Christopher Bellamy

Banff 2013 meeting report

The 12th Banff Conference on Allograft Pathology was held in Comandatuba, Brazil, from August 19–23, 2013, and was preceded by a 2‐day Latin American Symposium on Transplant Immunobiology and Immunopathology. The meeting was highlighted by the presentation of the findings of several working groups formed at the 2009 and 2011 Banff meetings to: (1) establish consensus criteria for diagnosing antibody‐mediated rejection (ABMR) in the presence and absence of detectable C4d deposition; (2) develop consensus definitions and thresholds for glomerulitis (g score) and chronic glomerulopathy (cg score), associated with improved inter‐observer agreement and correlation with clinical, molecular and serological data; (3) determine whether isolated lesions of intimal arteritis (“isolated v”) represent acute rejection similar to intimal arteritis in the presence of tubulointerstitial inflammation; (4) compare different methodologies for evaluating interstitial fibrosis and for performing/evaluating implantation biopsies of renal allografts with regard to reproducibility and prediction of subsequent graft function; and (5) define clinically and prognostically significant morphologic criteria for subclassifying polyoma virus nephropathy. The key outcome of the 2013 conference is defining criteria for diagnosis of C4d‐negative ABMR and respective modification of the Banff classification. In addition, three new Banff Working Groups were initiated.

Noninvasive ductal carcinoma of the breast: the relevance of histologic categorization.

A consecutive series of 130 review-confirmed cases of noninvasive ductal carcinoma of breast (DCIS) in women without previous breast carcinoma was analyzed. Histologic variables assessed included histologic pattern, nuclear grade, necrosis, and involved duct counts. These were correlated with presentation, extent of DCIS in the breast, completeness of excision, and outcome. Comedo DCIS had an occult presentation significantly more often than noncomedo DCIS. Micropapillary DCIS was significantly more likely than other patterns to involve multiple quadrants of breast, irrespective of nuclear grade or necrosis. Solid DCIS was significantly more often completely excised when compared with all other patterns, while high-grade DCIS was significantly more often incompletely excised compared with low-grade DCIS. Follow-up showed invasive recurrence in 16% of cases treated by primary local excision only and 3% cases treated by mastectomy or with re-excision. Of local excision cases with follow-up longer than 3 years, 22% had invasive recurrence. Invasive recurrence only followed high-grade DCIS and most often followed comedo DCIS. The need for strict definition of categories of DCIS is stressed.

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.

Persistence of apoptotic cells without autoimmune disease or inflammation in CD14-/- mice

Interaction of macrophages with apoptotic cells involves multiple steps including recognition, tethering, phagocytosis, and anti-inflammatory macrophage responses. Defective apoptotic cell clearance is associated with pathogenesis of autoimmune disease. CD14 is a surface receptor that functions in vitro in the removal of apoptotic cells by human and murine macrophages, but its mechanism of action has not been defined. Here, we demonstrate that CD14 functions as a macrophage tethering receptor for apoptotic cells. Significantly, CD14−/− macrophages in vivo are defective in clearing apoptotic cells in multiple tissues, suggesting a broad role for CD14 in the clearance process. However, the resultant persistence of apoptotic cells does not lead to inflammation or increased autoantibody production, most likely because, as we show, CD14−/− macrophages retain the ability to generate anti-inflammatory signals in response to apoptotic cells. We conclude that CD14 plays a broad tethering role in apoptotic cell clearance in vivo and that apoptotic cells can persist in the absence of proinflammatory consequences.

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

AbstractAims. To investigate the efficacy of letrozole 2.5mg and 10mg 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 2.5mg (n=12) or letrozole 10mg (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 ≥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 2.5mg and 10mg treatment groups, respectively. There were five complete clinical responses and seven partial clinical responses in the patients treated with 2.5mg letrozole, and nine partial responses and three patients with stable disease in patients treated with 10mg letrozole. Assessed by ultrasound and mammography, the 12 patients treated with 2.5mg had one complete response, nine partial responses and two with no change. In the 12 patients treated with 10mg letrozole, imaging gave eight partial responses and four with no change. One patient treated with the 2.5mg 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.

Tissue-resident macrophages protect the liver from ischemia reperfusion injury via a heme oxygenase-1-dependent mechanism.

Kupffer cells are the resident macrophage population of the liver and have previously been implicated in the pathogenesis of hepatic ischemia-reperfusion injury (IRI). Kupffer cells are the major site of expression of hepatic heme oxygenase-1 (HO-1), which has been shown to have anti-inflammatory actions and to protect animals and cells from oxidative injury. Kupffer cells and circulating monocytes were selectively ablated using liposomal clodronate (LC) in the CD11b DTR mouse before induction of hepatic ischemia. Kupffer cell depletion resulted in loss of HO-1 expression and increased susceptibility to hepatic IRI, whereas ablation of circulating monocytes did not affect IRI phenotype. Targeted deletion of HO-1 rendered mice highly susceptible to hepatic IRI. In vivo, HO-1 deletion resulted in pro-inflammatory Kupffer cell differentiation characterized by enhanced Ly6c and MARCO (macrophage receptor with collagenous structure) expression as well as decreased F4/80 expression, mirrored by an expansion in immature circulating monocytes. In vitro, HO-1 inhibition throughout macrophage differentiation led to increased cell numbers, and pro-inflammatory Ly6c+ CD11c- F4/80- phenotype. These data support a critical role for tissue-resident macrophages in homeostasis following ischemic injury, and a co-dependence of HO-1 expression and tissue-resident macrophage differentiation.

p53 Deficiency in liver reduces local control of survival and proliferation, but does not affect apoptosis after DNA damage.

Despite good evidence for p53 dysfunction in human hepatocellular carcinomas, little is known of the significance of p53 to normal hepatocytes and whether p53 dysfunction is relevant to early hepatocarcinogenesis. We have therefore examined the consequences of targeted p53 deficiency in hepatocytes for regulation of apoptosis, proliferation, and ploidy. p53 deficiency was silent in normal liver and did not affect progression from diploidy to polyploidy in the aging liver. However, in primary culture the absence of p53 resulted in increased hepatocyte proliferation indices and decreased sensitivity to proliferation inhibition by TGFβ. Moreover, p53‐deficient cells continued to survive and proliferate under conditions of minimal trophic support that led to growth arrest and apoptosis of wild‐type cells. In vivo, p53‐deficient mice had enhanced proliferative responses to both xenobiotic hepatomitogen and CCl4‐induced liver necrosis, although lack of persistent proliferation showed that other control mechanisms are important. There was no simple relationship between p53 and apoptosis after DNA damage because UV irradiation led to p53‐independent apoptosis, even though p53 was stabilized. However, p53 did couple DNA damage to growth arrest, and abnormal mitoses after γ‐irradiation of regenerating p53 null livers demonstrated circumstances where loss of G1 and G2 checkpoints may generate abnormal ploidy. Thus p53 becomes important when hepatocytes are released from G0 and stressed, sensitizing them to mitogen and cytokine regulators of cell cycle progression and apoptosis. Hence p53 deficiency is likely to be significant in an environment of persistent regenerative stimuli and unfavorable trophic support or in the presence of other enabling genetic lesions. This model is relevant to human hepatocarcinogenesis, which almost always occurs against a background of chronic hepatocellular destruction in hepatitis and cirrhosis. In that context, by reducing the need for cytokine support and disabling DNA damage‐induced growth arrest, p53 deficiency should facilitate the expansion of preneoplastic clones in chronic liver disease.—Bellamy, C. O. C., Clarke, A. R., Wyllie, A. H., Harrison, D.J. p53 deficiency in liver reduces local control of survival and proliferation, but does not affect apoptosis after DNA damage. FASEB J. 11, 591–599 (1997)

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.

The expression of Ki-S1 and BCL-2 and the response to primary tamoxifen therapy in elderly patients with breast cancer

Ki-S1, a marker of proliferation, and bcl-2, thegene product of which is an antagonist ofapoptosis, have been measured in 51 ER-positive primarybreast cancers before and during tamoxifen treatment andthen related to clinical response. Both markers weredetected in the majority of tumours before treatmentand, quantitatively, initial expression of Bcl-2 protein, butnot Ki-S1, was significantly related to the percentagereduction in tumour volume as assessed by ultrasound.Staining for both markers was lower in posttreatment samples than in those taken prior totreatments, but concordant decreases in staining indices wereseen in only 11 of the 51 tumours.The results demonstrate, using clinical material, that theresponse to tamoxifen may involve changes in proliferationand/or susceptibility to cell-death.

Thrombotic microangiopathy associated with interferon beta.

Recombinant interferon beta is commonly used in the treatment of multiple sclerosis. In this letter, cases of thrombotic microangiopathy that were reported in South Scotland appear to be related to the use of a particular preparation of interferon beta.