Elevation of liver biochemistry has been reported with anti-tumor necrosis factor agents, but overt liver failure rarely reported. Autoimmune hepatitis has been more commonly reported with infliximab than adalimumab (ADA). Our case, however, describes the first reported case of ADA-associated severe cholestatic injury. A 39-year-old female with Crohn’s disease developed severe jaundice after initiation of ADA. All serologic tests and imaging studies were normal. Liver biopsy showed prominent pericentral canalicular cholestasis, without features of steatosis or sclerosing cholangitis, consistent with drug-induced cholestasis. The serum total bilirubin peaked at 280 μmol/L, and improvement was seen after 5 wk with eventual normalization of liver enzymes at 10 wk. Our case describes the first reported case of ADA-associated severe cholestatic liver disease and the first histopathologic examination of this adverse drug effect. Clinicians need to be aware of this potential drug-induced liver injury when prescribing this commonly used biologic medication.
Crohn’s disease; Cholestasis; Adalimumab; Anti-tumor necrosis factor agents; Drug-induced liver injury
Adherence to disease-modifying therapies (DMTs) results in the reduction of the number and severity of relapses and delays the progression of multiple sclerosis (MS). Patients with lower adherence rates experience more inpatient visits and higher MS-related medical costs. Fingolimod, the first oral DMT approved by the US Food and Drug Administration, may improve the access and compliance to MS treatment when compared to injectable DMTs.
This retrospective cohort study used pharmacy claims from Medco Health Solutions, Inc., of patients who initiated DMTs between October 2010 and February 2011. Initiation was defined as no prescription fills for the same DMT in the prior 12 months. Patients without a DMT prescription fill 12 months before the index date were considered naïve users. Compliance was measured via proportion of days covered (PDC) and medication possession ratio (MPR) for 12 months post-index. Discontinuation was defined as a ≥60-day gap of index DMT supply. Cox proportional hazard models compared time to discontinuation between cohorts.
Of 1,891 MS patients (mean age: 45.7; female: 76.4%), 13.1% initiated fingolimod, 10.7% interferon beta-1b, 20.0% intramuscular interferon beta-1a, 18.8% subcutaneous interferon beta-1a, and 37.4% glatiramer acetate. Patients initiating fingolimod had highest average PDC and MPR in both experienced (fingolimod: mean PDC=0.83, 73.7% with PDC≥0.8; mean MPR=0.92, 90.5% with MPR≥0.8) and naïve DMT users (fingolimod: mean PDC=0.80, 66.7% with PDC≥0.8; mean MPR=0.90, 87.4% with MPR≥0.8). The proportion of patients discontinuing index DMT within 12 months was significantly lower for the fingolimod cohort (naïve: 31.3%; experienced: 25.7%). Adjusted results found that patients receiving self-injected DMTs discontinued significantly sooner than fingolimod users. This association was generally stronger in experienced DMT users.
Fingolimod initiators were more compliant, less likely to discontinue treatment, and discontinued later than patients who initiated self-injected DMT.
Multiple sclerosis; Compliance; Patient adherence; Medication persistence; Discontinuation; Fingolimod
To determine whether Ginkgo biloba extract (ginkgo) improves cognitive function in persons with multiple sclerosis (MS).
Persons with MS from the Seattle and Portland VA clinics and adjacent communities who scored 1 SD or more below the mean on one of 4 neuropsychological tests (Stroop Test, California Verbal Learning Test II [CVLT-II], Controlled Oral Word Association Test [COWAT], and Paced Auditory Serial Addition Task [PASAT]) were randomly assigned to receive either one 120-mg tablet of ginkgo (EGb-761; Willmar Schwabe GmbH & Co, Germany) or one placebo tablet twice a day for 12 weeks. As the primary outcome, we compared the performance of the 2 groups on the 4 tests at exit after adjusting for baseline performance.
Fifty-nine subjects received placebo and 61 received ginkgo; 1 participant receiving placebo and 3 receiving ginkgo were lost to follow-up. Two serious adverse events (AEs) (myocardial infarction and severe depression) believed to be unrelated to the treatment occurred in the ginkgo group; otherwise, there were no significant differences in AEs. The differences (ginkgo − placebo) at exit in the z scores for the cognitive tests were as follows: PASAT −0.2 (95% confidence interval [CI] −0.5 to 0.1); Stroop Test −0.5 (95% CI −0.9 to −0.1); COWAT 0.0 (95% CI −0.2 to 0.3); and CVLT-II 0.0 (95% CI −0.3 to 0.3); none was statistically significant.
Treatment with ginkgo 120 mg twice a day did not improve cognitive performance in persons with MS.
Classification of evidence:
This study provides Class I evidence that treatment with ginkgo 120 mg twice a day for 12 weeks does not improve cognitive performance in people with MS.
Germline mutations in the RAS/ERK signaling pathway underlie several related developmental disorders collectively termed neuro-cardio-facial-cutaneous (NCFC) syndromes. Patients with these disorders manifest varying degrees of cognitive impairment, but the developmental basis of their brain abnormalities remains largely unknown. Among NCFC syndromes, neurofibromatosis type 1 (NF1) is an exception, as it is caused by loss-of-function heterozygous mutations. Here, we show that bi-allelic Nf1 inactivation promotes Erk-dependent, ectopic Olig2 expression specifically in transit-amplifying progenitors, leading to increased gliogenesis at the expense of neurogenesis in neonatal and adult subventricular zone (SVZ). Nf1-deficient brains exhibit enlarged corpus callosum - a structural brain defect recently linked to severe learning deficits in NF1 patients. Strikingly, these NF1-associated developmental defects are rescued by transient treatment with an MEK/ERK pathway inhibitor during neonatal stages. These studies reveal a critical role for Nf1 in maintaining postnatal SVZ-derived neurogenesis, and identify a potential therapeutic window for treating NF1-associated brain abnormalities.
Neurofibromatosis type 1; NF1; tumor suppressor gene; neural stem cells; glial cells; subventricular zone (SVZ)
Most patients with non–small cell lung cancer (NSCLC) have responded poorly to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). We investigated the involvement of insulin-like growth factor 1 receptor (IGF-1R) signaling in primary resistance to EGFR TKIs and the molecular determinants of resistance to IGF-1R TKIs.
Phosphorylated IGF-1R/insulin receptor (pIGF-1R/IR) was immunohistochemically evaluated in a NSCLC tissue microarray. We analyzed the antitumor effects of an IGF-1R TKI (PQIP or OSI-906), either alone or in combination with a small-molecular inhibitor (PD98059 or U0126) or with siRNA targeting K-Ras or MAPK/extracellular signal-regulated kinase kinase (MEK), in vitro and in vivo in NSCLC cells with variable histologic features and EGFR or K-Ras mutations.
pIGF-1R/IR expression in NSCLC specimens was associated with a history of tobacco smoking, squamous cell carcinoma histology, mutant (mut) K-Ras, and wild-type (wt) EGFR, all of which have been strongly associated with poor response to EGFR TKIs. IGF-1R TKIs exhibited significant antitumor activity in NSCLC cells with wt EGFR and wt K-Ras but not in those with mutations in these genes. Introduction of mut K-Ras attenuated the effects of IGF-1R TKIs on NSCLC cells expressing wt K-Ras. Conversely, inactivation of MEK restored sensitivity to IGF-TKIs in cells carrying mut K-Ras.
The mutation status of both EGFR and K-Ras could be predictive markers of response to IGF-1R TKIs. Also, MEK antagonism can abrogate primary resistance of NSCLC cells to IGF-1R TKIs.
EGFR; K-Ras; IGF-1R; lung cancer; TKI
Lung cancer is the deadliest cancer in the United States and worldwide. Tobacco use is the one of the primary causes of lung cancer and smoking cessation is an important step towards prevention, but patients who have quit smoking remain at risk for lung cancer. Finding pharmacologic agents to prevent lung cancer could potentially save many lives. Unfortunately, despite extensive research, there are no known effective chemoprevention agents for lung cancer. Clinical trials in the past, using agents without a clear target in an unselected population, have shown pharmacologic interventions to be ineffective or even harmful. We propose a new approach to drug development in the chemoprevention setting: reverse migration, that is, drawing on our experience in the treatment of advanced cancer to bring agents, biomarkers, and study designs into the prevention setting. By identifying molecular drivers of lung neoplasia and using matched targeted agents, we hope to personalize therapy to each individual to develop more effective, tolerable chemo-prevention. Also, advances in risk modeling, using not only clinical characteristics but also biomarkers, may help us to select patients better for chemoprevention efforts, thus sparing patients at low risk for cancer the potential toxicities of treatment. Our institution has experience with biomarker-driven clinical trials, as in the recently reported Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial, and we now propose to bring this trial design into the prevention setting.
Chemoprevention; Lung cancer; Targeted therapies
Treatment for non–small cell lung cancer has been improving, with personalized treatment increasingly becoming a reality in the clinic. Unfortunately, these advances have largely been confined to the treatment of adenocarcinomas. Treatment options for squamous cell carcinoma (SCC) of the lung have lagged behind, partly because of a lack of understanding of the oncogenes driving SCC. Cytotoxic chemotherapy continues to be the only treatment option for many of our patients, and no genetic tests are clinically useful for patients with SCC. Recent advances in basic science have identified mutations and alterations in protein expression frequently found in SCCs, and clinical trials are ongoing to target these changes.
Metastasis is a critical event in the progression of head and neck squamous cell carcinoma (HNSCC) and closely correlates with clinical outcome. We previously showed that the farnesyl transferase inhibitor SCH66336 has antitumor activities in HNSCC by inducing insulin-like growth factor binding protein 3 (IGFBP-3) secretion, which in turn inhibits tumor growth and angiogenesis. In this study, we found that SCH66336 at a sublethal dose for HNSCC inhibited the migration and invasion of HNSCC cells. The inhibitory effect of SCH66336 was associated with the blockade of the IGF-1 receptor (IGF-1R) pathway via suppressing IGF-1R itself and Akt expression. Consistent with previous work, induction of IGFBP-3 by SCH66336 also contributed in part to the anti-invasive effect. SCH66336 treatment also reduced the expression and activity of the urokinase-type plasminogen activator (uPA) and matrix metalloproteinase 2 (MMP-2), both important regulators of tumor metastasis. The effect of SCH66336 on uPA activity was inhibited partly by knockdown of IGFBP-3 using siRNA. The inhibitory effect of SCH66336 on migration or invasion was attenuated partly or completely by knockdown of IGFBP-3, Akt, or IGF-1R expression, respectively. Our results demonstrate that the IGF-1R pathway plays a major role in the proliferation, migration, and invasion of HNSCC cells, suggesting that therapeutic obstruction of the IGF-1R pathway would be a useful approach to treating patients with HNSCC.
Insulin-like growth factor binding protein-3; insulin-like growth factor-1 receptor; farnesyl transferase inhibitor; head and neck squamous cell carcinoma; invasion; SCH66336
Cellulases are of great interest for application in biomass degradation, yet the molecular details of the mode of action of glycoside hydrolases during degradation of insoluble cellulose remain elusive. To further improve these enzymes for application at industrial conditions, it is critical to gain a better understanding of not only the details of the degradation process, but also the function of accessory modules.
We fused a carbohydrate-binding module (CBM) from family 2a to two thermophilic endoglucanases. We then applied neutron reflectometry to determine the mechanism of the resulting enhancements.
Catalytic activity of the chimeric enzymes was enhanced up to three fold on insoluble cellulose substrates as compared to wild type. Importantly, we demonstrate that the wild type enzymes affect primarily the surface properties of an amorphous cellulose film, while the chimeras containing a CBM alter the bulk properties of the amorphous film.
Our findings suggest that the CBM improves the efficiency of these cellulases by enabling digestion within the bulk of the film.
Cellulases; Endoglucanases; Carbohydrate-Binding modules; Cellulose model films; Neutron reflectometry
The development of second primary tumors (SPT) or recurrence alters prognosis for curatively-treated head and neck squamous cell carcinoma (HNSCC) patients. 13-cis-retnoic acid (13-cRA) has been tested as a chemoprevention agent in clinical trials with mixed results. Therefore, we investigated if genetic variants in the PI3K/PTEN/AKT/MTOR pathway could serve as biomarkers to identify which patients are at high risk of an SPT/recurrence while also predicting response to 13-cRA chemoprevention.
A total of 137 pathway SNPs were genotyped in 440 patients from the Retinoid Head and Neck Second Primary Trial and assessed for SPT/recurrence risk and response to 13-cRA. Risk models were created based on epidemiology, clinical, and genetic data.
Twenty-two genetic loci were associated with increased SPT/recurrence risk with six also being associated with a significant benefit following chemoprevention. Combined analysis of these high-risk/high-benefit loci identified a significant (P = 1.54×10−4) dose-response relationship for SPT/recurrence risk, with patients carrying 4–5 high-risk genotypes having a 3.76-fold (95%CI:1.87–7.57) increase in risk in the placebo group (n=215). Patients carrying 4–5 high-risk loci showed the most benefit from 13-cRA chemoprevention with a 73% reduction in SPT/recurrence (95%CI:0.13–0.58) compared to those with the same number of high-risk genotypes who were randomized to receive placebo. Incorporation of these loci into a risk model significantly improved the discriminatory ability over models with epidemiology, clinical, and previously identified genetic variables.
These results demonstrate that loci within this important pathway could identify individuals with a high-risk/high-benefit profile and are a step towards personalized chemoprevention for HNSCC patients.
Patients with autoimmune lymphoproliferative syndrome (ALPS) and lymphoproliferation (LPR) mice are deficient in Fas, and accumulate large numbers of αβ-TCR+, CD4−, CD8− double negative (DN) T cells. The function of these DN T cells remains largely unknown. The common γ subunit of the activating Fc receptors, FcRγ, plays an important role in mediating innate immune responses. We have shown previously that a significant proportion of DN T cells express FcRγ, and that this molecule is required for TCR transgenic DN T cells to suppress allogeneic immune responses. Whether FcRγ plays a critical role in LPR DN T cell-mediated suppression of immune responses to auto and allo-antigens is not known. Here, we demonstrated that FcRγ+, but not FcRγ− LPR DN T cells could suppress Fas+ CD4+ and CD8+ T cell proliferation in vitro and attenuated CD4+ T cell-mediated graft-versus host disease. Although FcRγ expression did not allow LPR DN T cells to inhibit the expansion of Fas-deficient cells within the LPR context, adoptive transfer of FcRγ+, but not FcRγ−, DN T cells inhibited lymphoproliferation in generalized lymphoproliferative disease (GLD) mice. Furthermore, FcRγ acted in a cell-intrinsic fashion to limit DN T cell accumulation by increasing the rate of apoptosis in proliferated cells. These results indicate that FcRγ can confer Fas-dependent regulatory properties on LPR DN T cells, and suggest that FcRγ may be a novel marker for functional DN Tregs.
NSC-743380 is a novel STAT3 inhibitor that suppresses the growth of several NCI-60 cancer cell lines derived from different tissues and induces regression of xenograft tumors in vivo at various doses. To evaluate the antitumor activity of NSC-743380 in lung cancer cells, we analyzed the susceptibility of 50 NSCLC cell lines to this compound using cell viability assay. About 32% (16 of 50) of these cell lines were highly susceptible to this compound, with a 50% inhibitory concentration (IC50) of <1 µM. In mechanistic studies, the increased numbers of apoptotic cells as well as increased PARP cleavage showed that cytotoxic effects correlate with apoptosis induction. Treatment with NSC-743380 inhibited transcription factor STAT3 activation and induced ROS production in sensitive human lung cancer cell lines but not in resistant cells. Blocking ROS generation with the antioxidant NDGA dramatically abolished NSC-743380-induced growth suppression and apoptosis, but had minimal effect on NSC-743380-induced STAT3 inhibition, suggesting that STAT3 inhibition is not caused by ROS production. Interestingly, knockdown of STAT3 with use of shSTAT3 induced ROS generation and suppressed tumor cell growth. Moreover, scavenging ROS induced by STAT3 inhibition also diminished antitumor activity of STAT3 inhibition. In vivo administration of NSC-743380 suppressed tumor growth and p-STAT3 in lung tumors. Our results indicate that NSC-743380 is a potent anticancer agent for lung cancer and that its apoptotic effects in lung cancer cells are mediated by induction of ROS through STAT3 inhibition.
Drug development; Lung Cancer; STAT3; Reactive oxygen species
The purpose of this study was to characterize insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF-1R) expression in patients with non-small cell lung cancer (NSCLC).
A total of 459 patients who underwent curative resection of NSCLC were studied (median follow-up duration, 4.01 years). Expression of the IR and IGF-1R protein in tumor specimens was assessed immunohistochemically using tissue microarrays.
The cytoplasmic IR score was higher in patients with adenocarcinoma (ADC) than in those with squamous cell carcinoma (SCC) whereas cytoplasmic IGF-1R score was higher in patients with SCC than those with ADC. Neither IR nor IGF-1R expression was associated with sex, smoking history, or clinical stage. Patients with positive IR or IGF-1R expression levels had poor recurrence-free (RFS) (3.8 vs. 3.3 years; 3.8 vs. 2.0 years, respectively), but similar overall survival (OS). Patients with high expression levels of IR and IGF-1R had shorter RFS and OS compared to those with low levels of IR and/or IGF-1R expression. Finally, a multivariate analysis revealed the impact of IR, but not of IGF-1R, as an independent predictive marker of NSCLC survival: hazard ratio (HR) for OS, 1.005 (95% confidence interval [CI], 1.001 – 1.010], HR for RFS, 1.005 (95% CI, 1.001 – 1.009), when IR score was tested as a continuous variable.
Overexpression of IR predicts a poor survival among patients with NSCLC, especially those with SCC. These results might serve as future guidance to the clinical trials involving IR or IGR-1R targeting agents.
Carcinoma; Non-Small-Cell Lung; Receptor; Insulin; Receptor; IGF Type 1; Prognosis; Survival
Understanding oncogenes and tumor suppressor genes expression patterns is essential for characterizing lung cancer pathogenesis. We have previously demonstrated that mGprc5a/hGPRC5A is a lung-specific tumor suppressor evidenced by inflammation-mediated tumorigenesis in Gprc5a-knockout mice. The implication of GPRC5A in human lung cancer pathogenesis, including that associated with inflammatory chronic obstructive pulmonary disease (COPD), a risk factor for the malignancy, remains elusive.
We sought to examine GPRC5A immunohistochemical expression in histologically normal bronchial epithelia (NBE) from lung disease-free never- and ever-smokers (n = 13 and n = 18, respectively), from COPD patients with (n = 26) and without cancer (n = 24) and in non-small cell lung cancers (NSCLCs) (n = 474). Quantitative assessment of GPRC5A transcript expression in airways (n = 6), adjacent NBEs (n = 29) and corresponding tumors (n = 6) from 6 NSCLC patients was also performed.
GPRC5A immunohistochemical expression was significantly lower in tumors compared to uninvolved NBE (p < 0.0001) and was positively associated with adenocarcinoma histology (p < 0.001). GPRC5A airway expression was highest in lung disease-free NBE, decreased and intermediate in NBE of cancer-free COPD patients (p = 0.004) and further attenuated and lowest in epithelia of COPD patients with adenocarcinoma and SCC (p < 0.0001). Furthermore, GPRC5A mRNA was significantly decreased in NSCLCs and corresponding NBE compared to uninvolved normal lung (p = 0.03).
Our findings highlight decreased GPRC5A expression in the field cancerization of NSCLC, including that associated with lung inflammation. Assessment of the use of GPRC5A expression as a risk factor for NSCLC development in COPD patients is warranted.
Field cancerization; Chronic obstructive pulmonary disease; Non–small-cell lung cancer; g-protein coupled receptor family C; group 5; member A; gene expression
Multiple sclerosis (MS) is a chronic disease that affects mainly adults in the prime of their lives. However, few studies report the impact of high annual relapse rates on outcomes. The purpose of this study was to identify high relapse activity (HRA) in patients with MS, comparing differences in outcomes between patients with and without HRA.
A retrospective longitudinal study was conducted using the MarketScan® Commercial Claims and Encounters and Medicare Supplemental Database. Patients had to have at least one ICD-9 for MS (340.XX) in 2009 and one in 2008, be older than 18 years, and have continuous enrolment in the years 2009–2010. HRA was defined as having ≥2 relapses in 2009. Multivariate analyses compared all-cause and MS-specific emergency room (ER) visits, hospitalizations, and all-cause costs, excluding disease modifying therapy (DMT) costs, in 2010 between patients with and without HRA, controlling for baseline characteristics. A subgroup analysis using treatment exposure was also performed.
19,219 patients were included: 5.3% (n=1,017) had ≥2 relapses in 2009. Patients with HRA were more likely to have all-cause and MS-specific resource utilization than patients without HRA. Mean total all-cause non DMT costs were $12,057 higher for the HRA group. In the subgroup analysis, HRA treatment-naïve patients were more likely to start treatment, and HRA treatment-experienced patients were more likely to discontinue or switch index DMT (P<0.01).
Patients with ≥2 relapses annually have higher resource utilization and costs. The difference in cost was over twice as large in treatment-naïve patients versus treatment-experienced patients. HRA was also associated with an increased likelihood of starting DMT treatment (treatment-naïve patients), and switching or discontinuing DMT therapy (treatment-experienced patients).
Plaque psoriasis is a chronic disease characterized by scaly plaques on the skin that can itch and bleed. Psoriasis covering over 10% of the body is classified as moderate to severe, and can impact patient quality of life.
To assess the relationship between plaque psoriasis self-reported severity symptoms and health-related quality of life, work productivity, and activity impairment among patients with moderate-to-severe psoriasis.
The study sample included 199 patients recruited from internet panels, of which 179 respondents had plaque psoriasis and 20 had plaque and inverse psoriasis. Itching, pain, and scaling symptoms were studied. A structural equation modeling framework was used to estimate the effect of these symptoms on patient outcomes. First, each severity variable was regressed on a set of covariates to generate a predicted severity score. These predicted values were placed in a second-stage model with patient mental and physical scores (Short-Form 12 questionnaire), work productivity, and activity impairment indicators as dependent variables.
Itching severity had a marginal negative effect (P < 0.06) on patients’ Short-Form 12 physical and mental component scores. Pain severity also negatively affected physical and mental health scores (P < 0.02). Patients were more likely to miss work because of itching (odds ratio [OR]: 2.31, 95% confidence interval [CI]: 1.30, 4.10), pain (OR: 1.78, 95% CI: 1.25, 2.52), and scaling (OR: 2.15, 95% CI: 1.31, 3.52) symptoms. These symptoms also lowered self-reported productivity. As itching (OR: 1.74, 95% CI: 1.03, 2.95), scaling (OR: 1.84, 95% CI: 1.16, 2.90), and pain symptoms (OR: 1.53, 95% CI: 1.12, 2.09) increased, so did the odds that a patient would be less productive at work.
Plaque psoriasis significantly affects patient quality of life. In addition to greater mental and physical pain, patients are more likely to miss work and have diminished productivity as symptom severity increases.
psoriasis; severity; activity impairment; work productivity loss; structural equation modeling
A health economic model was constructed to predict the 5-year incidence of coronary heart disease and diabetes and associated costs after treatment in patients using second-generation antipsychotic agents.
We assessed the potential clinical and economic impact of coronary heart disease (CHD) and diabetes arising after the use of second-generation (“atypical”) antipsychotic agents for the treatment of chronic schizophrenia. We compared the use of these medications in patients with a higher risk of cardiometabolic adverse events (in a higher-risk scenario) and in patients with a lower risk (in a lower-risk scenario). Our U.S.-based analysis estimated the costs of CHD and diabetes arising from antipsychotic medication–related cardiometabolic effects.
We constructed a health economic model to predict the 5-year incidence of CHD and diabetes and associated costs after treatment. In this cost-consequence model, we used CHD risk functions derived from the Framingham Heart Study and diabetes risk functions derived from the Atherosclerosis Risk in Communities (ARIC) study. Patient characteristics and treatment effects on cardiometabolic risk factors were estimated from the Clinical Trials of Antipsychotic Treatment Effectiveness (CATIE) study.
We evaluated two cost-consequence scenarios: the incidence of CHD and diabetes predicted for 1,000 patients with chronic schizophrenia in a higher-risk scenario based on data from CATIE associated with olanzapine (Zyprexa) and in a lower-risk scenario with ziprasidone (Geodon). We evaluated rates of adverse outcomes for each scenario and the cost of treatment for CHD and diabetes. All costs were reported in 2011 U.S. dollars. Because Medicaid is often the payer for patients with chronic schizophrenia, all costs in this analysis were derived from the perspective of Medicaid.
Over a period of 5 years in 1,000 patients with chronic schizophrenia, the higher-risk scenario with olanzapine showed a 9% increased incidence of CHD and a 59% increased incidence of diabetes, compared with no change in treatment from baseline. By contrast, the lower-risk scenario with ziprasidone showed a 9% reduced incidence of CHD and a 10% reduced incidence of diabetes. The higher-risk scenario led to increased CHD-related costs of $83,206 and to increased diabetes-related costs of $456,399.
Our study underscores the importance of monitoring the established risk factors for CHD and diabetes in patients using second-generation antipsychotic drugs. Lower-risk agents from this class may lead to substantially decreased costs in the management of CHD and diabetes when compared with higher-risk agents.
second-generation antipsychotic agents; Medicaid; schizophrenia; cardiometabolic
Mutations in the v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) play a critical role in cancer cell growth and resistance to therapy. Most mutations occur at codons 12 and 13. In colorectal cancer, the presence of any mutant KRas amino acid substitution is a negative predictor of patient response to targeted therapy. However, in non–small cell lung cancer (NSCLC), the evidence that KRAS mutation is a predictive factor is conflicting.
We used data from a molecularly targeted clinical trial for 215 patients with tissues available out of 268 evaluable patients with refractory NSCLC to examine associations between specific mutant KRas proteins and progression-free survival and tumor gene expression. Transcriptome microarray studies of patient tumor samples and reverse-phase protein array studies of a panel of 67 NSCLC cell lines with known substitutions in KRas and in immortalized human bronchial epithelial cells stably expressing different mutant KRas proteins were used to investigate signaling pathway activation. Molecular modeling was used to study the conformations of wild-type and mutant KRas proteins. Kaplan–Meier curves and Cox regression were used to analyze survival data. All statistical tests were two-sided.
Patients whose tumors had either mutant KRas-Gly12Cys or mutant KRas-Gly12Val had worse progression-free survival compared with patients whose tumors had other mutant KRas proteins or wild-type KRas (P = .046, median survival = 1.84 months) compared with all other mutant KRas (median survival = 3.35 months) or wild-type KRas (median survival = 1.95 months). NSCLC cell lines with mutant KRas-Gly12Asp had activated phosphatidylinositol 3-kinase (PI-3-K) and mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) signaling, whereas those with mutant KRas-Gly12Cys or mutant KRas-Gly12Val had activated Ral signaling and decreased growth factor–dependent Akt activation. Molecular modeling studies showed that different conformations imposed by mutant KRas may lead to altered association with downstream signaling transducers.
Not all mutant KRas proteins affect patient survival or downstream signaling in a similar way. The heterogeneous behavior of mutant KRas proteins implies that therapeutic interventions may need to take into account the specific mutant KRas expressed by the tumor.
Breast cancer is one of the most prevalent forms of cancer in the world. More than 250,000 American women are diagnosed with breast cancer annually. Fortunately, the survival rate is relatively high and continually increasing due to improved detection techniques and treatment methods. The quality of life of breast cancer survivors is ameliorated by minimizing adverse effects on their physical appearance. Breast reconstruction is important for restoring the survivor’s appearance. In breast reconstructive surgery, there is a need to develop technologies for quantifying surgical outcomes and understanding women’s perceptions of changes in their appearance. Methods for objectively measuring breast anatomy are needed in order to help breast cancer survivors, radiation oncologists, and surgeons quantify changes in appearance that occur with different breast reconstructive surgical options. In this study, we present an automated method for computing a variant of the normalized Breast Retraction Assessment (pBRA), a common measure of symmetry, from routine clinical photographs taken to document breast cancer treatment procedures.
BRA; pBRA; Automated Detection; Digital Photographs; Umbilicus; Nipple Complex; Breast Cancer
TCRαβ+ CD4−CD8−NK− double negative T cells (DN T cells) can act as regulatory T cells to inhibit allograft rejection and autoimmunity. Their role in graft-versus-host disease and mechanisms of suppression remain elusive. In this study, we demonstrate that DN T cells can inhibit CD4+ T cell-mediated GVHD in a semi-allogeneic model of bone marrow transplantation. Furthermore, we present evidence of a novel autocrine IFNγ signaling pathway in Fas-deficient C57BL/6.lpr (B6.lpr) DN T cells. B6.lpr DN T cells lacking IFNγ or its receptor were impaired in their ability to suppress syngeneic CD4+ T cells responding to alloantigen stimulation both in vitro and in vivo. Autocrine IFNγ signaling was required for sustained B6.lpr DN T cell IFNγ secretion in vivo and for upregulation of surface Fas ligand expression during TCR stimulation. Fas ligand (FasL) expression by B6.lpr DN T cells permitted lysis of activated CD4+ T cells and was required for suppression of GVHD. Collectively, our data indicate that DN T cells can inhibit GVHD and that IFNγ plays a critical autocrine role in controlling the regulatory function of B6.lpr DN T cells.
We evaluated the ability of histopathologic response criteria to predict overall survival (OS) and disease-free survival (DFS) in patients with surgically resected non-small cell lung cancer (NSCLC) treated with or without neoadjuvant chemotherapy.
Tissue specimens from 358 patients with NSCLC were evaluated by pathologists blinded to the patient treatment and outcome. The surgical specimens were reviewed for various histopathologic features in the tumor including percentage of residual viable tumor cells, necrosis, and fibrosis. The relationship between the histopathologic findings and OS was assessed.
The percentage of residual viable tumor cells and surgical pathologic stage were associated with OS and DFS in 192 patients with NSCLC receiving neoadjuvant chemotherapy in multivariate analysis (p = 0.005 and p = 0.01, respectively). There was no association of OS or DFS with percentage of viable tumor cells in 166 patients with NSCLC who did not receive neoadjuvant chemotherapy (p = 0.31 and p = 0.45, respectively). Long-term OS and DFS were significantly prolonged in patients who had ≤10% viable tumor compared with patients with >10% viable tumor cells (5 years OS, 85% versus 40%, p < 0.0001 and 5 years DFS, 78% versus 35%, p < 0.001).
The percentages of residual viable tumor cells predict OS and DFS in patients with resected NSCLC after neoadjuvant chemotherapy even when controlled for pathologic stage. Histopathologic assessment of resected specimens after neoadjuvant chemotherapy could potentially have a role in addition to pathologic stage in assessing prognosis, chemotherapy response, and the need for additional adjuvant therapies.
Lung cancer; Neoadjuvant chemotherapy; Histopathology
Hip arthroplasty frequently requires potent postoperative analgesia, often provided with an epidural or posterior lumbar plexus local anesthetic infusion. However, American Society of Regional Anesthesia guidelines now recommend against epidural and continuous posterior lumbar plexus blocks during administration of various perioperative anticoagulants often administered after hip arthroplasty. A continuous femoral nerve block is a possible analgesic alternative, but whether it provides comparable analgesia to a continuous posterior lumbar plexus block after hip arthroplasty remains unclear. We therefore tested the hypothesis that differing the catheter insertion site (femoral versus posterior lumbar plexus) after hip arthroplasty has no impact on postoperative analgesia.
Preoperatively, subjects undergoing hip arthroplasty were randomly assigned to receive either a femoral or posterior lumbar plexus stimulating catheter inserted 5 to 15 cm or 0 to 1 cm past the needletip, respectively. Postoperatively, patients received perineural ropivacaine, 0.2% (basal 6 mL/hour, bolus 4 mL, 30 min lockout) for at least two days. The primary end point was the average daily pain scores as measured with a numeric rating scale (0–10) recorded in the 24-h period beginning at 07:30 the morning after surgery, excluding twice-daily physical therapy sessions. Secondary end points included pain during physical therapy, ambulatory distance, and supplemental analgesic requirements during the same 24-h period, as well as satisfaction with analgesia during hospitalization.
The mean (SD) pain scores for subjects receiving a femoral infusion (n = 25) were 3.6 (1.8) versus 3.5 (1.8) for patients receiving a posterior lumbar plexus infusion (n = 22) resulting in a group difference of 0.1 (95% confidence interval −0.9 to 1.2; P = 0.78). Because the confidence interval was within a prespecified −1.6 to 1.6 range, we conclude that the effect of the two analgesic techniques on postoperative pain was equivalent. Similarly, we detected no differences between the two treatments with respect to the secondary end points, with one exception: subjects with a femoral catheter ambulated a median (10th–90th percentiles) 2 (0–17) m the morning after surgery, compared with 11 (0–31) m for subjects with a posterior lumbar plexus catheter (data nonparametric; P = 0.02).
After hip arthroplasty, a continuous femoral nerve block is an acceptable analgesic alternative to a continuous posterior lumbar plexus block when using a stimulating perineural catheter. However, early ambulatory ability suffers with a femoral infusion.
Although the risk of radiation-induced spontaneous malignancy and genetic anomalies from occupational radiological procedures is relatively low – and perhaps slightly lower still for the general population – patients and endoscopists in particular, should be aware of the cumulative risk associated with all exposure. Radiation dose has a direct linear relationship with fluoroscopy duration; therefore, limiting fluoroscopy time is one of the most modifiable methods of reducing exposure during fluoroscopic procedures. This retrospective study analyzed more than 1000 endoscopic retrograde cholangiopancreatography procedures and aimed to determine the specific patient, physician and procedural factors that affect fluoroscopy duration.
Fluoroscopy during endoscopic retrograde cholangiopancreatography (ERCP) has a logarithmic relationship with radiation exposure, and carries a known risk of radiation exposure to patients and staff. Factors associated with prolonged fluoroscopy duration have not been well delineated.
To determine the specific patient, physician and procedural factors that affect fluoroscopy duration.
A retrospective analysis of 1071 ERCPs performed at two tertiary care referral hospitals over an 18-month period was conducted. Patient, physician and procedural variables were recorded at the time of the procedure.
The mean duration of 969 fluoroscopy procedures was 4.66 min (95% CI 4.38 to 4.93). Multivariable analysis showed that the specific patient factors associated with prolonged fluoroscopy duration included age and diagnosis (both P<0.0001). The endoscopist was found to play an important role in the duration of fluoroscopy (ie, all endoscopists studied had a mean fluoroscopy duration significantly different from the reference endoscopist). In addition, the following procedural variables were found to be significant: number of procedures, basket use, biopsies, papillotomy (all P<0.0001) and use of a tritome (P=0.004). Mean fluoroscopy duration (in minutes) with 95% CIs for different diagnoses were as follows: common bile duct stones (n=443) 5.12 (3.05 to 4.07); benign biliary strictures (n=135) 3.94 (3.26 to 4.63); malignant biliary strictures (n=124) 5.82 (4.80 to 6.85); chronic pancreatitis (n=49) 4.53 (3.44 to 5.63); bile leak (n=26) 3.67 (2.23 to 5.09); and ampullary mass (n=11) 3.88 (1.28 to 6.48). When no pathology was found (n=195), the mean fluoroscopy time was 3.56 min (95% CI 3.05 to 4.07). Comparison using t tests determined that the only two diagnoses for which fluoroscopy duration was significantly different from the reference diagnosis of ‘no pathology found’ were common bile duct stones (P<0.0001) and malignant strictures (P<0.0001).
Factors that significantly affected fluoroscopy duration included age, diagnosis, endoscopist, and the number and nature of procedures performed. Elderly patients with biliary stones or a malignant stricture were likely to require the longest duration of fluoroscopy. These identified variables may help endoscopists predict which procedures are associated with prolonged fluoroscopy duration so that appropriate precautions can be undertaken.
ERCP; Fluoroscopy time; Radiation
Pancreatic neuroendocrine tumors (PNETs) are relatively rare tumors that arise in the endocrine cells of the pancreas. Historically, somatostatin analogues have been used in this disease primarily for symptom control and, to a limited extent, disease stability. More recently, sunitinib and everolimus have been approved for advanced stage PNETs based on a survival benefit. However, both agents have a <10% actual response rate and cause nontrivial side effect profiles that limit duration of therapy. In locally advanced disease, there is a paucity of data to support an optimal neoadjuvant approach with the expectation of down-staging to allow for curative resection. We describe in this case a young woman who was successfully down-staged using a chemotherapy regimen of capecitabine and temozolomide with minimal toxicity.
Pancreatic neuroendocrine tumor; Temozolomide; Capecitabine