High resolution TCSPC imaging of diffuse light with a one-dimensional SPAD array scanning system.

We report a time-correlated single-photon counting (TCSPC) imaging system based on a line-scanning architecture. The system benefits from the high fill-factor, active area, and large dimension of an advanced CMOS single-photon avalanche diode (SPAD) array line-sensor. A two-dimensional image is constructed using a moving mirror to scan the line-sensor field-of-view (FOV) across the target, to enable the efficient acquisition of a two-dimensional 0.26 Mpixel TCSPC image. We demonstrate the capabilities of the system for TCSPC imaging and locating objects obscured in scattering media - specifically to locate a series of discrete point sources of light along an optical fibre submerged in a highly scattering solution. We demonstrate that by selectively imaging using early arriving photons which have undergone less scattering than later arriving photons, our TCSPC imaging system is able to locate the position of discrete point sources of light than a non-time-resolved imaging system.

A phase 1, single centre, open label, escalating dose study to assess the safety, tolerability and immunogenicity of a therapeutic human papillomavirus (HPV) DNA vaccine (AMV002) for HPV-associated head and neck cancer (HNC).

BACKGROUND: We conducted a phase 1 dose escalation study (ACTRN12618000140257 registered on 30/01/2018) to evaluate the safety, tolerability and immunogenicity of a therapeutic human papillomavirus (HPV) DNA vaccine (AMV002) in subjects previously treated for HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). METHODS: Eligible subjects had to have no evidence of recurrent and/or metastatic disease at least 12 weeks following the completion of treatment. Three dosing cohorts each consisted of four subjects: group 1: 0.25 mg/dose, group 2: 1 mg/dose, group 3: 4 mg/dose. AMV002 was delivered intradermally on days 0, 28 and 56. Incidence and severity of treatment-emergent adverse events (TEAE) including local reaction at the injection site, and vaccination compliance were recorded. T cell and antibody responses to HPV16 E6 and E7 were measured by interferon gamma (IFN-γ) enzyme-linked immunosorbent spot (ELISpot) assay and enzyme-linked immunosorbent assay (ELISA). RESULTS: All subjects completed the vaccination programme and experienced mild discomfort at the injection site(s). Pre-immunisation, cell-mediated responses to HPV16 E6 and E7 were evident in all subjects, and E7-specific antibodies were detected in 11 (91.7%), reflecting previous exposure to HPV. Post-vaccination, 10 of 12 (83.3%) subjects responded to one or more of the E6 and/or E7 peptide pools, while 2 (16.7%) did not show additional vaccine-induced cell-mediated responses. Vaccination resulted in a ≥ 4-fold increase in anti-HPV16 E7 antibody titre in one subject in group 3. CONCLUSIONS: AMV002 was well tolerated at all dose levels and resulted in enhanced specific immunity to virus-derived tumour-associated antigens in subjects previously treated for HPV-associated OPSCC.

The outcome of the first 165 orthotopic liver transplants in Scotland.

The Scottish Liver Transplant Unit is now in its sixth year of existence. We present the outcome of the first 165 transplants which have at least 12 months follow up. The overall patient (n = 143) survival rates at 1, 3 and 5 years were 86.6%, 79.3% and 74.7% and the graft survival rates were 76.9%, 69.1% and 64.8%. The one year survival rate for patients with chronic liver disease (n = 113) was 89.2% compared with 76.6% for acute liver failure (Breslow = 0.05). The one year survival rate for the first 71 patients receiving their primary graft was 81.7% compared with 91.5% for the subsequent 71 patients (Breslow = 0.09). The majority of deaths (n = 29) were due to sepsis (n = 7), at operation (n = 6) or due to graft vascular insufficiency (n = 4). There were two cases of de novo haematological malignancy. The outcome of the first 165 transplants in Scotland compares very well with other countries throughout the world.

Ascites in hepatic cirrhosis: recognition, investigation and treatment

La cirrosis hepática es la causa más común de ascitis. Es causada por insuficiencia hepática que lleva a cambios complejos renales y circulatorios interrelacionados, que resultan en retención de sodio y agua e hipertensión portal, localizando el sodio y el agua en el peritoneo. La ascitis es una complicación importante de la cirrosis, que implica generalmente un pobre pronóstico a largo plazo. La investigación de la ascitis es importante, porque no simpre se debe a cirrosis, puede ser la consecuencia de complicaciones de esta, tales como carcinoma hepatocelular y puede estar asociado con infección, la cual es fatal, sino es tratada. La mayoría de pacientes responden a tratamiento con restricción de sodio y diuréticos. Este tratamiento toma tiempo y cada vez más médicos recurren a la paracentesis terapéutica con restricción de sodio y uso de diuréticos para prevenir la recurrencia de la ascitis. La paracentesis sin embargo no está libre de complicaciones, por lo que es particularmente importante dar coloides como reemplazo, para prevenir la hipovolemia que puede llevar a insuficiencia renal. Los pacientes que ni responden a este tratamiento pueden ser ayudados con un procedimiento de TIPS ó un shunt peritoneo venoso. Sin embargo esos pacientes tiene una función hepática muy pobre y se considerará la posibilidad del transplante hepático. La infección es una complicación muy seria de la ascitis (peritonitis bacteriana espontánea) y generalmente tiene un pobre pronóstico. La profilaxis antibiótica es importante para prevenir la recurrencia y se considerará el transplante hepático.

A randomized trial comparing transjugular intrahepatic portosystemic stent-shunt with variceal band ligation in the prevention of rebleeding from esophageal varices.

The aim of this study was to compare transjugular intrahepatic portosystemic stent-shunt (TIPSS) with variceal band ligation (VBL) in the secondary prophylaxis of esophageal variceal hemorrhage in patients with cirrhosis. Fifty-eight patients with cirrhosis who presented with the first episode of esophageal variceal hemorrhage were randomized to TIPSS (31) or VBL (27), 24 hours after control of bleeding. Shunt function was assessed after 1 month and then at 6 monthly intervals thereafter. VBL was performed weekly until variceal eradication, and then at 3 months, 6 months, and yearly thereafter. Mean follow-up in the TIPSS group was 15.7 (+/-10.2) months; in the VBL group, it was 16.8 (+/-10.9) months. Results for rebleeding and mortality were analyzed on an intention-to-treat basis and using the Kaplan-Meier method. The frequency and the severity of variceal rebleeding was significantly lower in the TIPSS group (9.8%), compared with the VBL group (51.9%) (P < .0006). Although mortality rates were not significantly different, 8 of the patients who rebled in the VBL group required TIPSS therapy for uncontrolled bleeding. No significant differences were found in the frequency of other complications such as encephalopathy and sepsis. Patients in the VBL group required significantly greater time in the intensive care unit during the period of this study (<0.03). The total direct cost of treatment incurred was pound sterling 1,373 ($2,200) per patient, the cost being less in the patients treated with TIPSS compared with VBL. The results of this study show that TIPSS is superior to VBL for the secondary prophylaxis of variceal hemorrhage in patients with cirrhosis.

Measurement of spleen size and its relation to hypersplenism and portal hemodynamics in portal hypertension due to hepatic cirrhosis.

AIMS: Splenomegaly is common in portal hypertension due to hepatic cirrhosis, but there are little data comparing different methods of spleen measurement. We have compared ultrasound with radionuclide imaging in measuring splenomegaly. The relation of splenomegaly to hypersplenism and portal hemodynamic factors was also studied. RESULTS: Ultrasound and radionuclide measures of spleen volume gave comparable results (r = 0.95, p < 0.0001). Phagocytic activity of the spleen measured by radionuclide uptake increased as the volume of the spleen increased (r = 0.46, p < 0.03) but was not related to diminishing liver phagocytic activity. Spleen volume was correlated negatively with leukocyte counts (r = 0.43, p < 0.05) but not with hemoglobin or platelet counts. Spleen radionuclide uptake was negatively correlated with hemoglobin (r = 0.48, p < 0.04) and leukocyte counts (r = 0.46, p < 0.04) but not with platelet counts. Spleen volume was related to portal vein cross-sectional area (r = 0.91, p < 0.0001) and portal vein blood flow volume (r = 0.57, p < 0.008) but not to portal vein blood flow velocity, portal pressure gradient, or azygos blood flow. CONCLUSIONS: Spleen size measured by ultrasonography and radionuclide studies gives comparable results. Spleen phagocytic activity in cirrhosis increases as the spleen enlarges but not in relation to decreased hepatic phagocytic activity. Spleen phagocytic activity probably contributes to anemia and leukopenia in the splenomegaly of cirrhosis, but other factors must contribute to thrombocytopenia. Portal hemodynamics are probably important in the splenomegaly, but the interrelation is complex.

Clinical evaluation of liver disease.

The clinical history and examination is essential in the evaluation of patients with liver disease. This chapter details important points in the clinical history and examination allowing the physician to identify likely causes of liver damage and their investigation. The evaluation should allow the physician to differentiate acute and chronic liver diseases, and in the latter case separate those with obstructive or chronic parenchymal liver disease. It should also allow identification of important complications such as encephalopathy, ascites and portal hypertension. Identification of these main features or complications of liver disease by the clinical evaluation leads to a logical plan of investigation and prompt diagnosis and management of the liver disease.

A comparative study of emergency transjugular intrahepatic portosystemic stent-shunt and esophageal transection in the management of uncontrolled variceal hemorrhage.

OBJECTIVES: Transjugular intrahepatic portosystemic stent-shunts (TIPSS) have been shown to reduce portal hypertension consistently and have recently been reported to arrest active variceal hemorrhage. This retrospective and nonrandomized study compares the results of TIPSS with esophageal transection (ET) and devascularization in patients with uncontrolled variceal hemorrhage admitted to a single center with an interest in variceal bleeding. PATIENTS AND METHODS: Two hundred and sixty cirrhotic patients have been referred with variceal bleeding over the past 7 yr. In 41 patients (15.8%), hemorrhage was uncontrolled despite two treatments with sclerotherapy. Thirty-eight patients were eligible for analysis. Nineteen were considered for ET and 19 for TIPSS. Patients in the two groups were well matched for age, sex, etiology of liver disease, and its severity and complications. They have been followed for 13 patient years (TIPSS-7, longest 20 months; ET-6, longest 23 months). Data for survival and rebleeding were analyzed by the Kaplan-Meier method on an intention-to-treat basis. RESULTS: Seven of the 19 were considered unfit for surgery, and 12 underwent esophageal transection and devascularization. TIPSS was undertaken successfully in 17 patients, the Palmaz stent being used in 4 and the Wallstent in 13. Successful TIPSS reduced the mean portal pressure gradient from 22.2 (SE 1.2) to 9.7 (SE 0.7) mm Hg (p < 0.001). Mortality within 30 days of the initial bleed was 42% in the TIPSS group compared with 79% in the ET group (p < 0.05). Rebleeding occurred in 15.6% patients with TIPSS, compared with 26.2% in the ET group. Encephalopathy in the two groups of patients was not significantly different (TIPSS 25% and ET 22%). TIPSS was followed by active infection in 20% compared with 36% after ET. CONCLUSIONS: This study shows that the overall mortality in this group of patients is high whatever the type of treatment used. TIPSS can be performed successfully on these patients who are often not suitable for surgery. Mortality rates were significantly lower in patients treated by TIPSS. Compared with ET, TIPSS should be regarded as the preferred mode of treatment for uncontrolled variceal hemorrhage in patients with cirrhosis.

Analysis of prognostic variables in the prediction of mortality, shunt failure, variceal rebleeding and encephalopathy following the transjugular intrahepatic portosystemic stent-shunt for variceal haemorrhage.

BACKGROUND/AIMS: The aim of this study was to analyse prognostic variables predicting mortality, shunt insufficiency, variceal rebleeding and encephalopathy following transjugular intrahepatic portosystemic stent-shunt for variceal haemorrhage. METHODS: Sixty-eight patients with cirrhosis who successfully underwent transjugular intrahepatic portosystemic stent-shunt for variceal haemorrhage were studied. Mean age was 54.8 years (s.e. 1.5); 41 were males and 27 were females. Mean Child score was 8.3 (s.e. 0.3). Cirrhosis was alcohol related in 47. The patients have been followed up for a mean of 10.8 (s.e. 1.1) months. The univariate association between 30 prognostic variables and post-treatment encephalopathy was tested by the Chi-squared or Wilcoxon rank-sum tests and multiple logistic regression was used to test the significance of factors adjusted for one another. Cox's proportional hazard regression was used to test the univariate and multivariate significance of the other three outcomes. RESULTS: Transjugular intrahepatic portosystemic stent-shunt was performed successfully in 89.5% of patients. Twenty-two patients have died and eight have been transplanted. Fourteen patients died within 30 days of transjugular intrahepatic portosystemic stent-shunt and death was predicted independently by hyponatraemia (p < 0.001) and by severe liver disease (Child C, p < 0.001). Eight patients died during follow up and survival in the long term was predicted independently by the presence of encephalopathy (p < 0.001) prior to transjugular intrahepatic portosystemic stent-shunt (p < 0.001). Shunt insufficiency was predicted by an initial portal pressure gradient of greater than 18 mmHg (p < 0.01). None of the variables analysed predicted variceal rebleeding. Encephalopathy following transjugular intrahepatic portosystemic stent-shunt was only predicted indepedently by its presence prior to transjugular intrahepatic portosystemic stent-shunt (p < 0.001). CONCLUSIONS: The results of this study suggest that patients with severe liver disease and hyponatraemia are liable to die early, and the presence of encephalopathy prior to transjugular intrahepatic portosystemic stent-shunt independently determines long-term survival. Patients in these groups should be considered high risk and worked up for orthotopic liver transplantation early. Shunt function in patients with an initial portal pressure gradient of > 18 mmHg requires close supervision. Encephalopathic patients should have smaller shunts and prophylactic measures to prevent worsening encephalopathy.

Laparoscopy and histology in the diagnosis of chronic liver disease.

We compared laparoscopy with histology in identifying fatty change, fibrosis, the degree of inflammatory activity, cirrhosis and the cause of liver disease. Laparoscopic liver biopsy was performed in 145 consecutive patients. The laparoscopist and the histologist were provided with similar clinical and biochemical information. Both scored the appearances on respective examinations for the degree of fatty change, fibrosis and activity, presence or absence of cirrhosis; and provided a provisional diagnosis. The final diagnosis was determined by clinicopathological conference and clinical follow-up. Laparoscopy was successfully performed in 142 patients (97.9%). Compared with histology, the sensitivity and specificity of laparoscopy for identifying fatty change were 96.4% and 100%, 100% and 95% for fibrosis and 94% and 95% for inflammatory activity, respectively. For cirrhosis, laparoscopy was 100% sensitive and 97.1% specific. Histology missed 10 cases of cirrhosis (6.1%). Histology did, however, provide additional information in 9 patients (6.3%) which contributed to the final diagnosis. Overall, histology is required in addition to laparoscopy in cases where the aetiology is unclear. The sensitivity and specificity in identifying fatty change, fibrosis, activity and cirrhosis are similar for laparoscopy and histology. The combination of information gained on laparoscopy with histology provides the diagnosis in most patients. Laparoscopy may replace the need for liver biopsy in patients in whom the aetiological diagnosis is not in question and the biopsy is being performed to stage the disease. We used it as an integral part of the work-up of a patient with liver disease.

The platelet count as a predictor of variceal hemorrhage in primary biliary cirrhosis.

BACKGROUND: Variceal bleeding is a common, life-threatening complication of primary biliary cirrhosis (PBC) that remains difficult to predict. OBJECTIVE: The aim of this study was to identify whether certain biochemical and hematological parameters may be used as predictors of variceal bleeding in patients with PBC. METHODS: Cox proportional hazard regression analysis was used to test whether various prognostic factors were significantly associated with the time of first bleeding in 63 patients with proven PBC, of whom 11 had subsequent bleeding. RESULTS: Both the first available platelet count and the bilirubin level were of significant value in predicting variceal bleeding, but only the platelet count was an independent predictor of bleeding. In the group of patients who subsequently bled, there was a progressive drop in the platelet count over the follow-up period, with a proportional increase in the risk of bleeding; a platelet count below 200 x 10(9)/L was strongly associated with variceal bleeding (p < 0.001). None of the patients with platelet count above 200 x 10(9)/L bled over a total of 136 patient-years follow-up. In the group who did not bleed, no change in platelet count was identified during follow up. CONCLUSION: We conclude that the platelet count can be used as a predictor of variceal bleeding in PBC.

Primary pulmonary hypertension developing 11 years after a splenorenal shunt for portal hypertension in hepatic cirrhosis.

OBJECTIVE: To describe a patient with pulmonary and portal hypertension and to review the pathogenesis and management of this condition. PATIENT: A 22-year-old woman with portal hypertension and liver cirrhosis who later developed pulmonary hypertension. INTERVENTIONS: The patient received antibiotic therapy and underwent a splenectomy and proximal splenorenal shunt for portal hypertension. She later received hydralazine, digoxin and warfarin for pulmonary hypertension. MAIN OUTCOME MEASURES: After undergoing a splenorenal shunt the patient made a good recovery. However, she later developed pulmonary hypertension and died after undergoing a hysterectomy and a bilateral salpingo-oophorectomy. CONCLUSIONS: The concomitant development of portal and pulmonary hypertension in the same patient has a poor prognosis. The treatment available for patients with these conditions is unsatisfactory and most patients eventually die as a result of cardiovascular disease. Cardiopulmonary and liver transplantation should be considered in suitable patients.

Portal and systemic haemodynamic response to acute and chronic administration of low and high dose isosorbide-5-mononitrate in patients with cirrhosis.

Oral isosorbide-5-mononitrate (Is-5-Mn) was given in doses of 10 and 40 mg acutely and chronically (twice daily for four weeks), allowing a nitrate free interval to 25 patients with cirrhosis. Both 10 mg and 40 mg Is-5-Mn reduced the hepatic venous pressure gradient acutely and chronically, without evidence of tolerance. This was achieved by a reduction in the wedged hepatic venous pressure. The effect on mean azygos blood flow was variable with no significant mean change seen acutely or after chronic use with either dose. The variability was dependent not on the dose used but on the initial azygos flow; the flow in patients with initially low values increased and those with high azygos flows decreased after nitrate challenge. The development of the porto-collateral flow seems an important parameter in predicting haemodynamic response to Is-5-Mn.