2016 Comprehensive Update of the Banff Working Group on Liver Allograft Pathology: Introduction of Antibody-Mediated Rejection.

The Banff Working Group on Liver Allograft Pathology reviewed and discussed literature evidence regarding antibody-mediated liver allograft rejection at the 11th (Paris, France, June 5-10, 2011), 12th (Comandatuba, Brazil, August 19-23, 2013), and 13th (Vancouver, British Columbia, Canada, October 5-10, 2015) meetings of the Banff Conference on Allograft Pathology. Discussion continued online. The primary goal was to introduce guidelines and consensus criteria for the diagnosis of liver allograft antibody-mediated rejection and provide a comprehensive update of all Banff Schema recommendations. Included are new recommendations for complement component 4d tissue staining and interpretation, staging liver allograft fibrosis, and findings related to immunosuppression minimization. In an effort to create a single reference document, previous unchanged criteria are also included.

Functional Immune Anatomy of the Liver-As an Allograft.

The liver is an immunoregulatory organ in which a tolerogenic microenvironment mitigates the relative "strength" of local immune responses. Paradoxically, necro-inflammatory diseases create the need for most liver transplants. Treatment of hepatitis B virus, hepatitis C virus, and acute T cell-mediated rejection have redirected focus on long-term allograft structural integrity. Understanding of insults should enable decades of morbidity-free survival after liver replacement because of these tolerogenic properties. Studies of long-term survivors show low-grade chronic inflammatory, fibrotic, and microvascular lesions, likely related to some combination of environment insults (i.e. abnormal physiology), donor-specific antibodies, and T cell-mediated immunity. The resultant conundrum is familiar in transplantation: adequate immunosuppression produces chronic toxicities, while lightened immunosuppression leads to sensitization, immunological injury, and structural deterioration. The "balance" is more favorable for liver than other solid organ allografts. This occurs because of unique hepatic immune physiology and provides unintended benefits for allografts by modulating various afferent and efferent limbs of allogenic immune responses. This review is intended to provide a better understanding of liver immune microanatomy and physiology and thereby (a) the potential structural consequences of low-level, including allo-antibody-mediated injury; and (b) how liver allografts modulate immune reactions. Special attention is given to the microvasculature and hepatic mononuclear phagocytic system.

Banff fibrosis study: multicenter visual assessment and computerized analysis of interstitial fibrosis in kidney biopsies.

Increasing interstitial fibrosis (IF) in native and kidney transplant biopsies is associated with functional decline and serves as a clinical trial end point. A Banff 2009 Conference survey revealed a range in IF assessment practices. Observers from multiple centers were asked to assess 30 renal biopsies with a range of IF and quantitate IF using two approaches on trichrome, Periodic acid-Schiff (PAS) and computer-assisted quantification of collagen III immunohistochemistry (C-IHC) slides, as well as assessing percent of cortical tubular atrophy% (TA%) and Banff total cortical inflammation score (ti-score). C-IHC using whole slide scans was performed. C-IHC assessment showed a higher correlation with organ function (r = -0.48) than did visual assessments (r = -0.32--0.42); computerized and visual C-IHC assessment also correlated (r = 0.64-0.66). Visual assessment of trichrome and C-IHC showed better correlations with organ function and C-IHC, than PAS, TA% and ti-score. However, visual assessment of IF, independent of approach, was variable among observers, and differences in correlations with organ function were not statistically significant among C-IHC image analysis and visual assessment methods. C-IHC image analysis correlated among three centers (r > 0.90, p < 0.0001, between all centers). Given the difficulty of visual IF assessment standardization, C-IHC image could potentially accomplish standardized IF assessment in multicenter settings.

IgG4-related disease: a novel, important but easily missed condition.

Immunoglobulin G4-related disease (IgG4-RD) is a multisystem, fibroinflammatory condition unrecognised in medical science until the last decade. It is characterised by progressive scarring and dysfunction of affected organs and tissues including the pancreas, hepatobiliary tree, kidneys, salivary glands, retroperitoneum and lungs. The diagnosis is made with the presence of numerous IgG4 positive plasma cells within a histologically-distinct chronic inflammatory process; most patients also have elevated serum IgG4. Though early cases were all identified in Japan, subsequent reports clearly demonstrate that IgG4-RD exists worldwide. There are no data confirming the prevalence of IgG4-RD in the West but it is thought to be very rare. Limited awareness of the condition and its heterogeneous presentation frequently results in misdiagnosis. Prompt and correct diagnosis is critical, as a rapid reversal of even advanced disease is often seen with corticosteroid therapy. We present three cases that illustrate some of the typical features of this condition.

A taxonomic revision of Neobuprestis kerremans (Coleoptera : Buprestidae) with the description of a new genus and two new species.

The genus Neobuprestis Kerremans 1903 is redefined and a new genus Burnsiellus gen. n. is defined. The putative relationships of Neobuprestis and Burnsiellus gen. n. are discussed. A key to the species of the two genera are provided. Balthasarella Obenberger 1958 is made a subgenus of Neobuprestis and its type species B. melandryoides Obenberger 1958 is synonymised with Strigoptera frenchi Blackburn 1892. Strigoptera marmorata Blackburn (1892), Neobuprestis albosparsa Carter (1924), Neobuprestis trisulcata Carter (1932) are transferred to Burnsiellus gen. n. from Neobuprestis. Two new species are described: Neobuprestis (Balthasarella) williamsi sp. n., Burnsiellus lobatum sp.n.

C4d immunopositivity is uncommon in ABO-compatible liver allografts, but correlates partially with lymphocytotoxic antibody status.

AIMS: To determine whether C4d immunopositivity helps recognition of humoral rejection in dysfunctional liver allografts. METHODS AND RESULTS: C4d immunopositivity was retrospectively evaluated in liver allografts. There were three staining patterns: portal venular plexus, sinusoidal and hepatocellular. The latter was related to ischaemic necrosis and not scored as positive. C4d immunopositivity was not encountered in 10 preperfusion or 15 consecutive early protocol biopsies. However, three of 12 early protocol biopsy specimens from crossmatch-positive patients were C4d+, two showing repeated positivity on at least one further biopsy specimen, while others remained negative. C4d was also positive in 2/16 early moderate acute cellular rejections, 3/14 cases of centrilobular necroinflammation, 3/11 biliary obstructions, 3/13 chronic rejections and 1/10 primary non-functional allografts. CONCLUSION: C4d immunopositivity is uncommon in liver allografts. There is a weak positive correlation with a positive lymphocytotoxic crossmatch and some patterns of allograft dysfunction. The morphological associations resemble those reported in lymphocytotoxic crossmatch-positive patients, plus occasional sinusoidal and hepatocellular injury. Although the practical utility of C4d immunohistochemistry seems limited, it may identify a small subgroup of individuals in whom chronic humoral microvascular injury contributes to allograft dysfunction.

Transplant histopathology for the general histopathologist.

The number of patients undergoing solid organ transplants and surviving long-term has increased enormously in the last 10 years. This means that pathologists in non-specialist transplant centres are increasingly involved in the interpretation of biopsy and autopsy material from allograft recipients. This includes evaluation of allograft histology, or specimens from other native tissues, which nonetheless still have to be assessed in the setting of transplantation and immunosuppressive therapy. In this first review article we will provide an overview of the pathology of lung transplantation, and briefly describe heart and pancreatic transplants, as well as aspects of general surgical pathology and the role of the autopsy in these patients.

Minimal evidence of transdifferentiation from recipient bone marrow to parenchymal cells in regenerating and long-surviving human allografts.

Liver, small intestine, and heart allografts in residence for 4 days to 16 years were analyzed by simultaneous XY fluorescent in situ hybridization to search for evidence of the recently described process of transdifferentiation of recipient bone marrow stem cells to allograft parenchymal cells. These studies were carried out in an effort to find conditions associated with maximal levels of engraftment or expansion of the recipient parenchymal cells. Despite prolonged survival up to 16 years, regeneration after severe preservation injury or use of split livers, only rare, isolated and tentatively identified recipient hepatocytes were detected in liver allografts. In intestinal allografts, despite survival of up to 8 years and extensive mucosal regeneration because of severe damage from acute rejection, there was no crypt replacement by recipient epithelial cells. In cardiac allografts, no recipient myocytes were detected despite recipient survival for 2-3 days and 3-4 weeks after myocardial infarcts at 5 and 8 years after transplantation. Parenchymal cell transdifferentiation from recipient bone marrow stem cells was rare to nonexistent in severely injured, regenerating, and long-surviving allografts. The rare isolated recipient parenchymal cells tentatively identified did not appear to behave as stem cells: they did not form clusters and did not increase with time after transplantation. Because of the extremely low frequency, interpretation was difficult. Regardless of these results, a more vigorous search for conditions that promote transdifferentiation is warranted.

Raising our sites: dissemination of supported education.

In order to promote replication of supported education, an exemplary rehabilitation model for adults with psychiatric disabilities, funds were accessed through a Community Action Grant from the Center for Mental Health Services of the Substance Abuse and Mental Health Services Administration. Three communities in Michigan participated in a multistage process designed to maximize community ownership by encouraging local adaptations involving all stakeholder groups and providing technical assistance. The stages in the process were organizing the community for supported education development, acquiring knowledge about supported education basics, collecting information (needs assessment and barrier identification), and developing the plan. All three sites have begun implementation, providing services to adults with psychiatric disabilities who wish to pursue post-secondary education. The approach employed has applicability for other local communities.

Observed maternal strategies and children's health locus of control in low-income Mexican American families.

This study examined the relationship among mothers' health locus of control (HLOC) beliefs, their socialization strategies, and their children's HLOC beliefs in 80 low-income Mexican American families. Maternal socialization strategies were assessed from videotaped interactions of mothers and children engaged in a structured task. Factor analysis of the coded strategies yielded 4 factors: Tell Answer, Teaching, Clarify, and Reinforce. Findings indicated that maternal-health-internally scores negatively predicted mothers' use of the Tell Answer strategies and positively predicted their use of Teaching strategies. Mothers who believed that Powerful Others (e.g., health professionals) controlled their health were more likely to use the Tell Answer strategy. In contrast, mothers who believed that health was due to chance were less likely to use Teaching. Maternal use of Teaching strategies predicted children's internal HLOC, whereas maternal Tell Answer strategies predicted children's external HLOC. Findings suggest that mothers' HLOC beliefs influence the socialization strategies they use and that these strategies are associated with children's HLOC beliefs.

Liver transplantation for alcoholic cirrhosis: long term follow-up and impact of disease recurrence.

BACKGROUND: Alcoholic liver disease has emerged as a leading indication for hepatic transplantation, although it is a controversial use of resources. We aimed to examine all aspects of liver transplantation associated with alcohol abuse. METHODS: Retrospective cohort analysis of 123 alcoholic patients with a median of 7 years follow-up at one center. RESULTS: In addition to alcohol, 43 (35%) patients had another possible factor contributing to cirrhosis. Actuarial patient and graft survival rates were, respectively, 84% and 81% (1 year); 72% and 66% (5 years); and 63% and 59% (7 years). After transplantation, 18 patients (15%) manifested 21 noncutaneous de novo malignancies, which is significantly more than controls (P=0.0001); upper aerodigestive squamous carcinomas were overrepresented (P=0.03). Thirteen patients had definitely relapsed and three others were suspected to have relapsed. Relapse was predicted by daily ethanol consumption (P=0.0314), but not by duration of pretransplant sobriety or explant histology. No patient had alcoholic hepatitis after transplantation and neither late onset acute nor chronic rejection was significantly increased. Multiple regression analyses for predictors of graft failure identified major biliary/vascular complications (P=0.01), chronic bile duct injury on biopsy (P=0.002), and pericellular fibrosis on biopsy (P=0.05); graft viral hepatitis was marginally significant (P=0.07) on univariate analysis. CONCLUSIONS: Alcoholic liver disease is an excellent indication for liver transplantation in those without coexistent conditions. Recurrent alcoholic liver disease alone is not an important cause of graft pathology or failure. Potential recipients should be heavily screened before transplantation for coexistent conditions (e.g., hepatitis C, metabolic diseases) and other target-organ damage, especially aerodigestive malignancy, which are greater causes of morbidity and mortality than is recurrent alcohol liver disease.

Dual Y-chromosome painting and immunofluorescence staining of archival human liver transplant biopsies.

Combining fluorescence in situ hybridization (FISH) and indirect immunofluorescence staining of protein markers provides a highly specific method for identifying chromosomes in phenotypically defined cells and tissues. We developed a technique enabling dual chromosome painting and immunofluorescence staining of archival formalin-fixed, paraffin-embedded material, and used this to phenotype chimeric cells in female-to-male human liver transplants.

Letrozole as primary medical therapy for locally advanced and large operable breast cancer.

AIMS: To investigate the efficacy of letrozole 2.5 mg and 10 mg used as primary neoadjuvant therapy for patients with locally advanced and large operable breast cancer. PATIENTS AND METHODS: Twenty-four postmenopausal patients with locally advanced or large operable breast cancer were treated in two consecutive series with letrozole 2.5 mg (n = 12) or letrozole 10 mg (n = 12). Response at three months was measured by change in tumor volume according to WHO criteria (partial response was defined as a reduction in tumor volume > or = 65%). Tumor volumes were assessed clinically, by ultrasound and mammography, and pathologically. RESULTS: All 24 patients were estrogen receptor-positive, were considered 'receptor-rich', and mean age was 77.6 years and 71.6 years in the letrozole 2.5 mg and 10 mg treatment groups, respectively. There were five complete clinical responses and seven partial clinical responses in the patients treated with 2.5 mg letrozole, and nine partial responses and three patients with stable disease in patients treated with 10 mg letrozole. Assessed by ultrasound and mammography, the 12 patients treated with 2.5 mg had one complete response, nine partial responses and two with no change. In the 12 patients treated with 10 mg letrozole, imaging gave eight partial responses and four with no change. One patient treated with the 2.5 mg dose had a complete clinical and pathological response. There was no significant difference between the two doses in effect on tumor volume, and no recordable side effects associated with either dose. CONCLUSION: Letrozole used in a neoadjuvant setting is highly effective, producing clinically beneficial reductions in tumor volume allowing all patients to have breast conserving surgery, and has an acceptable safety profile.

Contact sensitization pretransplantation predicts acute hepatic allograft rejection.

The loss of hepatic allografts to the rejection processes is now relatively rare, and the reduction of adverse effects related to immunosuppressive therapy is becoming more important as patients survive longer after transplantation. We therefore investigated the response to a contact neoantigen before liver transplantation as a predictor of acute rejection after transplantation. Forty-one patients with chronic liver disease were sensitized with 0.1% diphenylcyclopropenone while on the waiting list for orthotopic liver transplantation. Fourteen days later an elicitation reaction was performed with 5 different concentrations of diphenylcyclopropenone. Nineteen responded to diphenylcyclopropenone (score range, 1-9). Twenty-two patients had no response. Three patients died before transplantation (all nonresponders). Twelve (63%) of 19 responders had treatment for acute rejection compared with 1 of 19 nonresponders (P < .0001). In addition univariate analysis revealed recipient age, donor age, Child-Pugh class, and immunosuppressive agent to be associated with acute rejection. On multivariate analysis only skin test response was a significant predictor of acute rejection (P = .02). All nonresponders had no or only mild rejection on biopsy, but 12 of 19 responders had moderate or severe acute rejection on biopsy. All patients requiring additional therapy to a single course of corticosteroids for acute rejection had skin test scores greater than 1. We concluded that patients who do not respond to diphenylcyclopropenone sensitization before transplantation develop at most mild acute rejection and that skin test scores identify patients with troublesome rejection. Evaluation of skin test responses to a contact neoantigen may facilitate tailoring of immunosuppressive therapy.

Changes in non-structural carbohydrate composition during bulbing in sweet and high-solid onions in field experiments.

The composition of non-structural carbohydrate (NSC) content of predominantly long-day onion germplasm has been assessed over several years and in a bi-location trial. It was observed that genetic rather than environmental factors determined the NSC composition of onion bulbs. Glucose was the NSC component which was most closely correlated with genotype. Fructose was the only NSC component that was significantly affected by environment. Sucrose and 1-kestose (DP3 fructans) were not correlated to a large extent to the other NSC components, indicating their transient role in the fructan metabolism. Strong negative correlations were observed between reducing sugars (i.e. fructose and glucose) and dry matter content (DM). Furthermore, it was shown that accessions differed significantly in their fructan accumulation pattern; high DM accessions showed accumulation of fructans over the whole bulbing period, whereas, low DM accessions quickly reached a plateau. Implications for the breeding of high quality onions are discussed.

Arteriolitis in renal transplant biopsies is associated with poor graft outcome.

AIMS: The Banff 1997 classification of renal allograft pathology identifies arteriolitis as a finding of uncertain significance. We sought to improve our understanding of arteriolitis by correlating its occurrence with histopathological and clinical parameters. METHODS AND RESULTS: Twenty allograft kidney biopsies from 19 patients, showing arteriolitis, were identified. Arterioles were defined as small vessels with: (1) wall thickness of 1-3 myocytes; (2) diameter less than one-third of an adjacent glomerulus; and (3) discontinuous or absent elastica. Arteriolitis was defined as mural infiltration by lymphocytes. Other histological findings were categorized according to the Banff 1997 working formulation. Ten biopsies (50%) showed type IIA rejection, seven (35%) showed type I rejection, and three (15%) showed borderline change. Two patients with borderline change had acute rejection in the next biopsy. None of the seven patients with type I rejection had previous or subsequent type II rejection on biopsy. A total 11/20 biopsies (10/19 patients) showing arteriolitis had type IIA rejection in the index or next biopsy. On follow-up, graft loss due to rejection occurred in 5/19 (26%) patients (median 126 days); all had shown type IIA rejection on a previous biopsy. Chronic allograft nephropathy developed in a further 4/19 (21%) patients (median 157 days), of whom three had shown only type I rejection on biopsy. CONCLUSION: Arteriolitis is associated with acute rejection, often type II rejection, and is associated with poor graft outcome. Other causes of arteriolitis were not encountered in this series.

The effects of neoadjuvant anastrozole (Arimidex) on tumor volume in postmenopausal women with breast cancer: a randomized, double-blind, single-center study.

Anastrozole, an orally active, nonsteroidal aromatase inhibitor, was evaluated in a randomized, double-blind, single-center study to determine its efficacy as neoadjuvant therapy in postmenopausal women with newly diagnosed, estrogen receptor-rich, locally advanced or large (>3 cm), operable breast cancers. Twenty-four eligible patients were recruited into the study and received either 1 mg (n = 12) or 10 mg (n = 12) of anastrozole daily over a 3-month period. Tumor volumes were estimated clinically, by using caliper measurements and ultrasound (at baseline and after 1, 2, and 3 months' treatment) and by mammography (at baseline and after 3 months). Tumor volume was also measured in surgical specimens. Twenty-one patients were classified as T2, two patients as T3, and one patient as T4B at baseline. Three patients had clinical evidence of lymph node involvement. When considering the difference between the volume as measured by each assessment and the actual pathological volume, the interquartile range and the difference between the maximum and minimum values were smaller for ultrasound when compared with those measured with calipers and mammography. Therefore, of the three clinical assessments of tumor volume used in this study, the data suggest that ultrasound may be the most accurate. The median reductions in tumor volumes as measured by ultrasound for those patients with a measurable 12-week assessment were 80.5 and 69.6% for anastrozole (1 and 10 mg, respectively) after 12 weeks of treatment and 75.5% when both doses were grouped together. Moreover, of these patients, 11 of 12 given 1 mg and 7 of 11 given 10 mg of anastrozole were found on ultrasound to have a >50% reduction in tumor volume after 12 weeks of treatment. Of the 17 patients who would have required a mastectomy at initiation of treatment, 15 were suitable for breast conservation after anastrozole treatment. These results suggest that anastrozole is highly effective as neoadjuvant therapy in postmenopausal women with estrogen receptor-rich, large, operable breast cancer. Future studies comparing anastrozole with tamoxifen as a neoadjuvant treatment should be considered.