Sickle cell disease and coronavirus disease-2019 (COVID-19) infection: a single-center experience.

PURPOSE: Sickle cell disease (SCD) has been found to be associated with an increased risk of hospitalization and death from coronavirus disease-2019 (COVID-19). We sought to study clinical outcomes in patients with SCD and a diagnosis of COVID-19 infection. METHODS: We conducted a retrospective analysis of adult patients (>18 years) with SCD who were diagnosed with COVID-19 infection between 1 March 2020 and 31 March 2021. Data on baseline characteristics and overall outcomes were collected and analyzed using SAS 9.4 for Windows. RESULTS: A total of 51 patients with SCD were diagnosed with COVID-19 infection in the study period, out of which 39.3% were diagnosed and managed in the outpatient setting/emergency room (ER) and 60.3% in the inpatient setting. Disease-modifying therapy such as hydroxyurea did not impact inpatient vs outpatient/ER management (P > 0.05). Only 5.71% (n = 2) required intensive care unit admission and were mechanically ventilated and 3.9% (2 patients) died of complications of COVID-19 infection. CONCLUSION: We identified a lower mortality (3.9%) rate among patients in our cohort in comparison to previous studies and a higher burden of inpatient hospitalizations as compared to outpatient/ER management. Further prospective data are needed to validate these findings. Key messages What is already known on this topic COVID-19 has been shown to have a disproportionately unfavorable impact on African Americans, including longer hospital stays, higher rates of ventilator dependence, and a higher overall mortality rate. Limited data also suggest that sickle cell disease (SCD) is associated with an increased risk of hospitalization and death from COVID-19. What this study adds Our analysis did not show a higher mortality due to COVID-19 in patients with SCD. However, we identified a high burden of inpatient hospitalizations in this population. COVID-19-related outcomes did not improve with the use of disease-modifying therapies. How this study might affect research, practice, or policy These results will aid in decision making for triage of patients with COVID-19 and SCD and ensure the most appropriate use of healthcare resources. Our analysis underscores the need for more robust data to identify patients at higher risk of severe disease and/or mortality, necessitating inpatient hospitalization and aggressive management.

Alpha-synuclein inhibits Snx3-retromer-mediated retrograde recycling of iron transporters in S. cerevisiae and C. elegans models of Parkinson's disease.

We probed the role of alpha-synuclein (α-syn) in modulating sorting nexin 3 (Snx3)-retromer-mediated recycling of iron transporters in Saccharomyces cerevisiae and Caenorhabditis elegans. In yeast, the membrane-bound heterodimer Fet3/Ftr1 is the high affinity iron importer. Fet3 is a membrane-bound multicopper ferroxidase, whose ferroxidase domain is orthologous to human ceruloplasmin (Cp), that oxidizes external Fe+2 to Fe+3; the Fe+3 ions then channel through the Ftr1 permease into the cell. When the concentration of external iron is low (<1 µM), Fet3/Ftr1 is maintained on the plasma membrane by retrograde endocytic-recycling; whereas, when the concentration of external iron is high (>10 µM), Fet3/Ftr1 is endocytosed and shunted to the vacuole for degradation. We discovered that α-syn expression phenocopies the high iron condition: under the low iron condition (<1 µM), α-syn inhibits Snx3-retromer-mediated recycling of Fet3/Ftr1 and instead shunts Fet3/Ftr1 into the multivesicular body pathway to the vacuole. α-Syn inhibits recycling by blocking the association of Snx3-mCherry molecules with endocytic vesicles, possibly by interfering with the binding of Snx3 to phosphatidylinositol-3-monophosphate. In C. elegans, transgenic worms expressing α-syn exhibit an age-dependent degeneration of dopaminergic neurons that is partially rescued by the iron chelator desferoxamine. This implies that α-syn-expressing dopaminergic neurons are susceptible to changes in iron neurotoxicity with age, whereby excess iron enhances α-syn-induced neurodegeneration. In vivo genetic analysis indicates that α-syn dysregulates iron homeostasis in worm dopaminergic neurons, possibly by inhibiting SNX-3-mediated recycling of a membrane-bound ortholog of Cp (F21D5.3), the iron exporter ferroportin (FPN1.1), or both.

Utility of routine pretreatment evaluation of left ventricular ejection fraction in breast cancer patients receiving anthracyclines.

Anthracycline-based chemotherapy is widely used in the management of breast cancer. Despite the lack of clinical evidence, obtaining prechemotherapy left ventricular ejection fraction (LVEF) by echocardiogram or multigated acquisition scan is a widely adopted practice throughout the world. We present here the results of a retrospective analysis of breast cancer patients who had LVEF measurements in anticipation of an anthracycline chemotherapy to determine whether predefined cardiac risk factors predicted for poor cardiac function. Retrospective data were analyzed from 482 female breast cancer patients in whom LVEF was measured before starting anthracycline-based chemotherapy. Baseline demographics and multiple risk factors associated with congestive heart failure were collected. Twenty-six possible risk factors for CHF were defined, and the frequency of finding an abnormal LVEF as a function of total risk factors was assessed. Statistical tests include chi-squared and logistic regression analysis. The median age of the study population was 52 years. The original chemotherapy plan was changed in 7 patients (1.45%) based on LVEF findings, all of which had asymptomatic LV dysfunction (LVEF ranging 40%-50%). In 32 patients, despite normal LVEF results, anthracyclines were omitted secondary to prior cardiac issues. In 17 patients where LVEF was reported normal, anthracyclines were skipped based on patient's preference, tumor characteristics, or upstaging of the cancer based on imaging studies. No patient with ≤2 risk factors had an abnormal LVEF (N = 350). The probability of finding an abnormal LVEF in patients without any cardiac risk factors is extremely rare. Skipping baseline LVEF assessment may be an option in some patients with no cardiac risk factors undergoing anthracycline-based chemotherapy.

Pitfalls in anaphylaxis diagnosis and management at a university emergency department.

BACKGROUND: Some previous reports revealed suboptimal management of anaphylaxis (ANX) in the emergency department (ED). OBJECTIVE: To evaluate the recorded diagnosis and management of patients who presented with ANX at our university hospital ED and to assess how the management correlated with the severity of the case and the training level of the ED staff. METHODS: A descriptive study that involved reviewing the electronic medical records of patients who presented with ANX at the ED during a period of 4 years. RESULTS: When reviewing 1341 charts of potential cases, 60 met the criteria for ANX, but only 23% were correctly coded. Inaccurate coding was noted in 77%, mainly as an "allergic reaction." Systemic corticosteroids were administered in the ED to 85% of the patients and H1-antihistamines to 73%; only 20% received epinephrine. Ten patients required hospital admission, and, on discharge, only four patients (40%) were given epinephrine autoinjector prescriptions. Of the 50 who were discharged home, 48% were given epinephrine autoinjector prescriptions and 16% were given a referral for allergy evaluation. CONCLUSION: The observed low rates of appropriate diagnostic coding of ANX, of epinephrine administration, epinephrine autoinjector prescribing at discharge, and referral for allergy evaluation call for more education on these issues. Some of these pitfalls can be partly attributed to the setting in a university ED where health providers are usually busy in rendering urgent care.

UCP2 upregulation promotes PLCγ-1 signaling during skin cell transformation.

Uncoupling protein 2 (UCP2), whose physiological role is to decrease mitochondrial membrane potential and reactive oxygen species (ROS) production, is often overexpressed in human cancers. UCP2 upregulation has recently been proposed as a novel survival mechanism for cancer cells. However, until now, how exactly UCP2 promotes tumorigenesis remains inconclusive. Based on a widely used skin cell transformation model, our data demonstrated that UCP2 differentially regulated ROS. UCP2 upregulation decreased superoxide whereas it increased hydrogen peroxide production with concomitant increase in the expression and activity of manganese superoxide dismutase (MnSOD), the primary mitochondrial antioxidant enzyme. Furthermore, hydrogen peroxide was responsible for induction of lipid peroxidation, and PLCγ-1 activation in UCP2 overexpressed cells. Additionally, PLCγ-1 activation enhanced skin cell transformation, and pharmacological, and siRNA mediated inhibition of PLCγ-1, markedly reduced colony formation, and 3D cell growth. Moreover, hydrogen peroxide scavenger, catalase, suppressed lipid peroxidation, and dampened PLCγ-1 activity. Taken together, our data suggest that (i) UCP2 is an important regulator of mitochondrial redox status and lipid signaling; (ii) hydrogen peroxide might mediate UCP2's tumor promoting activity; and (iii) pharmacological disruption of PLCγ-1 and/or hydrogen peroxide may have clinical utility for UCP2 overexpressed cancers.

Mycobacterium tuberculosis and Mycobacterium marinum non-homologous end-joining proteins can function together to join DNA ends in Escherichia coli.

Mycobacterium tuberculosis and Mycobacterium smegmatis express a Ku protein and a DNA ligase D and are able to repair DNA double strand breaks (DSBs) by non-homologous end-joining (NHEJ). This pathway protects against DNA damage when bacteria are in stationary phase. Mycobacterium marinum is a member of this mycobacterium family and like M. tuberculosis is pathogenic. M. marinum lives in water, forms biofilms and infects fish and frogs. M. marinum is a biosafety level 2 (BSL2) organism as it can infect humans, although infections are limited to the skin. M. marinum is accepted as a model to study mycobacterial pathogenesis, as M. marinum and M. tuberculosis are genetically closely related and have similar mechanisms of survival and persistence inside macrophage. The aim of this study was to determine whether M. marinum could be used as a model to understand M. tuberculosis NHEJ repair. We identified and cloned the M. marinum genes encoding NHEJ proteins and generated E. coli strains that express the M. marinum Ku (Mm-Ku) and ligase D (Mm-Lig) individually or together (LHmKumLig strain) from expression vectors integrated at phage attachment sites in the genome. We demonstrated that Mm-Ku and Mm-Lig are both required to re-circularize Cla I-linearized plasmid DNA in E. coli. We compared repair of strain LHmKumLig with that of an E. coli strain (BWKuLig#2) expressing the M. tuberculosis Ku (Mt-Ku) and ligase D (Mt-Lig), and found that LHmKumLig performed 3.5 times more repair and repair was more accurate than BWKuLig#2. By expressing the Mm-Ku with the Mt-Lig, or the Mt-Ku with the Mm-Lig in E. coli, we have shown that the NHEJ proteins from M. marinum and M. tuberculosis can function together to join DNA DSBs. NHEJ repair is therefore conserved between the two species. Consequently, M. marinum is a good model to study NHEJ repair during mycobacterial pathogenesis.

Withaferin A suppresses the up-regulation of acetyl-coA carboxylase 1 and skin tumor formation in a skin carcinogenesis mouse model.

Withaferin A (WA), a natural product derived from Withania somnifera, has been used in traditional oriental medicines to treat neurological disorders. Recent studies have demonstrated that this compound may have a potential for cancer treatment and a clinical trial has been launched to test WA in treating melanoma. Herein, WA's chemopreventive potential was tested in a chemically-induced skin carcinogenesis mouse model. Pathological examinations revealed that WA significantly suppressed skin tumor formation. Morphological observations of the skin tissues suggest that WA suppressed cell proliferation rather than inducing apoptosis during skin carcinogenesis. Antibody Micro array analysis demonstrated that WA blocked carcinogen-induced up-regulation of acetyl-CoA carboxylase 1 (ACC1), which was further confirmed in a skin cell transformation model. Overexpression of ACC1 promoted whereas knockdown of ACC1 suppressed anchorage-independent growth and oncogene activation of transformable skin cells. Further studies demonstrated that WA inhibited tumor promotor-induced ACC1 gene transcription by suppressing the activation of activator protein 1. In melanoma cells, WA was also able to suppress the expression levels of ACC1. Finally, results using human skin cancer tissues confirmed the up-regulation of ACC1 in tumors than adjacent normal tissues. In summary, our results suggest that withaferin A may have a potential in chemoprevention and ACC1 may serve as a critical target of WA. © 2015 Wiley Periodicals, Inc.

The Shreveport Myeloma Experience: Survival, Risk Factors and Other Malignancies in the Age of Stem Cell Transplantation.

BACKGROUND: The overall prognosis of multiple myeloma has improved significantly over the last 15 years. We wondered whether the overall improvement would also be seen in unselected patients in an academic center in Northwest Louisiana with a high proportion of minority patients, and if second malignant neoplasms are relevant for our patients. MATERIALS AND METHODS: Between 1998 and 2009, 215 patients were treated for multiple myeloma at our center and had complete follow-up until May 2013. RESULTS: The mean survival of patients with multiple myeloma increased from 3.25 to 5.34 years, which is comparable to patients treated at larger centers. No prognostic difference was observed in the subgroups of myeloma patients. Among 215 patients followed for the development of secondary cancers, 16 already had a preexisting or concomitant malignancy (7.4%) and 10 developed secondary cancers. Our data indicate a significant background of histologically unrelated cancers and a cumulative incidence of new cancers of about 20% after 10 years of follow-up. Based on SEER data, preexisting or secondary cancers were not statistically increased in our population. CONCLUSIONS: The use of autologous transplantation and the introduction of new agents resulted in a significant improvement in the prognosis of multiple myeloma. Other cancers are not statistically increased before or after multiple myeloma is diagnosed and are not prognostically relevant.

Circumferential Aortic Endarterectomy Followed with Immediate Infrarenal Clamping Obviates Suprarenal Clamping for Juxtarenal Aortoiliac Occlusion.

BACKGROUND: Traditional open surgery for juxtarenal aortoiliac occlusive disease (AIOD) requires suprarenal aortic cross-clamping (SRCC), which is associated with high incidence of acute kidney injury (AKI). This study was to compare the outcomes of circumferential aortic endarterectomy followed by immediate infrarenal cross-clamping (IRCC) with the traditional approach of SRCC during surgery for juxtarenal AIOD. METHODS: A 10-year retrospective review of 87 patients who underwent open surgery for AIOD at our University Medical Center was performed. There were 52 males and 35 females (mean age of 52 years). Multivariate analysis was performed to assess operative time, blood loss, incidence of AKI, 30-day mortality, and recurrent aneurysm/pseudoaneurysm. RESULTS: Thirty-seven patients were found to have juxtarenal AIOD, which were divided into SRCC (n = 25) and IRCC (n = 12). Ten patients from the SRCC developed AKI versus 1 from the IRCC (30% vs. 8.3%, P = 0.04). SRCC demonstrated increased blood loss (1,681 vs. 591 mL, P = 0.004). Mean operative time was less in the IRCC group (5 vs. 7 hr, P = 0.0001). Thirty-day mortality in the SRCC group was 1 and 0 in the IRCC group, respectively. Recurrent aneurysm or pseudoaneurysm was not identified in endarterectomized aorta up to 4-year follow-up. CONCLUSIONS: Circumferential aortic endarterectomy followed with immediate IRCC is a feasible, safe, and effective approach for juxtarenal AIOD in properly selected patients. It may be associated with lower rates of AKI, intraoperative bleeding, operating room time, and length of hospital stay, when compared with the traditional SRCC.

Private Payer's Status Improves Male Breast Cancer Survival.

Survival from male breast cancer is influenced by many factors. This study assessed payer's status effect on survival of male breast cancer patients. This study included 8,828 male breast cancer patients diagnosed between 1998-2006 and followed to 2011 in the National Cancer Data Base. Cox regression was used to investigate the effect of payer's status and other factors on overall survival. Patients had 36.2%, 42.7%, 14.7%, and 6.5% of stage I to IV cancer, respectively. Payer status was private 47.7%, Medicare 42.6%, Medicaid 3.24%, unknown 3.59%, and uninsured 2.95%. Median overall survival (MOS) for all patients was 10.6 years. In multivariate analysis, Direct adjusted MOS was 12.46, 11.89, 9.99, 9.02, and 8.29 years for private, "unknown," Medicare, uninsured, and Medicaid payer's status, respectively. Patients with private and "unknown" payer's status showed a significant difference in survival compared to uninsured patients, while Medicaid and Medicare patients did not. Age, race, stage, grade, income, comorbidity, distance travelled, and diagnosing/treating facility were also significant predictors of survival. Treatment delay and cancer program did not have a significant influence on survival.

Effects of payer status on breast cancer survival: a retrospective study.

BACKGROUND: Breast cancer outcomes are influenced by multiple factors including access to care, and payer status is a recognized barrier to treatment access. To further define the influence of payer status on outcome, the National Cancer Data Base data from 1998-2006 was analyzed. METHOD: Data was analyzed from 976,178 female patients diagnosed with breast cancer registered in the National Cancer Data Base. Overall survival was the primary outcome variable while payer status was the primary predictor variable. Secondary predictor variables included stage, age, race, Charlson Comorbidity index, income, education, distance travelled, cancer program, diagnosing/treating facility, and treatment delay. Multivariate Cox regression was used to investigate the effect of payer status on overall survival while adjusting for secondary predictive factors. RESULTS: Uninsured (28.68%) and Medicaid (28.0%) patients had a higher percentage of patients presenting with stage III and stage IV cancer at diagnosis. In multivariate analysis, after adjusting for secondary predictor variables, payer status was a statistically significant predictor of survival. Patients with private, unknown, or Medicare status showed a decreased risk of dying compared to uninsured, with a decrease of 36%, 22%, and 15% respectively. However, Medicaid patients had an increased risk of 11% compared to uninsured. The direct adjusted median overall survival was 14.92, 14.76, 14.56, 13.64, and 12.84 years for payer status of private, unknown, Medicare, uninsured, and Medicaid respectively. CONCLUSION: We observed that patients with no insurance or Medicaid were most likely to be diagnosed at stage III and IV. Payer status showed a statistically significant relationship with overall survival. This remained true after adjusting for other predictive factors. Patients with no insurance or Medicaid had higher mortality.

External ultrasound for carotid atherosclerotic plaque treatment.

OBJECTIVES: The purpose of this study was to evaluate the efficacy of external ultrasound in the treatment of carotid atherosclerotic plaques. METHODS: In the prospective study, 357 patients with 363 carotid atherosclerotic plaques were divided into an ultrasound treatment group and a control group. For 30 days, conventional medical treatment was conducted on 54 plaques in the control group, whereas irradiation therapy in addition to conventional medical treatment was conducted on 309 plaques in the ultrasound group. Carotid sonography was conducted before and after treatment, and the maximum plaque thickness and area were measured in a longitudinal section. RESULTS: No patients withdrew from the treatment because of related side effects. After treatment, the maximum thickness and area of 79.94% of the plaques in the ultrasound group were reduced, whereas in the control group, the thickness and area of 18.52% were reduced. The mean changes in plaque thickness and area ± SD in the ultrasound and control groups were 0.22 ± 0.19 mm (7.61% ± 5.67%) versus 0.02 ± 0.05 mm (0.74% ± 1.64%) and 0.047 ± 0.039 cm(2) (13.28% ± 9.8%) versus 0.0044 ± 0.0102 cm(2) (1.1% ± 2.46%), respectively. Changes in both plaque thickness and area in the ultrasound group were significantly greater than those in the control group (P< .0001). Furthermore, the plaque echo type was another prognostic factor affecting efficacy (P < .05). CONCLUSIONS: External ultrasound treatment is safe and effective for carotid atherosclerotic plaques and is worthy of further research and applications. The efficacy in anechoic/hypoechoic plaques is significantly higher than that in mixed echoic and calcified echoic plaques.

Human milk and neurodevelopment in children with very low birth weight: a systematic review.

Human milk (HM) contains critical nutrients and possibly other neurotrophic factors that could benefit the less developed brain of preterm infants, particularly those with very low birth weight (VLBW). This study aims to systematically review the original studies to determine whether there is a reproducible independent effect of HM feeding on neurodevelopment outcome in preterm VLBW infants. Search of seven databases (PubMed, Cochrane, CINAHL, Embase, Proquest Research Library, Google Scholar, and Web of Science) identified 24 original studies. Each study was evaluated by two authors independently for 8 non-nutritive (study design, target population, a priori power calculation, adjustment for baseline growth status, postnatal complication, other confounders, observer blinding to feeding status, effect size) and 5 nutritive (definition and duration of HM intake, use of HM fortifier, source of HM data, infant formula used) methodology parameters, and consistency and directness of outcome measures. Thirteen reports of preterm infants with wide ranges of birth weights were excluded as none provided sufficient data to delineate the effects of HM feeding on developmental outcome of subjects with VLBW. Eleven reports included only VLBW children and 7 studies were reviewed after elimination of preliminary data from same cohort or lack of appropriate standardized testing or control group. These 7 studies (n = 18 to 704, median 219) were performed at <3 years (3 studies) and at 5 to 11 years (4 studies). Six studies were secondary analysis of data from other studies. Each study met or only partially met 4 to 10 methodological parameters. VLBW children with no neurological impairment fed HM achieved normal or low normal range of test scores. Formula feeding using older formulations was associated with a lower subtest score in 4 studies. There is no randomized clinical trial comparing the neurodevelopment outcome of HM versus formula or minimal HM feeding that included only children with VLBW. The role of HM in the neurodevelopment and cognitive function of VLBW children needs reassessment with high quality studies in the context of current formulations of HM fortifier and preterm formula.

Curative resection of pancreatic adenocarcinoma with major venous resection/repair is safe procedure but will not improve survival.

OBJECTIVE: To evaluate the safety and survival benefit of combined curative resection (CR) of the pancreas and major venous resection in the management of borderline resectable pancreatic adenocarcinoma. METHODS: In this IRB approved retrospective cohort study, patients who had pancreatic surgery (n=274) between 1998-2012 were reviewed. One hundred and seventy-five patients had malignant causes, of which 119 underwent CR. One hundred and two patients who did not require venous resection/repair (Group-I) were compared with 17 patients who had major vascular involvement (portal-vein/superior-mesenteric-vein) and underwent a vascular resection/repair (Group-II) during the CR. Demographics, operative and follow-up data were reviewed. RESULT: Type of the operations were: standard Whipple (n=53), pylorus-sparing-Whipple (n=41), total pancreatectomy (n=11), and distal pancreatectomy (n=13). In Group-II, venous involvement was excised and primarily repaired (n=12), or repaired using other veins (n=4) or a synthetic patch (n=1). Group-II had a significantly larger tumor size and more perineural invasion and peripancreatic soft tissue involvement (P<0.05). While complication rate, margin status, and duration of stay were not different between the groups, the median-overall-survival was higher for Group-I (15.34 months) than Group-II patients (7.18 months) (P=0.003). CONCLUSION: Pancreatic CR requiring intra-operative venous resection/repair is feasible and safe, but the survival of the patients who have pancreatic adenocarcinoma with venous involvement is poor irrespective of a successful venous resection.

Ceramide glycosylation by glucosylceramide synthase selectively maintains the properties of breast cancer stem cells.

Cancer stem cells are distinguished from normal adult stem cells by their stemness without tissue homeostasis control. Glycosphingolipids (GSLs), particularly globo-series GSLs, are important markers of undifferentiated embryonic stem cells, but little is known about whether or not ceramide glycosylation, which controls glycosphingolipid synthesis, plays a role in modulating stem cells. Here, we report that ceramide glycosylation catalyzed by glucosylceramide synthase, which is enhanced in breast cancer stem cells (BCSCs) but not in normal mammary epithelial stem cells, maintains tumorous pluripotency of BCSCs. Enhanced ceramide glycosylation and globotriosylceramide (Gb3) correlate well with the numbers of BCSCs in breast cancer cell lines. In BCSCs sorted with CD44(+)/ESA(+)/CD24(-) markers, Gb3 activates c-Src/ß-catenin signaling and up-regulates the expression of FGF-2, CD44, and Oct-4 enriching tumorigenesis. Conversely, silencing glucosylceramide synthase expression disrupts Gb3 synthesis and selectively kills BCSCs through deactivation of c-Src/ß-catenin signaling. These findings highlight the unexploited role of ceramide glycosylation in selectively maintaining the tumorous pluripotency of cancer stem cells. It speculates that disruption of ceramide glycosylation or globo-series GSL is a useful approach to specifically target BCSCs specifically.

Advance lung cancer inflammation index (ALI) at diagnosis is a prognostic marker in patients with metastatic non-small cell lung cancer (NSCLC): a retrospective review.

BACKGROUND: Systemic inflammation has been linked with cancer development, cancer cachexia and poor outcome. Advanced lung cancer inflammation index (ALI) was developed to assess degree of systemic inflammation at the time of diagnosis in metastatic non-small cell lung (NSCLC) cancer patients. METHODS: In a single institution retrospective review 173 patients with metastatic NSCLC diagnosed between Jan 1 2000 and June 30 2011 were included. ALI was calculated as (BMI x Alb / NLR) where BMI = body mass index, Alb = serum albumin, NLR (neutrophil lymphocyte ratio, a marker of systemic inflammation). Patients were divided into low inflammation (ALI ≥ 18) and high inflammation (ALI < 18) groups. Kaplan-Meier method was used to estimate progression free survival and overall survival. Log-rank test were used to compare the survivals among various factors. Multivariate Cox regression was used to perform survival analysis in order to estimate the hazards ratio for various factors. RESULTS: Among 173 patients median age was 57 years, 67% were male, 52% had adenocarcinoma. Patients with an ALI score of < 18 suggesting high systemic inflammation were significantly more likely to have more than 2 sites of metastatic disease, have poor performance status and less likely to receive any chemotherapy. Their median progression free survival and overall survival was 2.4 months and 3.4 months as opposed to 5.1 months and 8.3 months in patients with ALI >18 (P < 0.001). On multi-variate analysis ALI score of <18 (1.42, 95% CI 1.003-2.01) remained significantly associated with worse outcome. CONCLUSION: ALI (<18) at diagnosis is an independent marker of poor outcome in patients with advanced NSCLC.

Artemis is required to improve the accuracy of repair of double-strand breaks with 5'-blocked termini generated from non-DSB-clustered lesions.

Clustered DNA lesions are defined as ≥2 damage events within 20 bp. Oxidised bases, abasic (AP) sites, single-strand breaks and double-strand breaks (DSBs) exist in radiation-induced clusters, and these lesions are more difficult to repair and can be more mutagenic than single lesions. Understanding clustered lesion repair is therefore important for the design of complementary treatments to enhance radiotherapy. Non-DSB-clustered lesions consisting of opposing AP sites can be converted to DSBs by base excision repair, and non-homologous end-joining (NHEJ) plays a role in repairing these DSBs. Artemis is an endonuclease that removes blocking groups from DSB termini during NHEJ. Hence, we hypothesised that Artemis plays a role in the processing of DSBs or complex DSBs generated from non-DSB-clustered lesions. We examined the repair of clusters containing two or three lesions in wild-type (WT) or Artemis-deficient (ART(-/-)) mouse fibroblasts using a reporter plasmid. Each cluster contained two opposing tetrahydrofurans (an AP site analogue), which AP endonuclease can convert to a DSB with blocked 5' termini. Loss of Artemis did not decrease plasmid survival, but did result in more mutagenic repair with plasmids containing larger deletions. This increase in deletions did not occur with ClaI-linearised plasmid. Since Mre11 has been implicated in deletional NHEJ, we used small interfering RNA to reduce Mre11 in WT and ART(-/-) cells, but decreasing Mre11 did not change the size of deletions in the repair products. This work implicates Artemis in limiting the deletions introduced during repair of 5'-blocked termini DSBs generated from non-DSB-clustered lesions. Decreasing repair accuracy without decreasing repair capacity could result in mutated cells surviving irradiation. Inhibiting Artemis in normal cells could promote carcinogenesis, while in tumour cells enhanced mutagenic repair following irradiation could promote tumour recurrence.

Accuracy of multi-detector computed tomography, fluorodeoxyglucose positron emission tomography-CT, and CA 19-9 levels in detecting recurrent pancreatic adenocarcinoma.

CONTEXT: We compared the accuracy of fluorodeoxyglucose positron emission tomography-CT (FDG-PET-CT), multi-detector computed tomography (MDCT) and CA 19-9 levels in detecting pancreatic cancer recurrence in patients with resected CA 19-9 positive pancreatic adenocarcinomas. METHODS: We retrospectively evaluated 122 patients with pancreatic adenocarcinomas who underwent surgical resection of the tumor between January 2002 and December 2011. Twenty-five patients had MDCT, FDG-PET-CT and CA 19-9 levels performed no less than six weeks post-operation and within 8 weeks of each other for detection of tumor recurrence. Of these, 20 patients had high pre-operative CA 19-9 levels that dropped to a normal level postoperatively which will be the focus of this study. The sensitivity, specificity, positive and negative predictive value (PPV, NPV), and accuracy of MDCT, FDG-PET-CT, and CA 19-9 in detecting recurrence were compared. RESULTS: Operations performed included pyloric sparing pancreaticoduodenectomy (n=9), pancreaticoduodenectomy (n=7), distal pancreatectomy (n=3) and total pancreatectomy (n=1). Three patients had no recurrence, but local recurrence and distant metastasis were seen in 8 (40%) and 12 (60%) patients, respectively. In our study, sensitivity, specificity, PPV, NPV and diagnostic effectiveness (accuracy) were: 82%, 100%, 100%, 50%, 85% for MDCT; 82%, 100%, 100%, 50%, 85% for FDG-PET-CT and 94%, 100%, 100%, 75%, 95% for CA 19-9. The difference in recurrence detection accuracy of the tests was not statistically significant. A combination of CA 19-9 with MDCT or FDG-PET-CT was 100% accurate in detecting cancer recurrence in our patients. CONCLUSION: Our data suggests that CA 19-9 levels can be used reliably to detect recurrent pancreatic adenocarcinomas in patients with CA 19-9-positive primary tumors. Combination of CA 19-9 with MDCT or FDG-PET-CT is potentially the most accurate approach in detecting pancreatic cancer recurrence.

Commercial insurance triples chances of breast cancer survival in a public hospital.

Breast cancer survival is affected both by endogenous factors and exogenous factors such as socioeconomic status. This study explored the relationship between insurance status and overall survival of 987 female breast cancer patients in a population served by a public hospital. All patients were offered the same level of care regardless of ability to pay. Of the 987 breast cancer patients investigated, 54.6% were African-American. 54.1% of patients were insured (commercial insurance or Medicare), 27.1% with Medicaid, and 18.8% who were uninsured. Overall median survival was 15.5 years and was not statistically significant between Caucasian and African-American women. Median survival times were 15.8, 11.3, and 8.2 years for insured, Medicaid, and uninsured groups, respectively. Uninsured patients had worse overall survival rates compared with insured patients (p < 0.05). Adjusting for other factors (e.g., stage, age, race, body mass index, and income), insurance was a significant factor affecting survival with hazard ratios of 2.24 and 3.22 for Medicaid and uninsured patients, respectively, compared with insured patients. Even in a public hospital, after adjusting for potential risk factors, insurance status still proved to be an important factor in the survival of breast cancer patients. Further research is necessary to identify causal factors related to the survival disparities associated with insurance status.