Effect of severe hypoalbuminemia on toxicity of high-dose melphalan and autologous stem cell transplantation in patients with AL amyloidosis.

High-dose melphalan with stem cell transplantation (HDM/SCT) extends survival and induces hematologic and clinical responses in patients with light chain (AL) amyloidosis. Eighty percent of melphalan is bound to plasma proteins (60% albumin-bound). We hypothesized that patients with profound hypoalbuminemia have a greater free melphalan fraction and more toxicity. Patients with AL amyloidosis treated with HDM/SCT between 2011 and 2014 with severe hypoalbuminemia (SH), defined as serum albumin ⩽2 g/dL were studied retrospectively. Sixteen patients with SH were identified. Forty-one patients without severe hypoalbuminemia (WSH) treated between 2011 and 2012 served as control. The incidence of acute renal failure requiring hemodialysis was 25% among patients with SH, compared with 5% among patients WSH (P=0.05). Not all patients who needed dialysis required it long term; 6.25% for SH and 2.44% for WSH (P=0.49). The rates of grade 3 or 4 febrile neutropenia and gastrointestinal toxicities were not significantly different between the groups. Engraftment kinetics were similar for both groups. Grade 4 renal toxicity and grade 3 lightheadedness were more frequent in patients with SH undergoing HDM/SCT for AL amyloidosis. Further studies into the mechanism of increased renal toxicity in patients with SH are warranted.

Safety and efficacy of high-dose melphalan and auto-SCT in patients with AL amyloidosis and cardiac involvement.

In Ig light chain (AL) amyloidosis, cardiac involvement is associated with worse prognosis and increased treatment-related complications. In this retrospective cohort study, we assessed survival, hematologic and cardiac responses to high-dose melphalan and auto-SCT (HDM/SCT) in patients with AL amyloidosis and cardiac involvement, stratified by cardiac biomarkers brain natriuretic peptide and Troponin I, analogous to the Mayo cardiac staging. Forty-seven patients underwent HDM/SCT based upon functional measures; six patients had modified cardiac stage I disease, seventeen had modified cardiac stage II disease and twenty-four had modified cardiac stage III disease. Treatment-related mortality was 4% for all patients and 8% for patients with stage III disease. Three-year survival was 88% and EFS was 47%; these did not differ by stage. By intention-to-treat analysis, 27% of patients achieved a hematologic complete response and 32% a very good partial response, of whom 70 and 45%, respectively, have not required additional therapy at 36 months. Cardiac response was achieved in 53% of patients. We conclude that with appropriate patient selection and a risk-adapted treatment approach, HDM/SCT is safe and effective in patients with AL amyloidosis and cardiac involvement.

SCT in Jehovah's Witnesses: the bloodless transplant.

Auto-SCT and Allo-SCT are procedures conventionally associated with intensive transfusion support. This dependence has historically prevented SCT in individuals with religious or personal objections to transfusion. More recently, a growing body of literature supports the feasibility of 'bloodless transplants': SCT without the transfusion of RBCs, plts or plasma. It is possible to perform 'bloodless' autologous or reduced-intensity allogeneic transplants in properly selected patients. The success of these procedures depends on the transplantation technique and on meticulous attention to blood conservation and supportive care. In this study, the literature supporting bloodless transplantation will be reviewed. Supportive measures such as the optimal stimulation of erythropoiesis and thrombopoiesis in the transplant patient will be discussed, as will the prevention and management of bleeding during extreme thrombocytopenia. Many of these techniques, learned and refined in Jehovah's Witnesses, may help reduce bleeding and transfusion requirements in the general transplant population.

TP53 and progression from Barrett's metaplasia to oesophageal adenocarcinoma in a UK population cohort.

BACKGROUND AND AIMS: Oesophageal adenocarcinoma frequently develops on a background of metaplastic Barrett's epithelium. The development of malignancy is accompanied by genetic alterations, which may be promising biomarkers of disease progression. METHODS: A case control study was conducted nested within a large unselected population based cohort of Barrett's patients. Incident oesophageal malignancies and high grade dysplasias were identified. For each case up to five controls were matched on age, sex, and year of diagnosis. Biopsies from the time of diagnosis of Barrett's epithelium were stained immunohistochemically for TP53, cyclin D1, cyclooxygenase 2 (COX-2), and beta-catenin proteins. RESULTS: Twenty nine incident oesophageal malignancies and six cases of high grade dysplasia were identified. The odds of diffuse or intense TP53 staining were substantially elevated in biopsies from patients who developed oesophageal adenocarcinoma compared with controls (odds ratio (OR) 11.7 (95% confidence interval (CI) 1.93, 71.4)). This difference was also present when all cases were considered (OR 8.42 (95% CI 2.37, 30.0). Despite the association with TP53 staining, only 32.4% of cases had an initial biopsy showing diffuse/intense TP53 staining. There were no significant associations between cyclin D1, COX-2, or beta-catenin staining and case control status. The OR for positive staining for both TP53 and COX-2 was markedly increased in cases compared with controls (OR 27.3 (95% CI 2.89, 257.0)) although only 15% of cases had positive staining for both markers. CONCLUSIONS: Immunohistochemical detection of TP53 expression is a biomarker of malignant progression in Barrett's oesophagus but sensitivity is too low to act as a criterion to inform endoscopic surveillance strategies. Additional biomarkers are required which when combined with TP53 will identify, with adequate sensitivity and specificity, Barrett's patients who are at risk of developing cancer.

Coeliac disease-associated antibodies correlate with psoriasis activity.

BACKGROUND: Antigliadin antibodies (AGA) have been reported in patients with psoriasis. OBJECTIVES: To determine if AGA and other coeliac disease (CD)-associated antibodies correlate with clinical features and activity in patients with psoriasis. METHODS: Patients with psoriasis (n = 130) were investigated for serum IgG and IgA AGA, IgA antitransglutaminase antibody and IgA antiendomysial antibody. Disease characteristics and associated bowel and joint symptoms were determined. All patients were invited to undertake endoscopy with duodenal biopsy. RESULTS: A significantly higher proportion of patients with elevated CD-associated antibody levels was currently on or had previously required systemic immunosuppressants (methotrexate, ciclosporin or etretinate; P = 0.04) or psoralen plus ultraviolet A phototherapy (P = 0.03). One case of CD was diagnosed. CONCLUSIONS: The presence of CD-associated antibodies in psoriasis patients correlates with greater disease activity.

Esophagitis: optimizing diagnostic yield by biopsy orientation.

OBJECTIVES: There is poor correlation between gastroesophageal reflux (GER) symptoms, intraesophageal pH monitoring and endoscopic or histologic appraisal of esophagitis in the pediatric age group. To optimize the diagnosis of childhood esophagitis, histologic evaluation of esophageal pinch and suction biopsies after orientation were compared. METHODS: Thirty consecutive children with GER, age range 6 months to 7 years, were prospectively evaluated with upper gastrointestinal endoscopy and biopsy. Three pinch biopsies and one suction biopsy were examined after different methods of biopsy orientation. The suction biopsy orientated with x 10 magnification represented the standard against which the pinch biopsies were compared. RESULTS: After suction biopsy with tissue orientation using x 10 magnification 90% of biopsies were adequate for histologic appraisal. Ninety-three percent of esophageal pinch biopsies orientated with x 10 magnification were adequate for analysis. After pinch biopsy orientated without magnification 90% of biopsies were suitable for histologic appraisal. Finally, in the pinch biopsy group without formal orientation, only 63% of the biopsies were adequate for histologic analysis and diagnosis of esophagitis. CONCLUSION: Orientation of esophageal pinch biopsies improves histologic appraisal and hence increases the diagnostic yield of esophagitis in children with GER. The tissue fragments can be easily orientated in the endoscopy room before placement in fixative.

Early experience with chronic hepatitis C in Northern Ireland: epidemiology and response to monotherapy.

UNLABELLED: Chronic hepatitis C virus (HCV) infection has become a major health problem affecting an estimated 170 million people worldwide. The epidemiology of HCV and its response to treatment in Northern Ireland has not been described before. Our aims were to determine the epidemiology, histological stage, suitability for treatment and response to treatment in patients with hepatitis C presenting to one clinic in Northern Ireland. All patients were prospectively recruited with hepatitis C attending the Liver Clinic, Royal Victoria Hospital during the period December 1992 to June 1997. Sixty patients (33 male, mean age 44 years, range 19-84 years) who tested anti-HCV antibody positive were identified. The predominant genotypes were 1b (33%), 3a (28%) and 1a (26%). Most patients (78%) were asymptomatic at the time of detection and only four (7%) gave a history of jaundice. The most common modes of transmission were i.v. drug use in 30 (50%) and blood products in 20 (33%) patients. Forty-eight (86%) of the 56 patients tested were PCR positive for HCV RNA. Fifty-one patients (85%) underwent liver biopsy of whom 13 had cirrhosis (22% of original group). Twenty-nine patients were suitable for treatment, but three declined treatment and only 26 (43%) started interferon-alpha. During treatment 17 (65%) patients became PCR negative and eight (31%) remained PCR negative 12 months after completion of therapy. Liver histology was assessed before and after interferon treatment in 17 patients and showed no change in total necroinflammatory scores (p = 0.1) or staging of architectural change (p = 0.55). CONCLUSIONS: The epidemiology and response to therapy of HCV in Northern Ireland appear comparable to elsewhere in the UK. Only a minority of anti-HCV positive non-haemophiliac patients progress to have interferon therapy suggesting that the cost of treating chronic HCV may not be as great as initially thought.

Improvement in quality of colorectal cancer pathology reporting with a standardized proforma--a comparative study.

BACKGROUND: Histopathological evaluation is a critical component in the management of patients with colorectal cancer (CRC). It is the single most powerful prognostic indicator in CRC and determines if adjuvant chemotherapy is indicated. The aim of this study was to assess if the introduction of a comprehensive standardized pathology proforma improved the quality of histopathology reporting. METHODS: A standardized pathology proforma, based on the 1996 minimum dataset for colorectal histopathology reporting, was introduced in our pathology department in 1998. Pathology reports for all colonic resection specimens for 1996 (n = 85) and 2000 (n = 86) were identified, retrieved and entered on to database. Comparison was made with the minimum dataset published in the 1996 guidelines for the management of colorectal cancer. RESULTS: Demographic details were complete in all cases. Clinical data was incomplete in 57 (67%) patients in 1996 and 63 (73%) in 2000 (ns; chi2). There were 24 (28%) (7 Abdomino-perineal resections (APER)) and 40 (47%) (17 APER's) rectal specimens for 1996 and 2000, respectively. The presence or absence of pathological background abnormalities were commented on in 18 (21%) reports in 1996 and 80 (93%) reports in 2000 (P < 0.01; Fishers exact test (Fisher)). Histological differentiation was commented on in 73 (86%) and 86 (100%) in 1996 and 2000, respectively (P < 0.01; Fisher). Dukes' stage was stated in 33 (39%) reports in 1996 and 86 (100%) in 2000 (P < 0.01; Fisher) but Dukes' stage was calculable in 84 (99%) in 1996 and 86 reports (100%) for 2000 (ns; Fisher). The apical node was commented on in 34 (40%) reports in 1996 and 85 (99%) reports in 2000 (P < 0.01; Fisher). The median (IQR) number of nodes assessed in 1996 was 8 (5-12) compared to 12 (8-17) in 2000 (P < 0.001; Mann-Whitney (MW)). Complete resection was mentioned in 74 (87%) reports in 1996 and 86 (100%) in 2000 (P < 0.01; Fisher). Regarding rectal specimens, the circumferential resection margin (CRM) was commented on in 19 of 24 specimens in 1996 and 38 of 40 specimens in 2000 (ns; Fisher). Relationship to the peritoneal reflection was commented on in 1 (1%) rectal specimen in 1996 and 30 (35%) in 2000 (P < 0.001; Fisher). CONCLUSION: The introduction of a standardized proforma for reporting CRC resection specimens improves the quality of histopathological reporting. This aids decision-making regarding adjuvant chemotherapy or radiotherapy and further surveillance.

Vascular endothelial growth factor levels in serum and plasma following esophageal cancer resection--relationship to platelet count.

In patients with cancer circulating vascular endothelial growth factor (VEGF) may be tumor-derived and have prognostic significance. Activated platelets may also be a source of VEGF, releasing it in serum formation. Debate exists as to whether serum or plasma VEGF (S-VEGF, P-VEGF) is the most appropriate surrogate marker of tumor angiogenesis. As healing wounds produce VEGF that can spill over into the circulation, we aimed to investigate the potential confounding effects of cancer surgery on both perioperative S-VEGF and P-VEGF levels and to evaluate their relationship with platelet count. S-VEGF, P-VEGF and platelet counts were measured in 23 patients undergoing esophageal cancer resection. Samples were taken preoperatively and six weeks following surgery. Seven patients were also sampled on postoperative days 1, 5 and 10. VEGF was assayed using a commercial enzyme linked immunosorbent assay. S-VEGF and P-VEGF both rose after surgery (S-VEGF; day 5: 1017 [446-1224] pg/mL and day 10: 1231 [626-2046] pg/mL versus pre-op: 329 [189-599] pg/mL. P-VEGF; day 1: 55 [46-104] pg/mL and day 10: 58 [20-154] pg/mL versus pre-op: 23 [13-46] pg/mL), falling towards preoperative levels by six weeks. Platelet count correlated with S-VEGF (rho=0.281; p<0.05, Spearman's rank) and P-VEGF (rho=0.330; p<0.01, Spearman's rank). Platelets may contribute to VEGF levels in plasma as well as in serum. The effects of surgery on S-VEGF or P-VEGF levels are mainly transient. Care must be exercised when interpreting circulating VEGF levels in the early postoperative period.

Gastric corpus atrophy following eradication of Helicobacter pylori.

BACKGROUND: Atrophic gastritis can develop in patients with Helicobacter pylori infection leading to a reduction in basal acid output. Whether the atrophy that develops is reversible is controversial. OBJECTIVE: To investigate the effect of H. pylori eradication in infected subjects who had developed atrophy of the corpus mucosa. METHOD: Ten H. pylori positive patients with corpus atrophy were identified at oesophagogastroduodenoscopy (OGD). They received eradication therapy with amoxicillin, clarithromycin and omeprazole. Repeat OGD with biopsy was performed at least 3 months later. Fasting plasma gastrin was measured at baseline and at re-endoscopy. H. pylori eradication was confirmed by 13C urea breath testing. RESULTS: Median time to re-endoscopy was 5 months. There was improvement in corpus atrophy in 50% of patients after H. pylori eradication, and a significant reduction in plasma gastrin (P = 0.03). The index patients had a significant diminution of basal acid output compared to controls. CONCLUSION: Corpus atrophy as defined by the Sydney System is reversible in some patients after H. pylori eradication. Improvement in atrophy is associated with a fall in fasting plasma gastrin levels. This may have implications in the prevention of gastric carcinoma.

Testicular sperm extraction by Trucut needle and milking of seminiferous tubules: a technique with high yield and patient acceptability.

OBJECTIVE: To assess the sperm yield and patient acceptability of Trucut needle testicular biopsy followed by seminiferous tubule milking. DESIGN: Prospective case analysis. SETTING: The Regional Fertility Center, Royal Maternity Hospital, Belfast, Northern Ireland, United Kingdom. PATIENT(S): Forty-one males with obstructive azoospermia (normal testicular volume and FSH and LH levels). INTERVENTION(S): Trucut needle testicular biopsies under local anesthetic with milking of the seminiferous tubules. MAIN OUTCOME MEASURE(S): Quantitation of sperm retrieved per biopsy core and patient follow-up by questionnaire. RESULT(S): A mean of 105,634 sperm (range, 5,000-427,800) were retrieved, and the mean biopsy weight was 9.17 mg. Twenty-six subjects found the biopsy painless and 15 were pain-free after biopsy. CONCLUSION(S): The Trucut needle can be used in combination with seminiferous tubule milking to obtain large numbers of sperm in men with obstructive azoospermia.

Distribution of atrophy in Helicobacter pylori-infected subjects taking proton pump inhibitors.

BACKGROUND: Gastric atrophy is associated with Helicobacter pylori infection. Conflicting results have been obtained as to whether acid suppressant therapy hastens the development or changes the distribution of atrophy in the stomach. The aim of this study was to investigate whether concomitant proton pump inhibitor (PPI) therapy in H. pylori-infected individuals resulted in an increase or an alteration in atrophy distribution and whether this was reflected by the plasma gastrin. METHODS: Multiple gastric biopsy specimens were taken from the antrum and corpus from 46 H. pylori-infected subjects, 18 of whom were taking PPIs, and assessed histologically by the updated Sydney System. The control group was age- and sex-matched to the index group. Fasting gastrin levels were measured. RESULTS: In the control group there was no significant tendency for either antral or corpus atrophy to predominate (P = 0.44). In the treatment group there was a significant tendency for corpus as opposed to antral atrophy to develop (P < 0.001). There was no significant difference in the overall atrophy score between the treated and untreated groups (P = 0.76). Fasting gastrin levels were significantly higher in the treated group (P < 0.001). CONCLUSIONS: Treatment with PPIs in H. pylori-infected subjects does not lead to an overall increase in gastric atrophy. It does, however, result in an increased prevalence of corpus as opposed to antral atrophy. This is associated with a significantly higher gastrin level.

Microsatellite analysis provides evidence of neoplastic transformation in long-segment, but not in short-segment, Barrett's oesophagus.

It has been suggested that the high prevalence of short segments of specialised intestinal metaplasia (SIM) at the gastro-oesophageal junction is associated with the rising incidence of oesophageal adenocarcinoma. Our aims were to document the prevalence of short segments of SIM at the gastro-oesophageal junction in patients attending for routine endoscopy and to determine if there was molecular evidence of neoplastic transformation in those with SIM. Patients (n = 101) were recruited from randomly selected upper gastro-intestinal endoscopy lists. Biopsy specimens were taken at the squamo-columnar junction to assess the prevalence of SIM. Frozen sections were assessed for molecular evidence of neoplastic transformation using microsatellite analysis. Squamo-columnar biopsies were suitable for analysis in 95 patients, of whom 20 (21%) had oesophagitis and 2 (2%) had Barrett's oesophagus (>3 cm of endoscopically apparent columnar-lined oesophagus). Twenty patients had SIM at the gastro-oesophageal junction, including 2 with Barrett's oesophagus and 18 with short segments of SIM, one of whom had an associated intramucosal adenocarcinoma detected incidentally by histology. Three of the 20 cases with SIM exhibited novel microsatellite alleles, 2 with Barrett's oesophagus and 1 with short segment SIM and an associated adenocarcinoma. The 18 patients with short segments of SIM at the gastro-oesophageal junction were significantly older than those without SIM.

Case-based prediction of survival in colorectal cancer patients.

OBJECTIVE: To develop an approach to the prediction of survival in patients with colorectal cancer using nearest neighbor analysis and case-based reasoning. STUDY DESIGN: A total of 216 patients with full clinicopathologic records and five-year follow-up were the subjects of this study. They were divided into a core database of 162 cases and a test group of 54 cases, with follow-up on all patients. When the patient was still alive at the end of the follow-up period, censored survival time was used. For each of the test cases, the four closest neighbors from the database were retrieved and their median survival time recorded and used as the predicted estimate of survival. Case matching was based on a Euclidean multivariate distance measure for the three best predictor variables: patient age, Dukes stage and tubule configuration. Cases with the smallest distance from the test case were considered to be the most similar. The predicted survival times for the test cases were compared with the actual, observed survival in the test cases to determine the success of this approach. RESULTS: The results showed reasonable concordance between observed and predicted survival figures, although there was a large degree of spread. Classification of cases into < or = 60 and > 60 months' survival showed a correct classification rate of 63%. For the prediction of survival time, the distribution of differences between observed and predicted survival times for the uncensored test cases had a median value of--5 months but also showed a wide dispersion of values. Correlation of observed and predicted survival times, while not reaching statistical significance at P < .05, did show a strong positive association. CONCLUSION: Case-based approaches to the prediction of survival times in cancer patients are important. The results of the current study illustrate the difficulties in applying this approach to survival data and highlight the complexity of patient information and the inability to accurately predict patient outcome on a small subset of clinicopathologic features. While extensive work needs to be carried out to improve prediction power, this study illustrates the potential for case-based analyses. The ability to retrieve feature-matched cases from hospital patient databases has clear, independent advantages in patient management, but the ability to provide reliable, targeted prognostic estimates on individual cases should be a common goal in medical research.

Immunostaining for vasostatin I distinguishes between ileal and lung carcinoids.

Although chromogranin A (CgA) is a recognized marker of neuroendocrine tumours, little is known about the distribution of the CgA-derived peptides, vasostatin (VST) I or II, in these tumours. Rabbit polyclonal antiserum was raised to a fragment of VST I and used to immunostain sections (5 microns) of wax-embedded tumour tissue. Immunoreactivity (IR) was detected using swine anti-rabbit fluorescein secondary antibody and sections were viewed by fluorescence microscopy. Of 24 tumours from patients with lung carcinoids, one was weakly positive, while 23 of 26 ileal carcinoid tumours were immunoreactive. Metastatic deposits from patients with ileal carcinoids also tended to be immunoreactive (9/10). The difference in IR between lung and ileal carcinoid primary tumours did not appear to be related to the metastatic potential, since appendiceal tumours, which seldom metastasize, also tended to be immunoreactive (4/6) for VST I. The strongest IR was recorded in two patients with flushing as a result of ileal carcinoids; five other 'flushers' with ileal carcinoids were also immunopositive for VST I-like IR. By contrast, patients with flushing as a result of lung carcinoids were immunonegative for VST. In conclusion, VST I-like IR may assist in the identification of a secondary deposit from an unknown primary site.