GM-CSF enhances 3F8 monoclonal antibody-dependent cellular cytotoxicity against human melanoma and neuroblastoma

3F8 is a murine monoclonal IgG3 antibody specific for the tumor-associated antigen ganglioside GD2. Previous in vitro studies suggest that tumor regressions observed in a phase I clinical trial of 3F8 may be attributable to complement activation by 3F8 and to 3F8-dependent cellular cytotoxicity (ADCC) with lymphocytes. We now describe 3F8-mediated ADCC of GD2-positive tumor targets (melanoma and neuroblastoma) with human granulocytes and report that recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) enhanced this phenomenon. Cytotoxicity required binding of 3F8 to the low-affinity Fc receptor type III (CD16) on the granulocytes and was poor with tumor-binding monoclonal antibodies of other immunoglobulin (ie, non-IgG3) subclasses. GM-CSF (2 to 20 ng/mL) increased ADCC by 93% to 267% at limiting dilutions of 3F8 (1 microgram/mL). With most GD2-positive cell lines tested, this effect translated into a tenfold or greater augmentation in 3F8 efficiency at mediating ADCC. Comparable enhancement occurred whether GM-CSF was present in the ADCC assay or granulocytes were incubated with GM-CSF and washed before the assay. Nonoxidative mechanisms may be important for ADCC since 3F8 mediated ADCC with granulocytes from two children with chronic granulomatous disease; this cytotoxicity was also enhanced by GM-CSF. Since GM-CSF induces a neutrophilia in patients, our data suggest that this cytokine may have the potential of amplifying 3F8 antitumor activity in patients by increasing effector cell numbers and by priming granulocytes for greater cytotoxicity.     

Household Survey in Sierra Leone Reveals High Prevalence of Surgical Conditions in Children

Background

Although great efforts are being undertaken to reduce child morbidity and mortality globally, there is limited knowledge about the need for pediatric surgical care. Some data on surgical need is available from hospital registries, but it is difficult to interpret for countries with limited surgical capacity.

Methods

A cross-sectional two-stage cluster-based sample survey was undertaken in Sierra Leone, using the Surgeons OverSeas Assessment of Surgical Need tool. Data were collected and analyzed on numbers of children needing surgical care and pediatric deaths that may have been averted if surgical care had been available.

Results

A total of 1,583 children out of 3,645 individuals (43.3 %) were interviewed. Most (64.0 %, n = 1,013) participants lived in rural areas. At the time of interview, 279 (17.6; 95 % confidence interval (95 % CI): 15.7–19.5 %) had a possible surgical condition in need of a consultation. Children in the northern and eastern provinces of Sierra Leone were much more likely to report a surgical problem than those in the urban-west.

Conclusions

There is a high need for surgical care in the pediatric population of Sierra Leone. While additional resources should be allocated to address that need, more research is needed. Ideally, questions on surgically treatable conditions should be added to the frequently performed health care surveys on the pediatric population.     

Ratio of Cesarean Deliveries to Total Operations and Surgeon Nationality Are Potential Proxies for Surgical Capacity in Central Haiti

Background

The World Health Organization has a standardized tool to assess surgical capacity in low- and middle-income countries (LMICs), but it is often resource- and time-intensive. There currently exists no simple, evidence-based measure of surgical capacity in these settings. The proportion of cesarean deliveries in regard to the total operations (C/O ratio) has been suggested as a way to assess quickly the capacity for emergency and essential surgery in LMICs. This ratio has been estimated to be between 23.3 and 41.5 % in LMICs, but the tool’s utility has not been replicated.

Methods

We reviewed operative logbooks for the Partners In Health/Zanmi Lasante hospital in Cange, Haiti. We recorded data on all consecutive surgical patients from July 2008 to 2010 and calculated the C/O ratio by dividing the number of cesarean deliveries by the total number of operations performed. We also analyzed surgical data by surgeon nationality to provide additional information about local surgical capacity.

Results

A total of 3,641 operations were performed between 2008 and 2010. The C/O ratio decreased significantly between 2008–2009 and 2009–2010 (13.4 vs. 10.7 %, p = 0.001) as the surgical volume and resources increased. Nationality analysis demonstrated that Haitian surgeons were able to provide a spectrum of general and specialist surgical care.

Conclusions

In its inherent relation to essential surgical procedures and to the overall rate of cesarean deliveries in the region, the C/O ratio can provide an accessible assessment of regional surgical resources. In Haiti, the change in the C/O ratio demonstrated a relative increase in surgical capacity from 2008 to 2010. An additional analysis of surgeon nationality ensured that C/O ratio estimates more accurately reflect local practitioner activity, but deficiencies in the regional capacity to address the local burden of surgical disease may still exist.     

Usability of the Novel Liraglutide 3.0 mg Pen Injector Among Overweight or Obese Adult Patients With or Without Prior Injection Experience

Background:

Obesity is associated with multiple comorbidities and increased mortality, making it an important target for treatment. However, achieving and maintaining weight loss by diet and physical activity remains challenging, and may often require pharmacotherapy. Liraglutide 3.0 mg has recently been approved for weight management in the United States, Canada, and EU. The current analysis used a summative usability test to assess safety and effectiveness, ease of use, and training requirements for the novel liraglutide 3.0 mg pen injector.

Methods:

Of the 234 participants, half received instructions for use and video-based training and/or opportunity to handle the device. All participants (excluding pharmacists) performed 6 tasks followed by post- task interviews on task difficulty, device ease of use, and any use errors, close calls, and operational difficulties. Tasks included differentiation of correct box and pen injector, medication clarity assessment, normal, dose reversal, and end-of-content injection. Number/type of use errors, close calls, and operational difficulties were evaluated.

Results:

All assessed participants interpreted the instructions for use correctly. No potentially serious use errors, and low numbers of nonserious errors, were reported. Overall, participants committed 105 use errors related to handling, with no potential for harm. A total of 25 close calls and 44 operational difficulties were reported without any pattern indicative of a design flaw. Marked differences in the incidence of events were observed for trained versus untrained participants regardless of prior injection experience. Participants rated ease of use as 6.4/7.

Conclusions:

The liraglutide 3.0 mg pen injector is safe and easy to use for liraglutide administration. New device features allow for safe use after brief training.     

Hypertriglyceridemia: the importance of identifying patients at risk

This review aims to explain risk factors, consequences, and management strategies recommended for patients with hypertriglyceridemia. A search of PubMed was performed: ‘Hypertriglyceridemia’[Majr], limited to English‐language and published in the 5 years up to April 2016. Abstracts of the 680 results were screened for inclusion. Reference lists of publications included were also screened for inclusion.

Approximately 25% of the United States population has elevated (≥150 mg/dL) triglycerides (TG) putting them at an increased risk of cardiovascular disease, non-alcoholic fatty liver disease, and pancreatitis. Risk factors for hypertriglyceridemia include genetics, lifestyle and diet, renal disease, endocrine disorders, and certain medications. Guidelines recommend that all patients with hypertriglyceridemia are advised on lifestyle modification to reduce TG to <150 mg/dL; a reduction in body weight of 5–10% can reduce TG by approximately 20%. For patients with TG <400 mg/dL, the primary goal is to reduce low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol, with most guidelines recommending statin therapy. When TG is ≥500 mg/dL the primary goal is to reduce TG levels to lower the risk of pancreatitis. Statin therapy (if LDL-C is elevated) in combination with a fibrate, or long-chain omega-3 fatty acid may be required. The Food and Drug Administration withdrew approval for niacin and some fibrates in combination with statins in April 2016 citing unfavorable benefit-risk profiles. With the increasing incidence of associated conditions (e.g. obesity, metabolic syndrome, and type 2 diabetes mellitus), it is likely that primary care physicians will encounter more patients with hypertriglyceridemia.