Report from the first European Dermato-Epidemiology Network forum

Summary

The first European Dermato-Epidemiology Network (EDEN) forum was held on 30–31 March 2017 in Madrid, Spain. Dermatoepidemiology describes the study of causes, prevention, health services research and evaluation of interventions of skin diseases. EDEN aims to promote high-quality research, share expertise and facilitate collaboration. These aims were achieved during the EDEN forum by including a preconference course on skin cancer epidemiology; having excellent world-leading guest speakers on causality, quality of care, pharmacoepidemiology and missing data analysis; and including delegates who presented and discussed innovative research findings. The meeting brought together delegates from 11 different countries. We welcome everyone with an interest in clinical research and epidemiology related to skin disease to attend next year's meeting in March 2018 in Berlin.

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Utility of the immature platelet fraction in pediatric immune thrombocytopenia: Differentiating from bone marrow failure and predicting bleeding risk

Abstract

Background

Differentiating childhood immune thrombocytopenia (ITP) from other cause of thrombocytopenia remains a diagnosis of exclusion. Additionally factors that predict bleeding risk for those patients with ITP are currently not well understood. Previous small studies have suggested that immature platelet fraction (IPF) may differentiate ITP from other causes of thrombocytopenia and in combination with other factors may predict bleeding risk.

Methods

We performed a retrospective chart review of thrombocytopenic patients with an IPF measured between November 1, 2013 and July 1, 2015. Patients were between 2 months and 21 years of age with a platelet count <50 × 10⁹/l. Each patient chart was reviewed for final diagnosis and bleeding symptoms. A bleeding severity score was retrospectively assigned.

Results

Two hundred seventy two patients met inclusion criteria, 97 with ITP, 11 with bone marrow failure (BMF), 126 with malignancy, and 38 with other causes of thrombocytopenia. An IPF > 5.2% differentiated ITP from BMF with 93% sensitivity and 91% specificity. Absolute immature platelet number (AIPN) was significantly lower in ITP patients with severe to life-threatening hemorrhage than those without, despite similar platelet counts. On multivariate analysis, an IPF < 10.4% was confirmed as an independent predictor of bleeding risk at platelet counts <10 × 10⁹/l in patients with ITP.

Conclusions

IPF measurement alone has utility in both the diagnosis of ITP and identifying patients at increased risk of hemorrhage. Further study is required to understand the pathophysiological differences of ITP patients with lower IPF/AIPN.

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Early blood stream infection following allogeneic hematopoietic stem cell transplantation is a risk factor for acute grade III–IV GVHD in children and adolescents

Abstract

Background

Graft-versus-host disease (GVHD) remains a major cause of mortality and morbidity in allogeneic hematopoietic stem cell transplantation (HSCT). In adults, early blood stream infection (BSI) and acute GVHD (AGVHD) have been reported to be related. The impact of BSI on risk for AGVHD, however, has not been assessed in pediatric patients.

Procedure

We conducted a retrospective analysis to test the hypothesis that early BSI (before day +30) predisposes allogeneic pediatric transplant patients to severe AGVHD. We analyzed 293 allogeneic HSCT performed at Children's Healthcare of Atlanta between 2005 and 2014 that met eligibility criteria.

Results

The cumulative incidence of acute grade III–IV GVHD at 100 days after HSCT was 17.1%. In multivariate analysis, risk for acute grade III–IV GVHD was associated with HLA-mismatched donor (hazard ratio [HR] = 4.870, P < 0.001), and BSI between day 0 and +30 prior to AGVHD (HR = 3.010, P = 0.001).

Conclusions

These results indicate that early BSI appears to be a risk factor for acute grade III–IV GVHD. Further research is needed to determine if the link is causal.

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Blinatumomab activity in a patient with Down syndrome B-precursor acute lymphoblastic leukemia

Abstract

Persistent minimal residual disease (MRD) after consolidation may indicate chemotherapy insensitivity in B-precursor acute lymphoblastic leukemia (BP-ALL). Given the strong association of MRD and outcome in non-Down syndrome (non-DS) BP-ALL, it is likely that MRD levels are also of prognostic significance in DS BP-ALL. We report here the successful use of blinatumomab, a bispecific T-cell engager antibody construct, in a patient with DS BP-ALL and persistent MRD at the end of consolidation. Blinatumomab has been shown to have excellent results in patients with relapsed/refractory BP-ALL. This patient had no significant toxicity and achieved MRD negativity after only one cycle of blinatumomab.

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Reply to comment on: Insurance coverage decisions for pediatric proton therapy

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Comprehensive genetic analysis of donor cell derived leukemia with KMT2A rearrangement

Abstract

Background

Donor cell leukemia (DCL) occurs after allogeneic hematopoietic stem cell transplantation. Several mechanisms, including occult leukemic/preleukemic subclones in the donor graft and germline predisposition to leukemia, are proposed to be associated with DCL's molecular pathogenesis. We report a comprehensive genetic analysis of a patient with KMT2A-rearranged DCL after allogeneic bone marrow transplantation for refractory cytopenia of childhood.

Procedure

We performed a whole-exome sequencing of the recipient's peripheral blood before transplant and the donor's peripheral blood and the recipient's bone marrow at the time of DCL diagnosis. RNA sequencing was also performed to detect fusion genes in DCL blasts.

Results

There were no germline mutations that were associated with a predisposition to leukemia in the recipient and donor. Furthermore, there were no detectable somatic alterations except KMT2A-MLLT10 and other related gene fusions in DCL. KMT2A-MLLT10 was not detectable in the donor's bone marrow.

Conclusion

We propose a novel pattern of the molecular pathogenesis of DCL solely involving a genetic mutation acquired after transplant with no identifiable genetic factor related to the donor and recipient.

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Extreme hepatic resections for the treatment of advanced hepatoblastoma: Are planned close margins an acceptable approach?

Abstract

Background

Orthotopic liver transplantation (OLT) is considered the standard for children with hepatoblastoma (HB) in whom complete surgical resection is not possible. However, OLT is not always available or feasible.

Objective

To describe the outcome of children with HB who were initially deemed unresectable and underwent complex hepatectomy with planned close margins, and ultimately avoided OLT.

Methods

Demographic data, surgical and pathologic details, and survival information were collected from children treated for HB between January 2010 to December 2015.

Results

Among six children (median age 12 months (3–41 months)), PRETEXT classification was III (n = 2), III/IV (n = 1), and IV (n = 3). Patients received a median of six cycles (range 4–7) of platinum-based induction chemotherapy; five received doxorubicin. Experienced pediatric surgeons performed extended right and left hepatectomy in five and one patients, respectively, with assistance of an experienced liver transplant surgeon (n = 4). Microscopic margins were positive (n = 2) and negative but close (n = 4; 2–5 mm). Two patients required vascular reconstruction of the vena cava. At median follow-up of 3.3 years (1.7–4.6 years), there was no evidence of local recurrence. One patient had recurrence of pulmonary disease 3 months after surgery.

Conclusions

Patients with advanced HB treated with complex surgical resections with positive or close negative margins had good outcomes without OLT. We suggest that planned positive or close microscopic margins in highly selected HB patients may spare the morbidity of OLT and offer an alternative for those ineligible for OLT. Our experience illustrates the importance of a multidisciplinary team specialized in the management of liver tumors.

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Analysis of infantile fibrosarcoma reveals extensive T-cell responses within tumors: Implications for immunotherapy

Abstract

Background

Infantile fibrosarcoma (IFS) is a rare pediatric malignancy with relatively good prognosis, but the risk of progression or recurrence after therapy exists. To understand the immune microenvironment of IFS and determine if immunotherapy is a potential treatment, we analyzed T-cell responses in IFS tumors.

Procedure

IFS tumors were analyzed by immunohistochemistry and multicolor flow cytometry to characterize immune cell infiltration and function. Tumor infiltrating lymphocytes (TILs) were expanded in vitro and evaluated for recognition of autologous tumor cells. Real-time PCR was applied to evaluate tumor expression of chemokines/cytokines and tumor antigens.

Results

Significant infiltration of both CD4⁺ and CD8⁺ T cells was found in seven of 10 IFS but rarely found in age- and sex-matched rhabdomyosarcoma tumors. The TILs from recurrent IFS tumors expressed high levels of costimulatory molecules such as CD28, 4-1BB, and OX40, but little or no coinhibitory molecules such as PD-1 and CTLA4, Tim3, Lag3, and CD39. Upon activation, large portions of TILs produced IFN-γ and TNF-α. Eighteen out of 40 T cell lines generated from surgically removed tumors could recognize autologous tumor cells. Moreover, we found that IFS tumors expressed high levels of T-cell chemokines such as CXCL10 and CXCL16, and also classic tumor antigens such as CTAG2, GAGE, and NY-ESO-1, whose expression could be further enhanced by treatment with epigenetic modulator decitabine.

Conclusions

IFS tumors are highly immunogenic and expansion of TILs followed by adoptive cell transfer could be a potential immunotherapy for IFS patients undergoing tumor recurrence.

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Initial testing (stage 1) of M6620 (formerly VX-970), a novel ATR inhibitor, alone and combined with cisplatin and melphalan, by the Pediatric Preclinical Testing Program

Abstract

Background

M6620 is a novel inhibitor of the DNA damage repair enzyme ATR, and has potentiated the activity of cisplatin and irinotecan in non-small cell lung cancer and colon cancer xenografts, respectively.

Procedures

M6620 was tested in vitro at concentrations ranging from 1.0 nM to 10.0 μM and at 75 nM in combination with cisplatin or melphalan. M6620 was tested against 24 solid tumor xenografts alone and in combination with cisplatin. Cisplatin was administered intraperitoneally on days 1 and 8 at a dose of 5 mg/kg. M6620 was administered intravenously on days 2 and 9 at 20 mg/m² approximately 16 hr after cisplatin.

Results

The median relative IC₅₀ (rIC₅₀) value for M6620 was 0.19 μM (range 0.03–1.38 μM). M6620 reduced the mean IC₅₀ of cisplatin and melphalan by 1.48- and 1.95-fold, respectively. M6620 as a single agent in vivo induced significant differences in event-free survival (EFS) distribution in 5 of 24 (21%) solid tumor xenografts, but induced no objective responses. Cisplatin as a single agent induced significant differences in EFS distribution compared to control in 18 of 24 (75%) solid tumor xenografts. Three objective responses to cisplatin were observed. The M6620 and cisplatin combination induced significant differences in EFS distribution compared to control in 21 of 24 (88%), with four objective responses.

Conclusions

M6620 showed modest potentiation of cisplatin and melphalan activity for some cell lines. M6620 showed little single-agent activity and the addition of M6620 to cisplatin significantly prolonged time to event for a minority of tested xenografts across several histologies.

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Markers in blood and saliva for prediction of orthodontically induced inflammatory root resorption: a retrospective case controlled-study

Hormonal and enzymatic factors may render certain individuals more susceptible to orthodontically induced inflammatory root resorption (OIIRR). The objectives of this study are (1) to identify biochemical key ...

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'Follow the Money' in Extreme Skin Cancer Care

Specialists report a rise in every ultraviolet-related type of skin cancer, but controversy over excessive treatment persists.
Medscape Medical News

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Impact of resveratrol on bone repair in rats exposed to cigarette smoke inhalation: histomorphometric and bone-related gene expression analysis

Publication date: Available online 15 September 2017
Source:International Journal of Oral and Maxillofacial Surgery
Author(s): F.C. Franck, B.B. Benatti, D.C. Andia, F.R. Cirano, R.C. Casarin, M.G. Corrêa, F.V. Ribeiro
This study investigated the effect of resveratrol on bone healing and its influence on the gene expression of bone-related markers in rats exposed to cigarette smoke. Two calvarial defects were created in each of 60 rats, which were assigned equally (n=20) to three groups: (1) resveratrol (10mg/kg)+smoke exposure (SMK+RESV); (2) placebo+smoke exposure (SMK+PLA); or (3) placebo+no smoke exposure (NS+PLA). Substances were administered daily for 30days following surgery. Smoke inhalation was started 7days before surgery and continued for 30days after surgery. One defect was processed for histomorphometric analysis and the other was used for mRNA quantification of bone-related gene expression by qPCR. The remaining defect was smaller in the SMK+RESV (2.27±0.61mm, P=0.0003) and NS+PLA (2.17±0.74mm, P=0.0005) groups than in the SMK+PLA group (3.12±0.47mm). Higher levels of Runx2 were observed in the NS+PLA group than in the smoke exposure groups (vs. SMK+PLA, P=0002; vs. SMK+RESV, P=0.052); levels of Lrp-5 were also higher in the no smoke exposure group (vs. SMK+RESV, P=0.009; vs. SMK+PLA, P=0.003). Resveratrol therapy decreased RANKL/OPG expression when compared to placebo (SMK+RESV vs. SMK+PLA, P=0.017). Dkk1 levels were decreased in the SMK+RESV group when compared to the SMK+PLA (P=0.006) and NS+PLA groups (P=0.005). In conclusion, resveratrol optimizes the repair of critical-sized bone defects, up-regulating the gene expression of important bone remodelling markers in rats exposed to cigarette smoke inhalation.



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Periodontal screening and referral behaviour of general dental practitioners in Flanders

Abstract

Objectives

The objective of this study was to investigate the screening and referral behaviour of Flemish dentists concerning periodontitis and more specific, the use of the Dutch Periodontal Screening Index (DPSI).

Materials and methods

An online questionnaire was electronically distributed through the different professional dental societies. It consisted of two parts: the first aimed at describing the profile of the dentist. The second part inquired the screening method, when this was applied, periodontal risk factors and referral behaviour.

Results

One thousand fifty dentists attended to the questionnaire. One hundred fifty-nine questionnaires were excluded since they did not match the target audience. Sixty-four percent of Flemish dentists used DPSI as a periodontal screening method, 28% screened based on probing pocket depth, 4% used solely radiographs and 4% had no screening method at all. The usage of DPSI is influenced by the year of graduation: the longer the dentists were graduated, the less they used DPSI. No influence of sex, education centre and location was found. Referral behaviour is influenced by different patient- and dentist-related factors.

Conclusions

Regarding the screening behaviour, there seems a consensus among Flemish dentists that a periodontal probe should be used. For referral, there is no consensus about if and when to refer to a specialist.

Clinical relevance

It is encouraging that 92% of the Flemish general dental practitioners use a probe when screening for periodontitis. However, DPSI is mainly used by younger dentists. An effort should be made to encourage all dentists to use this, so that in every patient, periodontitis can be detected timely, securing the best treatment outcome.

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Frequency, location, and association with dental pathology of mucous retention cysts in the maxillary sinus. A radiographic study using cone beam computed tomography (CBCT)

Abstract

Objectives

The purpose of the present study was to evaluate the frequency, locations, and dimensions of mucous retention cysts of the maxillary sinus and analyze potential associated dental pathology.

Materials and methods

A total of 156 cone beam computed tomography (CBCT) scans were included in the analysis, resulting in an evaluation of 310 maxillary sinuses. The presence of mucous retention cysts (MRC) manifesting as dome-shaped radiopacities in the sinus was diagnosed. Their locations were recorded, and dimensions (mm) were measured in coronal and sagittal/axial slices. The patients were grouped into (a) patients/sinuses with MRCs (test), and (b) patients/sinuses with healthy or any other changes (control) for further comparison and evaluation.

Results

There were 40 sinuses (12.9%) with a presence of a total of 56 MRCs. The mean age of involved patients was 29.0 years. The analysis showed that gender, age, sinus side, status of dentition, endodontic status, and periodontal status did not have a significant influence on the presence of MRCs when compared between test and control groups. Age and endodontic status exhibited a significant association with cyst location.

Conclusions

Most of the sinuses analyzed (79.5%) did not present any MRC, and only 28.6% of the cysts diagnosed were found on the floor of the maxillary sinus. The mean dimension of the MRCs measured 6.28 ± 2.93 mm. No influencing factors on the presence or absence of MRCs were found in the present study.

Clinical relevance

Most MRCs were not located on the floor of maxillary sinus. Future studies should assess their impact on surgical interventions in the sinus.

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