PTH‐enhanced structural allograft healing is associated with decreased angiopoietin‐2–mediated arteriogenesis,mast cell accumulation,and fibrosis

Recombinant parathyroid hormone (rPTH) therapy has been evaluated for skeletal repair in animal studies and clinical trials based on its known anabolic effects, but its effects on angiogenesis and fibrosis remain poorly understood. We examined the effects of rPTH therapy on blood vessel formation and osseous integration in a murine femoral allograft model, which caused a significant increase in small vessel numbers, and decreased large vessel formation (p < 0.05). Histology showed that rPTH also reduced fibrosis around the allografts to similar levels observed in live autografts, and decreased mast cells at the graft‐host junction. Similar effects on vasculogenesis and fibrosis were observed in femoral allografts from Col1caPTHR transgenic mice. Gene expression profiling revealed rPTH‐induced angiopoietin‐1 (8‐fold), while decreasing angiopoietin‐2 (70‐fold) at day 7 of allograft healing. Finally, we show anti‐angiopoietin‐2 peptibody (L1‐10) treatment mimics rPTH effects on angiogenesis and fibrosis. Collectively, these findings show that intermittent rPTH treatment enhances structural allograft healing by two processes: (1) anabolic effects on new bone formation via small vessel angiogenesis, and (2) inhibition of angiopoietin‐2–mediated arteriogenesis. The latter effect may function as a vascular sieve to limit mast cell access to the site of tissue repair, which decreases fibrosis around and between the fractured ends of bone. Thus, rPTH therapy may be generalizable to all forms of tissue repair that suffer from limited biointegration and excessive fibrosis. © 2013 American Society for Bone and Mineral Research.     

Plasma Cytokine Analysis in Patients with Advanced Extremity Melanoma Undergoing Isolated Limb Infusion

Background

Preprocedure clinical and pathologic factors have failed to consistently differentiate complete response (CR) from progressive disease (PD) in patients after isolated limb infusion (ILI) with melphalan for unresectable in-transit extremity melanoma.

Methods

Multiplex immunobead assay technology (Milliplex MAP Human Cytokine/Chemokine Magnetic Bead Panel, Millipore Corp., Billerica, MA; and Magpix analytical test instrument, Luminex Corp., Austin, TX) was performed on pre-ILI plasma to determine concentrations of selected cytokines (MIP-1α, IL-1Rα, IP-10, IL-1β, IL-1α, MCP-1, IL-6, IL-17, EGF, IL-12p40, VEGF, GM-CSF, and MIP-1β) on a subset of patients (n = 180) who experienced CR (n = 23) or PD (n = 24) after ILI. Plasma from normal donors (n = 12) was also evaluated.

Results

Of 180 ILIs performed, 28 % (95 % confidence interval 22–35, n = 50) experienced a CR, 14 % (n = 25) experienced a partial response, 11 % (n = 21) had stable disease, 34 % (n = 61) had PD, and 13 % (n = 23) were not evaluable for response. Tumor characteristics and pharmacokinetics appeared similar between CR (n = 23) and PD (n = 24) patients who underwent cytokine analysis. Although there were no differences in cytokine levels between CR and PD patients, there were differences between the melanoma patients and controls. MIP-1α, IL-1Rα, IL-1β, IL-1α, IL-17, EGF, IL-12p40, VEGF, GM-CSF, and MIP-1β were significantly higher in normal controls compared to melanoma patients, while IP-10 was lower (p < 0.001) in controls compared to melanoma patients.

Conclusions

Patients with unresectable in-transit melanoma appear to have markedly decreased levels of immune activating cytokines compared to normal healthy controls. This further supports a potential role for immune-targeted therapies and immune monitoring in patients with regionally advanced melanoma.     

Highly cited publications in pediatric neurosurgery: part 2

Purpose

Citation counting can be used to evaluate the impact an article has made on its discipline. This study characterizes the most cited articles related to clinical pediatric neurosurgery as of July 2013.

Methods

A list of search terms was computed using Thomson Reuters Web of Science® (WOS) to capture the 100 most cited articles in the overall literature and the top 50 articles from 2002 to 2012 related to clinical pediatric neurosurgery from non-dedicated pediatric neurosurgical journals. The following information was recorded for each article: number of authors, country of origin, citation count adjusted for number of years in print, topic, and level of evidence.

Results

The 100 most cited articles appeared in 44 journals. Publication dates ranged from 1986 to 2008; two were class 1 evidence, nine class 2, 26 class 3, and 52 class 4. Citations ranged from 90 to 321 (mean?=?131); average time-adjusted citation count was 10. The 50 most cited articles from 2002 to 2012 appeared in 31 journals; four were class 2 evidence, 15 class 3, and 21 class 4. Citations ranged from 68 to 245 (mean?=?103); average time-adjusted citation count was 13.

Conclusion

Overall, papers from non-pediatric neurosurgical journals had higher citation counts and improved level of evidence grades compared to articles from pediatric neurosurgical periodicals. An original paper related to clinical pediatric neurosurgery in a non-pediatric neurosurgical journal having a total citation count of 100–150 or more and an average citation count of 10–15 per year or more can be considered a high-impact publication.     

Bridging Hepatocellular Carcinoma to Transplant: Transarterial Chemoembolization Response,Tumor Biology,and Recurrence after Transplantation in a 12-Year Transplant Cohort

PurposeTo evaluate tumor response to transarterial chemoembolization as well as biologic characteristics of the tumor as predictors of recurrence after transplantation in patients with hepatocellular carcinoma (HCC) who were bridged or down-staged to liver transplantation.Materials and MethodsAn institutional review board-approved, Health Insurance Portability and Accountability Act-compliant, single-institution retrospective analysis was performed on all patients with HCC who were treated with the use of conventional transarterial chemoembolization or transarterial chemoembolization with drug-eluting embolics (DEE) over a 12-year period and who subsequently underwent liver transplantation (n = 142). Treatment response was based on modified Response Evaluation Criteria in Solid Tumors (mRECIST) imaging criteria and then correlated with tumor characteristics and recurrence. Of the 142 patients followed after transplantation, 127 had imaging after transarterial chemoembolization but before transplantation. Imaging response and post-transplantation recurrence were correlated with patient demographics, liver function, and tumor morphology. HCC recurred in 9 patients (mean time from transplantation, 526 days). Recurrence was analyzed with the use of univariate and multivariate statistics. Kaplan-Meier recurrence-free survival curves were calculated based on immediate imaging response before transplantation with the use of the log-rank test.ResultsBefore transplantation, 57% of patients (72/127) demonstrated complete response (CR) and 24% (31/127) showed partial response (PR). Complete pathologic necrosis occurred in 54% (39/72) of CR patients and 20% (6/31) of PR patients. Poor treatment response, defined as stable disease (SD) or progressive disease (PD), occurred in 18% of patients (24/127) before transplantation and was present in 67% of cases of recurrence (6/9; P < .001). Post-transplantation recurrence was present in 1.4% of patients (1/71) with CR and in 6.5% of patients (2/31) with PR. In patients with SD after transarterial chemoembolization, HCC recurred in 18.8% of transplant patients (3/16) and in 43% of patients (3/7) with PD. Larger pretreatment tumor size (P = .05), higher Child-Pugh score (P = .002), higher tumor grade at explantation (P = .04), and lymphovascular invasion at explantation (P = .008) also were associated with increased incidence of post-transplantation recurrence.ConclusionsPoor tumor response to transarterial chemoembolization before transplantation identifies patients at increased risk for post-transplantation recurrence.     

The Pregnancy,Arsenic, and Immune Response (PAIR) Study in rural northern Bangladesh

Background

Arsenic exposure and micronutrient deficiencies may alter immune reactivity to influenza vaccination in pregnant women, transplacental transfer of maternal antibodies to the foetus, and maternal and infant acute morbidity.

Objectives

The Pregnancy, Arsenic, and Immune Response (PAIR) Study was designed to assess whether arsenic exposure and micronutrient deficiencies alter maternal and newborn immunity and acute morbidity following maternal seasonal influenza vaccination during pregnancy.

Population

The PAIR Study recruited pregnant women across a large rural study area in Gaibandha District, northern Bangladesh, 2018–2019.

Design

Prospective, longitudinal pregnancy and birth cohort.

Methods

We conducted home visits to enrol pregnant women in the late first or early second trimester (11–17 weeks of gestational age). Women received a quadrivalent seasonal inactivated influenza vaccine at enrolment. Follow-up included up to 13 visits between enrolment and 3 months postpartum. Arsenic was measured in drinking water and maternal urine. Micronutrient deficiencies were assessed using plasma biomarkers. Vaccine-specific antibody titres were measured in maternal and infant serum. Weekly telephone surveillance ascertained acute morbidity symptoms in women and infants.

Preliminary Results

We enrolled 784 pregnant women between October 2018 and March 2019. Of 784 women who enrolled, 736 (93.9%) delivered live births and 551 (70.3%) completed follow-up visits to 3 months postpartum. Arsenic was detected (≥0.02 μg/L) in 99.7% of water specimens collected from participants at enrolment. The medians (interquartile ranges) of water and urinary arsenic at enrolment were 5.1 (0.5, 25.1) μg/L and 33.1 (19.6, 56.5) μg/L, respectively. Water and urinary arsenic were strongly correlated (Spearman's ⍴ = 0.72) among women with water arsenic ≥ median but weakly correlated (⍴ = 0.17) among women with water arsenic < median.

Conclusions

The PAIR Study is well positioned to examine the effects of low-moderate arsenic exposure and micronutrient deficiencies on immune outcomes in women and infants. Registration : NCT03930017.     

Percutaneous pars interarticularis screw fixation: a technical note

Purpose

A conventional midline posterior approach is used for most of the described surgical techniques. We describe a technique of percutaneous fixation of the pars interarticularis, augmented where necessary by grafting the defect, which minimises muscle injury.

Method

A 4.5 mm partially threaded dynamic compression screw is placed over a wire inserted percutaneously across the pars interarticularis defect. Compression is achieved across the pars interarticularis defect on placement of the screw. The screw is locked in a compressed state.

Results

The patient is mobilised the same day with a corset for comfort and discharged the following day. Aerobic fitness is maintained for 3 months; then, focused rehabilitation performed until a CT scan confirms healing at 5–6 months, at which stage full (sports) activity is resumed.

Conclusions

The minimal tissue injury and small incision used allow for the minimising of complications and for a rapid recovery and discharge from hospital. With adolescents, we have the opportunity to treat symptomatic pars interarticularis defects with minimal disruption to their academic and physical development.