The causes, significance and consequences of inflammatory fibrosis in kidney transplantation: The Banff i-IFTA lesion.

Inflammation within areas of interstitial fibrosis and tubular atrophy (i-IFTA) is associated with adverse outcomes in kidney transplantation. We evaluated i-IFTA in 429 indication- and 2052 protocol-driven biopsy samples from a longitudinal cohort of 362 kidney-pancreas recipients to determine its prevalence, time course, and relationships with T cell-mediated rejection (TCMR), immunosuppression, and outcome. Sequential histology demonstrated that i-IFTA was preceded by cellular interstitial inflammation and followed by IF/TA.

Glutathione S-transferase Pi expression predicts response to adjuvant chemotherapy for stage C colon cancer: a matched historical control study.

Background: This study examined the association between overall survival and Glutathione S-transferase Pi (GST Pi) expression and genetic polymorphism in stage C colon cancer patients after resection alone versus resection plus 5-fluourouracil-based adjuvant chemotherapy.

Methods: Patients were drawn from a hospital registry of colorectal cancer resections. Those receiving chemotherapy after it was introduced in 1992 were compared with an age and sex matched control group from the preceding period.

Src tyrosine kinase phosphorylation of nuclear receptor HNF4α correlates with isoform-specific loss of HNF4α in human colon cancer.

Src tyrosine kinase has long been implicated in colon cancer but much remains to be learned about its substrates. The nuclear receptor hepatocyte nuclear factor 4α (HNF4α) has just recently been implicated in colon cancer but its role is poorly defined. Here we show that c-Src phosphorylates human HNF4α on three tyrosines in an interdependent and isoform-specific fashion.

Clinicopathological correlates and prognostic significance of glutathione S-transferase Pi expression in 468 patients after potentially curative resection of node-positive colonic cancer.

Aims: This study investigated the association between glutathione S-transferase Pi (GST Pi) expression, histopathology and overall survival in 468 patients after resection of stage C colonic adenocarcinoma.

Methods And Results: Data were drawn from a prospective hospital registry of consecutive bowel cancer resections with a minimum follow-up of 5 years. Nuclear and cytoplasmic GST Pi expression, assessed by both intensity of staining and percentage of stained cells at both the central part of the tumour and the invasive tumour front, were evaluated retrospectively by tissue microarray immunohistochemistry on archival specimens.

Proteomic comparison of colorectal tumours and non-neoplastic mucosa from paired patient samples using iTRAQ mass spectrometry.

Quantitative mass spectrometry using iTRAQ was used to identify differentially expressed proteins from 16 colorectal cancer (CRC) tumours compared to patient-paired adjacent normal mucosa. Over 1400 proteins were identified and quantitated, with 118 determined as differentially expressed by >1.3-fold, with false discovery rate < 0.

Clinicopathological correlates and prognostic significance of maspin expression in 450 patients after potentially curative resection of node-positive colonic cancer.

Aims: The tumour suppressor maspin has been investigated for its association with conventional histopathological features in colorectal cancer and for its potential as an independent predictor of survival and response to adjuvant chemotherapy. The aim of this study was to examine associations between maspin expression, other histopathology and survival in a large consecutive series of patients after potentially curative resection of node-positive colonic adenocarcinoma.

Methods And Results: Nuclear and cytoplasmic maspin expression in both superficial and deep parts of the tumour were assessed retrospectively by tissue microarray and immunohistochemistry in specimens from 450 patients whose other histopathology had been recorded in a prospective hospital registry of large bowel cancer resections from 1971 to 2001 with a minimum follow-up of 5 years.

Fascin expression predicts survival after potentially curative resection of node-positive colon cancer.

Fascin, an actin-bundling protein, is expressed in many neoplasms including colorectal cancer. It is considered to be a mediator of tumor cell invasion and an indicator of aggressive phenotype; however, there are few reports on the association between fascin and prognosis in colorectal cancer. The aims of this study were to: (a) investigate the expression of fascin in the central part of the tumor and at the invasive front in patients who had a potentially curative resection for node-positive colonic carcinoma; (b) examine the method of scoring fascin expression; and (c) investigate the association between fascin expression and overall survival and other clinicopathologic features.

Tumor budding and survival after potentially curative resection of node-positive colon cancer.

Purpose: The aim of this study was to investigate the relationship between tumor budding and other pathology features and overall survival after resection of clinicopathological stage III colon cancer.

Methods: The number of buds and other histopathological features were assessed in 477 patients who were operated on between 1971 and 2001, with follow-up to December 2006. Overall survival was analyzed using the Kaplan-Meier method and Cox regression.

Transcriptome changes of chronic tubulointerstitial damage in early kidney transplantation.

Background: Tubulointerstitial damage (TID) is a key feature of chronic kidney transplant failure; however, the associated gene expression changes are poorly defined.

Methods: This pilot study used RNA from 59 protocol kidney transplant biopsies at implantation, 1, 3, and 12 months (n=18 patients), processed into cDNA and hybridized to 8K human cDNA microarrays. Gene expression was correlated with graft histology categorized by the Banff schema.

Epithelial-to-mesenchymal transition in early transplant tubulointerstitial damage.

It is unknown whether epithelial-to-mesenchymal transition (EMT) leads to tubulointerstitial fibrosis in renal transplants. In this study, interstitial fibrosis and markers of EMT were followed in protocol transplant biopsies in 24 patients. Tubulointerstitial damage (TID) increased from 34 to 54% between 1 and 3 mo after transplantation.

Treatment of subclinical rejection diagnosed by protocol biopsy of kidney transplants.

Background: Subclinical rejection (SCR) causes chronic allograft damage, which may be prevented by antirejection therapy.

Methods: A pilot study of the effect of routine treatment of SCR was performed in 88 recipients of either a kidney (n=59) or combined kidney-pancreas transplant (n=29) undergoing protocol biopsy (PBX) surveillance at 1 and 3 months, using calcineurin inhibitors, mycophenolate mofetil, and corticosteroid therapy.

Results: SCR was seen in 46.

Calcineurin inhibitor nephrotoxicity: longitudinal assessment by protocol histology.

Background: The role and burden of cyclosporine (CsA) nephrotoxicity in long-term progressive kidney graft dysfunction is poorly documented.

Methods: The authors evaluated 888 prospective protocol kidney biopsy specimens from 99 patients taken regularly until 10 years after transplantation for evidence of CsA nephrotoxicity.

Results: The most sensitive histologic marker of CsA nephrotoxicity was arteriolar hyalinosis, predicted by CsA dose and functional CsA nephrotoxicity.

Evolution and pathophysiology of renal-transplant glomerulosclerosis.

Background: Glomerulosclerosis (GS) is characteristic of chronic allograft nephropathy and graft failure; however, its natural history and pathophysiology are poorly defined.

Methods: We evaluated 959 prospective protocol kidney-transplant biopsies from 120 recipients taken regularly up to 10 years after transplantation for evidence of glomerular injury.

Results: GS exhibited a nonlinear triphasic time course.

Delta analysis of posttransplantation tubulointerstitial damage.

Background: Chronic interstitial fibrosis (CIF) is an adverse prognostic feature of chronic allograft nephropathy.

Methods: We evaluated the evolution, onset, potential causes, and outcomes of tubulointerstitial damage using 959 protocol kidney biopsy specimens obtained regularly until 10 years after transplantation. Specimens were scored by the Banff schema and analyzed for time-specific change or "delta damage" from sequential biopsy-pairs (n=839).

Natural history, risk factors, and impact of subclinical rejection in kidney transplantation.

Background: Subclinical rejection (SCR) is defined as histologically proven acute rejection in the absence of immediate functional deterioration.

Methods: We evaluated the impact of SCR in 961 prospective protocol kidney biopsies from diabetic recipients of a kidney-pancreas transplant (n=119) and one kidney transplant alone taken regularly up to 10 years after transplantation.

Results: SCR was present in 60.

The natural history of chronic allograft nephropathy.

Background: With improved immunosuppression and early allograft survival, chronic allograft nephropathy has become the dominant cause of kidney-transplant failure.

Methods: We evaluated the natural history of chronic allograft nephropathy in a prospective study of 120 recipients with type 1 diabetes, all but 1 of whom had received kidney-pancreas transplants. We obtained 961 kidney-transplant-biopsy specimens taken regularly from the time of transplantation to 10 years thereafter.