Greater visceral (odds ratio [OR], 1.19; 95% CI, 1.02-1.39 per SD) and intramuscular (OR, 1.16; 95% CI, 1.01-1.34 per SD) adiposity were associated with increased odds of RDI less than 0.85. Greater muscle mass was associated with a decreased odds of hematologic toxic effects (OR, 0.84; 95% CI, 0.71-0.98 per SD). Relative dose intensity less than 0.85 was associated with a 30% increased risk of death (hazard ratio, 1.30; 95% CI, 1.02-1.65). Lower RDI partially explained the association of adiposity with breast cancer-specific mortality (mediation proportion, 0.20; 95% CI, 0.05-0.55).

Conclusions And Relevance: Excess adiposity, presenting as larger visceral or intramuscular adiposity, was associated with lower RDI. Lower RDI partially mediated the association of adiposity with worse breast cancer-specific survival. Body composition may help to identify patients likely to experience toxic effects and subsequent dose delays or reductions, which could compromise chemotherapeutic efficacy.
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http://dx.doi.org/10.1001/jamaoncol.2019.4668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902178PMC
February 2020

Expression of Cathepsins B, D, and G by the Embryonic Stem Cell-Like Population within Human Keloid Tissues and Keloid-Derived Primary Cell Lines.

Plast Reconstr Surg 2019 12;144(6):1338-1349

From the Gillies McIndoe Research Institute; the Wellington Regional Plastic, Maxillofacial and Burns Unit, Hutt Hospital; and the University of Auckland.

Background: The authors have previously shown that an embryonic stem cell-like population within keloid-associated lymphoid tissues in keloid lesions expresses components of the renin-angiotensin system that may be dysregulated. The authors hypothesized that cathepsins B, D, and G are present within the embryonic stem cell-like population in keloid lesions and contribute to bypass loops of the renin-angiotensin system.

Methods: 3,3'-Diaminobenzidine immunohistochemical staining for cathepsins B, D, and G was performed on formalin-fixed paraffin-embedded sections in keloid tissue samples of 11 patients. Immunofluorescence immunohistochemical staining was performed on three of these keloid tissue samples, by co-staining with CD34, tryptase, and OCT4. Western blotting, reverse transcription quantitative polymerase chain reaction, and enzyme activity assays were performed on five keloid tissue samples and four keloid-derived primary cell lines to investigate protein and mRNA expression, and functional activity, respectively.

Results: 3,3'-Diaminobenzidine immunohistochemical staining demonstrated expression of cathepsins B, D, and G in all 15 keloid tissue samples. Immunofluorescence immunohistochemical staining showed localization of cathepsins B and D to the endothelium of microvessels within the keloid-associated lymphoid tissues and localization of cathepsin G to the tryptase-positive perivascular cells. Western blotting confirmed semiquantitative levels of cathepsins B and D in keloid tissue samples and keloid-derived primary cell lines. Reverse transcription quantitative polymerase chain reaction showed quantitative transcriptional activation of cathepsins B and D in keloid tissue samples and keloid-derived primary cell lines and cathepsin G in keloid tissue samples. Enzyme activity assays demonstrated functional activity of cathepsins B and D.

Conclusion: Cathepsins B, D, and G are expressed by the embryonic stem cell-like population within the keloid-associated lymphoid tissues of keloid lesions and may act to bypass the renin-angiotensin system, suggesting a potential therapeutic target using renin-angiotensin system modulators and cathepsin inhibitors.
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http://dx.doi.org/10.1097/PRS.0000000000006275DOI Listing
December 2019

Current Status of Immunotherapies for Treating Pancreatic Cancer.

Curr Oncol Rep 2019 05 17;21(7):60. Epub 2019 May 17.

Johns Hopkins University School of Medicine, 1650 Orleans Street, Room 488, Baltimore, MD, 21287, USA.

Purpose Of Review: Despite all efforts, pancreatic ductal adenocarcinoma (PDAC) remains a disease that causes substantial morbidity and mortality, with a 5-year survival rate of 7%. Innovative paradigms for treating PDAC are urgently needed.

Recent Findings: We discuss the advances and difficulties in using immunotherapy and developing immunotherapeutic vaccines for PDAC. Current excitement about antigen-specific immunotherapy has been propelled by advances in multiple areas, such as next-generation sequencing to identify neoantigens and manufacturing to produce immunotherapeutic vaccines. Antigen-specific immunotherapy is being actively explored in clinical trials. As the field of immunotherapy matures and as our understanding of the complex interactions between tumor and host develops, we hope to identify new methods for treating and managing PDAC.
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http://dx.doi.org/10.1007/s11912-019-0811-5DOI Listing
May 2019

The Be-Well Study: a prospective cohort study of lifestyle and genetic factors to reduce the risk of recurrence and progression of non-muscle-invasive bladder cancer.

Cancer Causes Control 2019 Feb 17;30(2):187-193. Epub 2019 Jan 17.

Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY, 14263, USA.

Purpose: Bladder cancer is one of the top five cancers diagnosed in the U.S. with a high recurrence rate, and also one of the most expensive cancers to treat over the life-course. However, there are few observational, prospective studies of bladder cancer survivors.

Methods: The Bladder Cancer Epidemiology, Wellness, and Lifestyle Study (Be-Well Study) is a National Cancer Institute-funded, multi-center prospective cohort study of non-muscle-invasive bladder cancer (NMIBC) patients (Stage Ta, T1, Tis) enrolled from the Kaiser Permanente Northern California (KPNC) and Southern California (KPSC) health care systems, with genotyping and biomarker assays performed at Roswell Park Comprehensive Cancer Center. The goal is to investigate diet and lifestyle factors in recurrence and progression of NMIBC, with genetic profiles considered, and to build a resource for future NMIBC studies.

Results: Recruitment began in February 2015. As of 30 June 2018, 1,281 patients completed the baseline interview (774 KPNC, 511 KPSC) with a recruitment rate of 54%, of whom 77% were male and 23% female, and 80% White, 6% Black, 8% Hispanic, 5% Asian, and 2% other race/ethnicity. Most patients were diagnosed with Ta (69%) or T1 (27%) tumors. Urine and blood specimens were collected from 67% and 73% of consented patients at baseline, respectively. To date, 599 and 261 patients have completed the 12- and 24-month follow-up questionnaires, respectively, with additional urine and saliva collection.

Conclusions: The Be-Well Study will be able to answer novel questions related to diet, other lifestyle, and genetic factors and their relationship to recurrence and progression among early-stage bladder cancer patients.
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http://dx.doi.org/10.1007/s10552-019-1130-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6422041PMC
February 2019

Expression of cancer stem cell markers in metastatic melanoma to the brain.

J Clin Neurosci 2019 Feb 24;60:112-116. Epub 2018 Oct 24.

Gillies McIndoe Research Institute, Wellington, New Zealand.

We have recently characterized cancer stem cell (CSC) subpopulations in different types of cancer. This study aimed to identify and characterize CSCs within metastatic melanoma (MM) to the brain. 3, 3-diaminobenzidine (DAB) immunohistochemical (IHC) staining of ten samples of MM to the brain demonstrated the expression of the embryonic stem cell (ESC) markers OCT4, NANOG, SALL4, SOX2 and pSTAT3. Protein expression of all five ESC markers except SALL4 were confirmed by Western blotting on five samples and transcriptional activation of all five markers was demonstrated using NanoString mRNA analysis on four samples. Immunofluorescence IHC staining suggested the presence of CSCs that stained for OCT4, SALL4, SOX2 or NANOG. Some of these cells also stained for Melan-A. Also, a pSTAT3/CD34 primitive subpopulation was detected on the endothelium of microvessels. These CSCs may be a novel therapeutic target for MM to the brain.
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http://dx.doi.org/10.1016/j.jocn.2018.10.068DOI Listing
February 2019

Cancer stem cells within moderately differentiated head and neck cutaneous squamous cell carcinoma express components of the renin-angiotensin system.

J Plast Reconstr Aesthet Surg 2019 Sep 22;72(9):1484-1493. Epub 2018 Nov 22.

Gillies McIndoe Research Institute, PO Box 7184, Newtown, Wellington 6242, New Zealand.

Purpose: To investigate the expression of components of the renin-angiotensin system (RAS): pro-renin receptor (PRR), angiotensin converting enzyme (ACE), angiotensin II receptor 1 (ATIIR1) and angiotensin II receptor 2 (ATIIR2) by the cancer stem cell (CSC) subpopulations in moderately differentiated head and neck cutaneous squamous cell carcinoma (MDHNCSCC).

Methodology: 3,3-Diaminobenzidine (DAB) immunohistochemical (IHC) staining for PRR, ACE, ATIIR1 and ATIIR2 was performed on formalin-fixed paraffin-embedded sections of ten MDHNCSCC tissue samples. Immunofluorescence (IF) IHC staining was used to localise components of the RAS. Western blotting (WB) and RT-qPCR were performed on snap-frozen MDHNCSCC tissue samples and MDHNCSCC-derived primary cell lines to investigate protein transcription expression of these proteins, respectively.

Results: DAB IHC staining demonstrated the presence of PRR, ACE, ATIIR1 and ATIIR2 in all ten MDHNCSCC tissue samples. IF IHC staining showed expression of PRR and ATIIR2 by the OCT4 cells, and ACE and ATIIR1 by the SOX2 cells, within the tumour nests (TNs) and the peritumoural stroma (PTS). PRR, ACE, ATIIR1 and ATIIR2 were expressed by the endothelium of the microvessels within the PTS. WB confirmed protein expression for PRR, ACE and ATIIR1 in MDHNCSCC tissue samples and MDHNCSCC-derived primary cell lines. RT-qPCR showed transcriptional activation of PRR, ACE, ATIIR1 and ATIIR2 in MDHNCSCC tissue samples; and PRR, ACE, ATIIR1 but not ATIIR2, in MDHNCSCC-derived primary cell lines.

Conclusion: PRR, ACE, ATIIR1 and ATIIR2 are expressed by the CSC subpopulations within the TNs, the PTS, and the endothelium of the microvessels within the PTS, in MDHNCSCC.
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http://dx.doi.org/10.1016/j.bjps.2018.11.013DOI Listing
September 2019

Factors That Influence Selectionof Urinary Diversion Among Bladder Cancer Patients in 3 Community-based Integrated Health Care Systems.

Urology 2019 03 22;125:222-229. Epub 2018 Nov 22.

Kaiser Permanente Center for Health Research, Portland, OR.

Objective: To assess the relative contributions of patient and surgeon factors for predicting selection of ileal conduit (IC), neobladder (NB), or continent pouch (CP) urinary diversions (UD) for patients diagnosed with muscle-invasive/high-risk nonmuscle invasive bladder cancer. This information is needed to enhance research comparing cancer survivors' outcomes across different surgical treatment options.

Methods: Bladder cancer patients' age ≥21 years with cystectomy/UD performed from January 2010 to June 2015 in 3 Kaiser Permanente regions were included. All patient and surgeon data were obtained from electronic health records. A mixed effects logistic regression model was used treating surgeon as a random effect and region as a fixed effect.

Results: Of 991 eligible patients, 794 (80%) received IC. One hundred sixty-nine surgeons performed the surgeries and accounted for a sizeable proportion of the variability in patient receipt of UD (intraclass correlation coefficient = 0.26). The multilevel model with only patient factors showed good fit (area under the curve = 0.93, Hosmer-Lemeshow test P = .44), and older age, female sex, estimated glomerular filtration rate <45, 4+ comorbidity index score, and stage III/IV tumors were associated with higher odds of receiving an IC vs neobladder/continent pouch. However, including surgeon factors (annual cystectomy volume, specialty training, clinical tenure) had no association (P = .29).

Conclusion: In this community setting, patient factors were major predictors of UD received. Surgeons also played a substantial role, yet clinical training and experience were not major predictors. Surgeon factors such as beliefs about UD options and outcomes should be explored.
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http://dx.doi.org/10.1016/j.urology.2018.09.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389399PMC
March 2019

Perioperative Intravesical Chemotherapy for Patients WithNon-Muscle-invasive Bladder Cancer: Understanding the Extent of and Sources of Variation in Guideline-recommended Use.

Urology 2019 02 23;124:107-112. Epub 2018 Oct 23.

Kaiser Permanente Northern California Division of Research, Oakland, CA.

Objective: To examine intravesical chemotherapy (IVC) use according to non-muscle-invasive bladder cancer patient disease risk, and the contributions of multilevel factors to variation in proficient use among patients with low-intermediate disease.

Methods: This study included 988 patients diagnosed with non-muscle-invasive bladder cancer in an integrated health system in Northern California from 2015-2017. We calculated IVC receipt by disease risk, and among patients with low-intermediate risk disease, assessed the relationship between multilevel factors and IVC receipt using a logistic regression model with random intercepts for provider and service area, and patient-, provider-, and service area-level fixed effects. We further assessed the association of provider- and service area-level factors with IVC use by examining intraclass correlation coefficients.

Results: Similar proportions of low-intermediate (36%) and high-risk (34%) patients received IVC. In the multivariate analysis, including low-intermediate risk patients, service area volume was strongly and statistically significantly associated with IVC use (adjusted odds ratio, high- vs low-volume: 0.08, 95% Confidence Interval: 0.01-0.58). Provider- and service area-level intraclass correlation coefficients were large, (38%, P = .0009 and 39% P = .03, respectively) indicating that much of the variance in IVC use was explained by factors at these levels.

Conclusion: Our findings highlight opportunities to improve proficient use of IVC. Future research should assess provider- and practice-level barriers to IVC use among low-intermediate risk patients.
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http://dx.doi.org/10.1016/j.urology.2018.10.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202079PMC
February 2019

Role of liquid biopsies in colorectal cancer.

Curr Probl Cancer 2018 11 29;42(6):593-600. Epub 2018 Aug 29.

Department of GI Oncology, Johns Hopkins Hospital, Baltimore, MD.

Colorectal cancer (CRC) is the third most common cancer worldwide, with a global incidence of over 1 million cases. In the era of personalized medicine, tumor sampling is essential for characterizing the molecular profile of individual tumors. This provides pivotal information regarding optimal sequencing of therapy and emergence of drug resistance, allowing for timely therapy adjustment. However, tumor tissue sampling offers static information in a single time point and area of disease at the time of biopsy, which may not entirely represent the heterogeneity of molecular alterations. Moreover, tumor biopsies often involve invasive procedures with potential risks to patients. Less invasive, safer, and real-time methods such as liquid biopsies have generated increasing interest as a surrogate of solid tumor biopsies. Liquid biopsy allows for noninvasive survey with detection of cell-free circulating tumor DNA (ctDNA) or circulating tumor cells. Blood-based assays are the most widely studied. Additionally, the quantity of ctDNA detected has been shown to correlate with tumor burden and enables assessment of tumor heterogeneity. In this article, we discuss the concept of liquid biopsies including ctDNA and circulating tumor cell, and their current application in the diagnosis and management of CRC. We suggest that liquid biopsies can be successfully used to characterize the molecular profile of CRC, monitor disease, detect minimal residual disease after surgery, and identify therapeutic targets and mechanisms of drug resistance. This strategy could potentially imply an early change in treatment, sparing unnecessary side effects, and minimizing health costs. Combined radiological and liquid biopsy assessments will likely become more standard in CRC oncology. However, large prospective studies are needed to definitively establish the role of liquid biopsy.
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http://dx.doi.org/10.1016/j.currproblcancer.2018.08.004DOI Listing
November 2018

Biotic and abiotic substrates for enhancing Acinetobacter baumannii biofilm formation: New approach using extracellular matrix and slanted coverslip technique.

J Gen Appl Microbiol 2019 May 14;65(2):64-71. Epub 2018 Sep 14.

Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio.

Acinetobacter baumannii has been well recognized as a problematic human pathogen and several reports has shown the incidence of multidrug and pandrug-resistant A. baumannii strains in infirmary infections. A. baumannii grows only on an air-liquid interface and does not form a contiguous biofilm. Extracellular matrices (ECM) and slanted glass coverslips are (SGC) used as biofilm substrates and biofilms have been investigated by SEM, confocal and crystal violet staining. ECM has shown enhanced biofilm formation under dynamic conditions rather than static conditions. SGC biofilm yield assay has shown higher levels of continuous layers and packed thicker biofilm formation with glass coverslip inserts, up to 1.7 to 3 times higher biofilm formation, than when compared with no glass coverslip inserts. A media immersed ECM study revealed that biofilm grown on extracellular matrixes formed thread-like pili structures, and that these structures had contact with the ECM and also showed excellent cell-to-cell interaction. In summary, A. baumannii showed higher biofilm formation capacities with ECM, while the prominent results were directly related with the biofilm formation capacity of A. baumannii. For the initial step of biofilm formation, adherence is an important factor and, consequently, strains with a comparatively high capability to adhere to extracellular matrices and slanted glass coverslips provide a new method of enhanced biofilm growth for in vitro assays. ECM can be used as a substrate for immersed biofilm formation studies and the SGC method for air-liquid interface exposed biofilm formation studies, and these substrates can provide better biofilm growth and easy handling for in vitro adherence and biofilm assays.
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http://dx.doi.org/10.2323/jgam.2018.05.004DOI Listing
May 2019

A Phase I Trial of a Guadecitabine (SGI-110) and Irinotecan in Metastatic Colorectal Cancer Patients Previously Exposed to Irinotecan.

Clin Cancer Res 2018 12 10;24(24):6160-6167. Epub 2018 Aug 10.

Johns Hopkins University School of Medicine, Baltimore, Maryland.

Purpose: Chemotherapeutic resistance eventually develops in all patients with metastatic colorectal cancer (mCRC). Gene silencing through promoter demethylation is one potential reversible mechanism of resistance with administration of hypomethylating agents. We evaluated the safety and tolerability of guadecitabine and irinotecan in patients with mCRC previously treated with irinotecan.

Patients And Methods: In this 3+3 dose-escalation study, patients with mCRC previously exposed to irinotecan received guadecitabine days 1 to 5 of a 28-day cycle and irinotecan 125 mg/m days 8 and 15 [dose level (DL) 1, guadecitabine 45 mg/m; DL -1: guadecitabine 30 mg/m; DL -1G: guadecitabine 30 mg/m with growth factor support (GFS); DL 1G: guadecitabine 45 mg/m with GFS].

Results: Twenty-two patients were treated across four DLs. Dose-limiting toxicities were neutropenic fever (DL 1 and -1G), biliary drain infection (DL -1), colonic obstruction (DL -1), and severe dehydration (DL 1G). Most common toxicities were neutropenia (82% any grade, 77% Grade 3/4), neutropenic fever (23%), leukopenia (73% any grade, 50% Grade 3/4), and injection site reactions (64% total, 0% Grade 3/4). Patients received a median of 4.5 cycles of treatment; 12/17 evaluable patients had stable disease as best response, with one having initial disease progression but subsequently durable partial response. Circulating tumor DNA showed decrease in global demethylation by LINE-1 after treatment.

Conclusions: We report the first study of chemo-priming with epigenetic therapy in gastrointestinal cancers. Guadecitabine 45 mg/m and irinotecan 125 mg/m with GFS was safe and tolerable in patients with mCRC, with early indication of benefit. These data have provided the basis for an ongoing phase II randomized, multicenter trial.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-0421DOI Listing
December 2018

Antibiofilm activity of an EDTA-containing nanoemulsion on multidrug-resistant Acinetobacter baumannii.

Artif Cells Nanomed Biotechnol 2018 2;46(sup2):737-743. Epub 2018 May 2.

b University of Texas Health Science Center at San Antonio , San Antonio , TX , USA.

Acinetobacter baumannii have evolved as an exceedingly troublesome pathogenic microorganisms and prevention and controlling this pathogen is considered to be a public health problem. Nanoemulsions (NE) are a distinctive type of decontaminator produced by integration of immiscible oil phase with aqueous phase under extreme shear forces. The effectiveness of NEs and their components was determined against four stains of A. baumannii by MBC, adherence assay, biofilm assay and SEM studies. NE dilutions ranging from 125 to 225 reduced adhesion by from 61.8 to 99.9% in NE-treated groups (p<.05) as determined by MBC. Four-day-old A. baumannii biofilms were treated with NE; LIVE/DEAD staining showed dead cell intensity of 56.2-92.0% in NE-treated groups. After NE treatment and observation by SEM, cell surfaces appeared to be remarkably disintegrated. Irregular boundaries were observed and margins of cell walls were unclear. The anti-adherence, anti-biofilm and morphological disruption effects of NE suggest that this material could be useful for the development of promising antimicrobial agents.
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http://dx.doi.org/10.1080/21691401.2018.1468771DOI Listing
June 2019

Breast Cancer Chemoprevention in an Integrated Health Care Setting.

JCO Clin Cancer Inform 2017 11;1:1-12

Hazel B. Nichols, Til Stürmer, and Chelsea Anderson, University of North Carolina Gillings School of Global Public Health; Hyman Muss, University of North Carolina School of Medicine, Chapel Hill, NC; Valerie S. Lee, Jean S. Lee, Janise M. Roh, and Lawrence H. Kushi, Kaiser Permanente Northern California, Oakland, CA; and Kala Visvanathan, Johns Hopkins Bloomberg School of Public Health and Johns Hopkins School of Medicine, Baltimore, MD.

Purpose: National guidelines encourage counseling high-risk women about pharmacologic breast cancer risk reduction. We evaluated the use of integrated health care data to identify and characterize breast cancer chemoprevention use. Chemoprevention included US Food and Drug Administration-approved use of tamoxifen and raloxifene and off-label use of aromatase inhibitors (AIs).

Patients And Methods: Using electronic medical and pharmacy records (EMRs) in the Kaiser Permanente Northern California health care system, we sampled cancer-free women age 35 to 69 years who used tamoxifen, raloxifene, exemestane, anastrozole, or letrozole from 2005 to 2013. Risk-benefit profiles were calculated for tamoxifen and raloxifene using published indices. The proportion of days covered was calculated from pharmacy records to assess adherence.

Results: Among 90 chemoprevention users (confirmed with EMR review from a sample of 371 women), 74% used tamoxifen, 11% used raloxifene, and 13% used an AI. For tamoxifen and raloxifene users, the risk-benefit index indicated 23% of women had insufficient evidence that benefits would outweigh risks. For all agents, adherence decreased from an average proportion of days covered of 75% at 1 year to 67% at 5 years. Automated EMR searches identified breast cancer chemoprevention users with 60% positive predictive value overall and 75% for tamoxifen after post hoc modifications.

Conclusion: Our study contributes to an emerging picture of breast cancer chemoprevention use in real-world settings, where evidence of net benefit is not uniform and nonadherence is common. Among breast cancer chemoprevention agents, our automated selection best performed for tamoxifen use. We also identified off-label use of AIs for chemoprevention, suggesting that expansion of risk-benefit indices to include AIs is warranted.
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http://dx.doi.org/10.1200/CCI.16.00059DOI Listing
November 2017

Muscle mass at the time of diagnosis of nonmetastatic colon cancer and early discontinuation of chemotherapy, delays, and dose reductions on adjuvant FOLFOX: The C-SCANS study.

Cancer 2017 Dec 7;123(24):4868-4877. Epub 2017 Sep 7.

Division of Research, Kaiser Permanente Northern California, Oakland, California.

Background: For many chemotherapy regimens dosed based on body surface area (BSA), patients experience dose reductions or delays or discontinue treatment, thereby reducing survival. Consideration of body composition may be useful in individualizing chemotherapy dosing, but to the authors' knowledge few studies to date have examined the association of body composition with chemotherapy tolerance in patients with colon cancer.

Methods: The authors identified patients with nonmetastatic colon cancer who were diagnosed from 2006 through 2011 at Kaiser Permanente and who received leucovorin calcium/calcium folinate, 5-fluorouracil, and oxaliplatin (FOLFOX) as initial adjuvant chemotherapy (533 patients). Patients' muscle mass was quantified using clinically acquired computed tomography scans. The authors quantified chemotherapy doses, treatment dates, and related toxicities using the electronic medical record. In logistic regression models adjusting for age, sex, and American Joint Committee on Cancer stage of disease, the authors examined associations of muscle tertiles with early treatment discontinuation (<6 cycles), treatment delay (>3 days off schedule for ≥3 times), and/or dose reduction (relative dose intensity ≤ 0.70, based on planned treatment).

Results: The average age of the patients at the time of diagnosis was 58.7 years; BSA was 1.9 m and body mass index was 28.7 kg/m . Compared with the highest sex-specific tertile of muscle mass, patients in the lowest tertile were more likely to experience toxicities and had twice the risk of adverse outcomes while receiving FOLFOX; for early discontinuation, the odds ratio (OR) was 2.34 (95% confidence interval [95% CI], 1.04-5.24; P for trend = .03), whereas the ORs were 2.24 (95% CI, 1.37-3.66; P for trend = .002) for treatment delay and 2.28 (95% CI, 1.19-4.36; P for trend = .01) for dose reduction.

Conclusions: Lower muscle mass is associated with greater toxicity and poor chemotherapy adherence among patients receiving FOLFOX. Many chemotherapy drugs are dosed based on BSA, but treatment may be better individualized if muscle mass is considered. Cancer 2017;123:4868-77. © 2017 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.30950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5716836PMC
December 2017

Long-term survival benefit of upfront chemotherapy in patients with newly diagnosed borderline resectable pancreatic cancer.

Cancer Med 2017 Jul 21;6(7):1552-1562. Epub 2017 Jun 21.

Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.

The use of neoadjuvant chemotherapy or radiation for borderline resectable pancreatic adenocarcinoma (BL-PDAC) is increasing. However, the impact of neoadjuvant chemotherapy and radiation therapy on the outcome of BL-PDAC remains to be elucidated. We performed a retrospective analysis of 93 consecutive patients who were diagnosed with BL-PDAC and primarily followed at Johns Hopkins Hospital between February 2007 and December 2012. Among 93 patients, 62% received upfront neoadjuvant chemotherapy followed by chemoradiation, whereas 20% received neoadjuvant chemoradiation alone and 15% neoadjuvant chemotherapy alone. Resectability following all neoadjuvant therapy was 44%. Patients who underwent resection with a curative intent had a median overall survival (mOS) of 25.8 months, whereas those who did not undergo surgery had a mOS of 11.9 months. However, resectability and overall survival were not significantly different between the three types of neoadjuvant therapy. Nevertheless, 22% (95% CI, 0.13-0.36) of the 58 patients who received upfront chemotherapy followed by chemoradiation remained alive for a minimum of 48 months compared to none of the 19 patients who received upfront chemoradiation. Among patients who underwent curative surgical resection, 32% (95% CI, 0.19-0.55) of those who received upfront chemotherapy remained disease free at least 48 months following surgical resection, whereas none of the eight patients who received upfront chemoradiation remained disease free beyond 24 months following surgical resection. Neoadjuvant therapy with upfront chemotherapy may result in long-term survival in a subpopulation of patients with BL-PDAC.
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http://dx.doi.org/10.1002/cam4.1104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5504321PMC
July 2017

Impact of body mass index on ovarian cancer survival varies by stage.

Br J Cancer 2017 Jul 6;117(2):282-289. Epub 2017 Jun 6.

Division of Research, Kaiser Permanente Northern California, Oakland, CA 94612, USA.

Background: Research on the effect of body mass index (BMI) on ovarian cancer survival is inconsistent, but previous studies did not consider the possible impact of ascites, bowel obstruction, or cachexia, which commonly occur in late-stage disease.

Methods: We evaluated the association of BMI, before and around the time of diagnosis, with overall and disease-specific survival in a cohort study of primary invasive epithelial ovarian cancers diagnosed from 2000 to 2013 in Kaiser Permanente Northern California (KPNC) (n=1184). Deaths were identified through December 2014, with a median follow-up of 37 months. Proportional hazards regression was used to estimate overall and ovarian cancer-specific mortality, accounting for prognostic variables including age at diagnosis, race, stage, grade, histology, comorbidities, treatment, post-treatment CA125 levels, ascites, and bowel obstruction.

Results: There was no evidence of an association between BMI and overall or ovarian cancer-specific survival. However, we found strong effect modification by stage (P<0.01). Compared with normal prediagnosis BMI (18.5-24.9 kg m), for women who were obese before diagnosis (BMI⩾35 kg m) ovarian cancer-specific survival was lower among those diagnosed at stages I/II (hazard ratio (HR): 3.40; 95% confidence interval (CI): 1.16-9.99), but increased among those diagnosed with stage IV disease (HR: 0.58; 95% CI: 0.35-0.96). Associations were attenuated after excluding those diagnosed with cachexia (n=82) and further adjustment for ascites and bowel obstruction, with no evidence of effect modification by these factors.

Conclusions: Associations of obesity with ovarian cancer survival may differ by stage, with decreased survival among those with localised disease and increased survival among those with late-stage disease. Stage-specific effects of obesity on survival suggest a tailored approach to improve prognosis may be appropriate.
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http://dx.doi.org/10.1038/bjc.2017.162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520512PMC
July 2017

Strategies for Increasing Pancreatic Tumor Immunogenicity.

Clin Cancer Res 2017 Apr;23(7):1656-1669

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland.

Immunotherapy has changed the standard of care for multiple deadly cancers, including lung, head and neck, gastric, and some colorectal cancers. However, single-agent immunotherapy has had little effect in pancreatic ductal adenocarcinoma (PDAC). Increasing evidence suggests that the PDAC microenvironment is comprised of an intricate network of signals between immune cells, PDAC cells, and stroma, resulting in an immunosuppressive environment resistant to single-agent immunotherapies. In this review, we discuss differences between immunotherapy-sensitive cancers and PDAC, the complex interactions between PDAC stroma and suppressive tumor-infiltrating cells that facilitate PDAC development and progression, the immunologic targets within these complex networks that are druggable, and data supporting combination drug approaches that modulate multiple PDAC signals, which should lead to improved clinical outcomes.
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http://dx.doi.org/10.1158/1078-0432.CCR-16-2318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5466881PMC
April 2017

Racial/Ethnic Disparities in Ovarian Cancer Treatment and Survival.

Clin Cancer Res 2016 Dec 12;22(23):5909-5914. Epub 2016 Aug 12.

Division of Research, Kaiser Permanente Northern California, Oakland, California.

Purpose: Among patients with ovarian cancer, African American (AA) women experience poorer survival compared with other race/ethnicity groups. This has been attributed to differences in access to health care.

Experimental Design: We evaluated racial/ethnic differences in chemotherapy dosing and survival in a cohort study among members of Kaiser Permanente Northern California, and thus with equivalent access to health care. Analyses included epithelial-invasive ovarian cancer cases (n = 793) receiving adjuvant first-line therapy of carboplatin and paclitaxel with curative intent, with median follow-up of 50 months. Relative dose intensity (RDI) was computed for carboplatin and paclitaxel separately as dose administered per week divided by expected dose per week, and average RDI (ARDI) was then calculated for the regimen. Proportional hazards regression was used to calculate HRs and 95% confidence intervals (CIs) after adjusting for relevant covariates.

Results: Compared with whites, AAs were more likely to have dose reduction (ARDI < 85%), treatment delay, and early discontinuation. Hispanics were also more likely to have dose reduction, but less likely to have early discontinuation or treatment delay. After controlling for prognostic factors including ARDI, AA women had the worst survival. Compared with whites, adjusted HRs (95% CI) for overall mortality were 1.56 (1.01-2.39) for AAs; 0.89 (0.61-1.31) for Asians; and 1.41 (0.98-2.04) for Hispanics. Findings for ovarian cancer-specific mortality were similar.

Conclusions: Disparities in ovarian cancer treatment and survival in AA persisted among women with equal access to care. These findings warrant further evaluation of biological, personal, and social factors that may be responsible for these differences. Clin Cancer Res; 22(23); 5909-14. ©2016 AACR.
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http://dx.doi.org/10.1158/1078-0432.CCR-16-1119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5135649PMC
December 2016

Race/ethnicity, genetic ancestry, and breast cancer-related lymphedema in the Pathways Study.

Breast Cancer Res Treat 2016 08 22;159(1):119-29. Epub 2016 Jul 22.

Division of Research, Kaiser Permanente Northern California, Oakland, CA, 94612, USA.

Breast cancer-related lymphedema (BCRL) is a serious chronic condition after breast cancer (BC) surgery and treatment. It is unclear if BCRL risk varies by race/ethnicity. In a multiethnic prospective cohort study of 2953 BC patients, we examined the association of self-reported BCRL status with self-reported race/ethnicity and estimated genetic ancestry. Hazard ratios (HR) and 95 % confidence intervals (CI) were calculated by multivariable Cox proportional hazards models, with follow-up starting 6 months post-BC diagnosis. Estimates were further stratified by body mass index (BMI). By 48 months of follow-up, 342 (11.6 %) women reported having BCRL. Younger age at BC diagnosis, higher BMI at baseline, and lower physical activity were associated with greater BCRL risk. African American (AA) women had a 2-fold increased risk of BCRL compared with White women (HR = 2.04; 95 % CI 1.35-3.08). African genetic ancestry was also associated with an increased risk (HR = 2.50; 95 % CI 1.43, 4.36). Both risks were attenuated but remained elevated after adjusting for known risk factors and became more pronounced when restricted to the nonobese women (adjusted HR = 2.31 for AA and HR = 3.70 for African ancestry, both p < 0.05). There was also evidence of increased BCRL risk with Hispanic ethnicity in the nonobese women. Nonobese AA women had a higher risk of BCRL than White women, which cannot be fully explained by known risk factors. This is the first large-scale, prospective study demonstrating differences in BCRL risk according to race/ethnicity as assessed by both self-report and genetic ancestry data, with a potential ancestry-obesity interaction.
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http://dx.doi.org/10.1007/s10549-016-3913-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010992PMC
August 2016

Mismatch Repair Deficiency and Response to Immune Checkpoint Blockade.

Oncologist 2016 10 13;21(10):1200-1211. Epub 2016 Jul 13.

The Swim Across America Laboratory, Baltimore, Maryland, USA the Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins Kimmel Cancer Center, Baltimore, Maryland, USA

: More than 1.6 million new cases of cancer will be diagnosed in the U.S. in 2016, resulting in more than 500,000 deaths. Although chemotherapy has been the mainstay of treatment in advanced cancers, immunotherapy development, particularly with PD-1 inhibitors, has changed the face of treatment for a number of tumor types. One example is the subset of tumors characterized by mismatch repair deficiency and microsatellite instability that are highly sensitive to PD-1 blockade. Hereditary forms of cancer have been noted for more than a century, but the molecular changes underlying mismatch repair-deficient tumors and subsequent microsatellite unstable tumors was not known until the early 1990s. In this review article, we discuss the history and pathophysiology of mismatch repair, the process of testing for mismatch repair deficiency and microsatellite instability, and the role of immunotherapy in this subset of cancers.

Implications For Practice: Mismatch repair deficiency has contributed to our understanding of carcinogenesis for the past 2 decades and now identifies a subgroup of traditionally chemotherapy-insensitive solid tumors as sensitive to PD-1 blockade. This article seeks to educate oncologists regarding the nature of mismatch repair deficiency, its impact in multiple tumor types, and its implications for predicting the responsiveness of solid tumors to immune checkpoint blockade.
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http://dx.doi.org/10.1634/theoncologist.2016-0046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5061538PMC
October 2016

Validation of self-reported comorbidity status of breast cancer patients with medical records: the California Breast Cancer Survivorship Consortium (CBCSC).

Cancer Causes Control 2016 Mar 21;27(3):391-401. Epub 2016 Jan 21.

University of Southern California, Health Sciences Campus, NOR 4443, Mail Code:9175, Los Angeles, CA, 90089-9175, USA.

Purpose: To compare information from self-report and electronic medical records for four common comorbidities (diabetes, hypertension, myocardial infarction, and other heart diseases).

Methods: We pooled data from two multiethnic studies (one case-control and one survivor cohort) enrolling 1,936 women diagnosed with breast cancer, who were members of Kaiser Permanente Northern California.

Results: Concordance varied by comorbidity; kappa values ranged from 0.50 for other heart diseases to 0.87 for diabetes. Sensitivities for comorbidities from self-report versus medical record were similar for racial/ethnic minorities and non-Hispanic Whites, and did not vary by age, neighborhood socioeconomic status, or education. Women with a longer history of comorbidity or who took medications for the comorbidity were more likely to report the condition. Hazard ratios for all-cause mortality were not consistently affected by source of comorbidity information; the hazard ratio was lower for diabetes, but higher for the other comorbidities when medical record versus self-report was used. Model fit was better when the medical record versus self-reported data were used.

Conclusions: Comorbidities are increasingly recognized to influence the survival of patients with breast or other cancers. Potential effects of misclassification of comorbidity status should be considered in the interpretation of research results.
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http://dx.doi.org/10.1007/s10552-016-0715-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5792190PMC
March 2016

Efficacy of PD-1 blockade in tumors with MMR deficiency.

Immunotherapy 2016 8;8(1):1-3. Epub 2015 Dec 8.

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, 1650 Orleans Street, Room 407, Baltimore, MD 21287, USA.

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http://dx.doi.org/10.2217/imt.15.97DOI Listing
June 2016

Exploring Death Anxiety and Burnout Among Staff Members Who Work In Outpatient Hemodialysis Units.

Nephrol Nurs J 2014 Sep-Oct;41(5):479-85, 518

Outpatient hemodialysis unit staff members are at risk for psychological stress, including death anxiety, unresolved grieving, and burnout, due tofrequent interactions with chronically ill patients who have a high mortality rate. Experiencing death anxiety and burnout may impair the ability to build interpersonal relationships, decrease job satisfaction, and impact quality of patient care. A quantitative study to evaluate the effect of educational classes on the level of death anxiety and burnout among hemodialysis caregivers revealed a decrease in participants' level of death anxiety and a decrease in emotional exhaustion in one area that was directly related to the work environment Information from the study can be used to decrease psychological stress through education and support for staff members who work in the hemodialysis unit environment.
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September 2015

Impact of Chemotherapy Dosing on Ovarian Cancer Survival According to Body Mass Index.

JAMA Oncol 2015 Sep;1(6):737-45

Division of Research, Kaiser Permanente Northern California, Oakland6Division of Hematology and Oncology, Department of Internal Medicine, University of California Davis School of Medicine, Sacramento.

Importance: Optimal chemotherapy dosing in obese patients remains uncertain, with variation in practice. Dose reduction strategies are often used to avoid chemotoxicity, but recent American Society of Clinical Oncology guidelines recommend full dose.

Objective: To evaluate the impact of body mass index (BMI) on chemotherapy dosing and of dose reduction on ovarian cancer survival.

Design, Setting, And Participants: Cohort study in Kaiser Permanente Northern California (KPNC) health care setting of patients with primary invasive epithelial ovarian cancers diagnosed from January 2000 through March 2013. Analyses focused on 806 patients receiving adjuvant first-line therapy of carboplatin and paclitaxel with curative intent.

Main Outcomes And Measures: Overall and ovarian cancer-specific mortality. Deaths were identified through the KPNC Mortality Linkage System, with median follow-up of 52.5 months. Hazard ratios (HRs) and 95% CIs were estimated from proportional hazards regression, accounting for prognostic variables including age at diagnosis, race, stage, grade, histologic type, chemotoxic effects, comorbidities, cancer antigen 125 levels, and BMI at diagnosis.

Results: The strongest predictor of dose reduction was a high BMI. Compared with normal-weight women, obese class III women received 38% and 45% lower doses in milligrams per kilogram of body weight of paclitaxel and carboplatin, respectively (P < .001 for each agent). They also received lower relative dose intensity (RDI) for each agent and the combined regimen, calculated as average RDI (ARDI). Mean ARDI was 73.7% for obese class III women and 88.2% for normal-weight women (P < .001). Lower ARDI (<70%) was associated with worse overall (HR, 1.62 [95% CI, 1.10-2.37]) and ovarian cancer-specific survival (HR, 1.69 [95% CI, 1.12-2.55]). Women who were obese at diagnosis appeared to have better survival. In multivariable-adjusted analyses considering joint effects by BMI and ARDI, compared with women with normal weight and no dose reduction, normal-weight women with dose reduction (ARDI < 85%) experienced worse survival (HR, 1.50 [95% CI, 1.02-2.21]). For each BMI category, those with ARDI less than 85% had worse survival than those without dose reduction. The improved survival among obese women was no longer apparent with dose reduction.

Conclusions And Relevance: Lower RDI was an independent predictor of ovarian cancer mortality. This finding was strongest among normal-weight women but seen at all levels of BMI. Our results suggest that body size should not be a major factor influencing dose reduction decisions in women with ovarian cancer.
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http://dx.doi.org/10.1001/jamaoncol.2015.1796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4567489PMC
September 2015

History of Recreational Physical Activity and Survival After Breast Cancer: The California Breast Cancer Survivorship Consortium.

Am J Epidemiol 2015 Jun 29;181(12):944-55. Epub 2015 Apr 29.

Recent epidemiologic evidence suggests that prediagnosis physical activity is associated with survival in women diagnosed with breast cancer. However, few data exist for racial/ethnic groups other than non-Latina whites. To examine the association between prediagnosis recreational physical activity and mortality by race/ethnicity, we pooled data from the California Breast Cancer Survivorship Consortium for 3 population-based case-control studies of breast cancer patients (n=4,608) diagnosed from 1994 to 2002 and followed up through 2010. Cox proportional hazards models provided estimates of the relative hazard ratio for mortality from all causes, breast cancer, and causes other than breast cancer associated with recent recreational physical activity (i.e., in the 10 years before diagnosis). Among 1,347 ascertained deaths, 826 (61%) were from breast cancer. Compared with women with the lowest level of recent recreational physical activity, those with the highest level had a marginally decreased risk of all-cause mortality (hazard ratio=0.88, 95% confidence interval: 0.76, 1.01) and a statistically significant decreased risk of mortality from causes other than breast cancer (hazard ratio=0.63, 95% confidence interval: 0.49, 0.80), and particularly from cardiovascular disease. No association was observed for breast cancer-specific mortality. These risk patterns did not differ by race/ethnicity (non-Latina white, African American, Latina, and Asian American). Our findings suggest that physical activity is beneficial for overall survival regardless of race/ethnicity.
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http://dx.doi.org/10.1093/aje/kwu466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4462332PMC
June 2015

A hybrid approach to identify subsequent breast cancer using pathology and automated health information data.

Med Care 2015 Apr;53(4):380-5

*Department of Research & Evaluation, Kaiser Permanente Southern California, Pasadena †Division of Research, Kaiser Permanente Northern California, Oakland, CA ‡Department of Population Medicine & Harvard Pilgrim Health Care Institute, Harvard Medical School, Boston, MA.

Purpose: Many cancer registries do not capture recurrence; thus, outcome studies have often relied on time-intensive and costly manual chart reviews. Our goal was to build an effective and efficient method to reduce the numbers of chart reviews when identifying subsequent breast cancer (BC) using pathology and electronic health records. We evaluated our methods in an independent sample.

Methods: We developed methods for identifying subsequent BC (recurrence or second primary) using a cohort of 17,245 women diagnosed with early-stage BC from 2 health plans. We used a combination of information from pathology report reviews and an automated data algorithm to identify subsequent BC (for those lesions without pathologic confirmation). Test characteristics were determined for a developmental (N=175) and test (N=500) set.

Results: Sensitivity and specificity of our hybrid approach were robust [96.7% (87.6%-99.4%) and 92.1% (85.1%-96.1%), respectively] in the developmental set. In the test set, the sensitivity, specificity, and negative predictive value were also high [96.9% (88.4%-99.5%), 92.4% (89.4%-94.6%), and 99.5% (98.0%-99.0%), respectively]. The positive predictive value was lower (65.6%, 55.2%-74.8%). Chart review was required for 10.9% of the 17,245 women; 2946 (17.0%) women developed subsequent BC over a 14-year period. The date of subsequent BC identified by the algorithm was concordant with full chart reviews.

Conclusions: We developed an efficient and effective hybrid approach that decreased the number of charts needed to be manually reviewed by approximately 90%, to determine subsequent BC occurrence and disease-free survival time.
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http://dx.doi.org/10.1097/MLR.0000000000000327DOI Listing
April 2015