Strømme syndrome was first described by Strømme et al. (1993) in siblings presenting with "apple peel" type intestinal atresia, ocular anomalies and microcephaly. The etiology remains unknown to date. We describe the long-term clinical follow-up data for the original pair of siblings as well as two previously unreported siblings with a severe phenotype overlapping that of the Strømme syndrome including fetal autopsy results. Using family-based whole-exome sequencing, we identified truncating mutations in the centrosome gene CENPF in the two nonconsanguineous Caucasian sibling pairs. Compound heterozygous inheritance was confirmed in both families. Recently, mutations in this gene were shown to cause a fetal lethal phenotype, the phenotype and functional data being compatible with a human ciliopathy [Waters et al., 2015]. We show for the first time that Strømme syndrome is an autosomal-recessive disease caused by mutations in CENPF that can result in a wide phenotypic spectrum.
Hoeller S, Zihler D, Zlobec I, Obermann EC, Pileri SA, Dirnhofer S & Tzankov A (2010) Histopathology 56, 217–228 BOB.1, CD79a and cyclin E are the most appropriate markers to discriminate classical Hodgkin’s lymphoma from primary mediastinal large B‐cell lymphoma Aims: To clarify which immunohistochemical markers could be helpful in distinguishing between classical Hodgkin’s lymphoma (cHL) and primary mediastinal B‐cell lymphoma (PMBCL) to more narrowly define ‘B‐cell lymphoma, unclassifiable, with features intermediate between diffuse large B‐cell lymphoma and cHL’. Methods and results: Two hundred and 83 cHLs and 51 PMBCLs were analysed on validated tissue microarray platforms with antibodies to BOB.1, CD15, CD20, CD23, CD30, CD79a, cyclin E, LMP‐1, MUM1p, p63 and Oct2. The marker cut‐off scores were calculated using receiver–operating characteristic curves. Markers with the highest positive predictive value for cHL were: CD15, cyclin E, LMP‐1 (all 100%), MUM1p (93%) and CD30 (83%). High sensitivity was achieved only by CD30 (92%) and cyclin E (79%). Nineteen percent of PMBCLs were also positive for CD30, which led to a lower specificity of CD30 as regards cHL (81%) compared with cyclin E (100%). The antibodies with the highest positive predictive value for PMBCL were: CD23 (98%), p63 (96%), BOB.1 (94%) and CD79a (90%), with high sensitivity for BOB.1 (100%), CD79a (89%) and p63 (82%). Conclusions: The use of at least three of the most accurate immunohistochemical markers, cyclin E, CD79a and BOB.1, may be helpful in the differential diagnosis of cHL and PMBCL.
The original article to which this Erratum refers was published in Human Mutation 37(4):359–363 (DOI:10.1002/humu22960). On page 362, a variant is written incorrectly as “c.2734C>T.” However, the correct name of this variant should be printed as “c.2734G>T.” The authors regret the error and note that the variant is listed correctly in Table 1.
Abstract OBJECTIVES Recent trials have begun to explore immune checkpoint inhibitors for non-small cell lung cancer in the neoadjuvant setting, but data on tumour response and surgical outcome remain limited. METHODS Retrospective evaluation of clinical data from patients with non-small cell lung cancer treated with immune checkpoint inhibitors followed by lung resection was performed at 2 large volume institutions (1 North American, 1 European). Data were analysed using Chi-squared, Fisher’s and Wilcoxon rank-sum tests where appropriate. RESULTS Thirty-seven patients were identified from 2017 to 2019. Forty-nine per cent were Stage IIIB and IV. Forty-six per cent received immunotherapy alone and 54% in combination with chemo- and/or radiotherapy. Sixteen per cent of cases were successfully performed minimally invasively. Twenty patients were operated with lobectomy (6 of these with wedges or segments of a neighbouring lobe, 2 with sleeve resections and 1 with a chest wall resection), 4 with bilobectomies, 11 with pneumonectomy (including 5 extrapleural pneumonectomies and 1 atrial resection) and 1 with a wedge resection. Overall, 10 patients (27%) developed postoperative complications and the 90-day mortality was zero. One-year recurrence-free survival was 73% for stage II/IIIA and 55% for stage IIIB/stage IV. The major pathologic response rate was 34%. CONCLUSION In this retrospective study, lung resection after immunotherapy (alone or in combination) is safe, although often requires complex surgery. Due to increasing number of clinical trials adopting immunotherapy in the neoadjuvant setting, it is likely that this therapy will become part of standard of care. Immunotherapy may also allow surgery to have a role for selected patients with advanced disease.
Abstract Critically ill COVID-19 patients are characterized by a severely dysregulated cytokine profile and elevated neutrophil counts, which are thought to contribute to disease severity. However, to date it remains unclear how neutrophils contribute to pathophysiology during COVID-19. Here, we assessed the impact of the dysregulated cytokine profile on the tightly regulated cell death program of neutrophils. We show that in a subpopulation of neutrophils, canonical apoptosis was skewed towards rapidly occurring necroptosis. This phenotype was characterized by abrogated caspase-8 activity and increased RIPK1 levels, favoring execution of necroptosis via the RIPK1-RIPK3-MLKL axis, as further confirmed in COVID-19 biopsies. Moreover, reduction of sFas-L levels in COVID-19 patients and hence decreased signaling to Fas directly increased RIPK1 levels and correlated with disease severity. Our results suggest an important role for Fas signaling in the regulation of cell death program ambiguity via the ripoptosome in neutrophils during COVID-19 and a potential therapeutic target to curb inflammation and thus influence disease severity and outcome.
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