Reproducibility of the NEPTUNE descriptor-based scoring system on whole-slide images and histologic and ultrastructural digital images

The multicenter Nephrotic Syndrome Study Network (NEPTUNE) digital pathology scoring system employs a novel and comprehensive methodology to document pathologic features from whole-slide images, immunofluorescence and ultrastructural digital images. To estimate inter- and intra-reader concordance of this descriptor-based approach, data from 12 pathologists (eight NEPTUNE and four non-NEPTUNE) with experience from training to 30 years were collected. A descriptor reference manual was generated and a webinar-based protocol for consensus/cross-training implemented. Intra-reader concordance for 51 glomerular descriptors was evaluated on jpeg images by seven NEPTUNE pathologists scoring 131 glomeruli three times (Tests I, II, and III), each test following a consensus webinar review. Inter-reader concordance of glomerular descriptors was evaluated in 315 glomeruli by all pathologists; interstitial fibrosis and tubular atrophy (244 cases, whole-slide images) and four ultrastructural podocyte descriptors (178 cases, jpeg images) were evaluated once by six and five pathologists, respectively. Cohen’s kappa for inter-reader concordance for 48/51 glomerular descriptors with sufficient observations was moderate (0.40<kappa ≤0.60) for 17 and good (0.60<kappa ≤0.80) for 8, for 52% with moderate or better kappas. Clustering of glomerular descriptors based on similar pathologic features improved concordance. Concordance was independent of years of experience, and increased with webinar cross-training. Excellent concordance was achieved for interstitial fibrosis and tubular atrophy. Moderate-to-excellent concordance was achieved for all ultrastructural podocyte descriptors, with good-to-excellent concordance for descriptors commonly used in clinical practice, foot process effacement, and microvillous transformation. NEPTUNE digital pathology scoring system enables novel morphologic profiling of renal structures. For all histologic and ultrastructural descriptors tested with sufficient observations, moderate-to-excellent concordance was seen for 31/54 (57%). Descriptors not sufficiently represented will require further testing. This study proffers the NEPTUNE digital pathology scoring system as a model for standardization of renal biopsy interpretation extendable outside the NEPTUNE consortium, enabling international collaborations

Implementation of Novel Biomarkers in the Diagnosis, Prognosis, and Management of Acute Kidney Injury: Executive Summary from the Tenth Consensus Conference of the Acute Dialysis Quality Initiative (ADQI)

Detection of acute kidney injury is undergoing a dynamic revolution ofbiomarker technology allowing greater, earlier, and more accuratedetermination of diagnosis, prognosis, and with powerful implication formanagement. Biomarkers can be broadly considered as any measurablebiologic entity or process that allows differentiation between normalfunction and injury or disease. The ADQI (Acute Dialysis QualityInitiative) had its Ninth Consensus Conference dedicated to synthesisand formulation of the existing literature on biomarkers for thedetection of acute kidney injury in a variety of settings. In the papersthat accompany this summary, ADQI workgroups fully develop key conceptsfrom a summary of the literature in the domains of early diagnosis,differential diagnosis, prognosis and management, and concurrentphysiologic and imaging measures

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Pemphigus foliaceus

A 55-year-old woman presented after a four-year history of impetiginized eczema that was distributed over her face, scalp, chest, and back and a recent diagnosis of breast cancer. A skin biopsy specimen for direct immunofluorescence demonstrated intercellular IgG4. Anti-desmoglein 1 and 3 antibodies were present. Indirect immunofluorescence testing was positive on monkey but not rat esophagus. These findings were consistent with a diagnosis of pemphigus foliaceus in association with a malignant condition. After many years of the use of topical glucocorticoids and oral antibiotics, the patient’s disease was ultimately managed with methotrexate and a small dose of prednisone. Increasing data supports a role for a steroid-sparing effect of methotrexate in pemphigus vulgaris and likely pemphigus foliaceus

Plate-like osteoma cutis

Osteoma cutis is the aberrant development of bone within the skin. The bone formation may be de novo (primary) or result from an injury to the skin (secondary). Here we present a healthy 53-year-old man with no known abnormalities in calcium or phosphate metabolism with plate-like osteoma cutis of the scalp. Plate- or plaque-like osteoma cutis was initially described as a congenital condition but has now been reported several times in the literature as an idiopathic process that occurs in adults. Treatment options are limited and are only required if the lesion is bothersome to the patient

Plate-like osteoma cutis

Osteoma cutis is the aberrant development of bone within the skin. The bone formation may be de novo (primary) or result from an injury to the skin (secondary). Here we present a healthy 53-year-old man with no known abnormalities in calcium or phosphate metabolism with plate-like osteoma cutis of the scalp. Plate- or plaque-like osteoma cutis was initially described as a congenital condition but has now been reported several times in the literature as an idiopathic process that occurs in adults. Treatment options are limited and are only required if the lesion is bothersome to the patient

Pemphigus foliaceus

A 55-year-old woman presented after a four-year history of impetiginized eczema that was distributed over her face, scalp, chest, and back and a recent diagnosis of breast cancer. A skin biopsy specimen for direct immunofluorescence demonstrated intercellular IgG4. Anti-desmoglein 1 and 3 antibodies were present. Indirect immunofluorescence testing was positive on monkey but not rat esophagus. These findings were consistent with a diagnosis of pemphigus foliaceus in association with a malignant condition. After many years of the use of topical glucocorticoids and oral antibiotics, the patient’s disease was ultimately managed with methotrexate and a small dose of prednisone. Increasing data supports a role for a steroid-sparing effect of methotrexate in pemphigus vulgaris and likely pemphigus foliaceus

Primary cutaneous follicle-center lymphoma

We present a 64-year-old man with a three-year history of pruritic, pink papules and nodules of the face who was found to have a clonal lymphoproliferative B-cell disease that was characterized by a clonal IGH rearrangement. Although morphologic features present in the biopsy specimen were consistent with a reactive process, additional clinicopathologic correlation (anatomic presentation of lesions on the face, the absence of t(14:18) translocation, and bcl-2 and MUM1 expression) reinforced suspicion of a cutaneous B-cell lymphoma. Systemic work-up with CT/PET and a bone marrow biopsy ultimately excluded systemic disease and primary cutaneous follicle-center lymphoma (PCFCL) was a strong diagnostic consideration. The patient was treated with systemic rituximab with a partial resolution of the facial lesions. The case demonstrates both clinical and pathologic challenges to the diagnosis of primary cutaneous B-cell lymphoma (PCBCL). Furthermore, despite a newly refined classification system, the case also specifically highlights the persistent requirement for flexible clinical reasoning and pathologic correlation. Such reasoning is necessary to generate individualized strategies for diagnosis and treatment when cutaneous B-cell lymphoma is suspected