Sentinel lymph node biopsy: a rational approach for staging T2N0 oral cancer

OBJECTIVES/HYPOTHESIS: For oral cancer patients, the presence of neck nodal metastases is the most important disease prognosticator. However, a significant proportion of clinically N0 patients harbor occult microscopic nodal metastasis. Our objective was to determine the feasibility and accuracy of sentinel node biopsy (SNB) in the staging of T2N0 oral carcinoma patients. STUDY DESIGN: Prospective analysis. METHODS: Twenty patients with previously untreated N0 oral cavity squamous cell carcinoma were studied. Each patient had an SNB performed using preoperative technetium sulfur colloid lymphoscintigraphy, intraoperative gamma probe guidance, and intraoperative peritumoral injection of 1% isosulfan blue. All patients underwent neck dissection.The sentinel lymph nodes (SLNs) were sectioned in 2- to 3-mm intervals, formalin fixed, and sectioned at three levels. The non-SLNs were sectioned in a routine manner for histologic examination. RESULTS: SLNs were identified in all patients (100%) and accurately predicted the pathologic nodal status in 18 of 20 patients (90%). Tumor was found exclusively in the SLNs in six patients (30%). Two patients had positive SLNs at multiple neck levels. Two patients had a negative SLN and a positive non-SLN (false-negative findings). Occult nodal metastases were present in 60% of the cohort. CONCLUSIONS: SNB is a technically feasible and accurate procedure for staging the neck in oral carcinoma patients. However, SNB accuracy is lower for floor of the mouth lesions. The rate of occult nodal metastases identified in this cohort is higher than previously reported in the literature. These results suggest that SNB warrants further multi-institutional studies.     

A randomised, double-blind, parallel group study to compare subcutaneous interferon alpha-2a plus podophyllin with placebo plus podophyllin in the treatment of primary condylomata acuminata.

OBJECTIVES--The primary objective was to determine if six weeks treatment with subcutaneous interferon alpha-2a (IFN) and podophyllin 25% W/V administered twice per week, preceded by IFN alpha-2a three times weekly for one week showed a greater complete response rate in patients with primary condylomata acuminata when assessed at week 10 than treatment with podophyllin and placebo injections in the same schedule. The secondary objective was to compare recurrence rates in complete responders at six months in the two treatment groups. DESIGN--Randomised, double-blind parallel group study. SETTING--Multicentre study in six genitourinary clinics within the U.K. PATIENTS--One hundred and twenty-four patients with primary anogenital warts. MAIN OUTCOME MEASURES--Complete response rate at week 10, and recurrence rate at week 26 in complete responders. RESULTS--At week 10 analysis of the efficacy population showed complete response in 36% (15/42 patients) of IFN-treated group and 26% (11/43 patients) in the placebo group (no significant difference). Analysis of the safety population at week 26 showed persistence of the complete response in 57% (8/14 patients) of the IFN-treated group and 80% (12/15 patients) of the placebo group (no significant difference). Adverse effects were more common in IFN-treated patients, involved particularly application site reaction and malaise but were generally mild. CONCLUSIONS--At the dose and with the regime described treatment with IFN alpha-2a in combination with podophyllin is no more effective in the treatment of primary anogenital warts than podophyllin alone and is associated with more adverse events.     

The Rodent Tibia Fracture Model: A Critical Review and Comparison With the Complex Regional Pain Syndrome Literature

Distal limb fracture is the most common cause of complex regional pain syndrome (CRPS), thus the rodent tibia fracture model (TFM) was developed to study CRPS pathogenesis. This comprehensive review summarizes the published TFM research and compares these experimental results with the CRPS literature. The TFM generated spontaneous and evoked pain behaviors, inflammatory symptoms (edema, warmth), and trophic changes (skin thickening, osteoporosis) resembling symptoms in early CRPS. Neuropeptides, inflammatory cytokines, and nerve growth factor (NGF) have been linked to pain behaviors, inflammation, and trophic changes in the TFM model and proliferating keratinocytes were identified as the primary source of cutaneous cytokines and NGF. Tibia fracture also activated spinal glia and upregulated spinal neuropeptide, cytokine, and NGF expression, and in the brain it changed dendritic architecture. B cell-expressed immunoglobulin M antibodies also contributed to pain behavior, indicating a role for adaptive immunity. These results modeled many findings in early CRPS, but significant differences were also noted.

Incidence,risk factors,and mortality from pneumonia developing late after hematopoietic stem cell transplantation

The incidence, etiology, outcome, and risk factors for developing pneumonia late after hematopoietic stem cell transplantation (SCT) were investigated in 1359 patients transplanted in Seattle. A total of 341 patients (25% of the cohort) developed at least one pneumonic episode. No microbial or tissue diagnosis (ie clinical pneumonia) was established in 197 patients (58% of first pneumonia cases). Among the remaining 144 patients, established etiologies included 33 viral (10%), 31 bacterial (9%), 25 idiopathic pneumonia syndrome (IPS, 7%), 20 multiple organisms (6%), 19 fungal (6%), and 16 Pneumocystis carinii pneumonia (PCP) (5%). The overall cumulative incidence of first pneumonia at 4 years after discharge home was 31%. The cumulative incidences of pneumonia according to donor type at 1 and 4 years after discharge home were 13 and 18% (autologous/syngeneic), 22 and 34% (HLA-matched related), and 26 and 39% (mismatched related/unrelated), respectively. Multivariate analysis of factors associated with development of late pneumonia after allografting were increasing patient age (RR 0.5 for <20 years, 1.2 for >40 years, P=0.009), donor HLA-mismatch (RR 1.6 for unrelated/mismatched related, P=0.01), and chronic graft-versus-host disease (GVHD; RR 1.5, P=0.007). Our data suggest that extension of PCP prophylaxis may be beneficial in high-risk autograft recipients. Further study of long-term anti-infective prophylaxis based on patient risk factors after SCT appear warranted.     

Chronic Neuron- and Age-Selective Down-Regulation of TNF Receptor Expression in Triple-Transgenic Alzheimer Disease Mice Leads to Significant Modulation of Amyloid- and Tau-Related Pathologies

Neuroinflammation, through production of proinflammatory molecules and activated glial cells, is implicated in Alzheimer''s disease (AD) pathogenesis. One such proinflammatory mediator is tumor necrosis factor α (TNF-α), a multifunctional cytokine produced in excess and associated with amyloid β–driven inflammation and cognitive decline. Long-term global inhibition of TNF receptor type I (TNF-RI) and TNF-RII signaling without cell or stage specificity in triple-transgenic AD mice exacerbates hallmark amyloid and neurofibrillary tangle pathology. These observations revealed that long-term pan anti–TNF-α inhibition accelerates disease, cautions against long-term use of anti–TNF-α therapeutics for AD, and urges more selective regulation of TNF signaling. We used adeno-associated virus vector–delivered siRNAs to selectively knock down neuronal TNF-R signaling. We demonstrate divergent roles for neuronal TNF-RI and TNF-RII where loss of opposing TNF-RII leads to TNF-RI–mediated exacerbation of amyloid β and Tau pathology in aged triple-transgenic AD mice. Dampening of TNF-RII or TNF-RI+RII leads to a stage-independent increase in Iba-1–positive microglial staining, implying that neuronal TNF-RII may act nonautonomously on the microglial cell population. These results reveal that TNF-R signaling is complex, and it is unlikely that all cells and both receptors will respond positively to broad anti–TNF-α treatments at various stages of disease. In aggregate, these data further support the development of cell-, stage-, and/or receptor-specific anti–TNF-α therapeutics for AD.CME Accreditation Statement: This activity (“ASIP 2013 AJP CME Program in Pathogenesis”) has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Society for Clinical Pathology (ASCP) and the American Society for Investigative Pathology (ASIP). ASCP is accredited by the ACCME to provide continuing medical education for physicians.The ASCP designates this journal-based CME activity (“ASIP 2013 AJP CME Program in Pathogenesis”) for a maximum of 48 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.CME Disclosures: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose.Alzheimer''s disease (AD) pathophysiology is described by chronic and progressive neurodegeneration involving the genesis of extracellular amyloid β (Aβ) plaques, intraneuronal filamentous inclusions called neurofibrillary tangles (NFTs), synapse loss, inflammation, and neuronal cell death, ultimately leading to severe memory loss and cognitive impairment. Neuroinflammation is a highly enigmatic process contributing to disease pathogenesis in AD, where elevated levels of proinflammatory molecules have been associated with Aβ-induced inflammation, neurotoxicity, and cognitive decline.^1–4 In AD-afflicted brains, microglia intimately co-localize with Aβ plaques and serve as major sources of proinflammatory mediators, including cytokines and chemokines.⁵ The pleiotropic proinflammatory cytokine tumor necrosis factor α (TNF-α) is produced in excess concurrently with increased Aβ plaque deposition, an observation that suggests that TNF-α levels reflect the pathologic progression of AD.^6–8 Moreover, three TNF-α promoter polymorphisms have been associated with late-onset AD, and two of the three polymorphisms are linked to increased TNF-α production, further connecting this cytokine to the exacerbated chronic inflammatory disease status in AD.⁹ We and others have demonstrated that TNF-α expression is enhanced in AD mouse models where TNF-α is prepathologically up-regulated in 6-month-old triple-transgenic AD (3xTg-AD) mice,^10,11 which corresponds with an enhancement of F4/80-positive microglial cell numbers.¹² In addition, when neuron-specific TNF-α is chronically overexpressed in 3xTg-AD mice using adeno-associated virus (AAV) vectors, there is increased severity of inflammation, intracellular Aβ, and Tau pathology that leads to neuronal cell death portending that excessive and unopposed TNF-α signaling enhances AD-associated pathology and is detrimental to neuronal viability.¹³TNF-α signals through two cognate transmembrane receptors, TNF receptor type I (TNF-RI) and TNF-RII, which are differentially expressed and regulated. TNF-RI is expressed constitutively on most cell types, whereas TNF-RII expression is induced and is restricted to specific cell populations, including hematopoietic cells, microglia, neurons, and endothelial cells.^14,15 TNF-R engagement to its ligand mediates distinct cellular responses through the activation of several downstream signal transduction cascades involving the NFκB and JNK pathways. In the context of AD, several reports demonstrate differential roles and activation of TNF-RI and TNF-RII such that genetic deletion of TNF-RI, but not TNF-RII, results in reduced plaque deposition in the APP23 mouse model.¹⁶ Moreover, in human brain tissue, TNF-RI protein levels are increased, whereas TNF-RII levels are reduced in patients with AD relative to nondemented control brain.¹⁷ Taken together, these data imply an overall negative role for excessive TNF signaling on AD pathophysiology but, perhaps more importantly, illustrate the complexity of this signaling pathway.Despite a large body of literature indicating detrimental roles for TNF-α, neuroprotective effects have also been reported. Early experiments revealed that TNF-α is protective in cultured neurons during glucose deprivation–induced injury and excitotoxicity by preserving Ca²⁺ homeostasis.¹⁸ Barger et al¹⁹ further demonstrated in dissociated neuronal cultures that pretreatment with TNF-α and Aβ peptide spares cells from Aβ-induced neuronal death, iron toxicity, and intracellular Ca²⁺ accumulation via an NF-κB–dependent mechanism. Moreover, neurons are vulnerable to ischemic injury and oxidative stress in TNF-R null mice, indicating that TNF-α is protective.²⁰ Mice lacking TNF-R expression exhibited reduced manganese superoxide dismutase activity and lacked a robust microglial response to kainic acid.²⁰ Similarly, cultured neurons pretreated with TNF-α resulted in a significant increase in manganese superoxide dismutase activity and a reduction in superoxide accumulation.²¹ These data add to the complexity of the TNF signaling pathway and suggest that strategies to modulate TNF-α in the disease setting may require selective tuning and specificity to ensure that protective signaling outcomes are not compromised.Nonetheless, given the compelling data supporting the pathologic role of TNF-α in AD, the potential of using anti–TNF-α therapeutics has become a viable strategy for subverting the disease course. Preclinical data by McAlpine et al²² demonstrate that transiently inhibiting soluble TNF signaling in the 3xTg-AD mouse model using a dominant-negative inhibitor in conjunction with enhanced systemic inflammation prevents AD-associated amyloid pathology. Tobinick et al²³ reported in a short-term, prospective, open-label pilot study that semiweekly perispinal administration of etanercept, a receptor decoy biological agent antagonizing the actions of TNF-α, in 15 patients with mild to severe AD led to significant and rapid cognitive improvements compared with untreated control patients as assessed by three separate tests measuring cognitive function.Although previous studies provide evidence suggesting that TNF-α inhibition in the short-term may lead to improved pathologic and functional outcomes, they lack data addressing the long-term consequences of blocking TNF-α in a global manner, where cell, stage, and receptor specificity were not examined. To this end, we recently demonstrated that long-term global inhibition of TNF-R signaling in 3xTg-AD mice where TNF-RI and TNF-RII were ablated in all cell types results in a robust increase in hallmark amyloid and NFT pathology. Furthermore, in the absence of TNF signaling, microglia seem nonresponsive to the developing amyloid pathology, which correlates with an impairment of microglial-mediated Aβ₄₂ phagocytosis activity in vitro.²⁴ These data suggest that caution should be taken with the use of broad long-term anti-TNF inhibitors and that a more selective strategy should be investigated.To add to our understanding of TNF signaling biology and the consequences of selectively modulating this pathway, we investigated the cell- and stage-specific role of TNF-R signaling in AD by using recombinant AAV (rAAV) vector–delivered siRNA technology to selectively knock down neuronal TNF-R signaling at stages preceding progressive pathology or in the presence of extant disease using the 3xTg-AD mouse model. We demonstrate that neuronal TNF-RI and TNF-RII exert differential actions where intact TNF-RII signaling results in suppressed Aβ plaque deposition and paired helical filament (PHF) formation in the context of progressive and established disease pathogenesis. In addition, we report a substantial reduction in Iba-1–positive microglia when rAAV2-delivered siTNF-RII or siTNF-RI+RII viral vectors are administered at 2 and 12 months of age. Taken together, these data demonstrate that selectively suppressing neuronal TNF-RI and/or TNF-RII leads to distinct and significant changes in AD pathogenesis, which is most likely a consequence of the divergent signaling pathways associated with these receptors. The present findings support further development and rigorous study of highly selective strategies designed to inhibit specific TNF-α–mediated signals and potentially disrupt the onset and/or progression of this debilitating disease.     

An international effort examining nursing student attitudes toward older people

Variations in culture and heritage can greatly impact an individual's beliefs, practices, and attitudes and may influence healthcare. The purpose of this research was to better understand the attitudes of student nurses toward older adults in the United States and Costa Rica. An exploratory quantitative research design was utilized for this study. Data were collected using the Kogan Old Persons scale from American and Costa Rican pre-licensure nursing students. Results revealed that total scores were very similar between students on the Kogan positive scale and the Kogan negative scale. Half of the individual items revealed significant differences between students of different cultures. Overall, nursing students reported positive attitudes toward older people with individual differences found between nationality and individual items. Understanding cultural variances and commonalities on student nurse attitudes toward older adults is important to the delivery of culturally diverse nursing education and culturally congruent care.