Mutant forms of DDX3X with diminished catalysis form hollow condensates that exhibit sex-specific regulation.

Mutations in the RNA helicase DDX3X, implicated in various cancers and neurodevelopmental disorders, often impair RNA unwinding and translation. However, the mechanisms underlying this impairment and the differential interactions of DDX3X mutants with wild-type (WT) X-linked DDX3X and Y-linked homolog DDX3Y remain elusive. This study reveals that specific DDX3X mutants more frequently found in disease form distinct hollow condensates in cells. Using a combined structural, biochemical, and single-molecule microscopy study, we show that reduced ATPase and RNA release activities contribute to condensate formation and the catalytic deficits result from inhibiting the catalytic cycle at multiple steps. Proteomic investigations further demonstrate that these hollow condensates sequester WT DDX3X/DDX3Y and other proteins crucial for diverse signaling pathways. WT DDX3X enhances the dynamics of heterogeneous mutant/WT hollow condensates more effectively than DDX3Y. These findings offer valuable insights into the catalytic defects of specific DDX3X mutants and their differential interactions with wild-type DDX3X and DDX3Y, potentially explaining sex biases in disease.

Presurgical sleep and pain behaviors predict insomnia symptoms and pain after total knee arthroplasty: a 12-month longitudinal, observational study.

OBJECTIVE: Up to 40% of individuals who undergo total knee arthroplasty (TKA) experience some degree of pain following surgery. Presurgical insomnia has been identified as a predictor of postsurgical pain; however, modifiable presurgical behaviors related to insomnia have received minimal attention. The objective of the present study was to develop a 2-item sleep and pain behavior scale (SP2) to investigate a maladaptive sleep and pain behavior and is a secondary analysis of a larger, parent study. METHODS: Patients (N = 109) completed SP2 at baseline and 12 months and questionnaires assessing sleep and pain at baseline (pre-TKA), 6 weeks, 3, 6, and 12 months post-TKA. SP2 demonstrated adequate preliminary psychometric properties. RESULTS: As hypothesized, even after controlling for baseline insomnia, pain, anxiety and other covariates, baseline SP2 predicted insomnia symptom severity at 6 weeks (ß = 2.828), 3 (ß = 2.140), 6 (ß = 2.962), and 12 months (ß = 1.835) and pain at 6 weeks (ß = 6.722), 3 (ß = 5.536), and 6 months (ß = 7.677) post-TKA (P < .05). Insomnia symptoms at 6-weeks post-TKA mediated the effect of presurgical SP2 on pain at 3 (95% CI: 0.024-7.054), 6 (95%CI: 0.495-5.243), and 12 months (95% CI: 0.077-2.684). CONCLUSIONS: This provides preliminary evidence that patients who cope with pain by retiring to their bed and bedroom have higher rates of post-surgical insomnia and pain and supports efforts to target this maladaptive sleep and pain behavior to reduce postsurgical pain.

Perioperative insomnia trajectories and functional outcomes after total knee arthroplasty.

ABSTRACT: Longitudinal total knee arthroplasty (TKA) studies indicate that a substantial percentage of patients continue to experience clinically significant pain and functional impairment after surgery. Insomnia has been associated with poorer surgical outcomes; however, previous work has largely focused on long-term postsurgical insomnia. This study builds on previous work by examining sleep and pain outcomes about perioperative insomnia trajectories. Insomnia symptoms (using the Insomnia Severity Index) during the acute perioperative period (2 weeks pre-TKA to 6 weeks post-TKA) were used to classify participants into perioperative insomnia trajectories: (1) No Insomnia (ISI < 8), (2) New Insomnia (baseline < 8; postoperative ≥ 8 or ≥6-point increase), (3) Improved Insomnia (baseline ≥ 8, postoperative < 8 or ≥6-point decrease), and (4) Persistent Insomnia (ISI ≥ 8). Insomnia, pain, and physical functioning were assessed in participants with knee osteoarthritis (n = 173; M age = 65 ± 8.3, 57.8% female) at 5 time points: 2 weeks pre-TKA, post-TKA: 6 weeks, 3 months, 6 months, and 12 months. Significant main effects were seen for insomnia trajectory and time, and trajectory-by-time interactions for postoperative insomnia, pain severity, and physical functioning ( P' s < 0.05). The Persistent Insomnia trajectory had the worst postoperative pain at all follow-ups and marked insomnia and physical functioning impairment post-TKA ( P' s < 0.05). The New Insomnia trajectory had notable long-term insomnia (6 weeks to 6 months) and acute (6 weeks) postoperative pain and physical functioning ( P' s < 0.05). Findings indicated a significant relationship between perioperative insomnia trajectory and postoperative outcomes. Results of this study suggest that targeting presurgical insomnia and preventing the development of acute postoperative insomnia may improve long-term postoperative outcomes, with an emphasis on persistent perioperative insomnia due to poorer associated outcomes.

Treatment planning system commissioning of the first clinical biology-guided radiotherapy machine.

PURPOSE: The RefleXion X1 is a novel radiotherapy machine designed for image-guided radiotherapy (IGRT) and biology-guided radiotherapy (BgRT). Its treatment planning system (TPS) generates IMRT and SBRT plans for a 6MV-FFF beam delivered axially via 50 firing positions with the couch advancing every 2.1 mm. The purpose of this work is to report the TPS commissioning results for the first clinical installation of RefleXion™ X1. METHODS: CT images of multiple phantoms were imported into the RefleXion TPS to evaluate the accuracy of data transfer, anatomical modeling, plan evaluation, and dose calculation. Comparisons were made between the X1, Eclipse™, and MIM™. Dosimetric parameters for open static fields were evaluated in water and heterogeneous slab phantoms. Representative clinical IMRT and SBRT cases were planned and verified with ion chamber, film, and ArcCHECK@ measurements. The agreement between TPS and measurements for various clinical plans was evaluated using Gamma analysis with a criterion of 3%/2 mm for ArcCHECK@ and film. End-to-end (E2E) testing was performed using anthropomorphic head and lung phantoms. RESULTS: The average difference between the TPS-reported and known HU values was -1.4 ± 6.0 HU. For static fields, the agreements between the TPS-calculated and measured PDD10 , crossline profiles, and inline profiles (FWHM) were within 1.5%, 1.3%, and 0.5 mm, respectively. Measured output factors agreed with the TPS within 1.3%. Measured and calculated dose for static fields in heterogeneous phantoms agreed within 2.5%. The ArcCHECK@ mean absolute Gamma passing rate was 96.4% ± 3.4% for TG 119 and TG 244 plans and 97.8% ± 3.6% for the 21 clinical plans. E2E film analysis showed 0.8 mm total targeting error for isocentric and 1.1 mm for off-axis treatments. CONCLUSIONS: The TPS commissioning results of the RefleXion X1 TPS were within the tolerances specified by AAPM TG 53, MPPG 5.a, TG 119, and TG 148. A subset of the commissioning tests has been identified as baseline data for an ongoing QA program.

Sleep, Positive Affect, and Circulating Interleukin-6 in Women With Temporomandibular Joint Disorder.

OBJECTIVE: Systemic inflammation is commonly observed in idiopathic chronic pain conditions, including temporomandibular joint disorder (TMD). Trait positive affect (PA) is associated with lower inflammation in healthy controls, but those effects may be threatened by poor sleep. The associations between PA with proinflammatory cytokine activity and potential moderation by sleep in chronic pain are not known. We thus investigated the association between PA and circulating interleukin-6 (IL-6) and moderation of that association by sleep in a sample of women with TMD and sleep difficulties. METHODS: Participants (n = 110) completed the insomnia severity index and provided blood samples at five intervals throughout an evoked pain testing session. They then completed a 14-day diary assessing sleep and affect, along with wrist actigraphy. RESULTS: There was not a significant main effect of PA on resting or pain-evoked IL-6 (b = 0.04, p = .33). Diary total sleep time (b = -0.002, p = .008), sleep efficiency (b = -0.01, p = .005), sleep onset latency (b = 0.006, p = .010), and wake after sleep onset (b = 0.003, p = .033) interacted with PA to predict IL-6, such that PA inversely predicted IL-6 at higher levels of total sleep time and sleep efficiency and at lower levels of sleep onset latency and wake after sleep onset. Surprisingly, when sleep was poor, PA predicted greater IL-6. CONCLUSIONS: The potential salutary effects of PA on resting IL-6 erode when sleep is poor, underscoring the importance of considering sleep in conceptual and intervention models of TMD.

Recent technical advances in the study of nucleic acid modifications.

Enzyme-mediated chemical modifications of nucleic acids are indispensable regulators of gene expression. Our understanding of the biochemistry and biological significance of these modifications has largely been driven by an ever-evolving landscape of technologies that enable accurate detection, mapping, and manipulation of these marks. Here we provide a summary of recent technical advances in the study of nucleic acid modifications with a focus on techniques that allow accurate detection and mapping of these modifications. For each modification discussed (N6-methyladenosine, 5-methylcytidine, inosine, pseudouridine, and N4-acetylcytidine), we begin by introducing the "gold standard" technique for its mapping and detection, followed by a discussion of techniques developed to address any shortcomings of the gold standard. By highlighting the commonalities and differences of these techniques, we hope to provide a perspective on the current state of the field and to lay out a guideline for development of future technologies.

TET-mediated 5-methylcytosine oxidation in tRNA promotes translation.

Oxidation of 5-methylcytosine (5mC) in DNA by the ten-eleven translocation (TET) family of enzymes is indispensable for gene regulation in mammals. More recently, evidence has emerged to support a biological function for TET-mediated m5C oxidation in messenger RNA. Here, we describe a previously uncharacterized role of TET-mediated m5C oxidation in transfer RNA (tRNA). We found that the TET-mediated oxidation product 5-hydroxylmethylcytosine (hm5C) is specifically enriched in tRNA inside cells and that the oxidation activity of TET2 on m5C in tRNAs can be readily observed in vitro. We further observed that hm5C levels in tRNA were significantly decreased in Tet2 KO mouse embryonic stem cells (mESCs) in comparison with wild-type mESCs. Reciprocally, induced expression of the catalytic domain of TET2 led to an obvious increase in hm5C and a decrease in m5C in tRNAs relative to uninduced cells. Strikingly, we also show that TET2-mediated m5C oxidation in tRNA promotes translation in vitro. These results suggest TET2 may influence translation through impacting tRNA methylation and reveal an unexpected role for TET enzymes in regulating multiple nodes of the central dogma.

Identifying Structural Domains and Conserved Regions in the Long Non-Coding RNA lncTCF7.

Long non-coding RNA (lncRNA) biology is a rapidly growing area of study. Thousands of lncRNAs are implicated as key players in cellular pathways and cancer biology. However, the structure-function relationships of these novel biomolecules are not well understood. Recent structural studies suggest that lncRNAs contain modular structural domains, which play a crucial role in their function. Here, we hypothesized that such structural domains exist in lncTCF7, a conserved lncRNA implicated in the development and progression of several cancers. To understand the structure-function relationship of lncTCF7, we characterized its secondary structure using chemical probing methods. Our model revealed structural domains and conserved regions in lncTCF7. One of the modular domains identified here coincides with a known protein-interacting domain. The model reported herein is, to our knowledge, the first structural model of lncTCF7 and thus will serve to direct future studies that will provide fundamental insights into the function of this lncRNA.

RNA sequencing distinguishes benign from malignant pancreatic lesions sampled by EUS-guided FNA.

BACKGROUND AND AIMS: EUS-guided FNA (EUS-FNA) is the primary method used to obtain pancreatic tissue for preoperative diagnosis. Accumulating evidence suggests diagnostic and prognostic information may be obtained by gene-expression profiling of these biopsy specimens. RNA sequencing (RNAseq) is a newer method of gene-expression profiling, but published data are scant on the use of this method on pancreas tissue obtained via EUS-FNA. The aim of this study was to determine whether RNAseq of EUS-FNA biopsy samples of undiagnosed pancreatic masses can reliably discriminate between benign and malignant tissue. METHODS: In this prospective study, consenting adults presented to 2 tertiary care hospitals for EUS of suspected pancreatic mass. Tissue was submitted for RNAseq. The results were compared with cytologic diagnosis, surgical pathology diagnosis, or benign clinical follow-up of at least 1 year. RESULTS: Forty-eight patients with solid pancreatic mass lesions were enrolled. Nine samples were excluded because of inadequate RNA and 3 because of final pathologic diagnosis of neuroendocrine tumor. Data from the first 13 patients were used to construct a linear classifier, and this was tested on the final 23 patients (15 malignant and 8 benign lesions). RNAseq of EUS-FNA biopsy samples distinguishes ductal adenocarcinoma from benign pancreatic solid masses with a sensitivity of .87 (range, .58-.98) and specificity of .75 (range, .35-.96). CONCLUSIONS: This proof-of-principle study suggests RNAseq of EUS-FNA samples can reliably detect adenocarcinoma and may provide a new method to evaluate more diagnostically challenging pancreatic lesions.

Prenatal stress, regardless of concurrent escitalopram treatment, alters behavior and amygdala gene expression of adolescent female rats.

Depression during pregnancy has been linked to in utero stress and is associated with long-lasting symptoms in offspring, including anxiety, helplessness, attentional deficits, and social withdrawal. Depression is diagnosed in 10-20% of expectant mothers, but the impact of antidepressant treatment on offspring development is not well documented, particularly for females. Here, we used a prenatal stress model of maternal depression to test the hypothesis that in utero antidepressant treatment could mitigate the effects of prenatal stress. We also investigated the effects of prenatal stress and antidepressant treatment on gene expression related to GABAergic and serotonergic neurotransmission in the amygdala, which may underlie behavioral effects of prenatal stress. Nulliparous female rats were implanted with osmotic minipumps delivering clinically-relevant concentrations of escitalopram and mated. Pregnant dams were exposed to 12 days of mixed-modality stressors, and offspring were behaviorally assessed in adolescence (postnatal day 28) and adulthood (beyond day 90) to determine the extent of behavioral change. We found that in utero stress exposure, regardless of escitalopram treatment, increased anxiety-like behavior in adolescent females and profoundly influenced amygdala expression of the chloride transporters KCC2 and NKCC1, which regulate GABAergic function. In contrast, prenatal escitalopram exposure alone elevated amygdala expression of 5-HT1A receptors. In adulthood, anxiety-like behavior returned to baseline and gene expression effects in the amygdala abated, whereas deficits emerged in novel object recognition for rats exposed to stress during gestation. These findings suggest prenatal stress causes age-dependent deficits in anxiety-like behavior and amygdala function in female offspring, regardless of antidepressant exposure.

Use of a newly developed delivery device for percutaneous introduction of multiple lead configurations for spinal cord stimulation.

OBJECTIVE: The Epiducer lead delivery system is a novel lead delivery device that can be used to percutaneously implant S-Series paddle leads (St. Jude Medical, Plano, TX, USA) as well as multiple percutaneous leads obviating the need for laminectomy and/or multiple needle sticks, respectively. This study evaluates the safety and usage of the Epiducer lead delivery system. METHODS: An Institutional Review Board-approved observational data collection study was conducted to evaluate usage patterns of the Epiducer system. In addition to the number and frequency of different lead configurations, the following procedural aspects of the surgery were recorded during the evaluation: angle of entry, distance from entry to final lead placement, and physician feedback. Descriptive statistics on adverse events, procedural aspects, and patient outcomes were compiled. RESULTS: Data were collected from 163 patients across 25 investigational sites. Physicians successfully implanted patients using the Epiducer during 89% of the procedures. Seven possible lead configurations were implanted. There were 96% and 92% of physicians "satisfied" or "very satisfied" with accessing the epidural space and placing multiple leads with the Epiducer delivery system, respectfully. Eighty-nine percent of physicians were "satisfied" or "very satisfied" with implanting an S-Series paddle lead using the Epiducer delivery system. Ninety-five percent of physicians were "satisfied" or "very satisfied" with the Epiducer delivery system overall. Ten patients (6%) experienced adverse events. CONCLUSION: Results suggest that the Epiducer delivery system allows for the safe and successful percutaneous implantation of paddle leads and/or multiple lead configurations. Furthermore, physicians are satisfied with the Epiducer delivery system.

Prenatal exposure to escitalopram and/or stress in rats: a prenatal stress model of maternal depression and its treatment.

RATIONALE: A rigorously investigated model of stress and antidepressant administration during pregnancy is needed to evaluate possible effects on the mother. OBJECTIVE: The objective of this study was to develop a model of clinically relevant prenatal exposure to an antidepressant and stress during pregnancy to evaluate the effects on maternal care behavior. RESULTS: Female rats implanted with 28-day osmotic minipumps delivering the SSRI escitalopram throughout pregnancy had serum escitalopram concentrations in a clinically observed range (17-65 ng/ml). A separate cohort of pregnant females exposed to a chronic unpredictable mild stress paradigm on gestational days 10-20 showed elevated baseline (305 ng/ml), and acute stress-induced (463 ng/ml), plasma corticosterone concentrations compared to unstressed controls (109 ng/ml). A final cohort of pregnant dams were exposed to saline (control), escitalopram, stress, or stress and escitalopram to determine the effects on maternal care. Maternal behavior was continuously monitored over the first 10 days after parturition. A reduction of 35 % in maternal contact and 11 % in nursing behavior was observed due to stress during the light cycle. Licking and grooming behavior was unaffected by stress or drug exposure in either the light or dark cycle. CONCLUSIONS: These data indicate that: (1) clinically relevant antidepressant treatment during human pregnancy can be modeled in rats using escitalopram; (2) chronic mild stress can be delivered in a manner that does not compromise fetal viability; and (3) neither of these prenatal treatments substantially altered maternal care post parturition.

Neuroendocrine homeostasis after vagus nerve stimulation in rats.

BACKGROUND: The vagus nerve is important in maintaining HPA axis and sympatho-adrenal system (SAS) homeostasis, however little is known about the effect of vagus nerve stimulation (VNS), as used therapeutically, on these functions. Accordingly, the effect of VNS on plasma indices of HPA axis (ACTH, corticosterone), and SAS (norepinephrine, epinephrine) function were evaluated in rats. METHODS: Male rats, on day-0 (D0), underwent surgeries for implantation of catheters into the right jugular vein and programmable (VNP) or non-programmable (VND) neurocybernetic devices encircling the left cervical vagus. On D7, after a blood sample, the device in VNP rats was programmed to deliver 500 µs width, 0.25 mA current pulses at 20 Hz ('on' 30s, 'off' 5 min) followed by timed blood samples during the next 90 min. In acute studies, VNS was stopped at 60 min and the rats were perfused at 90 min to evaluate neuronal Fos immunoreactivity (Fos-IR). In chronic studies, the probe remained active. In these rats, the HPA axis response to airpuff-startle stressor (D17) and anterior pituitary CRF-receptor binding (D26) were evaluated. RESULTS: During acute VNS, plasma indices of HPA axis and SAS activity, as well as Fos-IR activation pattern in brain regions known to increase after stress, were not different between VND and VNP rats. During chronic VNS, stress-induced HPA axis responses exhibited a tendency toward faster recovery to baseline in VNP rats. CONCLUSIONS: Therapeutic VNS is not a stressor and does not compromise HPA axis or SAS homeostasis. Chronic VNS may facilitate development of efficient feedback mechanisms.

Corticotropin-releasing factor, interleukin-6, brain-derived neurotrophic factor, insulin-like growth factor-1, and substance P in the cerebrospinal fluid of civilians with posttraumatic stress disorder before and after treatment with paroxetine.

BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with altered concentrations of stress-related neurohormones, neurotrophins, and neuropeptides in plasma and serum; however, few studies have examined central alterations of these measures in individuals with PTSD. Furthermore, no study to date has evaluated the effects of successful antidepressant treatment on cerebrospinal fluid (CSF) abnormalities in PTSD. METHOD: Sixteen medication-free outpatients with chronic PTSD (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria) due to physical and/or sexual abuse or motor vehicle accidents (mean ± SD age = 36 ± 11.4 years, 12 women) and 11 nontraumatized healthy subjects (mean ± SD age = 35.3 ± 13.1 years, 7 women) underwent a lumbar puncture for collection of CSF. Seven PTSD patients had a repeat lumbar puncture 12 weeks later, after successful treatment of PTSD with paroxetine. CSF was analyzed for corticotropin-releasing factor (CRF), interleukin-6 (IL-6), brain-derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1), and substance P concentrations. The study was conducted between January 2003 and August 2004. RESULTS: Compared to nontraumatized healthy controls, patients with chronic PTSD had similar pretreatment concentrations of CSF CRF, IL-6, BDNF, IGF-1, and substance P. Posttreatment CSF measures did not change significantly in patients whose symptoms remitted with paroxetine. CONCLUSIONS: Chronic, moderate PTSD due to civilian trauma, without psychotic symptoms and without significant rates of comorbid depression, alcohol dependence, or substance dependence, is not associated with abnormalities in CSF CRF, IL-6, BDNF, IGF-1, or substance P levels. Despite substantial reduction in PTSD symptoms, antidepressant treatment does not alter normal central concentrations of these neurochemicals, with the possible exception of substance P.

Cardiac arrest and cardiopulmonary resuscitation dysregulates the hypothalamic-pituitary-adrenal axis.

Cardiac arrest and cardiopulmonary resuscitation (CA/CPR) increase the risk for affective disorders in human survivors. Postischemic anxiety- and depressive-like behaviors have been documented in animal models of CA/CPR; however, the stability of post-CA/CPR anxiety-like behavior over time and the underlying physiologic mechanisms remain unknown. The hypothalamic-pituitary-adrenal (HPA) axis and the corticotropin releasing factor (CRF) system may mediate the pathophysiology of anxiety and depression; therefore, this study measured CA/CPR-induced changes in CRF receptor binding and HPA axis negative feedback. Mice were exposed to CA/CPR or SHAM surgery and assessed 7 or 21 days later. Consistent with earlier demonstrations of anxiety-like behavior 7 days after CA/CPR, increased anxiety-like behavior in the open field was also present 21 days after CA/CPR. On postoperative day 7, CA/CPR was associated with an increase in basal serum corticosterone concentration relative to SHAM, but this difference resolved by postoperative day 21. The Dexamethasone Suppression Test showed that the CA/CPR group had enhanced negative feedback compared with SHAM controls at postoperative day 21. Furthermore, there was a gradual increase in CRF(1) receptor binding in the paraventricular nucleus of the hypothalamus and bed nucleus of the stria terminalis, as well as a transient decrease of both CRF(1) and CRF(2A) receptors in the dorsal hippocampus. Therefore, sustained changes in activity of the HPA axis and the CRF system after CA/CPR may contribute to the postischemic increase in affective disorders.

The antidepressant sertraline downregulates Akt and has activity against melanoma cells.

Melanoma is a common malignancy which is poorly responsive to chemotherapy and radiation. One of the major reasons melanoma responds poorly to these modalities is constitutive expression of Akt, which protects against apoptosis. The antidepressant sertraline was found to be a potent cytotoxic agent against A375 human melanoma. To determine the mechanism by which sertraline kills melanoma cells, Western blot analysis of signaling molecules, including phosphorylated Akt, caspase 9 and phospho-p70 S6 kinase was performed. Finally, the effects of sertraline on A375 xenografts in mice were assessed. Sertaline potently inhibited the phosphorylation of Akt, and caused cell death through induction of endoplasmic reticulum in vitro. Sertraline monotherapy demonstrated activity against A375 xenografts in vivo. Akt is a major cause of resistance of melanoma to current therapy. Antidepressants are commonly used to prevent interferon-induced depression. Use of antidepressants that decrease Akt may improve the efficacy of interferon and other therapies against melanoma. Further studies are needed to elucidate whether sertraline acts as an Akt inhibitor in melanoma.

Statins reduce the risk of lung cancer in humans: a large case-control study of US veterans.

BACKGROUND: Statins are commonly used cholesterol-lowering agents that are noted to suppress tumor cell growth in several in vitro and animal models. METHODS: We studied the association of lung cancer and the use of statins in patients enrolled in the Veterans Affairs (VA) Health Care System. A retrospective case-control study nested in a cohort study was conducted using prospectively collected data from the Veterans Integrated Service Networks 16 VA database from 1998 to 2004. We analyzed data on 483,733 patients from eight states located in south central United States. The primary variables of interest were lung cancer and the use of statins prior to the diagnosis of lung cancer. Multiple logistic regression analysis was done to adjust for covariates including age, sex, body mass index, smoking, diabetes, and race. Statistical software was used for statistical computing. RESULTS: Of the 483,733 patients in the study, 163,662 patients (33.8%) were receiving statins and 7,280 patients (1.5%) had a primary diagnosis of lung cancer. Statin use > 6 months was associated with a risk reduction of lung cancer of 55% (adjusted odds ratio, 0.45; 95% confidence interval, 0.42 to 0.48; p < 0.01). Furthermore, the protective effect of statin was seen across different age and racial groups and was irrespective of the presence of diabetes, smoking, or alcohol use. CONCLUSIONS: Statins appear to be protective against the development of lung cancer, and further studies need to be done to define the clinical utility of statins as chemo protective agents.

Neoadjuvant chemoradiotherapy for esophageal cancer using weekly Paclitaxel and Carboplatin plus infusional 5-Fluorouracil.

PURPOSE: To evaluate neoadjuvant therapy with weekly paclitaxel/carboplatin plus 5-fluorouracil (5-FU) with conformal radiotherapy in a phase II trial in resectable esophageal carcinoma. METHODS: Twenty-four patients with T2-4N0-1M0-1a esophageal carcinoma were treated with paclitaxel 45 mg/m(2) intravenously over 1 hour and carboplatin at an area under the concentration-time curve (AUC) of 2 intravenously over 30 minutes on days 1, 8, 15, 22, and 29. 5-Fluorouracil 225 mg/m(2) was delivered as a continuous infusion on days 1-33. Concurrent conformal radiation was delivered to a dose of 45 Gy. Responders underwent surgical resection within 8 weeks of completing chemoradiotherapy. Kaplan-Meier survival analysis and log-rank test of survival dependent on pathologic response were performed. RESULTS: Progressive disease was discovered at surgery in three patients. Of the remaining 21 patients, pathologic complete response (pCR) was demonstrated in 12 (pCR rate of 57%) and partial response (PR) occurred in 9, including 4 with near complete response. Median follow-up in all patients was 23 months. Overall survival among all 24 patients was 48% at 3 years, with a median of 31 months. Disease-free survival was 57% at 3 years, with a median of 38 months. Differences in survival time based on pCR vs. PR showed a trend favoring pCR for disease-free survival (P = .12) but not overall survival (P > .20). Grade 3/4 toxicities included esophagitis in 33% of patients, hypotension in 29%, stomatitis in 25%, neutropenia in 13%, and anemia in 8%. CONCLUSION: This study demonstrates the activity of neoadjuvant paclitaxel, carboplatin, 5-FU, and conformal radiotherapy in the treatment of localized esophageal cancer. Evaluation with a larger number of patients and longer follow-up will be required to definitively assess the long-term efficacy of this regimen.