Mariam F. Eskander

Rivastigmine is a potent inhibitor of acetyl- and butyrylcholinesterase in Alzheimer's plaques and tangles

Acetylcholinesterase and butyrylcholinesterase activities emerge in association with plaques and tangles in Alzheimers disease. These pathological cholinesterases, with altered properties, are suggested to participate in formation of plaques. The present experiment assessed the ability of rivastigmine, a clinically utilized agent that inhibits acetylcholinesterase and butyrylcholinesterase activities, to inhibit cholinesterases in plaques and tangles. Cortical sections from cases of Alzheimers disease were processed using cholinesterase histochemistry in the presence or absence of rivastigmine. Optical densities of stained sections were utilized as a measure of inhibition. The potency of rivastigmine was compared with those of other specific inhibitors. Optimum staining for cholinesterases in neurons and axons was obtained at pH 8.0. Cholinesterases in plaques, tangles and glia were stained best at pH 6.8. Butyrylcholinesterase-positive plaques were more numerous than acetylcholinesterase-positive plaques. Rivastigmine inhibited acetylcholinesterase in all positive structures in a dose-dependent manner (10(-6)-10(-4) M). However, even at the highest concentration, faint activity remained. In contrast, rivastigmine resulted in complete inhibition of butyrylcholinesterase in all structures at 10(-5) M. Rivastigmine was equipotent to the specific acetylcholinesterase inhibitor BW284C51 and more potent than the butyrylcholinesterase inhibitors iso-OMPA and ethopropazine. In conclusion, rivastigmine is a potent inhibitor of acetylcholinesterase and a more potent inhibitor of butyrylcholinesterase in plaques and tangles. Unlike other cholinesterase inhibitors tested, rivastigmine inhibited cholinesterases in normal and pathological structures with the same potency. Thus, at the therapeutic concentrations used, rivastigmine is likely to result in inhibition of pathological cholinesterases, with the potential of interfering with the disease process.

Neoadjuvant therapy versus upfront surgical strategies in resectable pancreatic cancer: A Markov decision analysis.

BACKGROUND Neoadjuvant therapy is gaining acceptance as a valid treatment option for borderline resectable pancreatic cancer; however, its value for clearly resectable pancreatic cancer remains controversial. The aim of this study was to use a Markov decision analysis model, in the absence of adequately powered randomized trials, to compare the life expectancy (LE) and quality-adjusted life expectancy (QALE) of neoadjuvant therapy to conventional upfront surgical strategies in resectable pancreatic cancer patients. METHODS A Markov decision model was created to compare two strategies: attempted pancreatic resection followed by adjuvant chemoradiotherapy and neoadjuvant chemoradiotherapy followed by restaging with, if appropriate, attempted pancreatic resection. Data obtained through a comprehensive systematic search in PUBMED of the literature from 2000 to 2015 were used to estimate the probabilities used in the model. Deterministic and probabilistic sensitivity analyses were performed. RESULTS Of the 786 potentially eligible studies identified, 22 studies met the inclusion criteria and were used to extract the probabilities used in the model. Base case analyses of the model showed a higher LE (32.2 vs. 26.7 months) and QALE (25.5 vs. 20.8 quality-adjusted life months) for patients in the neoadjuvant therapy arm compared to upfront surgery. Probabilistic sensitivity analyses for LE and QALE revealed that neoadjuvant therapy is favorable in 59% and 60% of the cases respectively. CONCLUSION(S) Although conceptual, these data suggest that neoadjuvant therapy offers substantial benefit in LE and QALE for resectable pancreatic cancer patients. These findings highlight the value of further prospective randomized trials comparing neoadjuvant therapy to conventional upfront surgical strategies.

Surgical management of chronic pancreatitis: current utilization in the United States

BACKGROUND Surgical intervention is uncommon in chronic pancreatitis. Literature largely describes single institution or international experiences. This study describes US-based chronic pancreatitis surgical management. METHODS Retrospective analysis of chronic pancreatitis patients in the Healthcare Cost and Utilization Project Florida State Inpatient Database 2007-2011. Patients with malignancy or congenital abnormalities were excluded. Univariate analysis using the chi-square test. The number of readmissions, inpatient length of stay and cost using Wilcoxons signed-rank test. Multivariate analysis of surgery by logistic regression. RESULTS Twenty-one thousand four hundred and forty-five patients with chronic pancreatitis. 10.8% (2 307) underwent surgery including 1652 cholecystectomies, 564 drainage procedures and 498 pancreatectomies. Procedures decreased from 12.1% to 8.3% over time (P < 0.001), but intervention within 3 months increased (7.2% to 8.4%; P = 0.017). 15.3% (3 278) had pancreatic cysts/pseudocysts and 43.4% (9 312) had diabetes. The median numbers of admissions were 2 [interquartile range (IQR) 1,5] and 3 (IQR 2,7) among non-surgical and surgical patients, respectively (P < 0.001). Predictors of surgery were fewer co-morbidities, private insurance, and either diabetes mellitus or pancreatic cyst/pseudocyst. CONCLUSION Chronic pancreatitis leads to numerous inpatient readmissions, but surgical intervention only occurs in a minority of cases. Complicated patients are more likely to undergo surgery. The complexities of chronic pancreatitis management warrant early multidisciplinary evaluation and ongoing consideration of surgical and non-surgical options.

Keeping it in the family: the impact of marital status and next of kin on cancer treatment and survival

BACKGROUND This study examines the impact of marriage and next of kin identity on timing of diagnosis, treatment, and survival in cancer patients. METHODS Retrospective review of patients with 5 solid tumor types treated at an academic medical center from 2002 to 2012. Exposures of interest were marriage status at time of diagnosis and familial relationship with next of kin (NOK). Association with overall survival determined via Cox regressions and with early diagnosis (stage I to II) and receipt of surgery via logistic regressions. RESULTS Marriage was not associated with early diagnosis for any cancer type. After adjustment, being married was associated with significantly higher odds of receiving surgery only for pancreatic cancer and with improved survival for breast and lung cancers. Having a nuclear relationship with NOK was not associated with any outcomes. CONCLUSIONS Marriage status was associated with improved outcomes for certain cancers whereas familial relationship with NOK was not.

Nationwide Evaluation of Patient Selection for Minimally Invasive Distal Pancreatectomy Using American College of Surgeons' National Quality Improvement Program.

Objective: To assess current nationwide case selection factors for minimally invasive distal pancreatectomy (MIDP) and identify actual risk factors for adverse outcomes compared with open distal pancreatectomy (ODP). Background: Patient selection criteria that predict outcomes after MIDP remain unknown. As a result, widespread adoption of this surgical technique may have been delayed and its potential benefits possibly under-exploited. Methods: Retrospective cohort study of elective ODP and MIDP performed at 106 centers in 2014, using the pancreas-targeted American College of Surgeons’ National Quality Improvement Program (ACS-NSQIP) database. Exclusion criteria were neoadjuvant treatment or pancreatitis as only diagnosis. Primary outcome includes a composite major morbidity metric, reflecting adverse events including mortality and reoperation. Multivariable modeling was used to detect current selection factors and to identify actual risk factors of composite major morbidity. Results: A total of 928 patients underwent ODP (n = 472) or MIDP (n = 456) using a laparoscopic or robot-assisted approach, 24% for pancreatic ductal adenocarcinoma (PDAC). Current selection factors for MIDP were benign disease (odds ratio: OR: 1.56, CI: 1.10–2.21) and body mass index (BMI) 30–40 (OR: 1.41, CI: 1.04–1.91). Current selection factors for ODP were PDAC (OR: 0.45, CI: 0.31–0.64), benign tumor size >5 centimeters (OR: 0.40, CI: 0.23–0.67), and multivisceral procedures (OR: 0.39, CI: 0.26–0.59). Risk factors for composite major morbidity did not differ between ODP and MIDP. A trend was observed between MIDP and a lower risk of composite major morbidity compared with ODP (OR: 0.43, CI: 0.17–1.07). Conclusions: Current selection factors for ODP or MIDP (benign disease, tumor size, and BMI) do not mitigate the risk of major morbidity. We found no evidence that MIDP should be avoided based on tumor etiology or size, BMI, or patient physical status.

Neoadjuvant therapy versus upfront surgery for resected pancreatic adenocarcinoma: A nationwide propensity score matched analysis

Background. Neoadjuvant therapy is an emerging paradigm in pancreatic cancer care; however, its role for resectable disease remains controversial in the absence of conclusive randomized controlled trials. The purpose of the present study is to assess the impact of neoadjuvant therapy on survival in resected pancreatic cancer patients by clinical stage. Methods. A retrospective cohort study using the National Cancer Data Base from 2004 to 2012 including nonmetastatic pancreatic adenocarcinoma patients who underwent pancreatectomy and initiated chemotherapy. Propensity score matching within each stage was used to account for potential selection bias between patients undergoing neoadjuvant therapy and upfront surgery. Overall survival was compared by the Kaplan‐Meier method. Results. In the study, 1,541 and 7,159 patients received neoadjuvant therapy followed by surgery and upfront surgery succeeded by adjuvant therapy, respectively. In clinical stage III pancreatic cancer (n = 486), neoadjuvant therapy was associated with significant survival benefit after matching (median survival 22.9 vs 17.3 months; log‐rank P < .0001) compared with conventional upfront surgery followed by adjuvant therapy; however, no survival difference was found between the 2 treatment sequences in patients with clinical stage I (n = 3,149; median survival, 26.2 vs 25.7 months; P = .4418) and II (n = 5,065; median survival, 23.5 vs 23.0 months; P = .7751) disease after matching. Conclusion. The survival impact of neoadjuvant therapy is stage‐dependent. Neoadjuvant therapy does not disadvantage survival compared with conventional upfront surgery followed by adjuvant therapy in any stage, and is associated with a significant survival advantage in stage III pancreatic cancer.

Stereotactic body radiotherapy for unresected pancreatic cancer: A nationwide review

The role of conventional radiotherapy in the management of pancreatic cancer has yet to be elucidated. Over the past decade, stereotactic body radiotherapy (SBRT) has emerged as a novel therapeutic option in pancreatic cancer care. This study evaluated the survival impact of SBRT on patients with unresected pancreatic cancer.

Totally Implantable Venous Access Devices: A Review of Complications and Management Strategies

Objective: Totally implantable venous access devices (portacaths, or “ports”), are widely used for intermittent central venous access especially for cancer patients. Although ports have a superior safety margin compared with other long-term venous access devices, there are a number of complications associated with their use. Methods: This is a narrative review. We searched PubMed and Google Scholar for articles about complications related to the use of portacaths. “Similar articles” feature of PubMed and reference list of the existing literature were also reviewed for additional relevant studies. Results: In this review, we provide the latest evidence regarding the most common ones of these adverse events and how to diagnose and treat them. Immediate complications including pneumothorax, hemothorax, arterial puncture, and air embolism as well as late complications such as port infection, malfunction, and thrombosis are covered in detail. Conclusions: Physicians should be familiar with port complications and their diagnosis and management.

Regional variation in the treatment of pancreatic adenocarcinoma: Decreasing disparities with multimodality therapy

Background. Survival in pancreatic cancer remains poor with curative potential dependent on operative resection. We reviewed national adherence to practice guidelines to evaluate regional variation in the treatment and survival of patients with pancreatic cancer. Methods. Retrospective cohort review of adults with pancreatic adenocarcinoma using the National Cancer Data Base from 2006 to 2013. Overall survival was compared by the Kaplan‐Meier method and Cox proportional hazards models. Sequential multivariate logistic regression models were generated for odds of: a) diagnosis in stage I/II, b) resection, and c) receipt of multimodality therapy, defined as operative resection plus chemotherapy with or without radiation. Five geographic regions of the United States were used for analyses. Results. A total of 115,952 patients were identified. At least 22% of patients in all stages received no treatment, with only 38.4% and 32.3% of stage I and II patients receiving multimodality therapy. On unadjusted analysis, the Northeast had the greatest survival for all stages of disease, most pronounced for stage I where patients lived 2 to 3 more months (log‐rank P < .0001). While adjusted odds of early diagnosis and resection were comparable or greater across regions relative to the Northeast, patients who underwent resection in the Northeast were significantly more likely to receive multimodality therapy. Multivariate Cox modeling for patients receiving multimodality therapy accounted for differences in 3 of 4 remaining regions. Conclusion. Regional variations exist in pancreatic cancer treatment and survival. While providing multimodality cancer‐directed therapy can help mitigate these differences, survival with pancreatic cancer needs to be interpreted in the context of overall health, underlying risk factors, and life expectancy.

Evolution and impact of lymph node dissection during pancreaticoduodenectomy for pancreatic cancer

Background. Insufficient examination of lymph nodes after pancreaticoduodenectomy can lead some pancreatic cancer patients with N1 disease to be misclassified as N0. We examined trends in lymph node dissection throughout time and investigated how these changes affect lymph node status and its prognostic value. Methods. The National Cancer Data Base was queried for patients with nonmetastatic pancreatic adenocarcinoma (2004–2013) who underwent classic pancreaticoduodenectomy with antrectomy. Logistic regression was performed for odds of node positivity. Kaplan‐Meier curves and Cox proportional hazards models were used to assess the impact of lymph node status on overall survival for patients diagnosed during 2‐year intervals from 2004–2012. Results. Median number of examined lymph nodes was 10 (interquartile range 6–15) in 2004 vs 17 (interquartile range 12–24) in 2013. Number of lymph nodes examined was a significant predictor of N1 disease (P < .0001), with a plateau at 30 nodes. N1 disease increased from 64.4% to 68.0% (P < .0001). Survival for both N1 and N0 subgroups improved. In successive multivariate models, N0 versus N1 status was consistently protective for overall survival (P < .0001), but there was no change in the magnitude of its hazard ratio over time (overall hazard ratio 0.691; 95% confidence interval 0.660–0.723). Conclusion. Contemporary patients have an adequate number of nodes examined during standard pancreaticoduodenectomy. This, along with rising rates of N1 cancer detection and improved survival for both node‐positive and node‐negative patients, suggest more accurate classification of lymph node status. However, no increased benefit is achieved beyond 30 nodes. Overall, lymph node status remains a strong prognosticator for overall survival.