More than meets the eye: the changing face of histopathology.

This personal reflection on trends in histopathology over the past 50 years draws upon experience of professional training and practice in the specialty in the UK. Developments during this period often resulted from new therapies (and their adverse effects) necessitating greater precision in the histopathological classification of disease, for which morphology alone can be insufficient. Conversely, histopathology has contributed to advances in our understanding of disease, leading directly to novel and more effective treatments. New infections, some involving histopathology in their discovery, have also led to fresh diagnostic challenges. Increasingly, patients have benefited from fundamental changes in professionalism in pathology. Through audit, external quality assurance, continuing professional development, standardized reporting, and increasing specialization, the consistency and reliability of histopathological diagnoses have steadily improved. Regarding the specialty's future, some now see rivalry between the morphological and molecular approaches to diagnosis and classification, particularly for neoplastic disease. An integrated strategy led by the specialty is more likely to strengthen histopathology and ultimately to have the greatest benefit for patients.

Long-Term Prognostic Significance of Persisting Histological Activity Despite Biochemical Remission in Autoimmune Hepatitis.

OBJECTIVES: Biochemical remission is widely considered a satisfactory treatment end point in autoimmune hepatitis (AIH). The significance of persisting histological activity despite biochemical remission is unknown. We aimed to assess the frequency and prognostic significance of persisting histological inflammation in patients with AIH who had achieved biochemical remission with treatment. METHODS: We studied 120 patients (median age at diagnosis 57 years; 81% female) with AIH by International Criteria (59% definite), who received immunosuppressive treatment and underwent a follow-up liver biopsy after at least 6 months of sustained biochemical remission (defined as normal serum ALT and globulin). RESULTS: Fifty-five patients (46%) had persisting histological activity (Ishak histological activity index (HAI) ≥4). These patients had higher serum ALT (24 vs. 18 IU/l, P=0.003) and AST (27 vs. 23 IU/l, P=0.03) at the time of follow-up biopsy, compared with patients who achieved histological remission (HAI ≤3). They had less frequent regression of fibrosis on follow-up biopsy compared with those achieving histological remission (32 vs. 60%, P=0.004) and had excess mortality (standardized mortality ratio 1.4 vs. 0.7, P<0.05). The excess mortality was due to liver disease. On multivariate analysis, persisting histological activity was independently associated with all-cause death/transplantation (HR 3.1 (95% CI 1.2-8.1); P=0.02); an association with liver-related death/transplantation fell short of significance (HR 9.7 (95% CI 0.84-111.6; P=0.07). CONCLUSIONS: Persisting histological activity, despite biochemical remission, is frequent in patients with treated AIH and is associated with lower rates of fibrosis regression and reduced long-term survival.

Transmucosal gastric leak induced by proton pump inhibitors.

Despite their remarkable safety profile and lack of clinical side effects, proton pump inhibitors (PPIs) induce a transmucosal gastric leak to non-electrolyte probes of various sizes. The ex vivo addition of PPIs to isolated rat gastric corpus increases transmucosal permeability in a dose-dependent manner, which corresponds with PPIs' dose-dependent inhibition of acid secretion. Upon the addition of omeprazole, lansoprazole, or esomeprazole, a small decrease in transepithelial resistance and the concomitant stimulation of short circuit current was observed. Additionally, transepithelial flux of (14)C-[D]-mannitol (MW 182.17) across the gastric mucosa increased by a mean of 68% immediately following the addition of 200 microM omeprazole. This flux increase was bidirectional. Omeprazole also increased the paracellular permeability to larger radiolabeled probes, including (14)C-sucrose (MW 342.3) and (14)C-polyethylene glycol (MW 4,000) by 118% and 350%, respectively. However, the flux of still larger probes, 10,000 and 70,000 MW dextrans, was not increased. Because PPIs are so widely used and are assumed to be innocuous, this transmucosal gastric leak must be further investigated, as it may carry considerable biomedical implications.

Clearance of hepatitis C virus is not associated with single nucleotide polymorphisms in the IL-1, -6, or -10 genes.

Hepatitis C virus (HCV) commonly causes a chronic infection, but a minority of patients are able to clear the virus and do not run the risk of developing HCV-induced organ damage. Genetic associations between immunoregulatory cytokines interleukin (IL)-1, -6, and -10 with clinical features of HCV, including virus clearance, have been inconsistent. We determined cytokine genotypes in 606 patients who had serologic evidence of HCV exposure, 190 (18%) of whom were consistently negative for HCV RNA, indicating successful virus clearance. There was no significant difference in genotype frequencies between HCV clearance and nonclearance groups for IL-1B (-511 and +3954), IL-1A (+4845), IL-1RN (+2018), IL-6 (-174), or IL-10 (-1082). We conclude that these single nucleotide polymorphisms are unlikely to play an important, if any, role in determining the likelihood of clearing HCV infection.

Prognostic significance of Akt, phospho-Akt and BAD expression in primary breast cancer.

Apoptotic markers in breast cancer are reported to have prognostic significance. The aim of this study was to assess the prognostic value of Akt, phospho-Akt and BAD expression in primary tumours from breast cancer patients. Expression of phospho-Akt did not correlate with menopausal status, nodal involvement or tumour size, although there was a significant correlation between phospho-Akt and oestrogen receptor status and tumour grade. No association was found between phospho-Akt and BAD. However, a significant correlation was found between Akt and BAD. Akt and phospho-Akt expression did not correlate with either disease-free survival (DFS) or overall survival (OS). Conversely, BAD immunostaining correlated significantly with increasing tumour size and with oestrogen receptor (ER) immunostaining in both frozen and paraffin sections. Expression of BAD appeared to be nucleolar in addition to its cytoplasmic and nuclear staining. Comparison of immunohistochemical staining on frozen sections and paraffin sections showed a reasonable concordance in Akt and BAD immunoreactivity. However, the results showed for the first time that strong BAD expression is related to a favourable prognosis but is not an independent prognostic factor. In conclusion, these results could provide the basis for understanding how Akt, phospho-Akt and BAD expression contributes to the prognosis of invasive breast cancer.

Alphastatin, a 24-amino acid fragment of human fibrinogen, is a potent new inhibitor of activated endothelial cells in vitro and in vivo.

Angiogenesis, the development of new blood vessels from existing vasculature, is crucial for the development and metastasis of solid tumors. Here, we show for the first time that a 24-amino acid peptide derived from the amino terminus of the alpha chain of human fibrinogen (termed "alphastatin") has potent antiangiogenic properties, inhibiting both the migration and tubule formation of human dermal microvascular endothelial cells in response to vascular endothelial growth factor (VEGF) or basic fibroblast growth factor (bFGF) in vitro. Moreover, alphastatin markedly inhibits the growth of tumors in a syngeneic murine model. Tumors from mice receiving daily injections of alphastatin for 12 days exhibited large areas of intravascular disruption and thrombosis with substantial cellular necrosis. Importantly, alphastatin administration had no detectable effect on vessels in such normal tissues as liver, lungs, and kidney. Taken together, these data indicate that alphastatin is a potent new antiangiogenic agent in vitro and antivascular agent in vivo.