Off-label Manner Research Articles

The Last Straw: Trends in Straw-Related Emergency Department Visits.

With the recent societal push for eco-sustainability, there has been an increase in the prevalence of reusable utensils, particularly multiuse straws. This study is the first to investigate the epidemiology of plastic, glass, and metal straw-related injuries (SRIs) presenting to the emergency department (ED). The National Electronic Injury Surveillance System database was examined for SRIs from January 2012 through December 2021. Cases were stratified by sex, age, diagnosis, mechanism of injury, and straw material to monitor epidemiological patterns. A total of 1,174 SRIs presented to the National Electronic Injury Surveillance System EDs from January 1, 2012 to December 31, 2021. The majority of injuries occurred among males (55.9%) aged 0-3 years old (43.8%). Injuries caused by reusable straws were significantly more common in patients 3 years old or younger (P < 0.001). Injuries most commonly affect the mouth (45.4%), eyes (22%), and internal structures (13.6%). Lacerations and oral injuries were significantly more common among reusable straw materials (P < 0.001). A 46.5% increase in injuries was noted from 2012 to 2021. The most common mechanism of injury was poking injury (53.5%), followed by stationary falls (19.4%), foreign body (18.7%), running and falling (5.9%), and other (2.4%). Of these cases, 46.3% of injuries were due to the improper use of straws. Metal straw injuries increased 12.8% over the study period. Although most injuries occurred as accidental poking while drinking, nearly half of all injuries were sustained while using straws in an off-label manner. Ensuring the proper use of straws and monitoring children when using a straw may help to decrease the incidence of SRI. Among the options for environmentally friendly straw materials, metal straws pose the greatest risk for injuries requiring ED presentation. Thus, their use should be avoided in the pediatric population.

Off-label use of intravenous immunoglobulin g in a highly complex pediatric hospital in Argentina. A prospective observational study

The World Health Organization recommends prioritizing safe and effective drugs proven by clinical or epidemiological studies. However, in population groups with little research, a drug can be used for an indication or pharmaceutical form different from that approved by the regulatory agency (off-label), extrapolating data from studies in adults and exposing pediatric patients. to develop an Adverse Drug Reaction (ADR) due to safety considerations that have not been systematically studied. Intravenous immunoglobulin (IVIg), a high-cost drug, is used with scant evidence in some low-prevalence pathologies. This paper describes and analyzes the off-label use of IVIg at the J. P. Garrahan Pediatric Hospital. Observational, descriptive, prospective study on off-label indications of IVIg. The sampling technique was non-probabilistic and for convenience during 7 months. 305 IVIg infusions were studied, corresponding to 111 patients. The indication classification showed that 22% (n=67) of the infusions were off-label. In neurology there was a higher percentage of off-label indications (46%) and within them 45% corresponded to the use in neurological disorders. 81% of the doses indicated off-label were in the range 0.8-1g/kg. The off-label infusions presented 61.5% (n=8) of the ADRs. Those from the Neurology service represented 87.5%; 75% being from the "Neurological disorders" group. In some cases, IVIg was indicated in an off-label manner, finding a statistically significant relationship with the appearance of ADR. This finding motivates the proposition of new hypotheses to carry out more studies.

Reflections on the regulatory field covering the development of paediatric medicinal products: a brief overview of current status and challenges.

Many medicinal products are initially developed and tested in adults, and often, only a limited amount of data on their safety and efficacy in children exist. Consequently, paediatric healthcare providers sometimes need to make informed decisions about using medicinal products in children based on available fragmentary data. Ethical guidelines emphasise the importance of protecting children and ensuring they receive safe and effective medical treatments. Paediatric clinical trials should be conducted to provide evidence-based care with specific attention to minimise risks to children. This highlights the dilemma of finding a balance between protecting children and adolescents (and avoiding unnecessary clinical trials) and obtaining reliable, robust and justified data to treat them adequately and not in an off-label manner with unknown risks. For years, paediatricians maintained that children and adolescents are not treated based on up-to-date scientific knowledge and justification. The slogan "children are not small adults" summarised the concerns in a catch phrase. Different stakeholders have taken a variety of actions to address this concern.

Off-label use of large diameter Concerto fibered coils through a 0.017 inch microcatheter for transvenous embolization of indirect carotid-cavernous fistulas: two case reports

BackgroundA carotid-cavernous fistula is an abnormal communication between the arteries and veins within the cavernous sinus. While conservative management may be prudent in low risk cases, many patients require intervention and endovascular embolization has evolved as the preferred method of treatment. Embolization can be performed via either the transarterial or transvenous approach. One major challenge of the transvenous approach is the complex and variable compartmentation of the cavernous sinus, which often requires the use of low profile microcatheters to navigate and reach the fistulous point. Fibered coils are also preferred when performing transvenous embolization of carotid-cavernous fistula, as they are of higher thrombogenicity and allow for faster occlusion of the fistula. However, most low profile (0.017-inch) microcatheters are not able to deploy fibered coils based on the manufacturer’s instructions.Case presentationWe present two successful cases of off-label use of Medtronic Concerto fibered coils via a 0.017-inch microcatheter during transvenous embolization of carotid-cavernous fistula in a 60-year-old and an 80-year-old Chinese female, respectively.ConclusionOur case series highlight the possibility of deploying large diameter (up to 10 mm) Concerto fibered coils through a low profile (0.017-inch) microcatheter in an off-label manner for transvenous embolization of indirect carotid-cavernous fistula.

Evaluation of adverse drug reactions to off-label use of drugs in children from spontaneously reported cases at a tertiary care hospital

Background: Off-label use of drugs (OLUDs) is relatively common in pediatric and this may be associated with adverse drug reactions (ADRs). The studies about the safety of drugs used in children cannot be applied to safety of drugs during OLUDs as drug is used in way that is different from that described in regulatory body. Hence, it is worthwhile to evaluate the off-label status of the suspected drugs causing ADRs. Aims and Objectives: The aim of the study was to analyze the pattern of ADRs occurring during OLUDs in pediatric patients from the spontaneously reported ADRs cases at the pharmacovigilance unit of a tertiary care hospital. Materials and Methods: Single center, retrospective, observational study was conducted in the department of pharmacology. ADRs spontaneously reported from January 2016 to December 2017, which occurred during OLUDs in children, where causality is certain, probable and possible. Results: A total of 46 ADRs occurred during OLUDs in 44 patients, these patients received 174 medicines among which 66 were off-labeled drugs. Off-label drugs mainly belonged to anti-infectives for systemic use (70.31%) and it is associated with 30 ADRs (68.18%). The most commonly affected organ system is skin and subcutaneous tissue (43.18%). Conclusion: OLUDs is associated with ADR, so caution should be taken while prescribing a drug in off-label manner in children.

Off-label Use of Recombinant Activated Factor VII for Cardiac Surgical Bleeding.

Recombinant activated factor VII has been widely used in an off-label manner for cardiac surgical bleeding. Recent reports have administered recombinant activated factor VII earlier in the course of bleeding and at lower doses than initially reported. This review will discuss the history, mechanism, current recommendations for use, and recent data on the use of recombinant activated factor VII in cardiac surgical bleeding.

Medical Malpractice Litigation Due to Off-Label Use of Bone Morphogenetic Protein.

Retrospective cohort study. To analyze the incidence and characteristics of malpractice lawsuits pertaining to the off-label use of Bone morphogenetic protein (BMP). BMP continues to be a popular alternative to the use of autologous bone graft during spinal fusion procedures. However, ~85% of BMP is used in an off-label manner, which may expose surgeons to claims of malpractice. Westlaw and VerdictSearch were queried for malpractice claims filed between 2000 and 2022 using the keywords "bone graft" and "spine." Case inclusion criteria were defined as a plaintiff's basis of litigation resting on a claim of medical malpractice due to off-label use of BMP. Additional collected data included the date of the case hearing, plaintiff's sex and age, defendants named in the lawsuit, verdict ruling, location of the filed claim, payment or settlement amount, sustained injuries, and additional allegations. Of 971 claims reviewed, 89 cases were due to off-label BMP use. The posterior approach was identified as the most common approach among the 89 cases. Of the 30 cases naming a surgeon defendant, 50% included allegations of insufficient informed consent. The most frequent adverse events were ectopic bone growth resulting in chronic pain or nerve damage. Zero cases involved heterotopic ossification, wound dehiscence, graft subsidence, hematoma, bladder retention, or retrograde ejaculation. A clear understanding that on-label BMP use is specific to single-level, anterior or anterolateral approaches between L2-S1 with vendor-specific cages is crucial for mitigating malpractice disputes. Though off-label use of BMP may incite litigation, the findings suggest court rulings are favorable for defendants as zero cases, resulting in plaintiff verdicts. Nevertheless, surgeons should balance the potential benefits of off-label use of BMP with the increased risk of litigation, and it may be advisable to disclose the use of BMP, whether on-label or off-label, in the informed consent.

Doxycycline for the treatment of breast cancer-related lymphedema.

Purpose: Secondary lymphedema is a common complication of cancer treatment for which no effective drug treatments yet exist. Level I clinical data suggests that doxycycline is effective for treating filariasis-induced lymphedema, in which it decreases tissue edema and skin abnormalities; however, this treatment has not been tested for cancer-related lymphedema. Over the past year, we used doxycycline in an off-label manner in patients with breast cancer-related secondary lymphedema. The purpose of this report was to retrospectively analyze the efficacy of this treatment. Methods: Patients who presented to our lymphedema clinic between January 2021 and January 2022 were evaluated, and barring allergies or contraindications to doxycycline treatment, were counseled on the off-label use of this treatment. Patients who wished to proceed were treated with doxycycline (200mg given orally once daily) for 6weeks. After IRB approval of this study, lymphedema outcomes were retrospectively reviewed. Results: Seventeen patients with a mean follow-up of 17.0 ± 13.2weeks were identified in our retrospective review. Although doxycycline treatment had no significant effect on relative limb volume change or L-Dex scores, we found a significant improvement in patient-reported quality of life. Analysis of patient responses to the Lymphedema Life Impact Scale showed a significant improvement in the total impairment score due to improvements in the physical and psychological well-being subscales (p = 0.03, p = 0.03, p = 0.04, respectively). Conclusion: This small, retrospective study did not show significant improvements in limb volume or L-Dex scores in patients with breast cancer-related lymphedema treated with doxycycline. However, our patients reported improvements in quality-of-life measures using a validated lymphedema patient-reported outcome instrument. Our results suggest that doxycycline may be of use in patients with breast cancer-related lymphedema; however, larger and more rigorous studies are needed.

Treatment of Non-Infectious Corneal Injury: Review of Diagnostic Agents, Therapeutic Medications, and Future Targets.

Corneal injuries can occur secondary to traumatic, chemical, inflammatory, metabolic, autoimmune, and iatrogenic causes. Ocular infection may frequently occur concurrent to corneal injury; however, antimicrobial agents are excluded from this present review. While practitioners may primarily rely on clinical examination techniques to assess these injuries, several pharmacological agents, such as fluorescein, lissamine green, and rose bengal, can be used to formulate a diagnosis and develop effective treatment strategies. Practitioners may choose from several analgesic medications to help with patient comfort without risking further injury or delaying ocular healing. Atropine, cyclopentolate, scopolamine, and homatropine are among the most frequently used medications for this purpose. Additional topical analgesic agents may be used judiciously to augment patient comfort to facilitate diagnosis. Steroidal anti-inflammatory agents are frequently used as part of the therapeutic regimen. A variety of commonly used agents, including prednisolone acetate, loteprednol, difluprednate, dexamethasone, fluorometholone, and methylprednisolone are discussed. While these medications are effective for controlling ocular inflammation, side effects, such as elevated intraocular pressure and cataract formation, must be monitored by clinicians. Non-steroidal medications, such as ketorolac, bromfenac, nepafenac, and diclofenac, are additionally used for their efficacy in controlling ocular inflammation without incurring side effects seen with steroids. However, these agents have their own respective side effects, warranting close monitoring by clinicians. Additionally, ophthalmologists routinely employ several agents in an off-label manner for supplementary control of inflammation and treatment of corneal injuries. Patients with corneal injuries not infrequently have significant ocular surface disease, either as a concurrent pathology or as an exacerbation of previously existing disease. Several agents used in the management of ocular surface disease have also been found to be useful as part of the therapeutic armamentarium for treatment of corneal injuries. For example, several antibiotics, such as doxycycline and macrolides, have been used for their anti-inflammatory effects on specific cytokines that are upregulated during acute injuries. There has been a recent wave of interest in amniotic membrane therapies (AMTs), including topical, cryopreserved and dehydrated variants. AMT is particularly effective in ocular injuries with violation of corneal surface integrity due to its ability to promote re-epithelialization of the corneal epithelium. Blood-based therapies, including autologous serum tears, plasma-enriched growth factor eyedrops and autologous blood drops, have additionally been explored in small case series for effectiveness in challenging and recalcitrant cases. Protection of the ocular surface is also a vital component in the treatment of corneal injuries. Temporary protective methods, such as bandage contact lenses and mechanical closure of the eyelids (tarsorrhaphy) can be particularly helpful in selective cases. Glue therapies, including biologic and non-biologic variants, can also be used in cases of severe injury and risk of corneal perforation. Finally, there are a variety of recently introduced and in-development agents that may be used as adjuvant therapies in challenging patient populations. Neurotrophic corneal disease may occur as a result of severe or chronic injury. In such cases, recombinant human nerve growth factor (cenegermin), topical insulin, and several other novel agents may be an alternate and effective option for clinicians to consider.

Off-label medication use in pediatrics and associated factors at public hospitals in east Gojjam zone, Ethiopia.

Objective:Due to a lack of appropriate pediatric preparations, health providers frequently use adult formulations in an off-label manner. This study aimed to assess pediatric off-label medication use patterns and associated factors in East Gojjam, Ethiopia.Methods:Institutional-based cross-sectional study was conducted from December 2020 to June 2021 at three randomly selected hospitals. Data were collected by using self-structured questionnaires and a data abstraction checklist from health care workers and prescriptions, respectively. The collected data were analyzed using SPSS version 25. Logistic regression analysis was used to assess the association between independent and dependent variables.Results:A total of 285 eligible health professionals from the pediatric unit and pharmacies, and 1,800 eligible prescriptions were involved in the study. The response rate of healthcare workers was 94.37%. Around 74.4% of professionals had good knowledge about off-label medication. Only 8% of participants had taken training on pediatric off-label medications. Of all prescriptions, 27.6% of them have contained at least one off-label medication. Phenobarbitone (16.1%) and phenytoin (12.7%) were the most frequently prescribed off-label medication. In all, 496 (27.6%) prescriptions contained off-label drugs in the form of overdose, cutting adult tablets into small portions, and formulating tablets/capsules into solution. Lack of information on off-label prescribing, shortage of pediatric drugs, and suitable dosage forms showed significant association with off-label prescribing with p-value < 0.001.Conclusion:Almost one-third of pediatric prescriptions contained off-label medication. Only a small number of healthcare workers had taken training on pediatric off-label medications. Lack of sufficient information on risks of off-label medication, shortage of pediatric medication, and suitable pediatric dosage forms were associated with the use of off-label medication compared to non-use. Further research should be done on the long-term effects associated with off-label prescribing in pediatrics to assess whether the potential risks are balanced with the therapeutical benefit.

Global Perspective of Paediatric Pharmacovigilance and its Importance: Where Have We Reached?

Pharmacovigilance is a tool proposed during the post-marketing process of the pharmaceutical product lifecycle to monitor drug safety in everyday life and to identify adverse drug reactions. The identification of adverse reactions, however, is a significant cause of concern and a challenge to pharmacovigilance structures. Regulators use three basic principles in determining the risk-benefit balance to decide whether to approve a drug or a biological product and to maintain it on the market: safety, quality and effectiveness. In particular, paediatric patients, especially new-borns and infants, are at risk of drug-related adverse reactions. Drugs are also prescribed in an unlicensed and/or off-label manner to new-borns, infants and teenagers, leading paediatric patients to a higher risk of experiencing adverse drug reactions (ADRs). ADRs in children &lt; 2 years of age are often reported and can often be alarming. The practise of paediatric pharmacovigilance needs to be strengthened by stimulating spontaneous paediatric reporting and successful post-marketing surveillance. The current study highlights the importance of paediatric pharmacovigilance and the role of different stakeholders like healthcare providers, regulators, and consumers in increasing the ADR reporting rate. Also, it discusses the pharmacovigilance tools and various initiatives that are taken by various regulatory authorities like the United States, the United Kingdom, Japan, and India.

Tablet Splitting in Elderly Patients with Dementia: The Case of Quetiapine.

Quetiapine is an atypical antipsychotic approved for treating schizophrenia, bipolar depression, and mania but is frequently used in an off-label manner to control the behavioral and psychological symptoms of dementia in elderly patients with dementia. Due to the need to personalize doses for elderly patients with dementia, quetiapine tablet manipulation is widespread in hospital settings, long-term care facilities, and patient homes. The aim of this study was to assess the impact of the different splitting techniques on quetiapine fumarate tablets by analysing the obtained sub-divided tablets and to discuss compliance with the European Pharmacopoeia limits on whole and split tablets. Quetiapine fumarate tablets of two dose strengths were taken at random (in a number able to assure a power of 0.8 during statistical comparison) and were split with a kitchen knife or tablet cutter. The weight and the drug content were determined for each half tablet. The obtained data were compared to the European Pharmacopoeia limits. The differences between the different splitting techniques were statistically tested. Data showed that split tablets, independently of the dose strength and the technique employed, were not compliant with the European Pharmacopoeia specifications for both entire and subdivided tablets in terms of weight and content uniformity. Thus, such a common practice could have potential effects on treatment efficacy and toxicity, especially when also considering the fragility of the elderly target population in which polypharmacotherapy is very common. These results indicate a compelling need for flexible quetiapine formulations that can assure more accurate dose personalization.

Impact of Early, Low-Dose Factor VIIa on Subsequent Transfusions and Length of Stay in Cardiac Surgery

Recombinant factor VII (rFVIIa) is used to treat cardiac surgical bleeding in an off-label manner. However, optimal dosing and timing of administration to provide efficacious yet safe outcomes remain unknown. Retrospective, observational study. Tertiary care academic center. Cardiac surgical patients (N = 214) who received low-dose rFVIIa for cardiac surgical bleeding. Patients were allocated into one of three groups based on timing of rFVIIa administration during the course of bleeding resuscitation based on the number of hemostatic products given before rFVIIa administration: group one = ≤one products (n = 82); group two = two-to-four products (n = 73); and group three= ≥five products (n = 59). Patients who received low-dose rFVIIa later in the course of bleeding resuscitation (group three) had longer intensive care unit stays (p = 0.014) and increased incidence of postoperative renal failure when compared with group one (p = 0.039). Total transfusions were lowest in patients who received rFVIIa early in the course of resuscitation (group one) (median, two [interquartile range (IQR), 1-4.75]) and highest in group three (median, 11 [IQR, 8-14]; p < 0.001). Subsequent blood product transfusions after rFVIIa administration were highest in group two (p = 0.003); however, the median for all three groups was two products. There were no differences in thrombosis, reexplorations, or mortality in any of the groups. This study identified no differences in adverse outcomes based on timing of administration of low-dose rFVIIa for cardiac surgical bleeding defined by stage of resuscitation, but the benefits of early administration remain unclear.

Evaluation of Psychotropic Drug Use in Adolescents Accessing a General Emergency Medical Department for Mental Disorders

Background: Given the paucity of data concerning the care of adolescents attending an emergency department (ED) for mental disorders, we performed an observational study with the aim to describe psychotropic drug use in an Italian ED. Methods: A retrospective chart review of adolescents (13–17 years) visited in the ED of the San Paolo University Hospital in Milan for mental disorders between January and June 2018 was conducted. Information concerning age, gender, type of disorder, psychotropic drug use in the ED and outcome of the visit were analyzed, using an anonymous patient code. Results: A total of 1298 adolescents, 13–17 years old, were visited in the ED, 56 (4%) of whom had a diagnosis of mental disorder (34 females and 22 males). The most common disorder was anxiety (21 patients), followed by predominant psychomotor disorder (13 patients). In all, 30 adolescents received a psychotropic drug. Benzodiazepines were the most commonly used drugs (73% of the subjects), and delorazepam was administered/prescribed to 17 adolescents, despite the fact that evidence on its safety, efficacy, and its off-label use in the pediatric population is lacking. Conclusions: One out of two adolescents attending the ED for an acute episode of mental disorder received a psychotropic drug prescription, mainly in an off-label manner. More evidence is needed to guide the pharmacological management of acute episodes of mental disorders.

Safety and Biopharmaceutical Challenges of Excipients in Off-Label Pediatric Formulations.

BackgroundOne of the major challenges in pediatric treatment is the lack of suitable drug preparations specifically designed and marketed for children. Most of the FDA approved drug formulations for adults have not been approved for use in pediatric patients. Shortage of suitable pediatric dosage information often leads health professionals to use adult formulations in an off-label manner. The aim of this work was to review the safety and biopharmaceutical challenges of commonly found excipients in off-label pediatric formulations as well as to show the current progress to alleviate pediatric toxicity related to excipients.MethodsResearch findings and medical case reports were searched from credible sources including Scopus, PubMed, OVID, Google Scholar, Embase, Cochrane Library, and Web of Science.ResultsAs several studies and clinical case reports have revealed, off-label adult formulations usage causes pediatric patients to become exposed to potentially harmful excipients, which are essential components of drug products. In addition to their toxicities, some of the excipients affect the biopharmaceutical property of different drugs. Immature organ and body composition, large body surface area and slower metabolism and elimination capabilities of pediatrics are the main causes of toxicities associated with different excipients. Recent studies have also shown that good progress is being made to develop safe and suitable excipients for pediatric use.ConclusionA risk and benefit assessment should be done before using off-label formulation as excipients cause mild to severe toxicities and biopharmaceutical problems to pediatric patients.

A review on the treatment and control of ectoparasite infestations in equids.

Ectoparasites infestations are a growing concern to horse owners and equine veterinarians alike. Ectoparasites cause significant health and welfare issues and can potentially can serve as vectors for a variety of pathogens. The prevalence of ectoparasites increases around the world, and especially in horses information on the successful prevention and treatment of ectoparasite infestations in scarce and in many instances anecdotal. This poses a challenge to the equine veterinarian and off-label use of drugs can lead to detrimental effects in horses. In this review we describe the current available evidence for the prevention and treatment of ectoparasite infestations in horses. Only a very limited number of products is approved for the use in horses and fortunately many of the other products that are used in an off-label manner appear to be safe in horses. Future research in this area should aim at providing PK/PD modelling data to assure appropriate and safe dose regimen to prevent and treat ectoparasite infestations in horses.

Cross-sectional study of drug utilisation in a Chinese neonatal unit.

ObjectiveThis study aimed to describe drug utilisation in a large Chinese neonatal unit and to compare the findings with those from other countries.MethodsData were collected from electronic medical records. Prescription drugs were defined as the number of unique medication names for each patient. Medicine doses were defined as the total number of doses of all medicines administered. Information was collected regarding drugs prescribed to inpatients between March 1 and April 1 2018 in the neonatal intensive care unit and the general neonatal ward of West China Second University Hospital.ResultsThe 319 neonates received 1276 prescription drugs and 11,410 medicine doses involving 81 drugs. Vitamin K1, hepatitis B vaccine, and cefoperazone-sulbactam were the three most frequently prescribed drugs. Antimicrobials were the most frequently used group of medicines, with cefoperazone-sulbactam and piperacillin-tazobactam the most frequently used in an off-label manner. Domperidone and simethicone were both widely used.ConclusionsThe most commonly prescribed antimicrobials differed greatly from those reported for other countries. The evidence base for the use of some medicines is poor, and is indicative of irrational prescribing.

Off-Label Use in Orthopaedic Surgery.

Surgeons frequently use orthopedic devices in an off-label manner. It is the responsibility of the surgeon to be familiar with the product and to use it based on scientific and clinical rationale. However, such practices are poorly publicized, and there remains paucity in the current literature surrounding the off-label use of orthopedic devices. Furthermore, the off-label use of devices is fraught with difficulty, including limitations in investigational studies and insurance reimbursement or coverage of use. Surgeons should be aware of the common off-label use in orthopedics. This review provides an overview of the off-label use in orthopedics and the obstacles associated with it; this review also offers clinical examples of its implementation.

Denosumab Therapy in the Management of Aneurysmal Bone Cysts: A Comprehensive Literature Review.

Aneurysmal bone cysts (ABCs) are uncommon lesions that involve the axial and appendicular bones. Although biologically benign, ABCs have the tendency to assume an aggressive behavior causing local destruction of the underlying bone and neighboring soft tissues. Morphologically, ABCs are composed of cyst-like cavities filled with blood and bounded by an array of diverse cells including fibroblasts, inflammatory infiltrates and osteoclast-like multinucleated giant cells. From a molecular perspective, the osteoclast-like multinucleated giant cells harbor high expression of receptor activator of nuclear factor kappa B (RANK) receptors, whereas the neoplastic stromal cells harbor high expression of RANK ligand (RANKL). The RANK-RANKL interaction has been implicated in the carcinogenesis of ABCs and giant cell tumor of bones (GCTBs). Currently, the optimal management of ABCs remains a hotly debated topic. There are a multitude of treatment modalities (that is, surgery, sclerotherapy, radiotherapy and selective arterial embolization), and each modality has its own benefits, morbidity and risk of complications. The local aggressiveness of ABC and its high rates of relapse following treatment has demanded the march towards discovering more innovative therapies. One of such therapies is denosumab, a monoclonal antibody targeted against the RANKL. Denosumab is already approved by the United States Food and Drug Administration (FDA) for the treatment of adults and skeletally mature adolescents with GCTB that is unamenable to surgery, or initial surgery is anticipated to result in significant morbidity. However, denosumab is not approved by the FDA for the management of ABCs. However, taking into consideration the morphological similarity between GCTBs and ABCs, some treating physicians have logically opted to use denosumab in an off-label manner to treat select ABCs. To the best of knowledge, no study has attempted to summarize the related literature on the use of denosumab in ABCs. Therefore, the primary aim of this study is to narratively review all the available literature about the efficacy and safety of the use of off-label denosumab in the management of patients with ABCs.

Characteristics Associated With Mortality in 372 Patients Receiving Low-Dose Recombinant Factor VIIa (rFVIIa) for Cardiac Surgical Bleeding

Activated recombinant factor VII (rFVIIa) has been used to treat cardiac surgical bleeding in an off-label manner. This observational report analyzes the outcomes with use of a low dose and early administration of rFVIIa for cardiac surgical bleeding. A retrospective, observational study. Single-center, tertiary care cardiothoracic surgical setting. A total of 6,862 patients underwent cardiac surgery from January 2012 to January 2018. Of those, 372 patients received rFVIIa perioperatively. An institutional policy directed low-dose, incremental aliquots of intravenous rFVIIa (0.5-1 mg). Characteristics and outcomes were compared among patients who survived (n = 328) and patients who died (n = 44). The median dose of rFVIIa was low at 13.29 μg/kg. Higher doses were given to patients who died (15.79 μg/kg v 12.99 μg/kg; p = 0.0133). Patients who died received more blood and component transfusions (median 9 products in those who died v 6 products in survivors; p = 0.0022), although the median transfusion requirement for all patients was 6 units per patient. The rate of reoperation was not different in the 2 groups. Mortality was associated with emergent/urgent surgical procedures (p = 0.0282), type of surgical procedure with aortic procedures being highest risk (p = 0.0014), cardiogenic shock (p = 0.0028), postoperative renal failure (p = 0.0035), postoperative cardiac arrest (p = 0.0006), and ischemic stroke (p = 0.0084). Mortality after life-threatening cardiac surgical bleeding treated with rFVIIa was more common in aortic procedures and emergent and urgent surgeries. Lower doses of rFVIIa than previously reported may achieve bleeding cessation because overall blood component transfusions were low in this cohort.