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Biomedical subjects

A Norman

Publications and source records attributed to A Norman.

At least 91 records · Page 5Linked to original sources
PubMed1996

The prognostic value of serum and immunohistochemical tumour markers in advanced gastric cancer.

Using a prospectively acquired database of 290 patients with advanced gastric adenocarcinoma, the prognostic significance of serum levels of carcinoembryonic antigen (CEA) (237 patients), alphafeto protein (AFP) (164 patients), beta-human chorionic gonadotrophin (beta HCG) (165 patients), CA19-9 (64 patients) and CA125 (104 patients) and tissue staining for C-erb B-2 (160 patients) and beta HCG (160 patients) was investigated. Serum was taken prior to 5-fluorouracil (5FU)-based chemotherapy and immunohistochemistry was performed on diagnostic specimens. In the univariate analysis, tumour markers of poor prognosis were CEA > or = 5 micrograms/l (P = 0.01; median survival (MS) 42 versus 35 weeks), serum beta HCG > or = 4 U/l (P = 0.02; MS 42 versus 25 weeks), CA125 > or = 35 U/ml (P = 0.03; MS 43 versus 31 weeks) and CA125 > or = 350 U/ml (P = 0.001; MS 42 versus 17 weeks). Other significant factors were poor performance status, the presence of metastases and poorly differentiated tumour histology. Tumours markers of poor prognosis in the multivariate analysis were serum beta HCG > or = 4 IU/l [hazard ratio (HR) 1.7; 95% confidence interval (CI) 2.8-1.1] and CA125 > or = 350 U/ml (HR 2.2; CI 4.2-1.2). There was a degree of subgroup variability in this model but, in general, other factors correlating with a poor survival were poor performance status, metastases and poorly differentiated tumour histology. This is the largest prognostic study of each tumour marker in advanced disease and demonstrates that serum beta HCG and CA125 in gastric cancer prior to chemotherapy do convey an independent poor prognosis which may reflect not just tumour burden but aggressive biology.

Adenocarcinoma↗
PubMed1996

An analysis of surveillance for stage I combined teratoma--seminoma of the testis.

We analysed 973 patients with stage I testicular tumours presenting between 1983 and 1994. The median ages at presentation for non-seminomatous germ cell tumour (teratoma) were 27 years, seminoma 36 years and combined tumour 33 years. These differences were statistically significant (Mann-Whitney P < 0.05), suggesting that combined tumours may have a separate natural history. We, therefore, analysed all stage I patients managed with surveillance (530 in total) post orchidectomy. The actuarial 5 year relapse-free survival and anatomical patterns of relapse were identical for non-seminomatous germ cell tumour (NSGCT) and combined tumour and both were statistically distinct from seminoma (P = 0.01, log-rank test, chi-square test P = 0.001). The association of seminoma within a histologically confirmed NSGCT has no influence on the clinical outcome.

Adult↗
PubMed1996

A genetic register for von Hippel-Lindau disease.

A genetic register for von Hippel-Lindau disease was set up in the north west of England in 1990. Population statistics, clinical features, age at onset, and survival of 83 people affected with von Hippel-Lindau (VHL) disease were studied. In addition, the effectiveness of the screening programme used and the occurrence of central nervous system haemangioblastomas in the general population were examined. The diagnostic point prevalence of heterozygotes in the North Western Region was 1 center dot 18/100 000 (1/85 000) people, with an estimated birth incidence of 2 center dot 20/100 000 (1/45 500) live births. The mutation rate was estimated directly to be 1 center dot 4 x 10(-6)/gene/generation (1/714 200). The mean age at onset of first symptoms was 26 center dot 25 years, with cerebellar haemangioblastoma being the most common presenting manifestation (34 center dot 9% of cases). The mean age at diagnosis of VHL disease was 30 center dot 87 years. Overall, 50 patients (60 center dot 2%) developed a cerebellar haemangioblastoma, 34 (41 center dot 0%) a retinal angioma, 21 (25 center dot 3%) a renal cell carcinoma, 12 (14 center dot 5%) a spinal haemangioblastoma, and 12 (14 center dot 5%) a phaeochromocytoma. Mean age at diagnosis of renal cell carcinoma (38 center dot 9 years) was significantly higher than that for cerebellar haemangioblastoma (30 center dot 0 years) and retinal angioma (21.1 years). Mean age at death was 40 center dot 9 years with cerebellar haemangioblastoma being the most common cause (47 center dot 7% of deaths). A total of 65 VHL manifestations were diagnosed asymptomatically following appropriate clinical and radiological screening tests, and failure to detect manifestations of VHL disease in spite of appropriate screening occurred on only two occasions. The use of DNA linkage analysis and direct mutation testing reduced the personal risk of carrying the VHL gene to below 1% in 14 people. In addition to the 83 clinically affected subjects, three obligate carriers who were considered to be lesion free in spite of extensive screening tests were identified. Fourteen percent of all CNS haemangioblastomas on the regionally based Cancer Registry were found to occur as part of VHL disease, but investigations for VHL in apparently sporadic disease appeared to be limited.

Adolescent↗
PubMed1996

Assessment of dimethylxanthine formation from caffeine in healthy adults: comparison between plasma and saliva concentrations and urinary excretion of metabolites.

Caffeine (CA), paraxanthine (PX), theobromine (TB) and theophylline (TP) were determined in plasma (i.e. total concentrations), ultrafiltrate of plasma (free concentrations) and saliva, by isocratic high performance liquid chromatography (HPLC), 0-24 h after a 200 mg oral load of CA in 10 healthy adults. Total metabolism of CA was established by determination of urinary metabolites, 24 h after CA ingestion, by gradient HPLC and capillary electrophoresis. Saliva concentrations of CA, PX, and TP were lower than plasma concentrations (p < 0.001), whereas TB concentrations in plasma and saliva were similar. Saliva concentrations of CA, PX, TB and TP were higher than the free plasma concentrations (p < 0.001). The area under the plasma concentration-time curve (AUC) showed that PX accounted for 63 +/- 13% of the dimethylxanthines in plasma, while TB accounted for 27 +/- 15% and TP for 10 +/- 2.6%. In contrast, the urine analyses showed that 78 +/- 11% of the excreted metabolites were metabolized through the PX pathway, 14 +/- 8% through the TB pathway and 9 +/- 4% through the TP pathway. The percentage of the AUC for PX, TB and TP in plasma was similar to the percentage of each dimethylxanthine excreted unmetabolized in urine. The percentages of the AUC for PX and TB were correlated to the percentages of PX (r = 0.78, p < 0.001) and TB (r = 0.88, p < 0.001) in urine. The AUC for PX in plasma was lower than (p < 0.001) and correlated to the total PX pathway value (r = 0.95, p < 0.001) and the value for PX plus its specific metabolites in urine. The AUC for TB in plasma was higher than (p < 0.001) and correlated to the total TB pathway value (r = 0.93, p < 0.001) and the value for TB plus its specific metabolites in urine. The AUC for TP in plasma was similar to both the TP pathway value and the value for TP plus its specific metabolites in urine. It is concluded that the AUC for dimethylxanthines in plasma underestimates the formation of PX, overestimates the formation of TB and gives a similar formation of TP from CA, as judged from the urinary metabolites formed through the PX, TB, and TP pathways.

Adult↗
PubMed1996

Elimination of theobromine metabolites in healthy adults.

The metabolism of theobromine (TB) (500 mg per os) was determined by measuring plasma and saliva concentrations of TB and its metabolites 0-24 h after the load, and urinary excretion 0-48 h after the load. TB and its six metabolites were separated and quantified by combining high performance liquid chromatography and capillary electrophoresis. The urine analyses showed that unchanged TB accounted for 21 +/- 4% (mean +/- SD) of total excretion, the remainder being 7-methylxanthine (7-X, 36 +/- 5%), 3-methylxanthine (3-X, 21 +/- 4%), 6-amino-5[N-methylformylamino]-1-methyluracil (6-AMMU, 11 +/- 4%), 7-methyluric acid (7-U, 10 +/- 2%), 3,7-dimethyluric acid (3,7-U, 1.3 +/- 0.6%) and 3-methyluric acid (3-U, 0.5 +/- 0.4%). In addition to TB, 7-X and 3-X were consistently found in plasma and saliva; 6-AMMU and 7-U were found in plasma and saliva at concentrations < or = 2 mumol l-1 and 0.2 mumol l-1, respectively. TB concentrations in plasma and saliva were similar, whereas the saliva concentrations for 7-X and 3-X were found to be 63 +/- 17% of the plasma concentrations for 7-X and 74 +/- 13% for 3-X, respectively. The high urinary-to-plasma concentration ratio of 7-U (200-300) suggests high excretion of 7-U by the kidneys. Excretion of 7-X, 3-X and 6-AMMU was also high (urinary-to-plasma concentration ratio 45-150), whereas the excretion of TB was significantly lower than its metabolites (urinary-to-plasma concentration ratio 4-6). N3-demethylation of TB accounted for 58 +/- 7% of the urinary metabolites, N7-demethylation for 27 +/- 6%, C8-oxidation of 7-X for 22 +/- 4%, C8-oxidation of 3-X for 2 +/- 2% and formation of 6-AMMU for 13 +/- 4%. The ratio of N3- to N7-demethylation of TB remained constant during the load, but the large interindividual variation observed in ratio makes it unsuitable as a function test for evaluation of liver disease.

Adult↗
PubMed1996

Faecal bile acid excretion during detoxification in patients with alcohol abuse.

BACKGROUND: We wanted to ascertain whether alcohol abuse is associated with a changed faecal bile acid excretion. METHODS: Faecal bile acid excretion was studied in seven chronic alcoholic subjects when admitted to hospital for detoxification. Bile acids in faeces and serum were quantified by gas-liquid chromatography and identified by mass spectrometry. RESULTS: Daily faecal bile acid excretion was on average 948 mumol in the patients at admission, compared with 400 mumol in eight healthy controls (P < 0.01). The daily faecal bile acid excretion decreased slowly during the detoxification period but was still higher in the patients than in controls after 9 days of detoxification (P < 0.05). Faecal bile acid excretion varied greatly between the different patients, with poor correlation to diarrhoea. In one patient the faecal bile acid excretion was remarkably high, amounting to an average of 6800 mumol day-1 during the first 3 days. The percentage metabolites of total faecal bile acids in the patients did not differ significantly from that of controls. The faecal wet weight was higher in the patients than in the controls, although significantly so only after the first 3 days of detoxification. CONCLUSIONS: Faecal bile acid excretion is increased after alcohol abuse. A gradual decrease in faecal bile acid excretion was observed during the 9-day observation period when the subjects abstained from alcohol.

Adult↗
PubMed1995

Epirubicin, cisplatin and infusional 5-fluorouracil (5-FU) (ECF) in hepatobiliary tumours.

Hepatobiliary tumours are rare, often present late and have a poor prognosis, with no current effective systemic therapy available. This study aimed to evaluate the activity and toxicity of epirubicin, cisplatin and continuous infusional 5-fluorouracil (5-FU) (ECF) in patients with these tumours. From March 1991 to November 1993, 25 patients with advanced biliary tumours and 7 with hepatoma were treated with epirubicin 50 mg/m2 and cisplatin 60 mg/m2 intravenously (i.v.) day 1, each given every 21 days and 5-FU 200 mg/m2/day given as a continuous 24 h i.v. infusion throughout the treatment course. 8 of the 20 (40%) evaluable patients with biliary tumours responded. Median duration of response was 10 months. 2 of the 7 (29%) patients with hepatoma responded. The regimen was well tolerated with minimal haematological and non-haematological toxicity. This novel regimen is active in advanced hepatobiliary tumours.

Adult↗
PubMed1995

Adjuvant chemotherapy for oesophagogastric cancer with epirubicin, cisplatin and infusional 5-fluorouracil (ECF): a Royal Marsden pilot study.

Previous trials of adjuvant chemotherapy for oesophagogastric cancer have shown only modest or no improvement in survival. However, the regimens used in these studies produce low response rates in patients with advanced disease. ECF is a new regimen which results in higher response rates and may therefore be more effective in the adjuvant setting. Twenty-nine patients who had undergone a potentially curative resection for oesphagogastric carcinoma were treated with ECF [epirubicin 50 mg m-2 and cisplatin 60 mg m-2 for 18 weeks]. The median age was 52.5 years. Three patients had oesophageal tumours, 14 had tumours of the oesophagogastric junction (OGJ) and 12 had gastric tumours. All were adenocarcinomas apart from one undifferentiated carcinoma. One patient had stage I disease, nine stage II, 17 stage II and two stage IV. The mean number of chemotherapy cycles per patient was 5.2 (range 2-8). The median follow-up was 8.4 months (1.5-36.3 months). Eleven patients relapsed during follow-up (38%). One patient had an anastomotic recurrence and ten patients distant metastases. Overall 3 year survival was 61.5% (95% confidence interval 42-79); 3 year survival in stage II was 50% (21.2-86.3) and in stage III 65.6% (40-86). Chemotherapy was well tolerated, with grade 3/4 toxicity as follows: leucopenia 13.5%, nausea and vomiting 10%, diarrhoea 3.5%, infection 3.5% and thrombocytopenia 3.5%. There were no treatment-related deaths. We conclude that ECF can be administered safely as adjuvant treatment to patients with surgically resected gastro-oesophageal carcinoma. The results, especially in patients with stage III disease, are encouraging and support the investigation of this regimen within a prospective randomised trial.

Adenocarcinoma↗
PubMed1995

The mutational spectrum in Waardenburg syndrome.

One hundred and thirty-four families or individuals with auditory-pigmentary syndromes such as Waardenburg syndrome (WS) or probable neurocristopathies were screened for mutations in the PAX3 and MITF genes. PAX3 mutations were found in 20/25 families with definite Type 1 WS and 1/2 with Type 3 WS, but in none of 23 with definite Type 2 WS or 36 with other neurocristopathies. The PAX3 mutations included substitutions of conserved amino acids in the paired domain or the homeodomain, splice-site mutations, nonsense mutations and frame-shifting insertions or deletions. No phenotype-genotype correlations were noted within WS1 families. With MITF, mutations likely to affect protein function were found in seven families, five of which had definite Type 2 WS. We conclude that Type 1 and Type 3 WS are allelic and are normally caused by loss of function mutations in PAX3; that Type 2 WS is heterogeneous, with about 20% of cases caused by mutations in MITF, and that individuals with auditory, pigmentary or neural crest syndromes which do not fit stringent definitions of Waardenburg syndrome are unlikely to have mutations in either the PAX3 or MITF genes. The molecular pathology of MITF/microphthalmia mutations appears to be different in humans and mice, with gene dosage having more significant effects in humans than in the mouse.

Amino Acid Sequence↗
PubMed1995

The prognostic value of CEA, beta HCG, AFP, CA125, CA19-9 and C-erb B-2, beta HCG immunohistochemistry in advanced colorectal cancer.

BACKGROUND: Evaluation of the prognostic significance of a group of tumour markers and their ability to predict response to chemotherapy may allow better targeting of palliative treatment in advanced colorectal cancer. PATIENTS AND METHODS: Using a prospectively acquired database of 377 patients (pts) with advanced colorectal adenocarcinoma, the prognostic significance of serum CEA (342 pts), beta HCG (203 pts), AFP (208 pts), CA125 (150 pts), CA-19-9 (76 pts) as well as C-erb B-2 (197 pts). Serum markers were taken prior to 5-FU based chemotherapy and immunohistochemistry was performed on diagnostic samples RESULTS: Tumour markers of poor prognostic significance in the univariate analysis were CEA > or = 5 micrograms/l (p = 0.006; median survival (MS 59 weeks vs 38 weeks) and CA125 > or = 35 U/ml (p = 0.01 MS 51 weeks vs. 30 weeks). Tumour markers elevated at greater than 10 times the normal value which correlated with a poor prognosis were CEA (p = 0.001; MS 47 weeks vs. 35 weeks), Serum beta HCG (p < 0.0001; MS 44 weeks vs. 7 weeks) and CA125 (p < 0.0001; MS 38 weeks vs. 15 weeks). Poor performance status ( > 2) and poorly differentiated tumour histology were also correlated to poor survival. In the multivariate analysis, tumour markers of independent poor prognosis were CEA > or = 5 micrograms/l (Hazard Ratio (HR) 1.8; 95% Confidence Internal (CI) 2.8-1.2), CEA > or = 50 micrograms/l (HR 1.6; CI 2.1-1.2), CA125 > or = 35 U/ml (HR 1.5; CI 2.3-1.0), CA 125 > or = 350 U/ml (HR 5.0; CI 9.6-2.6) and serum BHCG > or = 0 IU/l (HR 11.7; CI 30-4.5). Poor performance status (HR 6.7-5.0) and poorly differentiated histology (HR 2.8-1.0) were the other important factors in the model. No pretreatment tumour marker correlated with response to chemotherapy. CONCLUSIONS: This is the largest prognostic study of each tumour marker in advanced disease and it clarifies previous conflicting reports. Serum AFP, CA19-9 and immunohistochemical stains beta HCG and C-erb B-2 have no prognostic significance. Serum CEA, beta HCG, CA125 in advanced colorectal cancer prior to chemotherapy do convey an independent poor prognosis which may reflect not just tumour burden but aggressive biology.

Adenocarcinoma↗
PubMed1995

Cisplatin and protracted venous infusion 5-fluorouracil (CF)--good symptom relief with low toxicity in advanced pancreatic carcinoma.

PURPOSE: The combination of protracted venous infusion (PVI) 5-FU with moderate dose cisplatin was evaluated in patients with advanced pancreatic cancer. PATIENTS AND METHODS: Sixty-three patients with locally advanced or metastatic disease were treated with cisplatin (60 mg/m2 every 21 days) and PVI 5-FU (300 mg/m2/day) for a maximum of 24 weeks. All patients had histologically/cytologically confirmed tumour. Radiological response was assessed by CT scanning and toxicity, performance status and symptomatic response were assessed 3 weekly. RESULTS: The objective response rate was 16% with two radiological complete responses. The median survival was 7.6 months with a 1-year survival of 33% and a median progression-free survival of 6.6 months. Patients who had local disease only had a median survival of 14.8 months with a 1-year survival of 52%. Thirty-four percent of patients had an improvement in performance status on treatment and specific symptom response rates were weight loss 71%, dysphagia 100%, nausea and vomiting 70%, pain 60%, anorexia 50%, and reflux 81%. Chemotherapy was well tolerated with grade 3 or 4 toxicity being nausea/vomiting 5%, diarrhoea 7%, infection 4%, stomatitis 2%, plantar palmar syndrome 2%, anaemia 14%, leucopenia 5, neutropenia 10% and thrombocytopenia 8%. CONCLUSIONS: The CF regimen provides good symptomatic palliation with low toxicity in patients with advanced pancreatic cancer.

Adenocarcinoma↗
PubMed1995

Intestinal microbial bile acid transformation in healthy infants.

Following the establishment of functionally active intestinal flora in three healthy Swedish children from birth up to 24 months of age, we investigated the development of different 24-carbon bile acids. The fecal bile acids were group-separated into unconjugated, glycine-conjugated, taurine-conjugated, and sulfated, so that we could follow the changes between the different fractions of conjugates. In meconium, most (55-63%) of the bile acids were conjugated with taurine; only 11-32% were conjugated with glycine. Deconjugation was the first sign of intestinal microbial activity on the bile acids. Already at 1 month of age, most of the bile acids were deconjugated; among the conjugated bile acids, the glycine-conjugated dominated over the taurine-conjugated. An unidentified conjugate of cholic and chenodeoxycholic acids (C, CDC) that separated with the sulfated bile acids was found. The unconjugated bile acids and those that arose from hydrolysis of existing conjugates were separated and identified by gas-liquid chromatography coupled to mass spectrometry (GC-MS). Twenty-nine different bile acids were identified. In meconium, 16 different bile acids were identified. C and CDC were identified in all samples. The bile acid pattern changed during the course of the study. Many of the identified bile acids were only found in one or a few of the analyzed samples, and sometimes only in samples from one child. 6 alpha-hydroxylated bile acids, probably not microbially synthesized, were present at high percentages in the children.(ABSTRACT TRUNCATED AT 250 WORDS)

Bifidobacterium↗
PubMed1995

Partial trisomy 22 (q11.2-q13.1) as a result of duplication and pericentric inversion.

A case of a 27 year old male with a duplication of part of the long arm of chromosome 22 (22q11.2-q13.1) together with a pericentric inversion of the same chromosome is reported. Particular phenotypic features of note include absence of speech, persistent self-injury, lack of daily living skills, colobomata, and very poor vision. Similarities between this case and other case reports of duplications of the long arm of chromosome 22 are discussed.

Abnormalities, Multiple↗
PubMed1995

Royal Marsden phase III trial of fluorouracil with or without interferon alfa-2b in advanced colorectal cancer.

PURPOSE: Phase II studies have shown that the combination of interferon alfa-2b (IFN) and fluorouracil (5-FU) is active in patients with metastatic colon cancer. This study was designed to investigate whether treatment with the combination of IFN and 5-FU could improve the response rate, duration of response, or survival compared with treatment with 5-FU alone. PATIENTS AND METHODS: Patients with histologically confirmed advanced colorectal cancer were randomized to receive 5-FU 750 mg/m2/d by continuous infusion for 5 consecutive days followed by weekly bolus 5-FU 750 mg/m2 either with or without IFN 10 MU subcutaneously three times weekly. Treatment was continued until disease progression or unacceptable toxicity for up to 12 months. RESULTS: Radiologic response was observed in 26 of 106 assessable patients (25%): 10 of 52 (19%) in the group that received 5-FU plus IFN (all partial responses [PRs]) and 16 of 54 (30%) in the 5-FU-alone group (three complete responses [CRs] and 13 PRs) (P = .21). There was similarly no significant difference between the two groups in progression-free survival (median, 3 months), 1-year survival, or overall survival (median, 8 months). However, patients who received IFN did experience significantly more toxicity in the form of leukopenia (P = .013), lymphopenia (P = .01), depression (P = .014), and alopecia (P = .002), and were significantly more likely to be withdrawn due to adverse events (P = .003). There were four toxic deaths, all of which occurred in patients who had received IFN. CONCLUSION: At the doses and schedules used in this study, IFN affords no benefit to 5-FU in terms of response and survival and significantly increases toxicity for patients with advanced colorectal cancer.

Adult↗
PubMed1995

Impact of protracted venous infusion fluorouracil with or without interferon alfa-2b on tumor response, survival, and quality of life in advanced colorectal cancer.

PURPOSE: The aim of this study was to investigate the effects of adding interferon alfa-2b (IFN) to protracted venous infusion fluorouracil (PVI 5-FU) from the start of treatment in patients with advanced colorectal cancer. PATIENTS AND METHODS: Patients who attended our unit with histologically confirmed advanced colorectal cancer were randomized to receive either PVI 5-FU 300 mg/m2/d via Hickman line, and IFN 5 MU subcutaneously three times weekly, or PVI 5-FU alone. Treatment was given for a maximum of two 10-week blocks, with a 2-week gap for reassessment of all parameters. Quality of life (QL) was measured by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) pretreatment and every 6 weeks thereafter. RESULTS: A total of 160 patients were randomized, with 155 eligible for assessment. Radiologic response was observed in 43 patients (28%): 17 of 77 (22%) in the 5-FU-plus-IFN arm (all partial responses [PRs]) and 26 of 78 (33%) in the 5-FU-alone group (complete responses [CRs] and 22 PRs) (difference not significant). Symptomatic improvement occurred in the majority of patients, and equally in both arms: 61% to 80% depending on the symptom. There was no significant difference between the two groups in failure-free survival (median, 161 v 193 days) or overall survival (median, 328 v 357 days). However, patients who received IFN did experience significantly more toxicity in the form of leukopenia (P = .001), neutropenia (P = .04), mucositis (P = .008), and alopecia (P = .0002). There were no toxic deaths and few notable differences in QL between the two arms. CONCLUSION: This study confirms that PVI 5-FU is effective in treating the symptoms associated with metastatic colorectal carcinoma, with only mild to moderate toxicity and maintenance of QL. IFN 5 MU three times weekly does not enhance these palliative benefits.

Adolescent↗