Gyulnara G. Kasumova

Role of the CaMKII/NMDA Receptor Complex in the Maintenance of Synaptic Strength

During long-term potentiation (LTP), synapses undergo stable changes in synaptic strength. The molecular memory processes that maintain strength have not been identified. One hypothesis is that the complex formed by the Ca2+/calmodulin-dependent protein kinase II (CaMKII) and the NMDA-type glutamate receptor (NMDAR) is a molecular memory at the synapse. To establish a molecule as a molecular memory, it must be shown that interfering with the molecule produces a persistent reversal of LTP. We used the CN class of peptides that inhibit CaMKII binding to the NR2B subunit in vitro to test this prediction in rat hippocampal slices. We found that CN peptides can reverse saturated LTP, allowing additional LTP to be induced. The peptide also produced a persistent reduction in basal transmission. We then tested whether CN compounds actually affect CaMKII binding in living cells. Application of CN peptide to slice cultures reduced the amount of CaMKII concentrated in spines, consistent with delocalization of the kinase from a binding partner in the spine. To more specifically assay the binding of CaMKII to the NMDAR, we used coimmunoprecipitation methods. We found that CN peptide decreased synaptic strength only at concentrations necessary to disrupt the CaMKII/NMDAR complex, but not at lower concentrations sufficient to inhibit CaMKII activity. Importantly, both the reduction of the complex and the reduction of synaptic strength persisted after removal of the inhibitor. These results support the hypothesis that the CaMKII/NMDAR complex has switch-like properties that are important in the maintenance of synaptic strength.

Surgical Management of Gallbladder Cancer: Simple Versus Extended Cholecystectomy and the Role of Adjuvant Therapy

Objective: To assess if simple cholecystectomy with adjuvant therapy could provide outcomes comparable to extended cholecystectomy. Background: Current guidelines recommend extended/radical cholecystectomy for T2/T3 gallbladder cancer; however, many tumors are discovered incidentally at laparoscopic cholecystectomy. Methods: The national Cancer Data Base 2004 to 2014 was queried for patients with pT2/T3 gallbladder adenocarcinoma who underwent resection. Adjuvant therapy was defined as chemotherapy, with or without radiotherapy, within 90 days of surgery. Baseline characteristics and overall survival were compared by &khgr;2 and Kaplan-Meier method, respectively. One-to-one propensity score matching for receipt of adjuvant therapy was used to account for potential selection bias. Results: A total of 6825 patients were identified. Diagnosis was made predominantly (78.9%) at the time of surgery or on pathology; 31.8% (2168) received adjuvant therapy. The majority, 88.8% (6060), had a simple cholecystectomy. Patients who received adjuvant therapy versus surgery alone were more likely to: be younger, privately insured, have no comorbidities, pT3 disease, positive lymph nodes, positive resection margins, and extended cholecystectomy. After matching, median survival was significantly longer for extended cholecystectomy with adjuvant therapy (23.3 months) than cholecystectomy with adjuvant therapy (16.4 months), which was significantly longer than either simple (12.4 months) or extended (10.7 months) cholecystectomy alone (all log-rank P<0.001). Conclusions: Adjuvant therapy prolongs survival after resection of T2/T3 tumors. Simple cholecystectomy with adjuvant therapy appears to be superior to extended resection alone in the short term and may serve as a potential alternative to re-resection in select high-risk individuals.

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.

The Role of Venous and Arterial Resection in Pancreatic Cancer Surgery

Pancreatic cancer continues to carry a dismal prognosis with the majority of patients presenting at advanced stages of disease. Complete surgical resection remains essential for prolonging survival and increasing the possibility of cure. However, few patients will be resectable at diagnosis, with a significant portion presenting with borderline or locally advanced disease. The addition of vascular resection and reconstruction at the time of pancreatectomy enables expansion of the patient population able to undergo resection with curative intent and achieve tumor-free margins. This review provides an overview of the literature regarding the role of venous and arterial resection in the treatment of pancreatic cancer, with a focus on outcomes including survival, morbidity, and mortality.

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.

Upper extremity deep venous thrombosis after port insertion: What are the risk factors?

Background. Totally implantable venous access devices (ports) are widely used, especially for cancer chemotherapy. Although their use has been associated with upper extremity deep venous thrombosis, the risk factors of upper extremity deep venous thrombosis in patients with a port are not studied adequately. Methods. The Healthcare Cost and Utilization Projects Florida State Ambulatory Surgery and Services Database was queried between 2007 and 2011 for patients who underwent outpatient port insertion, identified by Current Procedural Terminology code. Patients were followed in the State Ambulatory Surgery and Services Database, State Inpatient Database, and State Emergency Department Database for upper extremity deep venous thrombosis occurrence. The cohort was divided into a test cohort and a validation cohort based on the year of port placement. A multivariable logistic regression model was developed to identify risk factors for upper extremity deep venous thrombosis in patients with a port. The model then was tested on the validation cohort. Results. Of the 51,049 patients in the derivation cohort, 926 (1.81%) developed an upper extremity deep venous thrombosis. On multivariate analysis, independently significant predictors of upper extremity deep venous thrombosis included age <65 years (odds ratio = 1.22), Elixhauser score of 1 to 2 compared with zero (odds ratio = 1.17), end‐stage renal disease (versus no kidney disease; odds ratio = 2.63), history of any deep venous thrombosis (odds ratio = 1.77), all‐cause 30‐day revisit (odds ratio = 2.36), African American race (versus white; odds ratio = 1.86), and other nonwhite races (odds ratio = 1.35). Additionally, compared with genitourinary malignancies, patients with gastrointestinal (odds ratio = 1.55), metastatic (odds ratio = 1.76), and lung cancers (odds ratio = 1.68) had greater risks of developing an upper extremity deep venous thrombosis. Conclusion. This study identified major risk factors of upper extremity deep venous thrombosis. Further studies are needed to evaluate the appropriateness of thromboprophylaxis in patients at greater risk of upper extremity deep venous thrombosis.

Genome-wide prediction of synthetic rescue mediators of resistance to targeted and immunotherapy

Most patients with advanced cancer eventually acquire resistance to targeted therapies, spurring extensive efforts to identify molecular events mediating therapy resistance. Many of these events involve synthetic rescue (SR) interactions, where the reduction in cancer cell viability caused by targeted gene inactivation is rescued by an adaptive alteration of another gene (the rescuer). Here we perform a genome-wide prediction of SR rescuer genes by analyzing tumor transcriptomics and survival data of 10,000 TCGA cancer patients. Predicted SR interactions are validated in new experimental screens. We show that SR interactions can successfully predict cancer patients’ response and emerging resistance. Inhibiting predicted rescuer genes sensitizes resistant cancer cells to therapies synergistically, providing initial leads for developing combinatorial approaches to overcome resistance proactively. Finally, we show that the SR analysis of melanoma patients successfully identifies known mediators of resistance to immunotherapy and predicts novel rescuers.