Denosumab Shows Promise in Treatment of Hypercalcemia of Malignancy

Denosumab, a RANKL inhibitor, shows efficacy in patients with hypercalcemia of malignancy not responding to bisphosphonates.

Aldo Battiste, MD

January 6, 2015 — Denosumab may effectively treat patients with hypercalcemia of malignancy (HCM) in patients not responding to bisphosphonates, according to the interim findings of a proof-of-concept study.

Mimi I. Hu, of the Department of Endocrine Neoplasia and Hormonal Disorders at the University of Texas MD Anderson Cancer Center in Houston and her team reported their findings in the August 29, 2013 advanced access publication of the Journal of the National Cancer Institute.

Denosumab is a fully human monoclonal antibody that binds RANKL (RANK ligand), a protein active in bone resorption in patients with HCM. Intravenous bisphosphonates are considered the standard of care, but are associated with incomplete responses and high rates of relapse.

This open-label study evaluated 15 patients with hematologic and solid tumor-related grade III hypercalcemia. Each patient had albumin-corrected serum calcium (CSC) levels greater than 12.5mg/dL. Each was treated with subcutaneous denosumab 120 mg on days 1, 8, 15, and 29, then once every 4 weeks.

Twelve patients (80%; 95% exact confidence interval [CI] = 52% to 96%) showed CSC of less than or equal to 11.5mg/dL (grade I), all responding by day 10, with a median response of 8 days (95% CI= 5 days not estimable).

The median duration of response was 26 days (95% CI = 7 days not estimable) and 10 patients had a complete response by day 10 (67%; 95% CI= 38% to 88%). A total of 11 patients (73%) showed a complete response over the course of the study, and the median time to a complete response was 9 days (95% CI = 5 to 35 days). By day 10, a median decrease in CSC from baseline of 2.7mg/dL was found.

Of the patients, 14 (93%) experienced adverse effects, 12 (80%) of which were considered serious. Seven of the patients (47%) withdrew from the study or because of adverse effects and there were 8 (53%) fatal adverse effects; none of the fatal adverse effects or withdrawals were considered denosumab related.

According to the researchers, the response was maintained for a median of 26 days, which was a “clinically meaningful outcome given that patients entered this study with hypercalcemia of grade 3 and greater with a median of only 18 days after receiving the last dose of intravenous bisphosphonate.”

“These interim results suggest that denosumab may offer a new treatment option for HCM in this challenging population,” the authors conclude.

This study was sponsored by the manufacturer of denosumab. Amgen. Amgen employees participated in the research.

J Natl Cancer Inst; August 29, 2013

 

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CT Indicated for Initial Evaluation of Acute Lower GI Bleeding

CT angiography shows feasibility and accuracy in depicting presence, location and cause of acute lower gastrointestinal hemorrhage.

Aldo Battiste, MD

January 7, 2015 – According to a feasibility study, computed tomographic angiography (CTA) accurately determines the presence and location of active or recent hemorrhage and should be considered as the initial diagnostic study in the evaluation of acute lower gastrointestinal hemorrhage.

Milagros Marti, MD, with the Department of Radiology, La Paz University Hospital in Madrid, Spain, and colleagues reported their findings in the January 2012 issue of Radiology.

 Acute lower gastrointestinal hemorrhage is a common presentation in the emergency department. It is responsible for 1%-2% of hospital emergencies, 15% of which are massive and life-threatening. Common diagnostic procedures for gastrointestinal hemorrhage include scintigraphy, colonoscopy, and conventional arteriography; however, these modalities often fail to localize the source of bleeding or are time-consuming, invasive and expensive. CTA is currently used as an alternative procedure for selecting patients for conventional angiography or surgery when upper endoscopy and colonoscopy are negative.

This study prospectively assessed the use of CT as the initial diagnostic examination for patients presenting to the emergency department with acute lower gastrointestinal hemorrhage. Only patients who were referred for diagnostic colonoscopy were included in this study. Colonoscopic and, when available, conventional angiographic, surgical and pathologic findings were used as the standard of reference for comparison with those of CTA. Specific radiographic findings utilized in this study included: (a) presence and location of actively extravasated blood found only on contrast-enhanced phases and (b) presence of hyperattenuating (>60 HU) intraluminal material on the unenhanced scans, indicating recent bleeding. The researchers also assessed for a likely cause of bleeding, when possible.

Evidence of active bleeding was shown on CTA in 14 (30%) of 47patients. Recent hemorrhage was suggested in an additional 6 (13%) patients. The sensitivity, specificity, positive predictive value and negative predictive value of CTA in predicting active or recent bleeding were 100% (19 of 19), 96% (27 of 28), 95% (19 of 20), and 100% (27 of 27), respectively. The findings of CTA and the standard of reference were concordant for determining definite or likely cause of bleeding in 44 of 47 patients (93% accuracy). There was concordance between CTA and the standard of reference in predicting the location of the lesions in 19 (100%) of 19 patients.

According to the researchers, CTA is “helpful for directing therapy and…for selecting the most appropriate hemostatic intervention: endoscopic, angiographic or surgical” and that “precise anatomic localization of the bleeding site allows targeted endovascular embolization” resulting in improved success rates of endovascular therapeutic techniques. Conversely, a negative CTA obviates or reduces the necessity of subsequent arteriography or surgery and might warrant more conservative treatment with the possibility of repeat CTA in instances of recurrent bleeding. Using this rationale, the authors conclude that, rather than restricting CTA to instances where colonoscopy is initially unsuccessful, it should be adopted as the initial diagnostic examination for patients suspected as having acute lower gastrointestinal hemorrhage.

The authors disclose no potential conflicts of interest.

Radiology; January 2012

 

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Adult Psychiatric Outcomes of Bullying and Being Bullied

Bullies and victims show elevated rates of young adult psychiatric disorders

Aldo Battiste, MD

January 8, 2015 – A longitudinal study has shown that bullying and victimization are associated with psychiatric disorders that extend into adulthood and that those involved as both bullies and victims are at a highly increased risk of depression and suicidality.

William E. Copeland, PhD of the Department of Psychiatry and Behavioral Sciences, Center for Developmental Epidemiology, Duke University Medical Center, Durham, North Carolina and colleagues reported their findings in the April 2013 issue of JAMA Psychiatry.

Longitudinal studies on bullying and victims of bullying have suggested a causal relationship with psychiatric disorders but they have only followed affected children for a few years into adolescence.

In this prospective study, a population-based sample consisting of 3 cohorts, aged 9, 11, and 13 were studied. Participants were assessed through age 16 and were categorized as bullies, victims, bullies and victims (bully/victims) or neither. Adult outcomes were assessed at ages 19, 21 and 24 to 26 years of age. Status was considered positive if the participant met criteria for a psychiatric disorder through self-report interviews using the Young Adult Psychiatric Assessment (YAPA). Childhood psychiatric problems and family hardship were detected using the Childhood and Adolescent Psychiatry Assessment.

Victims showed a higher prevalence of agoraphobia (odds ratio [OR], 4.6 [95% CI, 1.7-12.5]; P<.01), generalized anxiety (OR, 2.7 [95% CI, 1.1-6.3]; P<.001, and panic disorder (OR, 3.1 [95% CI, 1.5-6.5]; P<.01). Bully/victims were at increased risk of young adult depression (OR, 4.8 [95% CI, 1.2-19.4]; P<.05, panic disorder (OR, 14.5 [95% CI, 5.7-36.6]; P<.001); agoraphobia (young women only; OR, 26.7 [95% CI, 4.2-52.5]; P<.001), and suicidality (young men only; OR, 18.5, [95% CI, 6.2-55.1]; P,.001). Bullies were at risk for antisocial personality disorder only (OR, 4.1 [95% CI, 1.1-15.8]; P<.04).

The study indicates that being a victim and a perpetrator of bullying is associated with a very high risk of depression and equally affects young men and women. Only male bully/victims reported suicidality more often, whereas female bully/victims reported agoraphobia more often in early adulthood, indicating different tendencies by the sexes of dealing with distress caused by being a bully/victim.

According to the authors, this raises the question: “How does being involved in bullying and/or victimization lead to emotional disorders and suicidality?” They point out that victimization has been found to “alter hypothalamic-pituitary-adrenal activity, and abnormal cortisol excretion is associated with both an increase in depression.” The same mechanism can also cause alteration of telomere length, which is a biomarker of stress. Shortened telomeres have been found in children with a history of various forms of violence. They also site evidence for gene-environmental interaction by “variation in the serotonin transporter gene of children exposed to bullying.” They suggest that these aspects of stress response should be targets for future research efforts.

The authors conclude that bullying is not just a “harmless rite of passage or an inevitable part of growing up.” Children affected by bullying are at increased risk of emotional disorders in adulthood. Bully/victims are at highest risk and most likely to engage in suicidal ideation. They suggest that health professionals and school personnel enact effective interventions that reduce victimization, indicating this will “reduce human suffering and long-term health care costs and provide a (healthier) environment for children to grow up in.”

The authors report no conflicts of interest.

Original article, JAMA Psychiatry, February 2013