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1.  Comorbidity, Chemotherapy Toxicity, and Outcomes Among Older Women Receiving Adjuvant Chemotherapy for Breast Cancer on a Clinical Trial: CALGB 49907 and CALGB 361004 (Alliance) 
Journal of Oncology Practice  2014;10(5):e285-e292.
Comorbidity was associated with shorter overall survival but not toxicity or relapse among older women with breast cancer with good functional status.
We evaluated associations among comorbidity, toxicity, time to relapse (TTR), and overall survival (OS) in older women with early-stage breast cancer receiving adjuvant chemotherapy.
Cancer and Leukemia Group B 49907 (Alliance) randomly assigned women ≥ 65 years old with stages I-III breast cancer to standard adjuvant chemotherapy or capecitabine. We reviewed data from 329 women who participated in the quality of life companion study CALGB 70103 and completed the Physical Health Subscale of the Older American Resources and Services Questionnaire. This questionnaire captures data on 14 comorbid conditions and the degree to which each interferes with daily activities. A comorbidity burden score was computed by multiplying the total number of conditions by each condition's level of interference with function. Outcomes were grade 3 to 5 toxicity, TTR, and OS. Logistic regression was used to evaluate associations between comorbidity and toxicity, and Cox proportional hazards models for TTR and survival.
Number of comorbidities ranged from 0 to 10 (median 2); the comorbidity burden score ranged from 0 to 25 (median 3). The most common conditions were arthritis (58%) and hypertension (55%). Comorbidity was associated with shorter OS, but not with toxicity or TTR. The hazard of death increased by 18% for each comorbidity (hazard ratio [HR] = 1.18, 95% CI = 1.06 to 1.33) after adjusting for age, tumor size, treatment, node and receptor status. Comorbidity burden score was similarly associated with OS (HR = 1.08; 95% CI, 1.03 to 1.14).
Among older women enrolled onto a clinical trial, comorbidity was associated with shorter OS, but not toxicity or relapse.
PMCID: PMC4161730  PMID: 25074878
2.  An Assessment of Hepatitis E Virus in US Blood Donors and Recipients: No Detectable HEV RNA in 1939 Donors Tested and No Evidence For HEV Transmission to 362 Prospectively Followed Recipients 
Transfusion  2013;53(10 0 2):2505-2511.
Hepatitis E virus (HEV) infection has become relevant to blood transfusion practice because isolated cases of blood transmission have been reported and because HEV has been found to cause chronic infection and severe liver disease in immuno-compromised patients.
Study design and Methods
We tested for IgG and IgM antibodies to the hepatitis E virus (HEV) and for HEV RNA in 1939 unselected volunteer US blood donors. Subsequently, we tested the same parameters in pre- and serial post-transfusion samples from 362 prospectively followed blood recipients to assess transfusion risk.
IgG anti-HEV seroprevalence in the total 1939 donations was 18.8%: 916 of these donations were made in 2006 at which time the seroprevalence was 21.8% and the remaining 1023 donations were in 2012 when the seroprevalence had decreased to 16.0% (p<0.01). A significant (P<0.001) stepwise increase in anti-HEV seroprevalence was seen with increasing age. Eight of 1939 donations (0.4%) tested anti-HEV IgM positive; no donation was HEV RNA positive. Two recipients had an apparent anti-HEV seroconversion, but temporal relationships and linked donor testing showed that these were not transfusion transmitted HEV infections.
No transfusion-transmitted HEV infections were observed in 362 prospectively followed blood recipients despite an anti-HEV seroprevalence among donations exceeding 16%.
PMCID: PMC4542147  PMID: 23829163
Hepatitis E virus; transfusion transmitted; blood donor; recipient; seroconversion
3.  Investigation of Residual Hepatitis C Virus in Presumed Recovered Subjects 
Hepatology (Baltimore, Md.)  2012;57(2):483-491.
Recent studies have found hepatitis C virus (HCV) RNA in peripheral blood mononuclear cells (PBMCs) of the majority of presumed recovered subjects. We investigated this unexpected finding using samples from patients whose HCV RNA and anti-HCV status had been serially confirmed. HCV RNA was detected in PBMCs from 66/67 chronic HCV carriers. Subpopulation analysis revealed that the viral load (log copies/106 cells) in B cells (4.14 ± 0.71) was higher than in total PBMCs (3.62 ± 0.71, p<0.05), T cells (1.67 ± 0.88, p<0.05), and non-B/T cells (2.48 ± 1.15, p<0.05). HCV negative-strand RNA was not detected in PBMCs from any of 25 chronically infected patients. No residual viral RNA was detected in total PBMCs or plasma of 59 presumed recovered subjects (11 spontaneous, 48 treatment-induced) using nested real-time PCR with a detection limit of 2 copies/μg RNA (from ~1×106 cells). PBMCs from two healthy HCV-negative blood donors became HCV RNA positive, with B-cell predominance, when mixed in vitro with HCV RNA positive plasma, thus passively mimicking cells from chronic HCV carriers. No residual HCV was detected in liver or other tissues from two spontaneously recovered chimpanzees. Conclusion: 1) HCV RNA was detected in PBMCs of most chronic HCV carriers and was predominant in the B cell subpopulation; 2) HCV detected in PBMCs was in a non-replicative form; 3) HCV passively adsorbed to PBMCs of healthy controls in vitro becoming indistinguishable from PBMCs of chronic HCV carriers; 4) Residual HCV was not detected in the plasma or PBMCs of any spontaneous or treatment recovered subjects or in chimpanzee liver suggesting that the classic pattern of recovery from HCV infection is generally equivalent to viral eradication.
PMCID: PMC4523271  PMID: 22729600
HCV eradication; HCV recovery; PBMC; residual virus; viral adherence
4.  Glucagon-Like Peptide-1 Receptor Signaling in the Lateral Parabrachial Nucleus Contributes to the Control of Food Intake and Motivation to Feed 
Neuropsychopharmacology  2014;39(9):2233-2243.
Central glucagon-like peptide-1 receptor (GLP-1R) activation reduces food intake and the motivation to work for food, but the neurons and circuits mediating these effects are not fully understood. Although lateral parabrachial nucleus (lPBN) neurons are implicated in the control of food intake and reward, the specific role of GLP-1R-expressing lPBN neurons is unexplored. Here, neuroanatomical tracing, immunohistochemical, and behavioral/pharmacological techniques are used to test the hypothesis that lPBN neurons contribute to the anorexic effect of central GLP-1R activation. Results indicate that GLP-1-producing neurons in the nucleus tractus solitarius project monosynaptically to the lPBN, providing a potential endogenous mechanism by which lPBN GLP-1R signaling may exert effects on food intake control. Pharmacological activation of GLP-1R in the lPBN reduced food intake, and conversely, antagonism of GLP-1R in the lPBN increased food intake. In addition, lPBN GLP-1R activation reduced the motivation to work for food under a progressive ratio schedule of reinforcement. Taken together, these data establish the lPBN as a novel site of action for GLP-1R-mediated control of food intake and reward.
PMCID: PMC4104342  PMID: 24681814
5.  Frailty and Adherence to Adjuvant Hormonal Therapy in Older Women With Breast Cancer: CALGB Protocol 369901 
Journal of Clinical Oncology  2014;32(22):2318-2327.
Most patients with breast cancer age ≥ 65 years (ie, older patients) are eligible for adjuvant hormonal therapy, but use is not universal. We examined the influence of frailty on hormonal therapy noninitiation and discontinuation.
Patients and Methods
A prospective cohort of 1,288 older women diagnosed with invasive, nonmetastatic breast cancer recruited from 78 sites from 2004 to 2011 were included (1,062 had estrogen receptor–positive tumors). Interviews were conducted at baseline, 6 months, and annually for up to 7 years to collect sociodemographic, health care, and psychosocial data. Hormonal initiation was defined from records and discontinuation from self-report. Baseline frailty was measured using a previously validated 35-item scale and grouped as prefrail or frail versus robust. Logistic regression and proportional hazards models were used to assess factors associated with noninitiation and discontinuation, respectively.
Most women (76.4%) were robust. Noninitiation of hormonal therapy was low (14%), but in prefrail or frail (v robust) women the odds of noninitiation were 1.63 times as high (95% CI, 1.11 to 2.40; P = .013) after covariate adjustment. Nonwhites (v whites) had higher odds of noninitiation (odds ratio, 1.71; 95% CI, 1.04 to 2.80; P = .033) after covariate adjustment. Among initiators, the 5-year continuation probability was 48.5%. After adjustment, the risk of discontinuation was higher with increasing age (P = .005) and lower for stage ≥ IIB (v stage I) disease (P = .003).
Frailty is associated with noninitiation of hormonal therapy, but it does not seem to be a major predictor of early discontinuation in older patients.
PMCID: PMC4105485  PMID: 24934786
6.  Morphology, Projection Pattern and Neurochemical Identity of Cajal’s “Centrifugal Neurons”: The Cells of Origin of the Tectoventrogeniculate Pathway in Pigeon (Columba livia) and Chicken (Gallus gallus) 
The Journal of comparative neurology  2014;522(10):2377-2396.
The nucleus geniculatus lateralis pars ventralis (GLv) is a prominent retinal target in all amniotes. In birds, it is in receipt of a dense and topographically organized retinal projection. The GLv is also the target of substantial and topographically organized projections from the optic tectum and the visual wulst (Hyperpallium). Tectal and retinal afferents terminate homotopically within the external GLv-neuropil. Efferents from the GLv follow a descending course through the tegmentum, and can be traced into the medial pontine nucleus. At present, the cells of origin of the Tecto-GLv projection are only partially described. Here we have characterized the laminar location, morphology, projection pattern and neurochemical identity of these cells, by means of neural tracer injections and intracellular fillings in slice preparations and extracellular tracer injections in-vivo. The Tecto-GLv projection arises from a distinct subset of layer 10 bipolar neurons, whose apical dendrites show a complex transverse arborization at the level of layer 7. Axons of these bipolar cells arise from the apical dendrites and follow a course through the optic tract to finally form very fine and restricted terminal endings inside the GLv-neuropil. Double label experiments showed that these bipolar cells were ChAT immunoreactive. Our results strongly suggest that Tecto-GLv neurons form a pathway by which integrated tectal activity rapidly feeds back to the GLv and exerts a focal cholinergic modulation of incoming retinal inputs.
PMCID: PMC4011500  PMID: 24435811
Optic tectum; GLv; Slice; Vine-neuron; ChAT; Birds
7.  Religiously Integrated Cognitive Behavioral Therapy: A New Method of Treatment for Major Depression in Patients With Chronic Medical Illness 
Psychotherapy (Chicago, Ill.)  2014;52(1):56-66.
Intervention studies have found that psychotherapeutic interventions that explicitly integrate clients’ spiritual and religious beliefs in therapy are as effective, if not more so, in reducing depression than those that do not for religious clients. However, few empirical studies have examined the effectiveness of religiously (vs. spiritually) integrated psychotherapy, and no manualized mental health intervention had been developed for the medically ill with religious beliefs. To address this gap, we developed and implemented a novel religiously integrated adaptation of cognitive–behavioral therapy (CBT) for the treatment of depression in individuals with chronic medical illness. This article describes the development and implementation of the intervention. First, we provide a brief overview of CBT. Next, we describe how religious beliefs and behaviors can be integrated into a CBT framework. Finally, we describe Religiously Integrated Cognitive Behavioral Therapy (RCBT), a manualized therapeutic approach designed to assist depressed individuals to develop depression-reducing thoughts and behaviors informed by their own religious beliefs, practices, and resources. This treatment approach has been developed for 5 major world religions (Christianity, Judaism, Islam, Buddhism, and Hinduism), increasing its potential to aid the depressed medically ill from a variety of religious backgrounds.
PMCID: PMC4457450  PMID: 25365155
depression; religion; spirituality; medical illness; psychotherapy
8.  Habitat complexity reduces parasitoid foraging efficiency, but does not prevent orientation towards learned host plant odours 
Oecologia  2015;179(2):353-361.
It is well known that many parasitic wasps use herbivore-induced plant odours (HIPVs) to locate their inconspicuous host insects, and are often able to distinguish between slight differences in plant odour composition. However, few studies have examined parasitoid foraging behaviour under (semi-)field conditions. In nature, food plants of parasitoid hosts are often embedded in non-host-plant assemblages that confer both structural and chemical complexity. By releasing both naïve and experienced Cotesia glomerata females in outdoor tents, we studied how natural vegetation surrounding Pieris brassicae-infested Sinapis arvensis and Barbarea vulgaris plants influences their foraging efficiency as well as their ability to specifically orient towards the HIPVs of the host plant species on which they previously had a positive oviposition experience. Natural background vegetation reduced the host-encounter rate of naïve C. glomerata females by 47 %. While associative learning of host plant HIPVs 1 day prior to foraging caused a 28 % increase in the overall foraging efficiency of C. glomerata, it did not reduce the negative influence of natural background vegetation. At the same time, however, females foraging in natural vegetation attacked more host patches on host-plant species on which they previously had a positive oviposition experience. We conclude that, even though the presence of natural vegetation reduces the foraging efficiency of C. glomerata, it does not prevent experienced female wasps from specifically orienting towards the host-plant species from which they had learned the HIPVs.
PMCID: PMC4568006  PMID: 26001606
Cotesia glomerata; Pieris brassicae; Learning; Semi-field study; Host location
9.  Multiple Myeloma in the Very Old: An IASIA Conference Report 
Multiple myeloma (MM) in patients aged greater than 80 years poses an increasingly common challenge for oncology providers. A multidisciplinary workshop was held in which MM-focused hematologists/oncologists, geriatricians, and associated health-care team members discussed the state of research for MM therapy, as well as themes from geriatric medicine that pertain directly to this patient population. A summary statement of our discussions is presented here, in which we highlight several topics. MM disproportionately affects senior adults, and demographic trends indicate that this trend will accelerate. Complex issues impact cancer in seniors, and although factors such as social environment, comorbidities, and frailty have been well characterized in nononcological geriatric medicine, these themes have been inadequately explored in cancers such as MM, despite their clear relevance to this field. Therapeutically, novel agents have improved survival for MM patients of all ages, but less so for seniors than younger patients for a variety of reasons. Lastly, both MM- and treatment-related symptoms and toxicities require special attention in senior adults. Existing research provides limited insight into how best to manage these often complex patients, who are often not reflected in typical clinical trial populations. We hence offer suggestions for clinical trials that address knowledge gaps in how to manage very old and/or frail patients with MM, given the complicated issues that often surround this patient population.
PMCID: PMC4580557  PMID: 24700806
10.  Associations among survivorship care plans, experiences of survivorship care, and functioning in older breast cancer survivors: CALGB/Alliance 369901 
Survivorship care plans (SCP) are recommended for all cancer patients and could be especially useful to survivors 65 years and over (“older”). This study examined receipt of SCPs among older breast cancer survivors and whether SCPs were associated with improved patient-reported outcomes.
Three hundred and twenty-eight older women diagnosed with invasive, nonmetastatic breast cancer between 2007–2011 were recruited from 78 cooperative-group sites. Participants completed telephone interviews at baseline and 1-year posttreatment. Regression analyses examined SCP receipt (yes/no) and functioning (EORTC-QLQ-C30), cancer worry, and experiences of survivorship care (care coordination, knowledge).
Only 35 % of women received SCPs. For each 1-year increase in age, there was a 5 % lower odds of receiving an SCP (odds ratio (OR)=0.94, 95 % confidence interval (CI) 0.91–0.98, p=0.007). Besides age, no other factor predicted SCPs. SCP receipt was associated with greater knowledge and understanding of requisite follow-up care (p<0.05); however, functioning was not significantly different among those with vs. without SCPs.
Receipt of care plans was limited. SCPs improved understanding of breast cancer follow-up care among older survivors, but did not impact functioning one year post-treatment.
Implications for Cancer Survivors
To impact functioning and salient needs of the growing cohort of older survivors, survivorship care plans likely should be tailored to geriatric-specific issues. To improve functioning, SCP content should expand to include exercise, nutrition, polypharmacy, social support and management of symptom burden from cancer, and other comorbid conditions. To improve follow-up care for cancer survivors, SCPs should delineate shared care roles between oncology and primary care in managing recurrence surveillance, screening, and cancer sequelae.
PMCID: PMC4386650  PMID: 24917307
Survivorship care plan; Breast cancer; Cancer survivors; Older adults; Cancer survivorship and aging
11.  Early stage rectal cancer: clinical and pathologic prognostic markers of time to local recurrence and overall survival after resection 
Diseases of the colon and rectum  2014;57(4):449-459.
Resection without adjuvant therapy results in a low recurrence rate for patients with stage I (T1/2 N0) rectal cancer, in the range of 4% to 16% at 5 years. There are limited data, however, regarding clinical or pathologic prognostic markers for recurrence in this population.
To assess clinical and pathologic factors associated with local recurrence and overall survival in patients with early stage rectal cancer after resection.
Retrospective study.
This study was conducted at two tertiary care centers in Boston, MA.
From 2000 to 2008, 175 patients with stage I rectal cancer treated with local or total mesorectal excision without adjuvant therapy were identified.
Main Outcome Measures
Time to local recurrence after resection and overall survival were evaluated for all patients with complete follow up data. Perioperative data were reviewed to identify staging method, preoperative carcinoembryonic antigen, type of surgery, tumor size, number of lymph nodes resected, histological grade, circumferential resection margin, perineural invasion, lymphovascular invasion, and tumor ulceration. Data were analyzed using a Cox proportional hazards regression model.
Of the eligible cohort, 137 patients had complete follow up data for analysis of time to local recurrence, and 23 (16.8%) recurred locally. Among these 23 patients, the median time to recurrence was 1.1 years (0.1-7.8). On multivariate analysis, male gender, current alcohol use, and tumor ulceration were associated with heightened risk of local recurrence. Of the original cohort, 173 patients had complete follow up for overall survival analysis. Among these patients, the median overall survival was 12 years. On multivariable analysis, age at diagnosis >65 years and T2 pathologic stage were associated with decreased survival.
For patients with stage I rectal cancer treated with resection alone, these results provide important prognostic information and may help identify those who could benefit from additional therapy.
PMCID: PMC3954982  PMID: 24608301
rectal cancer; recurrence; survival; prognosis
12.  The South West Area Mesothelioma and Pemetrexed trial: a multicentre prospective observational study evaluating novel markers of chemotherapy response and prognostication 
British Journal of Cancer  2015;112(7):1175-1182.
Robust markers that predict prognosis and detect early treatment response in malignant pleural mesothelioma (MPM) would enhance patient care.
Consecutive patients with MPM who were considered fit for first-line chemotherapy were prospectively recruited. Patients of similar performance status opting for best supportive care were included as a comparator group. Baseline and interval CT, PET-CT and serum markers (mesothelin, fibulin-3 and neutrophil–lymphocyte ratio (NLR)) were obtained, and patients followed up for a minimum 12 months.
Seventy-three patients were recruited (58 chemotherapy/15 comparator arm). Baseline TGV (total glycolytic volume on PET-CT) was an independent predictor of worse overall survival (OS) (P=0.001). Change in interval TGV(baseline/after two cycles of chemotherapy) did not predict OS or chemotherapy response on CT. Baseline NLR<4 was an independent predictor of better OS (median survival 453 (IQR 272–576) days vs NLR⩾4, 257 (IQR 147–490), P=0.002). Although baseline serum mesothelin did not predict OS, a falling level at 8 weeks significantly predicted longer time to progression (TTP) (P<0.001).
Neutrophil–lymphocyte ratio and baseline TGV predict prognosis in malignant pleural mesothelioma (MPM), but PET-CT is unhelpful in monitoring chemotherapy response. Serum mesothelin is a useful early treatment response marker when measured serially during chemotherapy and may have a role in evaluating patients' treatment response.
PMCID: PMC4385956  PMID: 25756396
13.  The effect of chemotherapy on health-related quality of life in mesothelioma: results from the SWAMP trial 
British Journal of Cancer  2015;112(7):1183-1189.
The effect of chemotherapy on health-related quality of life (HRQoL) in malignant pleural mesothelioma (MPM) is poorly understood. Patient-individualised prognostication and prediction of treatment response from chemotherapy is useful but little evidence exists to guide practice.
Consecutive patients with MPM who were fit for first-line chemotherapy with pemetrexed and cisplatin\carboplatin were recruited and followed up for a minimum of 12 months. This study focussed on the HRQoL outcomes of these patients using the EQ-5D, EORTC QLQ-C30 and LC13.
Seventy-three patients were recruited of which 58 received chemotherapy and 15 opted for best supportive care (BSC). Compliance with HRQoL questionnaires was 98% at baseline. The chemotherapy group maintained HRQoL compared with the BSC group whose overall HRQoL fell (P=0.006) with worsening dyspnoea and pain. The impact of chemotherapy was irrespective of histological subtype although those with non-epithelioid disease had worse HRQoL at later time points (P=0.012). Additionally, those with a falling mesothelin or improvement on modified-RECIST CT at early follow-up had a better HRQoL at 16 weeks.
HRQoL was maintained following chemotherapy compared with a self-selected BSC group. Once chemotherapy is initiated, a falling mesothelin or improved RECIST CT findings infer a quality-of-life advantage.
PMCID: PMC4385962  PMID: 25756395
mesothelioma; chemotherapy; quality of life
14.  Mutational and Clinical Predictors of Pathologic Complete Response in the Treatment of Locally Advanced Rectal Cancer 
Preoperative chemoradiation (CRT) for locally advanced rectal adenocarcinoma achieves pathologic complete response (pCR) in 8–20 % of patients. Mutations in critical cancer genes may contribute to lack of pCR. We retrospectively evaluated our institutional experience to determine potential mutational and clinical predictors of pCR in patients treated with CRT.
Patients with locally advanced rectal adenocarcinoma treated with preoperative CRT (n = 79) were identified. A clinical cancer genotyping assay evaluated 140 hotspot mutation sites across 15 cancer genes in 47 patients with sufficient tissue. Mutational profiles were compared in pre- and post-CRT specimens and with pCR rate. Clinical variables were evaluated using logistic regression.
Genotyping identified mutations in KRAS (43 %), APC (17 %), BRAF (4 %), NRAS (4 %), PIK3CA (4 %), and TP53 (11 %). In the entire cohort, 21.5 % had a pCR. No patients with BRAF, NRAS, APC, or TP53 achieved a pCR. pCR rate was 23.5 % (4/17) in wild-type tumors versus 3.3 % (1/30) in those with a mutation. There was no difference in the mutation rates in pre- versus post-CRT specimens. On univariate analysis, clinical predictors of pCR included post-RT carcinoembriogenic antigen level of ≤2.5 and smaller tumor size. No patients with a pCR developed recurrence.
Patients without mutations in commonly mutated cancer genes may be associated with a higher likelihood of having a pCR after preoperative CRT. This should be confirmed in a prospective study.
PMCID: PMC4361942  PMID: 24006244
Rectal cancer; Mutation; Pathologic complete response
15.  Pancreatic Cancer Tumor Size on CT Scan vs. Pathologic Specimen: Implications for Radiation Treatment Planning 
Pancreatic cancer primary tumor size measurements are often discordant between CT and pathologic specimen after resection. Dimensions of the primary tumor are increasingly relevant in an era of highly conformal radiotherapy.
We retrospectively evaluated 97 consecutive patients with resected pancreatic cancer at two Boston hospitals. All patients had CT scans prior to surgical resection. Primary endpoints were maximum dimension (in mm) of the primary tumor in any direction as reported by the radiologist on CT and by the pathologist on resected gross fresh specimen. Endoscopic ultrasound (EUS) findings were analyzed if available.
Eighty-seven patients (90%) had pre-operative CT scans available for review, and 46 (47%) had EUS. Among proximal tumors (n = 69), 40 (58%) had pathologic duodenal invasion, which was seen on CT in only 3 cases. Pathologic tumor size was a median of 7 mm larger compared to CT size for the same patient (range: −15–43 mm, p < 0.0001), with 73 patients (84%) having a primary tumor larger on pathology than CT. EUS was somewhat more accurate, with pathologic tumor size being a median of only 5 mm larger compared to EUS size (range, −15–35 mm, p = 0.0003).
CT scans significantly under-represent pancreatic cancer tumor size compared to pathologic specimens in resectable cases. We propose a clinical target volume (CTV) expansion formula for the primary tumor based on our data. The high rate of pathologic duodenal invasion suggests a risk of duodenal under-coverage with highly conformal radiotherapy.
PMCID: PMC4362517  PMID: 20708856
Pancreatic cancer; CT; Pathology; Radiation; CTV formula
16.  Prevalence and significance of subcentimeter hepatic lesions in patients with localized pancreatic adenocarcinoma 
Practical radiation oncology  2012;2(4):e89-e94.
To determine the prevalence and significance of incidental hepatic and pulmonary sub-centimeter lesions in patients with localized pancreatic cancer.
This retrospective study included 101 patients treated for localized pancreatic adenocarcinoma from 1999 to 2007. Staging and follow-up imaging was reviewed to determine the frequency of sub-centimeter liver and pulmonary lesions. Using Cox regression, we calculated adjusted hazard ratios (HR) to determine the association between presence of liver and pulmonary lesions and overall survival.
Forty patients (39.6%) had sub-centimeter hepatic or pulmonary lesions on staging scans. Of these patients, 33 (82.5% of patients with lesions) had eventual metastases in the same organ as the lesions. Of this group, seven patients (17.5% of patients with lesions) eventually had a metastasis at the site of the original lesion. Liver lesions predicted the occurrence of metastatic disease to the liver compared to patients without lesions (67.7% with lesions vs. 44.4% without, p = .034). Sub-centimeter liver lesions at diagnosis were significantly associated with reduced overall survival (HR 1.65, p = 0.036).
Sub-centimeter lesions in the liver and lung are common in patients with localized pancreatic cancer. The presence of indeterminate lesions may be associated with reduced overall survival.
PMCID: PMC4350367  PMID: 24674191
17.  Differential Responses of Plasmacytoid Dendritic Cells to Influenza Virus and Distinct Viral Pathogens 
Journal of Virology  2014;88(18):10758-10766.
Plasmacytoid dendritic cells (pDCs) are key components of the innate immune response that are capable of synthesizing and rapidly releasing vast amounts of type I interferons (IFNs), particularly IFN-α. Here we investigated whether pDCs, often regarded as a mere source of IFN, discriminate between various functionally discrete stimuli and to what extent this reflects differences in pDC responses other than IFN-α release. To examine the ability of pDCs to differentially respond to various doses of intact and infectious HIV, hepatitis C virus, and H1N1 influenza virus, whole-genome gene expression analysis, enzyme-linked immunosorbent assays, and flow cytometry were used to investigate pDC responses at the transcriptional, protein, and cellular levels. Our data demonstrate that pDCs respond differentially to various viral stimuli with significant changes in gene expression, including those involved in pDC activation, migration, viral endocytosis, survival, or apoptosis. In some cases, the expression of these genes was induced even at levels comparable to that of IFN-α. Interestingly, we also found that depending on the viral entity and the viral titer used for stimulation, induction of IFN-α gene expression and the actual release of IFN-α are not necessarily temporally coordinated. In addition, our data suggest that high-titer influenza A (H1N1) virus infection can stimulate rapid pDC apoptosis.
IMPORTANCE Plasmacytoid dendritic cells (pDCs) are key players in the viral immune response. With the host response to viral infection being dependent on specific virus characteristics, a thorough examination and comparison of pDC responses to various viruses at various titers is beneficial for the field of virology. Our study illustrates that pDC infection with influenza virus, HIV, or hepatitis C virus results in a unique and differential response to each virus. These results have implications for future virology research, vaccine development, and virology as a whole.
PMCID: PMC4178854  PMID: 25008918
18.  Inherent transcriptional signatures of NK cells are associated with response to IFNα + rivabirin therapy in patients with Hepatitis C Virus 
Differences in the expression of Natural Killer cell receptors have been reported to reflect divergent clinical courses in patients with chronic infections or tumors. However, extensive molecular characterization at the transcriptional level to support this view is lacking. The aim of this work was to characterize baseline differences in purified NK cell transcriptional activity stratified by response to treatment with PEG-IFNα/RBV in patients chronically infected with HCV.
To this end we here studied by flow cytometer and gene expression profile, phenotypic and transcriptional characteristics of purified NK cells in patients chronically infected with HCV genotype-1 virus who were subsequently treated with PEG-IFNα/RBV. Results were further correlated with divergent clinical response obtained after treatment.
The pre-treatment transcriptional patterns of purified NK cells from patients subsequently undergoing a sustained virologic response (SVR) clearly segregated from those of non-responder (NR) patients. A set of 476 transcripts, including molecules involved in RNA processing, ubiquitination pathways as well as HLA class II signalling were differently expressed among divergent patients. In addition, treatment outcome was associated with differences in surface expression of NKp30 and NKG2D. A complex relationship was observed that suggested for extensive post-transcriptional editing. Only a small number of the NK cell transcripts identified were correlated with chronic HCV infection/replication indicating that inherent transcriptional activity prevails over environment effects such as viral infection.
Collectively, inherent/genetic modulation of NK cell transcription is involved in setting the path to divergent treatment outcomes and could become useful to therapeutic advantage.
Electronic supplementary material
The online version of this article (doi:10.1186/s12967-015-0428-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4353456  PMID: 25849716
NK cells; HCV infection; Clinical response; Regulation of NK cells
British journal of sports medicine  2014;48(13):1054-1058.
Obtaining the “when, where, and why” of healthy bouts of moderate-to-vigorous physical activity (MVPA) provides insights into natural physical activity
In Salt Lake City, Utah, adults wore accelerometer and GPS loggers for a week in a cross-sectional study to establish baseline travel and activity patterns near a planned Complete Street intervention involving a new rail line, new sidewalks, and a bike path.
At the end of the week research assistants met with the 918 participants who had at least three 10-hour days of good accelerometer readings. Accelerometer and GPS data were uploaded and integrated within a custom application, and participants were provided with maps and time information for past MVPA bouts of ≥ 3 minutes to help them recall bout details. Participants said that ‘getting someplace” was, on average, a more important motivation for their bouts than leisure or exercise. A series of recall tests showed that participants recalled most bouts they were asked about, regardless of duration of the bout, suggesting that participant perceptions of their shorter lifestyle bouts can be studied with this methodology. Visual prompting with a map depicting where each bout took place yielded more accurate recall than prompting with time cues alone.
These techniques provide a novel way to understand participant memories of the context and subjective assessments associated with healthy bouts of physical activity. Prompts with time-stamped maps that illustrate places of moderate-to-vigorous physical activity offer an effective method to improve understanding of activity and its supportive socio-physical contexts.
PMCID: PMC4324627  PMID: 24815545
Physical activity; neighborhood; mental recall; global positioning system; walking
20.  Upper abdominal normal organ contouring guidelines and atlas: A Radiation Therapy Oncology Group consensus 
Practical radiation oncology  2013;4(2):82-89.
To standardize upper abdominal normal organ contouring guidelines for Radiation Therapy Oncology Group (RTOG) trials.
Methods and Materials
Twelve expert radiation oncologists contoured the liver, esophagus, gastroesophageal junction (GEJ), stomach, duodenum, and common bile duct (CBD), and reviewed and edited 33 additional normal organ and blood vessel contours on an anonymized patient computed tomography (CT) dataset. Contours were overlaid and compared for agreement using MATLAB (MathWorks, Natick, MA). S95 contours, defined as the binomial distribution to generate 95% group consensus contours, and normal organ contouring definitions were generated and reviewed by the panel.
There was excellent consistency and agreement of the liver, duodenal, and stomach contours, with substantial consistency for the esophagus contour, and moderate consistency for the GEJ and CBD contours using a Kappa statistic. Consensus definitions, detailed normal organ contouring recommendations and high-resolution images were developed.
Consensus contouring guidelines and a CT image atlas should improve contouring uniformity in radiation oncology clinical planning and RTOG trials.
PMCID: PMC4285338  PMID: 24890348
21.  Interobserver Variability in Target Definition for Hepatocellular Carcinoma With and Without Portal Vein Thrombus: Radiation Therapy Oncology Group Consensus Guidelines 
Defining hepatocellular carcinoma (HCC) gross tumor volume (GTV) requires multimodal imaging, acquired in different perfusion phases. The purposes of this study were to evaluate the variability in contouring and to establish guidelines and educational recommendations for reproducible HCC contouring for treatment planning.
Methods and Materials
Anonymous, multiphasic planning computed tomography scans obtained from 3 patients with HCC were identified and distributed to a panel of 11 gastrointestinal radiation oncologists. Panelists were asked the number of HCC cases they treated in the past year. Case 1 had no vascular involvement, case 2 had extensive portal vein involvement, and case 3 had minor branched portal vein involvement. The agreement between the contoured total GTVs (primary + vascular GTV) was assessed using the generalized kappa statistic. Agreement interpretation was evaluated using Landis and Koch’s interpretation of strength of agreement. The S95 contour, defined using the simultaneous truth and performance level estimation (STAPLE) algorithm consensus at the 95% confidence level, was created for each case.
Of the 11 panelists, 3 had treated >25 cases in the past year, 2 had treated 10 to 25 cases, 2 had treated 5 to 10 cases, 2 had treated 1 to 5 cases, 1 had treated 0 cases, and 1 did not respond. Near perfect agreement was seen for case 1, and substantial agreement was seen for cases 2 and 3. For case 2, there was significant heterogeneity in the volume identified as tumor thrombus (range 0.58–40.45 cc). For case 3, 2 panelists did not include the branched portal vein thrombus, and 7 panelists contoured thrombus separately from the primary tumor, also showing significant heterogeneity in volume of tumor thrombus (range 4.52–34.27 cc).
In a group of experts, excellent agreement was seen in contouring total GTV. Heterogeneity exists in the definition of portal vein thrombus that may impact treatment planning, especially if differential dosing is contemplated. Guidelines for HCC GTV contouring are recommended.
PMCID: PMC4285340  PMID: 24969794
22.  Association between intensification of metformin treatment with insulin versus sulfonylureas and cardiovascular events and all-cause mortality among patients with diabetes 
Preferred second line medication for diabetes treatment after metformin failure remains uncertain.
We compared time to acute myocardial infarction [AMI], stroke, or death in a cohort of metformin initiators who added insulin or a sulfonylurea.
Retrospective cohort constructed using national Veterans Health Administration, Medicare, and National Death Index databases.
Veterans initially treated with metformin from 2001 through 2008 who subsequently added either insulin or sulfonylurea. Each insulin intensifier was propensity score matched by characteristics to five sulfonylurea intensifiers. Patients were followed through September, 2011 for primary analyses or September, 2009 for cause of death analyses.
Main Outcome Measures
Risk of a composite outcome of AMI, stroke hospitalization or all-cause death was compared between therapies using marginal structural Cox proportional hazard models to adjust for baseline and time-varying demographics, medications, cholesterol, hemoglobin A1c, creatinine, blood pressure, body mass index, and co-morbidities.
Among 178,341 metformin monotherapy patients, 2,948 and 39,990 added insulin or sulfonylurea, respectively. Propensity score matching yielded 2,436 metformin+insulin and 12,180 metformin+sulfonylurea patients. At intensification, the median (interquartile range) time on metformin was 14 months (5, 30) and HbA1c was 8.1% (7.2, 9.9). There were 172 versus 634 events for the primary outcome among those who added insulin versus sulfonylureas respectively (42 versus 33 events per 1000 person-years, adjusted hazard ratio [aHR] 1.30, 95% confidence interval [CI] 1.07, 1.58, p=0.009). AMI and stroke rates were statistically similar 41 versus 229 (10.2 and 11.9 per 1000 person years, aHR 0.88,95% CI 0.59, 1.30, p=0.52), while all-cause death rates were137 versus 444, respectively (33.7 and 22.7 per 1000 person-years, aHR 1.44, 95% CI,1.15, 1.79, p=0.001). There were 54 versus 258 secondary outcomes: AMI, stroke hospitalizations or cardiovascular deaths (22.8 vs. 22.5 events per 1000 person years aHR 0.98, 95% CI 0.71, 1.34. p=0.87).
Among patients with diabetes using metformin, the addition of insulin versus sulfonylurea was associated with an increased risk of a composite of nonfatal cardiovascular outcomes and all-cause mortality. These findings require further investigation to understand risks associated with insulin use in these patients.
PMCID: PMC4149288  PMID: 24915260
Diabetes mellitus; cardiovascular disease; insulin; treatment intensification; comparative effectiveness
23.  Common misconceptions about data analysis and statistics1 
Ideally, any experienced investigator with the right tools should be able to reproduce a finding published in a peer-reviewed biomedical science journal. In fact, the reproducibility of a large percentage of published findings has been questioned. Undoubtedly, there are many reasons for this, but one reason may be that investigators fool themselves due to a poor understanding of statistical concepts. In particular, investigators often make these mistakes: (1) P-Hacking. This is when you reanalyze a data set in many different ways, or perhaps reanalyze with additional replicates, until you get the result you want. (2) Overemphasis on P values rather than on the actual size of the observed effect. (3) Overuse of statistical hypothesis testing, and being seduced by the word “significant”. (4) Overreliance on standard errors, which are often misunderstood.
PMCID: PMC4317225  PMID: 25692012
24.  Lower Levels of Circulating Progenitor Cells Are Associated With Low Physical Function and Performance in Elderly Men With Impaired Glucose Tolerance: A Pilot Substudy From the VA Enhanced Fitness Trial 
Aging is marked by a decline in physical function. Although the biological underpinnings for this remain unclear, loss of regenerative capacity has been proposed as one cause of the loss of physical function that occurs over time. The quantity of circulating progenitor cells (CPCs) may be one reflection of regenerative capability. We sought to determine whether certain specific CPC subpopulations were associated with physical function.
Baseline CPCs were measured in 129 randomized participants in the Enhanced Fitness clinical trial based on the cell surface markers CD34, CD133, CD146, and CD14 and aldehyde dehydrogenase (ALDH) activity. Physical function was assessed using usual and rapid gait speed, 6-minute walk distance, chair stand time, and balance time.
Low counts of early angiogenic CPCs identified as CD34+, CD34+CD133+, and ALDH-bright (ALDHbr) cells were associated with low usual gait speed (p < .005, p < .001, and p < .007), rapid gait speed (p < .001, p < .003, and p < .001), and 6-minute walking distance (all comparisons p < .001), and longer time required to complete five chair stands (p < .006, p < .002, and p < .004). CPC counts of mature endothelial or monocytic markers were not associated with physical function.
The numbers of CD34+ and ALDHbr CPCs are significantly lower in patients with impaired physical function. Further studies are needed to determine the underlying causes for this association.
PMCID: PMC3814238  PMID: 23682163
Endothelial progenitor cells; Physical performance; Physical function; Aging; Progenitor cells biology.
25.  Molecular Signaling Network Motifs Provide a Mechanistic Basis for Cellular Threshold Responses 
Environmental Health Perspectives  2014;122(12):1261-1270.
Background: Increasingly, there is a move toward using in vitro toxicity testing to assess human health risk due to chemical exposure. As with in vivo toxicity testing, an important question for in vitro results is whether there are thresholds for adverse cellular responses. Empirical evaluations may show consistency with thresholds, but the main evidence has to come from mechanistic considerations.
Objectives: Cellular response behaviors depend on the molecular pathway and circuitry in the cell and the manner in which chemicals perturb these circuits. Understanding circuit structures that are inherently capable of resisting small perturbations and producing threshold responses is an important step towards mechanistically interpreting in vitro testing data.
Methods: Here we have examined dose–response characteristics for several biochemical network motifs. These network motifs are basic building blocks of molecular circuits underpinning a variety of cellular functions, including adaptation, homeostasis, proliferation, differentiation, and apoptosis. For each motif, we present biological examples and models to illustrate how thresholds arise from specific network structures.
Discussion and Conclusion: Integral feedback, feedforward, and transcritical bifurcation motifs can generate thresholds. Other motifs (e.g., proportional feedback and ultrasensitivity)produce responses where the slope in the low-dose region is small and stays close to the baseline. Feedforward control may lead to nonmonotonic or hormetic responses. We conclude that network motifs provide a basis for understanding thresholds for cellular responses. Computational pathway modeling of these motifs and their combinations occurring in molecular signaling networks will be a key element in new risk assessment approaches based on in vitro cellular assays.
Citation: Zhang Q, Bhattacharya S, Conolly RB, Clewell HJ III, Kaminski NE, Andersen ME. 2014. Molecular signaling network motifs provide a mechanistic basis for cellular threshold responses. Environ Health Perspect 122:1261–1270;
PMCID: PMC4256703  PMID: 25117432

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