The role of dendritic spines in epileptogenesis.

Epilepsy is a chronic central nervous system (CNS) disease associated with high morbidity. To date, there is no known disease-modifying therapy for epilepsy. A leading hypothesis for a mechanism of epileptogenesis is the generation of aberrant neuronal networks. Although the underlying biological mechanism is not clear, scientific evidence indicates that it is associated with a hyperexcitable synchronous neuronal network and active dendritic spine plasticity. Changes in dendritic spine morphology are related to altered expression of synaptic cytoskeletal proteins, inflammatory molecules, neurotrophic factors, and extracellular matrix signaling. However, it remains to be determined if these aberrant dendritic spine formations lead to neuronal hyperexcitability and abnormal synaptic connections or whether they constitute an underlying mechanism of seizure susceptibility. Focusing on dendritic spine machinery as a potential target for medications could limit or reverse the development of epilepsy.

The role of elotuzumab in the treatment of relapsed or refractory multiple myeloma.

PURPOSE: The pharmacology, pharmacokinetics, clinical efficacy and safety, cost, and place in therapy of elotuzumab for treatment of relapsed or refractory multiple myeloma (MM) are reviewed. SUMMARY: Elotuzumab is a humanized monoclonal antibody that targets the signaling lymphocytic activation molecule (SLAM) protein SLAMF7 and facilitates an antibody-dependent cellular cytotoxicity interaction between myeloma cells and natural killer cells. Elotuzumab has U.S. marketing approval for use in combination with lenalidomide and dexamethasone in patients with relapsed or refractory MM who have received 1-3 previous therapies; this regimen is among the preferred regimens for relapsed or refractory MM recommended by the National Comprehensive Cancer Network (NCCN). A Phase III trial involving 321 patients demonstrated a median progression-free survival duration of 19.4 months with elotuzumab plus lenalidomide and dexamethasone versus 14.9 months with lenalidomide and dexamethasone alone (hazard ratio for progression or death, 0.70; 95% confidence interval, 0.57-0.85; p < 0.001). Common adverse effects of elotuzumab-lenalidomide-dexamethasone therapy include hematologic toxicities, fatigue, pyrexia, diarrhea, constipation, muscle spasms, and cough. Elotuzumab plus bortezomib and dexamethasone is an NCCN-recommended alternative option for relapsed or refractory MM. CONCLUSION: While elotuzumab plus lenalidomide and dexamethasone is a promising regimen for patients with MM, it is only one of several regimens recommended by NCCN for relapsed or refractory MM. Key factors in patient selection for elotuzumab therapy include adverse effects, prior treatments received, and cost considerations.

Trends in the Incidence and Outcomes of Hospitalized Cancer Patients With Clostridium difficile Infection: A Nationwide Analysis.

Background: Patients with cancer have several risk factors for Clostridium difficile infection (CDI), but the impact of CDI on outcomes in this population needs elucidation. We analyzed the incidence of CDI and its impact on outcomes in patients with cancer using the National Hospital Discharge Survey (NHDS) database from 2001 to 2010. Methods: Diagnosis codes were used to identify patients with cancer and CDI events. Demographics, diagnoses, length of stay (LOS), and discharge information were abstracted. Multivariate linear and logistic regression models with weighted analysis were conducted to study CDI incidence and CDI-associated outcomes. Analyses were performed using SAS version 9.4. Results: During the 10-year study period, 20.1 million discharges had a cancer diagnosis. CDI developed in 1.09% of patients with cancer versus 0.77% of patients without cancer (adjusted odds ratio [aOR], 1.28; 95% CI, 1.28-1.29; P<.001). The incidence of CDI in patients with cancer increased during the 10-year study period (64.7 per 10,000 discharges in 2001-2002 to 109.1 in 2009-2010; P<.001). In multivariable analysis, compared with patients with cancer without CDI, patients with cancer and CDI had a longer mean LOS (5.67 days; 95% CI, 5.39-5.94) and higher rates of in-hospital mortality (aOR, 1.18; 95% CI, 1.16-1.20) and discharge to a care facility (aOR, 1.74; 95% CI, 1.72-1.75; all P<.001). Conclusions: In this national database, CDI incidence increased significantly in patients with cancer over the study period and was associated with prolonged hospitalization, increased mortality, and discharge to a care facility. Despite increased attention, CDI remained a serious infection and merits appropriate prevention and management.

Update on targeted therapies for advanced non-small cell lung cancer: nivolumab in context.

While the initial treatment of non-small cell lung cancer (NSCLC) usually relies on surgical resection followed by systemic cytotoxic chemotherapy and/or radiation therapy, recent advances in understanding of NSCLC biology and immunology have spurred the development of numerous targeted therapies. In particular, a class of immune modulatory drugs targeting the immune checkpoint pathways has demonstrated remarkable durable remissions in a select minority of advanced NSCLC patients, potentially heralding the elusive "cancer cure". This review focuses on the clinical evidence for one of these agents, nivolumab, and clarifies the role of this drug in the context of the other targeted therapies currently available for the treatment of NSCLC. We also discuss the impact of nivolumab on patient quality of life and health economics.

High Initiation of Adjuvant Hormonal Therapy Among Uninsured Stages I-III Breast Cancer Patients Treated in a Safety-Net Healthcare System.

OBJECTIVE: Despite benefits of adjuvant hormonal therapy (AHT), many eligible breast cancer patients do not complete therapy as recommended. Patterns of AHT use have not been well studied among uninsured breast cancer patients who fall into coverage gaps or are ineligible for public insurance programs. METHODS: We identified 291 patients newly diagnosed with stages I-III hormone receptor-positive breast cancer from January 2008 to December 2012. All patients were treated at a safety-net healthcare system and enrolled in an income-based medical assistance program that fills AHT prescriptions at low cost. We extracted and linked cancer registry, pharmacy claims, and medical record data to assess AHT initiation (defined as a new AHT prescription ≤18 months since diagnosis) and sociodemographic and healthcare utilization variables. Log-binomial regression was used to identify correlates of initiation. RESULTS: Overall, 239 (82%) patients initiated AHT. Tamoxifen (42%) and anastrozole (55%) were most commonly prescribed. The mean copay was $4.90 for tamoxifen and $6.00 for anastrozole. Although crude analyses revealed small, statistically significant prevalence ratios for race/ethnicity (Hispanic vs. white, other vs. white), year of diagnosis (2008 vs. 2012), primary care visit before diagnosis (any vs. none), and smoking status (current vs. never), there were no significant correlates of initiation in the adjusted model. CONCLUSION: Safety-net healthcare systems providing access to AHT (i.e., through reduced copays) could improve the number of eligible patients initiating therapy. Continuity and integration of care in these settings may reduce disparities frequently observed in uninsured, low-income breast cancer populations.

Venous thromboembolism treatment outcomes in cancer patients and effect of third-party payers on anticoagulant choice.

PURPOSE: The purpose of this study is to compare the rates of recurrent VTE among cancer patients treated with parenteral agents to the oral anticoagulants. METHODS: This single-center study was a retrospective chart review of cancer patients with recurrent VTE between January 1, 2009 and December 31, 2014. The primary outcome of the study is the rate of recurrent VTE in patients who received a parenteral anticoagulant (enoxaparin, dalteparin, fondaparinux) versus those who received oral anticoagulants (warfarin and rivaroxaban). Other outcomes investigated include risk factors associated with recurrent VTE events and influence of third-party payer on anticoagulant selection. RESULTS: Four hundred fifty-seven patients met inclusion criteria (178 in the oral anticoagulant group and 279 in the parenteral anticoagulant group). Patients with Medicare were more likely to have received an oral anticoagulant (P = 0.003) and patients with private insurance were more likely to have received a parenteral anticoagulant (P = 0.004). There were 23 recurrent VTE events, 12 events (6.7 %) in the oral anticoagulant group and 11 events (3.94 %) in the parenteral group (P = 0.182). The only significant risk factor noted to increase risk of recurrent VTE was the presence of an IVC filter (adjusted OR 4.38, 95 % CI 1.67-11.53, P = 0.003). CONCLUSIONS: While there is no statistical difference in VTE events between groups, the oral anticoagulant group numerically had a higher rate. Important associations were found to have an influence on anticoagulant selection and risk of recurrent VTE. These factors must be incorporated into decision making when treating cancer patients with VTE.

Toxic Effects of Sorafenib in Patients With Differentiated Thyroid Carcinoma Compared With Other Cancers.

IMPORTANCE: Sorafenib is approved by the US Food and Drug Administration for metastatic, radioactive iodine-refractory differentiated thyroid cancer. However, adverse effects common to the tyrosine kinase inhibitor class occur at a noticeably higher rate with sorafenib use in thyroid cancer patients. The mechanism for this increase in toxic effects is unknown. OBJECTIVE: To provide an overview of the adverse effect profile of sorafenib in differentiated thyroid cancer and summarizes the literature regarding the frequency and etiology of selected adverse effects, with particular emphasis on the hand-foot skin reaction. EVIDENCE REVIEW: A PubMed database search for relevant literature on this topic published within the last 15 years was conducted. Publications dealing with sorafenib and any of its common adverse effects were considered; this included randomized trials, observational studies, case reports or case series, and pertinent review articles. Given the lack of widespread literature on the topic, articles were generally not excluded from consideration unless there were serious flaws in study design. FINDINGS: The DECISION trial of sorafenib in patients with differentiated thyroid cancer demonstrated significantly higher rates of common adverse effects, most notably hand-foot skin reaction, diarrhea, and hypertension, compared with sorafenib experience in renal or hepatocellular cancer. Other phase 2 and 3 trials have also consistently shown these differences. This review details the putative mechanisms behind the increase in toxic effects, but further work is needed to fully explain the toxic effects differential seen when using the same drug in different cancers. CONCLUSIONS AND RELEVANCE: There is a distinct increase in the rate of occurrence of adverse effects of sorafenib when used in differentiated thyroid cancer compared with renal and hepatocellular cancer. While many theoretical explanations have been proposed, the exact mechanism for this differential in toxic effects remains unclear.

Choroid plexus papilloma-A case highlighting the challenges of extrapolating pediatric chemotherapy regimens to adult populations.

The treatment of adults who present with rare pediatric tumors is not characterized well in the literature. We report an instance of a 40-year-old African American woman with a diagnosis of choroid plexus carcinoma admitted to the intensive care unit for severe sepsis seven days after receiving chemotherapy consisting of carboplatin (350 mg/m(2) on Days 1 and 2 plus etoposide 100 mg/m(2) on Days 1-5). Her laboratory results were significant for an absolute neutrophil count of 0/µL and blood cultures positive for Capnocytophagia species. She was supported with broad spectrum antibiotics and myeloid growth factors. She eventually recovered and was discharged in stable condition. The management of adults with malignancies most commonly seen in pediatric populations presents substantial challenges. There are multiple age-specific differences in renal and hepatic function that explain the need for higher dosing in pediatric patients without increasing the risk of toxicity. Furthermore, differences in pharmacokinetic parameters such as absorption, distribution, and clearance are present but are less likely to affect patients. It is expected that the pediatric population will have more bone marrow reserve and, therefore, less susceptible to myelosuppression. The extrapolation of pediatric dosing to an adult presents a problematic situation in treating adults with malignancies that primarily effect pediatric patients. We recommend extrapolating from adult treatment regimens with similar agents rather than extrapolating from pediatric treatment regimens to reduce the risk of toxicity. We also recommend the consideration of adding myeloid growth factors. If the treatment is tolerated without significant toxicity, dose escalation can be considered.

Immune Checkpoint Inhibitors: New Insights and Current Place in Cancer Therapy.

The treatment of cancer has largely relied on killing tumor cells with nonspecific cytotoxic therapies and radiotherapy. This approach, however, has limitations including severe systemic toxicities, bystander effects on normal cells, recurrence of drug-resistant tumor cells, and the inability to target micrometastases or subclinical disease. An increased understanding of the critical role of the immune system in cancer development and progression has led to new treatment strategies using various immunotherapies. It is now recognized that established tumors have numerous mechanisms of suppressing the antitumor immune response including production of inhibitory cytokines, recruitment of immunosuppressive immune cells, and upregulation of coinhibitory receptors known as immune checkpoints. This review focuses on the immune checkpoint inhibitors, a novel class of immunotherapy first approved in 2011. Our objective is to highlight similarities and differences among the three immune checkpoint inhibitors approved by the U.S. Food and Drug Administration-ipilimumab, pembrolizumab, and nivolumab-to facilitate therapeutic decision making. We conducted a review of the published literature and conference proceedings and present a critical appraisal of the clinical evidence supporting their use in the treatment of metastatic melanoma and advanced squamous non-small cell lung cancer (NSCLC). We also compare and contrast their current place in cancer therapy and patterns of immune-related toxicities, and discuss the role of dual immune checkpoint inhibition and strategies for the management of immune-related adverse events. The immune checkpoint inhibitors have demonstrated a dramatic improvement in overall survival in patients with advanced melanoma and squamous NSCLC, along with acceptable toxicity profiles. These agents have a clear role in the first-line treatment of advanced melanoma and in the second-line treatment of advanced squamous NSCLC.

Role of obinutuzumab in the treatment of chronic lymphocytic leukemia.

PURPOSE: The pharmacology, pharmacokinetics, safety and efficacy, and place in therapy of obinutuzumab in the treatment of chronic lymphocytic leukemia (CLL) are reviewed. SUMMARY: Obinutuzumab, a fully humanized monoclonal antibody that targets the CD20 receptor on mature B cells, was recently approved for use in combination with chlorambucil in patients with previously untreated CLL. In a Phase III clinical trial including 671 patients with CLL and significant comorbidities, patients who received obinutuzumab-chlorambucil combination therapy had longer median progression-free survival than those who received rituximab plus chlorambucil (26.7 months versus 15.2 months, p < 0.001) or chlorambucil alone (11.1 months, p < 0.001). Overall survival was also improved with the use of obinutuzumab-chlorambucil versus chlorambucil alone (hazard ratio for death, 0.41, p = 0.002) and similar to survival with the use of rituximab plus chlorambucil. The main type of adverse effect reported in association with obinutuzumab use is infusion-related reactions (IRRs), which occurred in 66% of patients in the Phase III trial, with 20% of reactions categorized as grade 3 or 4; IRR risk can be reduced with appropriate dosing, premedication, patient monitoring, and immediate treatment of IRRs. Ongoing clinical trials are evaluating the effects of obinutuzumab in patients with newly diagnosed and relapsed or treatment-refractory CLL. CONCLUSION: In patients who are elderly or who have multiple comorbidities, the use of obinutuzumab, a CD20 monoclonal antibody, in combination with chlorambucil is an efficacious regimen for treatment-naive patients with symptomatic CLL.

Dosing considerations for obese patients receiving cancer chemotherapeutic agents.

OBJECTIVE: To examine the available trials evaluating the effect of obesity on the pharmacokinetic parameters of chemotherapy agents. DATA SOURCE: A PubMed search (January 1977-June 2013) was conducted for English-language articles evaluating obesity and its relationship to pharmacokinetic parameters of chemotherapy agents. Search terms included: chemotherapy, obesity, excess weight, overweight, neoplasm, pharmacokinetics, dosing, cancer, body mass index, toxicity, efficacy, body surface area. DATA SELECTION AND DATA EXTRACTION: All articles were critically evaluated, and all pertinent information was included. Studies were included if they addressed obesity and pharmacokinetic parameters. DATA SYNTHESIS: Obesity and cancer are preeminent health care challenges in the 21st century, with obese persons being at an increased risk of cancer. Given this background, it is troubling that limited information is available for dosing chemotherapy agents in obese patients. Pharmacokinetic parameters of other drug classes have been affected by increased weight. It is important to evaluate the effect on chemotherapy agents given their narrow therapeutic window. Dose capping has been used to limit excess toxicity in obese patients at the risk of providing a less-effective regimen. Data suggest an increased dose of carboplatin, cisplatin, ifosfamide, paclitaxel, and vincristine may be needed in obese patients. The literature also suggests that no dosing alteration may be necessary for obese patients receiving topoisomerase I and II inhibitors, 5-fluorouracil, methotrexate, and docetaxel. A dose decrease might be suitable for cyclophosphamide. CONCLUSION: Some cytotoxic agents used in practice have altered pharmacokinetics in obese patients. Studies prospectively validating dose individualization for obese patients are needed.

Risk of renal failure in cancer patients with bone metastasis treated with renally adjusted zoledronic acid.

PURPOSE: The purpose of this study was to evaluate the incidence of acute renal failure (ARF) in patients with mild to moderate renal dysfunction, receiving renally adjusted zoledronic acid (ZA) and compare it to patients with normal baseline renal function, receiving standard-dose ZA. METHODS: This was a retrospective study of patients receiving ZA for the treatment of bone metastasis due to cancer. Patients were divided into two groups: (1) normal group with baseline creatinine clearance (CrCl) of greater than 60 mL/min and standard ZA dose; (2) impaired group with baseline CrCl of 30-60 mL/min and renally adjusted ZA dose. Primary endpoint of ARF was defined as an increase in serum creatinine (SCr) of 0.5 mg/dL or 1.0 mg/dL from a baseline SCr of <1.4 mg/dL or ≥ 1.4 mg/dL, respectively. RESULTS: In total, 1,472 evaluable doses of ZA were given to 220 patients. Of these, 184 patients were in the normal group and 36 patients in the impaired group. There were 38 patients (20.7%) who developed ARF in the normal group versus 7 patients (19.4%) in the impaired group. There was no difference in the mean time to the incidence of ARF at 6.1 months in both groups. Incidence of ARF based on CrCl (≥ 25% decline in CrCl) was similar between groups (39.1% vs. 41.7%; p = 0.78). CONCLUSION: The incidence of ARF is similar between patients in the normal group and impaired group when the ZA dose is renally adjusted.

Retrospective analysis of the consequences of acid suppressive therapy on ketoconazole efficacy in advanced castration-resistant prostate cancer.

BACKGROUND: The area under the curve of a single ketoconazole dose has been shown to decrease significantly when administered with acid suppressive therapy. No published studies have examined the clinical impact of concurrent ketoconazole and acid suppressive therapy in patients with castration-resistant prostate cancer (CRPC). OBJECTIVE: To evaluate the effect of acid suppressive therapy on prostate-specific antigen (PSA) response rate in CRPC patients receiving ketoconazole. METHODS: This retrospective study evaluated CRPC patients treated with ketoconazole 3 times daily between January 1, 1999, and September 30, 2009. Patients included in the analysis had failed androgen deprivation therapy, and were subsequently initiated on ketoconazole. Response (PSA decline ≥50% maintained ≥4 weeks) was evaluated in patients receiving ketoconazole with (group 1 [G1]) or without (group 2 [G2]) concurrent acid suppressive therapy. RESULTS: Thirty patients (G1: 11 patients; G2: 19 patients) were included in the analysis. Mean age in G1 and G2 was 71.8 and 69.6 years, respectively. Most patients had received prior therapy with an antiandrogen (90.9% G1; 100% G2) and fewer patients received antiandrogen withdrawal therapy (27.3% G1; 21.1% G2). Median baseline PSA was 109.4 (G1) and 86.9 ng/mL (G2) (p = 0.55). Median duration of ketoconazole was 7.2 months in G1 and 5.8 months in G2 (p = 0.09). Ketoconazole adherence was 82% (G1) and 100% (G2). Median duration of concurrent acid suppressive therapy was 3.8 months (range 2.0-20.4) in G1. PSA response (72.7% and 47.4%; p = 0.26) and time to PSA response (1.2 vs 0.9 mo; p = 0.53) were statistically similar between G1 and G2, respectively. Median progression free survival was higher in G1 (11.5 vs 6.9 months in G2; p = 0.047). CONCLUSIONS: Use of concurrent acid suppressive therapy and ketoconazole in CRPC patients did not decrease PSA response rate, and progression free survival was unexpectedly higher compared with the non-acid suppressive therapy group. Larger studies are needed to verify the clinical impact of acid suppressive therapy in combination with ketoconazole.

Epidermal growth factor receptor monoclonal antibodies for the treatment of metastatic colorectal cancer.

Treatment of metastatic colorectal disease has evolved over the last decade. Two epidermal growth factor receptor (EGFR) monoclonal antibodies--cetuximab and panitumumab--have been developed in an effort to provide yet another therapeutic option. The EGFR is a transmembrane glycoprotein, expressed constitutively throughout the body and found on many epithelial tissues. The monoclonal antibodies bind to and inhibit the activation of the receptor in the body. This inhibition prevents tumor cell growth, angiogenesis, invasion, and metastasis, and induces apoptosis. Cetuximab and panitumumab exhibit nonlinear pharmacokinetics. Both monoclonal antibodies are approved for the treatment of refractory metastatic colorectal cancer. Cetuximab in combination with irinotecan has significantly better response rates and progression-free survival compared with those of cetuximab or irinotecan alone. Cetuximab and panitumumab as monotherapy have shown significantly better response rates and progression-free survival compared with best supportive care in patients refractory to irinotecan and oxaliplatin. In the Cetuximab Combined with Irinotecan in First Line Therapy for Metastatic Colorectal Cancer (CRYSTAL) trial, treatment-naïve patients received cetuximab in combination with the chemotherapy regimen infusional leucovorin, fluorouracil, and irinotecan (FOLFIRI) or FOLFIRI alone; the difference in progression-free survival was statistically significant but suggested only a modest benefit over FOLFIRI alone (8.9 vs 8 mo, p=0.036). Results of a preplanned analysis of the first 231 events in the Panitumumab Advanced Colorectal Cancer Evaluation (PACCE) trial favored the control group (chemotherapy regimen with folinic acid [leucovorin], fluorouracil, and oxaliplatin [FOLFOX] plus bevacizumab) instead of the control group plus panitumumab. For clinical consideration, many trials have shown that the intensity or absence of EGFR expression is not a clinically significant predictor of outcomes. Development and intensity of a rash are suggested to be a positive predictor of outcomes in patients. The most common adverse events of EGFR monoclonal antibody therapy are rash, diarrhea, and hypomagnesemia. Other serious but not common adverse events include hypersensitivity reactions and pulmonary toxicity. The availability of EGFR monoclonal antibodies has provided another weapon in the arsenal to treat refractory metastatic colorectal cancer. They have shown safety and efficacy in combination with other chemotherapy regimens and as monotherapy; however, their use as metastatic colorectal cancer therapy needs to be further explored.