Three Linked Vasculopathic Processes Characterize Kawasaki Disease: A Light and Transmission Electron Microscopic Study

Kawasaki disease is recognized as the most common cause of acquired heart disease in children in the developed world. Clinical, epidemiologic, and pathologic evidence supports an infectious agent, likely entering through the lung. Pathologic studies proposing an acute coronary arteritis followed by healing fail to account for the complex vasculopathy and clinical course.Specimens from 32 autopsies, 8 cardiac transplants, and an excised coronary aneurysm were studied by light (n=41) and transmission electron microscopy (n=7). Three characteristic vasculopathic processes were identified in coronary (CA) and non-coronary arteries: acute self-limited necrotizing arteritis (NA), subacute/chronic (SA/C) vasculitis, and luminal myofibroblastic proliferation (LMP). NA is a synchronous neutrophilic process of the endothelium, beginning and ending within the first two weeks of fever onset, and progressively destroying the wall into the adventitia causing saccular aneurysms, which can thrombose or rupture. SA/C vasculitis is an asynchronous process that can commence within the first two weeks onward, starting in the adventitia/perivascular tissue and variably inflaming/damaging the wall during progression to the lumen. Besides fusiform and saccular aneurysms that can thrombose, SA/C vasculitis likely causes the transition of medial and adventitial smooth muscle cells (SMC) into classic myofibroblasts, which combined with their matrix products and inflammation create progressive stenosing luminal lesions (SA/C-LMP). Remote LMP apparently results from circulating factors. Veins, pulmonary arteries, and aorta can develop subclinical SA/C vasculitis and SA/C-LMP, but not NA. The earliest death (day 10) had both CA SA/C vasculitis and SA/C-LMP, and an "eosinophilic-type" myocarditis.NA is the only self-limiting process of the three, is responsible for the earliest morbidity/mortality, and is consistent with acute viral infection. SA/C vasculitis can begin as early as NA, but can occur/persist for months to years; LMP causes progressive arterial stenosis and thrombosis and is composed of unique SMC-derived pathologic myofibroblasts

French dermatologists' opinions and practices with regard to adjuvant therapy in stage III melanoma

International audienceBackgroundIn 2018, the European Medicines Agency authorized adjuvant therapy for patients with resected stage III melanoma.ObjectivesThe objective of the present study (performed in France) was to assess dermatologists' and oncologists' opinions and prescribing habits in this context.MethodsFrom 28 May to 8 June 2021, we performed an online survey of members of the French Groupe de Cancérologie Cutanée (GCC) skin cancer interest group.ResultsThirty-eight practitioners replied to the survey. For BRAF-mutant melanoma, 58% of the practitioners favoured immunotherapy (IT). If they themselves were to suffer from melanoma with a BRAFV600 mutation, 65% would choose IT for stage IIIB disease, and 72% would choose IT for stage IIID disease. For stage IIIA melanoma with a positive sentinel lymphatic node (SLN) biopsy <1 mm, 32% of the practitioners stated that they would not offer adjuvant therapy. Sixty-three percent of the practitioners disagreed with restricting adjuvant therapy to patients aged 80 and over. Although 84% of the practitioners were aware of the cost of adjuvant therapy, 81% did not take account of this factor in their treatment decisions. In patients with a positive SLN biopsy, 90% of the practitioners stated that they would not recommend complete lymph node dissection. Eighty percent of the surveyed practitioners discussed the potential impact of treatments on fertility, respectively with their male and female patients. Of these practitioners, 63%–72% (depending on the situation) stated that they would recommend fertility preservation procedures.ConclusionsThis work points out some debated issues among French dermatologists and oncologists regarding adjuvant therapy in stage III melanoma. Our present results might prompt more comprehensive studies of these particular points

Interlaboratory development and validation of a HRM method applied to the detection of JAK2 exon 12 mutations in polycythemia vera patients.

BACKGROUND: Myeloproliferative disorders are characterized by clonal expansion of normal mature blood cells. Acquired mutations giving rise to constitutive activation of the JAK2 tyrosine kinase has been shown to be present in the majority of patients. Since the demonstration that the V617F mutation in the exon 14 of the JAK2 gene is present in about 90% of patients with Polycythemia Vera (PV), the detection of this mutation has become a key tool for the diagnosis of these patients. More recently, additional mutations in the exon 12 of the JAK2 gene have been described in 5 to 10% of the patients with erythrocytosis. According to the updated WHO criteria the presence of these mutations should be looked for in PV patients with no JAK2 V617F mutation. Reliable and accurate methods dedicated to the detection of these highly variable mutations are therefore necessary. METHODS/FINDINGS: For these reasons we have defined the conditions of a High Resolution DNA Melting curve analysis (HRM) method able to detect JAK2 exon 12 mutations. After having validated that the method was able to detect mutated patients, we have verified that it gave reproducible results in repeated experiments, on DNA extracted from either total blood or purified granulocytes. This HRM assay was further validated using 8 samples bearing different mutant sequences in 4 different laboratories, on 3 different instruments. CONCLUSION: The assay we have developed is thus a valid method, adapted to routine detection of JAK2 exon 12 mutations with highly reproducible results

Baseline Splenic Volume as a Prognostic Biomarker of FOLFIRI Efficacy and a Surrogate Marker of MDSC Accumulation in Metastatic Colorectal Carcinoma

International audienceBackground: Predictive biomarkers of response to chemotherapy plus antiangiogenic for metastatic colorectal cancer (mCRC) are lacking. The objective of this study was to test the prognostic role of splenomegaly on baseline CT scan. Methods: This study is a sub-study of PRODIGE-9 study, which included 488 mCRC patients treated by 5-fluorouracil, leucovorin and irinotecan (FOLFIRI) and bevacizumab in first line. The association between splenic volume, and PFS and OS was evaluated by univariate and multivariable Cox analyses. The relation between circulating monocytic Myeloid derived suppressor cells (mMDSC) and splenomegaly was also determined. Results: Baseline splenic volume > 180 mL was associated with poor PFS (median PFS = 9.2 versus 11.1 months; log-rank p = 0.0125), but was not statistically associated with OS (median OS = 22.6 versus 28.5 months; log-rank p = 0.1643). The increase in splenic volume at 3 months had no impact on PFS (HR 0.928; log-rank p = 0.56) or on OS (HR 0.843; log-rank p = 0.21). Baseline splenic volume was positively correlated with the level of baseline circulating mMDSC (r = 0.48, p-value = 0.031). Conclusion: Baseline splenomegaly is a prognostic biomarker in patients with mCRC treated with FOLFIRI and bevacizumab, and a surrogate marker of MDSC accumulation

Efficacy and safety of rituximab-based treatments in angioedema with acquired C1 inhibitor deficiency.

International audienceAngioedema (AE) due to acquired C1-inhibitor (C1-INH) deficiency (AAE–C1-INH) is related to excessive consumption of C1-INH or to anti–C1-INH antibodies, and is frequently associated with lymphoproliferative syndromes or monoclonal gammopathies. Standard of care for prophylactic treatment in this condition is not established. Rituximab may be effective to prevent attacks, especially if the lymphoid hemopathy is controlled, but data are scarce.ObjectiveTo evaluate efficacy of rituximab in AAE–C1-INH.MethodsA retrospective multicenter study was carried out in France, including patients with AAE–C1-INH treated with rituximab between April 2005 and July 2019.ResultsFifty-five patients with AAE–C1-INH were included in the study, and 23 of them had an anti–C1-INH antibody. A lymphoid malignancy was identified in 39 patients, and a monoclonal gammopathy in 9. There was no associated condition in 7 cases. Thirty patients received rituximab alone or in association with chemotherapy (n = 25). Among 51 patients with available follow-up, 34 patients were in clinical remission and 17 patients had active AE after a median follow-up of 3.9 years (interquartile range, 1.5-7.7). Three patients died. The presence of anti–C1-INH antibodies was associated with a lower probability of AE remission (hazard ratio, 0.29 [95% CI, 0.12-0.67]; P = .004). Relapse was less frequent in patients with lymphoma (risk ratio, 0.27 [95% CI, 0.09-0.80]; P = .019) and in patients treated with rituximab and chemotherapy (risk ratio, 0.31 [95% CI, 0.12-0.79]; P = .014).ConclusionsRituximab is an efficient and well-tolerated therapeutic option in AE, especially in lymphoid malignancies and in the absence of detectable anti–C1-INH antibodies

HRM analysis.

<p>HRM profiles of 7 patients known to harbor JAK2 exon 12 mutations compared to 7 controls. Analysis of total blood DNA on the ABI7500 fast instrument.</p