Learning to improve safety: false-positive pathology report results in wrongful surgery

BACKGROUND: A patient experienced a wrongful surgical resection, specifically, a radical retropubic prostatectomy because of a false-positive pathology report. FINDINGS FROM THE ROOT CAUSE ANALYSIS (RCA): The RCA team identified three antecedent events that contributed to this medical error: (1) a second (concurring) pathologist did not provide a written opinion, (2) a single pathologist who reviewed and signed the final report, and (3) a pathologist who did not review the case and reconfirm the diagnosis immediately prior to the surgical resection. RECOMMENDATIONS: The RCA team recommended that the concurring pathologist write his or her diagnostic findings on the referral form, two pathologists review and sign the final typed report, and a pathologist rereview the slides on the business day prior to a surgical resection. Because the prostate specific antigen (PSA) value can be helpful in select cases of prostate cancer, the team recommended the PSA value be referenced when reviewing prostate specimens obtained through fine-needle biopsy. TRACKING COMPLIANCE: Because a wrongful surgical resection is a rare event, emphasis was placed on measuring compliance with distinct elements that were part of the revised procedure. During a 12-month span, practitioners demonstrated sustained compliance to the enhanced process for analyzing and reporting results.     

Benign paratesticular Schwannoma

Scrotal masses are common findings on genitourinary exam. The majority of these masses are benign and can be identified via history and physical exam alone. Question as to the origin of these masses merits additional evaluation that typically consists of an imaging study (e.g., ultrasound) and possibly serum tumor markers (e.g., HCG and AFP). In the end, surgical exploration may be necessary. Herein, the authors describe a rare case of benign paratesticular Schwannoma and discuss the clinical presentation and treatment of scrotal masses.     

A brain-behaviour initiative for South Africa: the time is right

Background: Many have advocated for science and health research in developing world settings. However, there has been less focus on the value of basic and clinical neuroscience research in this context. The current paper focuses on the relevance of a brain-behaviour research initiative in South Africa. Methods: Workshops sponsored by the University of Cape Town Research Office and by the National Research Foundation have recently focused on the state of South African basic and clinical neuroscience, and on how to strengthen research in these areas. The context of the discussion included national science and health priorities, as well as local research opportunities. Results: Neuropsychiatric disorders account for the second largest proportion of the burden of disease in South Africa, but receive relatively little research funding. There is a critical need for research, and there are unique research opportunities, in areas such as trauma and resilience, impulsive behaviour (eg violence, sexual risk taking, and substance abuse), and neuroAIDS. Basic, clinical, and systems research can all make important contributions. Conclusion: There is a need to apprise policy-makers in developing world countries such as South Africa of the need for increased expenditure on basic and clinical neuroscience research. Local and international collaboration may be useful in increasing research capacity in South Africa, and ultimately in improving mental health services.     

The Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) trial: outcomes in patients receiving monotherapy

In the main Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) report, we investigated outcomes in 15 245 high-risk hypertensive subjects treated with valsartan- or amlodipine-based regimens. In this report, we analyzed outcomes in 7080 patients (46.4%) who, at the end of the initial drug adjustment period (6 months), remained on monotherapy. Baseline characteristics were similar in the valsartan (N=3263) and amlodipine (N=3817) groups. Time on monotherapy was 3.2 years (78% of treatment exposure time). The average in-trial blood pressure was similar in both groups. Event rates in the monotherapy group were 16% to 39% lower than in the main VALUE trial. In the first analysis, we censored patients when they discontinued monotherapy ("censored"); in the second, we counted events regardless of subsequent therapy (intention-to-treat principle). We also assessed the impact of duration of monotherapy on outcomes. No difference was found in primary composite cardiac end points, strokes, myocardial infarctions, and all-cause deaths with both analyses. Heart failure in the valsartan group was lower both in the censored and intention-to-treat analyses (hazard ratios: 0.63, P=0.004 and 0.78, P=0.045, respectively). Longer duration of monotherapy amplified between-group differences in heart failure. New-onset diabetes was lower in the valsartan group with both analyses (odds ratios: 0.78, P=0.012 and 0.82, P=0.034). Thus, despite lower absolute event rates in monotherapy patients, the relative risks of heart failure and new-onset diabetes favored valsartan. Moreover, these findings support the feasibility of comparative prospective trials in lower-risk hypertensive patients.     

Postprostatectomy cancer-free survival of African Americans is similar to non-African Americans after adjustment for baseline cancer severity

African American men with localized prostate cancer are less likely than White men to receive a radical prostatectomy. This disparity may exist because African American men have prostate cancers that are more biologically aggressive. We investigated if similar stage cancers of African American men and White men show differences in cancer control after radical prostatectomy. Men with localized prostate cancer who underwent radical prostatectomy during a 6-yr period were stratified by race, and time to prostate-specific antigen recurrence was measured. We used Chi-square and t-tests to compare baseline clinical and pathological factors based on race. Cox proportional hazards model was used to determine effects of race on cancer control while controlling for baseline measures of cancer severity. There were 1,228 cases evaluated. At baseline, African American men were treated at a significantly younger age than White men (P = 0.0027) but showed no significant difference in prostate-specific antigen PSA, Gleason score, pathology stage, maximum tumor dimension, and surgical margin status. Multivariable Cox proportional hazards analysis controlling for cancer severity at prostatectomy revealed that cancer-free survival was not worse among African Americans compared to other subjects (P = 0.16). The responsiveness of prostate cancers among African American men to radical prostatectomy was similar to White men of similar stage and grade. Early detection in African American men may facilitate diagnosis of cancer amenable to prostatectomy. Studies are needed to evaluate the possible interaction of prostate cancer stage and grade shift in African American men and the disease free survival in this population.     

ProNGF,a cytokine induced after myocardial infarction in humans,targets pericytes to promote microvascular damage and activation

Treatment of acute cardiac ischemia focuses on reestablishment of blood flow in coronary arteries. However, impaired microvascular perfusion damages peri-infarct tissue, despite arterial patency. Identification of cytokines that induce microvascular dysfunction would provide new targets to limit microvascular damage. Pro–nerve growth factor (NGF), the precursor of NGF, is a well characterized cytokine in the brain induced by injury. ProNGF activates p75 neurotrophin receptor (p75^NTR) and sortilin receptors to mediate proapoptotic responses. We describe induction of proNGF by cardiomyocytes, and p75^NTR in human arterioles after fatal myocardial infarction, but not with unrelated pathologies. After mouse cardiac ischemia-reperfusion (I-R) injury, rapid up-regulation of proNGF by cardiomyocytes and p75^NTR by microvascular pericytes is observed. To identify proNGF actions, we generated a mouse expressing a mutant Ngf allele with impaired processing of proNGF to mature NGF. The proNGF-expressing mouse exhibits cardiac microvascular endothelial activation, a decrease in pericyte process length, and increased vascular permeability, leading to lethal cardiomyopathy in adulthood. Deletion of p75^NTR in proNGF-expressing mice rescues the phenotype, confirming the importance of p75^NTR-expressing pericytes in the development of microvascular injury. Furthermore, deficiency in p75^NTR limits infarct size after I-R. These studies identify novel, nonneuronal actions for proNGF and suggest that proNGF represents a new target to limit microvascular dysfunction.The primary therapeutic goal after acute myocardial infarction (MI) is to limit the duration of ischemia and to establish reperfusion using angioplasty or thrombolysis. However, even with improved arterial flow, a significant proportion of patients experience microvascular damage that leads to decreased microvascular perfusion and chronically impaired heart function (Eltzschig and Collard, 2004; Bekkers et al., 2010). At this time, the proinflammatory cytokines induced by ischemia that mediate microvascular dysfunction or apoptosis after cardiac ischemia remain largely unknown.We considered whether nerve growth factor (NGF), and specifically its uncleaved precursor proNGF, could act as a potential proapoptotic and proinflammatory cytokine in the ischemic heart. NGF is initially synthesized as proNGF, which is normally cleaved intracellularly to release mature NGF (Heymach and Shooter, 1995). Mature NGF binds to the TrkA receptor tyrosine kinase to mediate survival and differentiative effects in neurons (Reichardt, 2006). Under pathological conditions, proNGF is secreted and acts as a distinct ligand to promote neuronal apoptosis by binding to the p75 neurotrophin receptor (p75^NTR), a member of the tumor necrosis factor receptor family, and the transmembrane receptor sortilin (Lee et al., 2001; Nykjaer et al., 2004). This receptor complex activates stress and apoptotic signaling molecules, such as JNK (c-Jun N-terminal kinase) and caspase-3 (Nykjaer et al., 2005; Jansen et al., 2007; Volosin et al., 2008; Hempstead, 2009).ProNGF and p75^NTR are present at low to undetectable levels in normal, uninjured adult tissues (Fanburg-Smith and Miettinen, 2001; Harrington et al., 2004; Lommatzsch et al., 2005; Hempstead, 2009). However, they are rapidly induced after acute neuronal injury and mediate cell death or degeneration after seizures or axotomy (Harrington et al., 2004; Volosin et al., 2008). In addition, proNGF is up-regulated in neurodegenerative diseases and aging (Pedraza et al., 2005; Jansen et al., 2007). However, ngf mRNA is expressed in many organs, and secreted mature NGF promotes sympathetic innervation during development and regulates sympathetic tone in the adult (Donovan et al., 1995; Glebova and Ginty, 2005; Habecker et al., 2008). In the adult heart, mature NGF is secreted tonically by cardiac myocytes to modulate synaptic transmission by sympathetic neurons (Luther and Birren, 2006). Additionally, within hours of cardiac ischemia-reperfusion (I-R) injury in rodents, ngf mRNA is induced (Hiltunen et al., 2001), and immunoreactivity to the mature NGF domain increases in human hearts after acute MI (Meloni et al., 2010). These studies, however, do not distinguish whether mature NGF or proNGF is induced after cardiac ischemia. P75^NTR expression is also induced in the vasculature after acute injury to the aorta (Donovan et al., 1995), and p75^NTR activation promotes vascular smooth muscle and endothelial cell death in vitro (Wang et al., 2000; Kim et al., 2004). Genetic deletion of p75^NTR in mice (p75^−/−) results in reduced apoptosis of vascular smooth muscle cells after vascular injury, suggesting that locally produced neurotrophins regulate this response (Kraemer, 2002).The induction of ngf mRNA by cardiomyocytes and of p75^NTR by vascular cells after injury suggests a potential paracrine role for NGF or proNGF in modulating vascular integrity. Microvascular endothelial survival depends on reciprocal interactions with neighboring pericytes during development, and pericytes maintain microvascular structure and function in the adult animal (Gaengel et al., 2009). Disruption of endothelial cell–pericyte communication during development leads to vascular hemorrhage and embryonic death, as is readily observed in platelet-derived growth factor B (Pdgfb)– or platelet-derived growth factor receptor β (Pdgfrb)–deficient mice, where pericyte recruitment to specific vascular beds is impaired (Lindahl et al., 1997; Hellström et al., 1999; Bjarnegård et al., 2004). In adult mice, TGF-β and bone morphogenetic proteins play critical roles in maintaining pericyte survival and promoting microvascular integrity (El-Bizri et al., 2008; Walshe et al., 2009). These observations suggest that disruption of endothelial cell–pericyte interactions during cardiac microvascular maturation may lead to cardiac dysfunction later in life.In this study, we examined the expression of proNGF and its receptors, p75^NTR and sortilin-related VPS10 domain containing receptor 2 (SorCS2), a sortilin family member (Willnow et al., 2008), in the infarcted myocardium after cardiac ischemia in human autopsy material and in an established mouse model of I-R injury. We observed the induction of proNGF by cardiac myocytes and arterioles, and of p75^NTR and SorCS2 by mural cells of arterioles in the peri-infarct region of individuals who died after a recent MI. Comparable induction patterns were observed in mouse tissue after I-R injury. To investigate the consequences of proNGF expression on the cardiac vasculature, we generated and analyzed a knockin mouse that expresses one allele of cleavage-resistant proNGF (proNgf-hemagglutinin [HA]/⁺). We found that proNGF overexpression targets p75^NTR- and SorCS2-immunoreactive pericytes in the perinatal period, leading to a reduction of pericyte processes, microvascular endothelial activation, and increased vascular permeability in young adulthood, culminating in a dilated cardiomyopathy and premature lethality. This phenotype is rescued in mice that are deficient in p75^NTR. Furthermore, deficiency in p75^NTR limits the infarct size expansion after myocardial I-R injury, when compared with infarct size in wild-type mice. These observations identify proNGF and p75^NTR as potential therapeutic targets to limit microvascular dysfunction in the ischemic heart.