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A P Dhillon

Publications and source records attributed to A P Dhillon.

At least 19 recordsLinked to original sources
PubMed2007

Impact of hepatic steatosis on viral kinetics and treatment outcome during antiviral treatment of chronic HCV infection.

Liver steatosis is highly prevalent in chronic hepatitis C virus (HCV) infection, especially in patients infected with genotype 3 virus, but its significance for the outcome of antiviral treatment is not fully understood. We have monitored steatosis in liver biopsies from 231 patients with chronic HCV infection who received pegylated recombinant interferon-alpha and ribavirin in a phase III study (DITTO trial). The degree of steatosis, along with relevant metabolic parameters, was correlated with the early disappearance of virus and with the final outcome of treatment. Our data suggest that the presence of steatosis impairs the early reduction of viral load during treatment in patients infected with HCV genotype 3 and non-3. Steatosis negatively affected the final outcome of treatment mainly in patients infected with HCV genotype non-3 virus. Based on these findings, we propose that interventions aiming at reducing hepatic steatosis prior to the onset of antiviral therapy may be of benefit to patients infected with HCV of the non-3 genotypes. Patients infected with genotype 3, on the other hand, should be offered early antiviral treatment.

Adult↗
PubMed2006

Genomic alteration is not associated with fatty and clear cell change in hepatocellular carcinomas and its precursor nodular lesions in cirrhotic liver.

BACKGROUND: The aim of this study was to investigate whether fatty and clear cell areas in large regenerative nodules (LRN), dysplastic nodules (DN), and hepatocellular carcinoma (HCC) show higher degree of genomic mutation compared to non-fatty/clear cell area in the same nodule or non-lesional tissue. METHODS: We examined 22 nodular lesions (9 HCC, 5 DN and 8 LRN) from seven cirrhotic livers removed at transplantation. Frozen sections were used for manual microdissection of areas with fatty/clear cell change. DNA from microdissected tissue was amplified using arbitrarily primed polymerase chain reaction (AP-PCR), and PCR products were run on polyacrilamide gel generating a "fingerprint" band pattern. Autoradiographs were analysed using Adobe Photoshop version 6.0. Fingerprints from lesional tissue were compared to reference tissue and the total number of bands in excess or defect was calculated and divided by the total number of bands identified, obtaining the genomic damage fraction (GDF). RESULTS: Increasing GDF average values were seen from cirrhotic liver (0.13+/-0.04), to LRN (0.16+/-0.1), DN (0.28+/-0.08) and HCC (0.30+/-0.07). A statistically significant difference in GDF values was documented between cirrhotic liver and DN (p=0.008) and HCC (p=0.005) and between HCC and LRN (p=0.02). No significant difference was documented between DN and HCC, and between LRN and cirrhotic liver. Eleven nodules containing fat/clear cell areas were compared to the other 11 nodules without fat/clear cell areas. The GDF was not different between the two groups: 0.29+/-0.11 versus 0.25+/-0.12; p=0.5. The average value of genomic damage fraction between fat/clear cell areas (0.29+/-0.11) and no fat/clear cell areas (0.25+/-0.1) within the same nodules were not significantly different (p=0.11). CONCLUSION: Fatty and clear cell change in nodular lesions in cirrhotic liver may be an epigenetic phenotypic modification caused by microenvironmental factors such as ischaemia rather than indicating areas of increased malignant potential per se.

Journal Article↗
PubMed2006

Transjugular liver biopsy: how good is it for accurate histological interpretation?

BACKGROUND: A transjugular liver biopsy (TJLB) specimen is often smaller or more fragmented than a percutaneous liver biopsy (PLB) specimen. Recently, for PLB, the minimum requirements to evaluate chronic hepatitis have been set at 20-25 mm length and > or =11 complete portal tracts. AIM: To evaluate and compare length of TJLB and PLB specimens, portal tract number, fragmentation and adequacy for histopathological diagnosis and staging. PATIENTS AND METHODS: 326 consecutive TJLB specimens in 274 patients (109 who had undergone a transplantation), always using three passes (19-G Tru-cut) and 40 consecutive PLB specimens (15-G Menghini). RESULTS: No technical failures occurred with the TJLB, and histological diagnosis was possible in 98.5%. The median (range) number of fragments was 5 (1-13) and the median total length was 22 (3-46) mm, with 65% of specimens > or =20 mm and 36% > or =25 mm; 60% of TJLB specimens were > or =28 mm long had > or =11 complete portal tracts. No difference in complete portal tract number or biopsy length was found between PLB and TJLB specimens. CONCLUSION: A TJLB specimen with three passes is adequate for histological diagnosis, with 89% of specimens being either > or =15 mm or having > or =6 complete portal tracts. Although adequate sampling remains a limitation for staging and grading of chronic hepatitis, TJLB is comparable to PLB in this respect.

Adolescent↗
PubMed2006

Epidermal growth factor receptor expression and activation in neuroendocrine tumours.

Epidermal growth factor receptor (EGFR) is expressed in many cancers and is associated with poor prognosis. EGFR activation pathways have been well characterised using tumour cell lines and are known to involve EGFR activation through autophosphorylation. Phosphorylation of downstream signalling molecules, such as ERK1/2 (extra-cellular regulated kinase 1 and 2) and PKB/Akt (protein kinase B), leads to enhanced tumour cell survival and proliferation. Although EGFR expression has been determined in neuroendocrine tumour tissue, its activation and subsequent effects on the downstream signalling molecules, ERK1/2 and Akt, have not been studied. We therefore planned to determine the role of EGFR in neuroendocrine tumours (NETs) by determining its pattern of expression and activation, and the subsequent activation of downstream signalling molecules ERK1/2 and Akt. Paraffin-embedded tumour tissue was available from 98 patients with NETs (39 foregut, 42 midgut, four hindgut, five paragangliomas, and four of unknown origin). Immunohistochemical evaluation was performed for the expression of EGFR, p-EGFR, p-Akt, and p-ERK1/2. Ninety-six percent of tumour samples were positive for EGFR expression; 63% were positive for activated EGFR; 76% were positive for activated Akt; and 96% were positive for activated ERK1/2. Importantly, the histological score for the activation of Akt and ERK1/2 correlated with the histological score for activated EGFR. These data provide a rationale for considering EGFR inhibitors in the treatment of NETs. Additionally, direct inhibition of Akt and ERK1/2 may provide further therapeutic options in the treatment of NETs in the future.

3-Phosphoinositide-Dependent Protein Kinases↗
PubMed2006

Rejection rates in a randomised trial of tacrolimus monotherapy versus triple therapy in liver transplant recipients with hepatitis C virus cirrhosis.

BACKGROUND: Reducing immunosuppression not only reduces complications but also may lessen recurrent hepatitis C virus (HCV) infection after liver transplantation. PATIENTS/METHODS: HCV-infected cirrhotic patients randomised to tacrolimus monotherapy (MT) or triple therapy (TT) using tacrolimus 0.1 mg/kg/day, azathioprine 1 mg/kg/day, and prednisolone 20 mg/day, tapering over 3 months. RESULTS: Twenty-seven patients (MT) and 29 (TT)--median follow up 661 days (range, 1-1603). Rejection episodes (protocol/further biopsies) within first 3 months and use of empirical treatment were evaluated. New rejection was diagnosed if repeat biopsy (5-day interval) did not show improvement. Treated rejection episodes: 20 MT (15 biopsy-proven) vs. 24 TT (21 biopsy-proven), with 19 (MT) vs. 24 (TT) methylprednisolone boluses. Overall: 35 episodes (MT) and 46 (TT). Fewer MT patients had histological rejection (70%) than TT patients (86%), with fewer episodes of rejection (18.5% vs. 10%), and more moderate rejection (22% vs. 41%). The MT group had higher early tacrolimus levels. Rates of renal dysfunction, retransplantation, and death were not significantly different. CONCLUSION: Tacrolimus monotherapy is a viable immunosuppressive strategy in HCV-infected liver transplant recipients.

Adult↗
PubMed2005

Classification tool for the systematic histological assessment of hepatocellular carcinoma, macroregenerative nodules, and dysplastic nodules in cirrhotic liver.

AIM: To design a classification tool for the histological assessment of hepatocellular carcinoma (HCC), dysplastic nodules (DN), and macroregenerative nodules (MRN) in cirrhotic liver. METHODS: Two hundred and twelve hepatocellular nodules (106 HCC; 74 MRN; 32 DN) were assessed systematically, quantitatively, and semiquantitatively as appropriate for 10 histological features that have been described as helpful in distinguishing small HCC, DN, and MRN in cirrhotic livers. The data were analyzed by multiple correspondence analysis (MCA). RESULTS: MCA distributed HCC, DN, and MRN as defined by traditional histological evaluation as well as the individual histological variables, in a "malignancy scale". Based on the MCA data representation, we created a classification tool, which categorizes an individual nodular lesion as MRN, DN, or HCC based on the balance of all histological features (i.e., vascular invasion, capsular invasion, tumor necrosis, tumor heterogeneity, reticulin loss, capillarization of sinusoids, trabecular thickness, nuclear atypia, and mitotic activity). The classification tool classified most (83%) of a validation set of 47 nodules in the same way as the routine histological assessment. No discrepancies were present for DN and MRN between the routine histological assignment and the classification tool. Of 25 HCC assigned by routine assessment in the validation set, 8 were assigned to the DN category by the classification tool. CONCLUSION: We have designed a classification tool for the histological assessment of HCC and its putative precursors in cirrhotic liver. Application of this tool systematically records histological features of diagnostic importance in the evaluation of small HCC.

Carcinoma, Hepatocellular↗
PubMed2005

Obstructive jaundice secondary to neuroendocrine tumour in a patient with von Recklinghausen's disease.

Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder, with variable clinical manifestations and unpredictable course, associated with an increased incidence of various tumours. Plexiform neurofibromas are hallmark lesions of NF1; they are slow-growing tumours, which account for substantial morbidity, including disfigurement and functional impairment, and may even be life-threatening. Neuroendocrine tumours (NETs), a rare diverse group of neoplasms, are occasionally associated with neurofibromatosis. Pancreatic NETs are tumours with an incidence of less than 1/100 000 population/year and complex patterns of behaviour, which often need complicated strategies for optimal management. We present the case of a young adult with NF1, having a unique concurrence of plexiform neurofibroma involving the liver with an ampullary NET, and we discuss step by step the management in a specialist centre.

Adult↗
PubMed2005

Safety and effectiveness of 100 mg/kg/day deferiprone in patients with thalassemia major: a two-year study.

Deferiprone at a dose of 75 mg/kg/day is not sufficiently effective to maintain iron stores at a level which has been considered safe in all patients with iron overload. Our main aim was to determine the safety of long-term therapy with high-dose (100 mg/kg/day) deferiprone. A secondary aim was to determine the efficacy of this high dose. Twelve thalassemia major patients received deferiprone at a dose of 100 mg/kg/day over 2 years. Transient aspartate aminotransferase increase (8 patients), gastrointestinal discomfort (3 patients) and arthralgia (2 patients) were the most commonly reported side effects. None of the patients discontinued therapy. The mean serum ferritin level fell from 3,901 +/- 3,618 to 1,790 +/- 2,205 microg/l after 2 years (p < 0.05). Five of the 12 patients continued to receive deferiprone for an additional 3 years. No new side effects were encountered. The mean serum ferritin level in this subgroup was initially 2,510 +/- 332 microg/l and dropped to 1,511 +/- 664 microg/l after 5 years (p < 0.05). Liver iron levels at the end of the 2-year study ranged from 1.0 to 30.9 mg/g dry weight, 3 of the patients having levels above 15 mg/g.

Adolescent↗
PubMed2005

Vascular invasion and herniation by hepatocellular carcinoma in cirrhosis: A wolf in sheep's clothing?

CONTEXT: Vascular invasion is an important diagnostic and prognostic feature of hepatocellular carcinoma (HCC) in cirrhosis. Intravascular free-floating tumor clusters (IvCs) of HCC are found histologically in the vicinity of HCC. Thrombus formation is not seen morphologically in association with these IvCs, which are usually covered by endothelium. OBJECTIVE: Our hypothesis is that these IvCs are the result of a nondestructive form of vascular invasion by HCC, and we tried to define this aspect of microvascular invasion more accurately. DESIGN: Tissue sections were stained with hematoxylin-eosin, and consecutive sections were stained for fibrin (Martius scarlet blue, fibrinogen), platelets (factor XIIIa), smooth muscle actin, and endothelium (CD34). We studied cirrhotic livers removed at transplantation between 1997 and 1999. Of the livers studied, 35 of 81 consecutive cirrhotic livers contained HCC, and 17 showed microscopic vascular invasion. Five of these 17 cases showed IvCs and were subjected to the study. MAIN OUTCOME MEASURE: Presence or absence of thrombus formation in association with IvC. RESULTS: Usually, IvCs were covered by endothelium, and no associated thrombus formation was seen. In 1 case of HCC, thrombus formation was seen focally in association with disruption of the endothelial coating. CONCLUSIONS: We propose that the endothelial-lined trabecular structure of HCC everts, frondlike, via vascular structures within the tumor capsule into peritumoral vascular lumens without destruction of the endothelial coating. This may protect these HCC tumor projections from thrombus formation but may also act as a barrier to tumor extravasation, and this may be exploited from a therapeutic point of view.

Actins↗
PubMed2004

Localized granulomatous reaction to a semi-permanent hyaluronic acid and acrylic hydrogel cosmetic filler.

Dermalive, an injectable skin filler composed of a combination of synthetic hyaluronic acid and acrylic hydrogel particles was recently developed for soft tissue augmentation. Dermalive produces longer term results than temporary injectable fillers and is associated with a reportedly low incidence of adverse reactions. We describe a marked local reaction to the injection of Dermalive in the nasolabial fold developing within 4 months with histological confirmation of a granulomatous response. To our knowledge there has been only one previous report of a local granulomatous reaction to Dermalive.

Acrylates↗
PubMed2004

Extramedullary haematopoiesis in massive hepatic necrosis.

AIMS: To determine the frequency of extramedullary haematopoiesis (EMH) in massive hepatic necrosis (MHN). METHODS AND RESULTS: Explanted livers of 11 adult patients transplanted consecutively for MHN were examined histologically and immunohistochemically for the presence of EMH. The aetiology of the liver damage was unknown in seven cases and drug induced in four. The presence of stem cell markers (CD34, c-kit), erythroid precursors (glycophorin A), myeloid precursors (myeloperoxidase) and megakaryocyte precursors (CD31) was investigated by immunohistochemistry. Erythroid, myeloid and megakaryocyte precursors were observed in all cases. Morphologically, haematopoietic blast cells were clustered in areas of collapse, separating islands of regenerating ductules and scattered between ductules, in a similar distribution to immunohistochemically identified c-kit-positive putative stem cells. No CD34+ cells other than endothelial cells were seen. All 11 patients were anaemic at the time of transplantation. CONCLUSIONS: EMH is a frequent finding in patients undergoing liver transplantation for MHN. This may be a consequence of the anaemia associated with this condition. Alternatively, the possibility that intrahepatic haematopoiesis is linked with hepatopoiesis is an additional, intriguing possibility that deserves further study.

Adolescent↗
PubMed2004

Natural history of hepatitis B in perinatally infected carriers.

OBJECTIVES: To establish natural seroconversion rates and incidence of hepatic pathology in perinatally infected hepatitis B carriers. METHODS: Seventy three perinatally infected hepatitis B carriers identified through maternal screening were evaluated. Fifty three were born to parents from the Indian subcontinent, nine were Oriental, six were Afro-Caribbean, and five were white. Median follow up was 10.24 (range 2.02-20.16) years. RESULTS: Only three of the children followed up had cleared hepatitis B surface antigen during this period, and 30% of the children had seroconverted to anti-HBe. Seroconversions to anti-HBe were observed in Asian (18/50) and white (4/5) children, but not in Oriental or Afro-Caribbean children. More girls (40%) than boys (23%) had seroconverted, but the difference was not significant. All children were asymptomatic with normal physical examination, growth, and development. Almost half (48%) of the hepatitis B e antigen (HBeAg) positive children had normal hepatic transaminases and liver function. Thirty five liver biopsies were performed in children with active virus replication (HBeAg or hepatitis B virus DNA positive) who were being considered for antiviral treatment as part of a clinical trial and were scored using the Ishak method. Two thirds (62%) of the children had mild hepatitis, 60% had mild fibrosis, and 18% had moderate to severe fibrosis. There was a weak correlation between histological evidence of hepatitis and hepatic transaminase activity, implying that biochemical monitoring of hepatic disease activity may be ineffective. CONCLUSIONS: These asymptomatic hepatitis B virus carrier children remain infectious in the medium to long term with notable liver pathology. They should receive antiviral treatment to reduce infectivity and to prevent further progression of liver disease. Hepatic transaminases alone are not a reliable marker of liver pathology, and liver histology is essential before consideration for antiviral treatment.

Adolescent↗
PubMed2004

Five-year trial of deferiprone chelation therapy in thalassaemia major patients.

Twelve thalassaemia major patients have been given deferiprone 75 mg/kg body weight daily as iron chelation therapy for 5 years. Their ages ranged from 18 to 34 years (mean 24.2) at the end of the study. Two patients were hepatitis C virus (HCV) mRNA positive and a further 5 were positive for HCV antibody. The mean serum ferritin level fell significantly from 4,302 +/- 2,245 microg/l SD at baseline to 3,032 +/- 1,155 microg/l at 2 years (p = 0.037) and 2,229 +/- 1,070 microg/l (p = 0.007) at 5 years. At the end of the study, liver iron ranged from 3.59 to 23.7 mg/g dry weight (mean 11.9 +/- 5.4), 3 patients having levels >15 mg/g. There was no significant change in serum AST levels, but ALT levels fell significantly at 2 years (p = 0.019) and 5 years (p = 0.001). Liver biopsy at the end of the study showed no evidence of hepatic fibrosis caused by deferiprone. Cardiac studies showed no overall change in left ventricular ejection fraction but a significant improvement in isovolumic relaxation time (p = 0.045). We conclude that in this albeit small group of thalassaemia major patients, deferiprone was a safe long-term method of iron chelation. In a minority, higher doses of deferiprone or a combination with desferrioxamine would be needed to lower liver iron below 15 mg/g.

Adolescent↗
PubMed2003

Focal nodular hyperplasia-like areas in cirrhosis.

AIMS: Focal nodular hyperplasia-like lesions have rarely been described in cirrhotic livers. We describe five cases of such lesions. METHODS AND RESULTS: Between 1998 and 2001, 146 liver transplants were performed at the Royal Free Hospital for cirrhosis of the liver. Nodular lesions identified in the livers removed at transplantation were defined histologically according to the International Working Party classification (Hepatology 1995; 22; 983). They were present in 63 of these livers, as follows: 36 dysplastic nodules, 121 macroregenerative nodules, and 71 hepatocellular carcinomas. In five patients, an additional 12 nodules (size range 4-23 mm, median 10.5 mm) showed histological features suggestive of focal nodular hyperplasia including mildly inflamed vascular fibrous septa, and ductular proliferation. Pre-transplantation imaging showed features suspicious for hepatocellular carcinoma, in three of these lesions (12, 23 and 23 mm diameter) from two different patients. These lesions were histologically indistinguishable from focal nodular hyperplasia occurring in non-cirrhotic livers, with fibrous scars and septa which contained vascular and ductular structures. CONCLUSIONS: It is important to recognize that these lesions may occur in the context of cirrhosis and that they should be considered in the differential diagnosis with hepatocellular carcinoma, dysplastic nodules and macroregenerative nodules.

Adult↗
PubMed2002

A pilot study of treatment of active ulcerative colitis with natalizumab, a humanized monoclonal antibody to alpha-4 integrin.

BACKGROUND: Alpha-4 integrins facilitate leucocyte migration across vascular endothelium. AIM: To assess the safety and efficacy of natalizumab (Antegren), a humanized antibody to alpha-4 integrin, in patients with active ulcerative colitis. METHODS: Ten patients with active ulcerative colitis, defined by a Powell-Tuck activity score > 4, received a single 3 mg/kg natalizumab infusion. The primary end-point was the change in Powell-Tuck score at 2 weeks post-infusion. RESULTS: Significant decreases in the median Powell-Tuck score were observed at 2 and 4 weeks post-infusion (7.5 and 6, respectively) compared to the median baseline score (10). Five of 10 patients achieved a good clinical response at 2 weeks and one more patient by 4 weeks, defined by a Powell-Tuck score of < or = 5. Significant improvements in quality of life scores were found at week 4. Rescue medication was required by two (20%), three (30%) and eight (80%) patients by weeks 2, 4 and 8, respectively (median, 34 days; range, 8-43 days). One patient remained in remission at 12 weeks. The median C-reactive protein at 2 weeks (6 mg/L) was lower than that pre-treatment (16 mg/L). CONCLUSIONS: A single 3 mg/kg infusion of natalizumab was well tolerated by ulcerative colitis patients. The positive efficacy demonstrated in this study merits further investigation by randomized, placebo-controlled trials.

Antibodies, Monoclonal↗
PubMed2002

Moderate alcohol intake increases fibrosis progression in untreated patients with hepatitis C virus infection.

Although excessive alcohol consumption in combination with hepatitis C virus (HCV) infection is known to increase the risk of liver cirrhosis, the effect of moderate alcohol intake remains to be elucidated. The aim of this study was to evaluate the effect of moderate alcohol consumption on fibrosis progression in HCV infection. A group of 78 patients with HCV infection and moderate alcohol consumption were analysed retrospectively. All patients had undergone two liver biopsies, with a median time between biopsies of 6.3 years, and had not received any antiviral therapy. Their lifetime drinking history was recorded. All patients except one had daily alcohol consumption below 40 g of ethanol (median 4.8 g/day, interquartile range 1.1-11.6 g/day) during the period between the biopsies. The patients whose liver fibrosis had deteriorated had a higher total alcohol consumption and higher drinking frequency between the biopsies. The degree of fibrosis progression was greater in patients with a total alcohol intake and drinking frequency above the median level for the group. A multiple logistic regression analysis showed that drinking frequency and time between biopsies were independently associated with fibrosis progression. Hence, even moderate alcohol intake seems to increase fibrosis progression in HCV-infected patients. From that point of view, total abstention ought to be recommended. If this is not achieved, occasional use of alcohol is probably less harmful than daily drinking for patients with low or moderate alcohol consumption.

Adult↗