The XV. Banff conference for allograft pathology was held in conjunction with the annual meeting of the American Society for Histocompatibility and Immunogenetics in Pittsburgh, PA (USA) and focused on refining recent updates to the classification, advances from the Banff working groups, and standardization of molecular diagnostics. This report on kidney transplant pathology details clarifications and refinements to the criteria for chronic active (CA) T cell–mediated rejection (TCMR), borderline, and antibody‐mediated rejection (ABMR). The main focus of kidney sessions was on how to address biopsies meeting criteria for CA TCMR plus borderline or acute TCMR. Recent studies on the clinical impact of borderline infiltrates were also presented to clarify whether the threshold for interstitial inflammation in diagnosis of borderline should be i0 or i1. Sessions on ABMR focused on biopsies showing microvascular inflammation in the absence of C4d staining or detectable donor‐specific antibodies; the potential value of molecular diagnostics in such cases and recommendations for use of the latter in the setting of solid organ transplantation are presented in the accompanying meeting report. Finally, several speakers discussed the capabilities of artificial intelligence and the potential for use of machine learning algorithms in diagnosis and personalized therapeutics in solid organ transplantation.

BACKGROUND. Monogenic IFN–mediated autoinflammatory diseases present in infancy with systemic inflammation, an IFN response gene signature, inflammatory organ damage, and high mortality. We used the JAK inhibitor baricitinib, with IFN-blocking activity in vitro, to ameliorate disease. METHODS. Between October 2011 and February 2017, 10 patients with CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures), 4 patients with SAVI (stimulator of IFN genes–associated [STING-associated] vasculopathy with onset in infancy), and 4 patients with other interferonopathies were enrolled in an expanded access program. The patients underwent dose escalation, and the benefit was assessed by reductions in daily disease symptoms and corticosteroid requirement. Quality of life, organ inflammation, changes in IFN-induced biomarkers, and safety were longitudinally assessed. RESULTS. Eighteen patients were treated for a mean duration of 3.0 years (1.5–4.9 years). The median daily symptom score decreased from 1.3 (interquartile range [IQR], 0.93–1.78) to 0.25 (IQR, 0.1–0.63) (P < 0.0001). In 14 patients receiving corticosteroids at baseline, daily prednisone doses decreased from 0.44 mg/kg/day (IQR, 0.31–1.09) to 0.11 mg/kg/day (IQR, 0.02–0.24) (P < 0.01), and 5 of 10 patients with CANDLE achieved lasting clinical remission. The patients’ quality of life and height and bone mineral density Z-scores significantly improved, and their IFN biomarkers decreased. Three patients, two of whom had genetically undefined conditions, discontinued treatment because of lack of efficacy, and one CANDLE patient discontinued treatment because of BK viremia and azotemia. The most common adverse events were upper respiratory infections, gastroenteritis, and BK viruria and viremia. CONCLUSION. Upon baricitinib treatment, clinical manifestations and inflammatory and IFN biomarkers improved in patients with the monogenic interferonopathies CANDLE, SAVI, and other interferonopathies. Monitoring safety and efficacy is important in benefit-risk assessment. TRIAL REGISTRATION. ClinicalTrials.gov NCT01724580 and NCT02974595. FUNDING. This research was supported by the Intramural Research Program of the NIH, NIAID, and NIAMS. Baricitinib was provided by Eli Lilly and Company, which is the sponsor of the expanded access program for this drug.

Polyomavirus nephropathy (PVN) remained inadequately classified until 2018 when the “Banff Working Group” published a new 3‐tier morphologic classification scheme derived from in‐depth statistical analysis of a large multinational patient cohort. Here we report a multicenter “modern era” validation study that included 99 patients with definitive PVN transplanted post 1/1/2009 and followed the original 2018 study design. Results validate the PVN classification, i.e. the three PVN disease classes predicted clinical presentation, allograft function and outcome independent of therapeutic intervention. PVN class 1 compared to classes 2 and 3 was diagnosed earlier (16.9 weeks post transplantation (median), P=0.004), and showed significantly better function at 24‐months post‐index biopsy (S‐Cr 1.75 mg/dl, geometric mean, versus class 2: P=0.037, versus class 3: P=0.013). Class 1 presented during long‐term follow‐up with a low graft failure rate: 5% class 1, versus 30% class 2, versus 50% class 3 (P=0.009). Persistent PVN was associated with an increased risk for graft failure (and functional decline in class 2 at 24‐months post diagnosis; S‐Cr with persistence: 2.48 mg/dl versus 1.65 with clearance, geometric means, P=0.018). In conclusion, we validate the 2018 Banff Working Group PVN classification that provides significant clinical information and enhances comparative data analysis.

The role of fine needle aspiration biopsy (FNAB) as the primary modality for the initial diagnosis of previously undiagnosed soft tissue sarcomas presents several important challenges. Most practicing pathologists are inexperienced with the wide array of soft tissue neoplasms and their morphologic heterogeneity, making them susceptible to misdiagnosis. However, in the hands of experienced cytopathologists, FNAB in conjunction with ancillary techniques has a diagnostic accuracy approaching 95% for the diagnosis of malignancy. FNAB has been shown to have a diagnostic yield nearly identical with core needle biopsy while avoiding significant clinical complications. Nevertheless, FNAB has certain limitations related to the accurate histologic grading and subtyping of certain subgroups of sarcomas. It may also be difficult to accurately distinguish between low-grade sarcomas and benign or borderline cellular lesions, especially in the spindle cell sarcoma subgroup. The aim of this review is to highlight the utility and limitations of FNAB in the primary diagnosis of soft tissue sarcomas, highlight diagnostically challenging lesions, and comment on the limitations of FNAB in providing a “definitive” diagnosis.

Haufen, i.e. discrete three-dimensional cast-like polyomavirus aggregates in the urine, mark polyoma BK-virus nephropathy (BKN) with positive and negative predictive values of greater than 95%. They are novel diagnostic biomarkers of BKN, an important infectious complication post kidney transplantation. Here, we describe technical details of Haufen detection by negative staining electron microscopy. We studied more than 400 urine samples from over 180 patients and developed easy-to-follow protocols for optimal specimen preservation and preparation, including sample clarification and concentration. We detail diagnostic clues to detect Haufen and illustrate pitfalls, including "Haufen-look-alikes," which can hamper the interpretation. Urinary Haufen detection by negative staining electron microscopy is a new application of an old, well-established diagnostic technique. The protocols described here are useful for pathologists and electron microscopists to search for Haufen in voided urine samples, to predict BKN noninvasively, and to help clinicians managing renal allograft recipients.