Serum prealbumin, retinol-binding protein, transferrin, and albumin levels in patients with large bowel cancer.

In a study of the levels of serum prealbumin (PALB), retinol-binding protein (RBP), transferrin (TF), and albumin (ALB) in patients with large bowel cancer, critical values were established as (g/liter): PALB, 0.15; RBP, 40 X 10(-3); TF, 2.0; and ALB, 30. Values consistently below these were taken as a sign of malnutrition. The proteins in this system were interrelated and tended to show a similar pattern of change. Metastatic colon cancer caused a relatively small decline of ALB compared to the mean in tumor-free patients. PALB was the most sensitive indicator of nutrition, and its levels and rates of change had a prognostic significance. A rapid fall of PALB often occurred 2--3 months prior to the patients's death; this preterminal phase in ambulant patients was frequently heralded by a progressive rise in the level of C-reactive protein in the absence of any obvious infection.

Upper limb anthropometry: the value of measurement variance studies.

If a test involves subjective evaluation then different observers will record different findings. This is true of upper limb anthropometry. Unless the interobserver measurement variation is quantified then the detection of real, rather than apparent, measurement changes is hindered. This paper uses a new statistical approach to interpret apparent measurement changes in the presence of observer variation.

The reflush effect--a prospective analysis of late perfusion.

This prospective randomized trial examines the effect of a "reflush" with preservation solution immediately prior to renal allograft implantation, using hyperosmolar citrate (HOC, n = 10) or phosphate-buffered sucrose (PBS140, n = 10) versus no reflush (n = 10). All kidneys had been stored in HOC. The HOC reflush did not alter the postpreservation intra- or extracellular electrolyte milieu, whereas the PBS140 reflush resulted in an apparent overall loss of both sodium and potassium from the kidney (P < 0.0005). A small amount of calcium was released into the venous effluent in both reflush groups. A similar amount of lactic acid was released into the venous effluent of the two reflush groups, reflected by a lower pH (P < 0.0005), and there was a similar loss of lactate dehydrogenase and creatine phosphokinase. An analysis of procoagulant activity in the first urine produced was performed as a marker of reperfusion injury. The median value was higher in the No Reflush group at 457.5 units, compared with 263.0 and 209.0 units for the PBS140 and HOC Reflush groups, respectively (P = 0.06). Reflushing the kidneys reduced the postoperative dialysis requirement (from 40% to 15%), but by the end of the first posttransplant week there was no significant difference between the renal functional analyses of the three groups, and there was no difference at one year. The proposed mechanism for the early renal functional improvement is a reduction in the calcium paradox and free radical formation, by release of calcium and ATP breakdown products into the venous effluent prior to implantation.

Improved porcine renal preservation with a simple extracellular solution--PBS140.

In this prospective randomized trial a porcine model of renal autotransplantation was used to compare quality of preservation, as reflected by detailed analysis of posttransplant renal function, following 24-hr cold storage in phosphate-buffered sucrose (PBS140), hyperosmolar citrate (HOC), and University of Wisconsin (UW) preservation solutions. There were 6 deaths with primary nonfunction: 3 of 5 HOC, 2 of 5 UW, but only 1 of 5 PBS140. Analysis of the whole group and separate analysis of the survivors demonstrated significantly better renal function following preservation with PBS140 when compared with both HOC and UW, with a lower peak serum creatinine (P = 0.02) and improved loop of Henle function (P = 0.02). The animals in the PBS140 group also demonstrated a more rapid return to normal creatinine, higher GFR, improved tubular function, and higher effective renal plasma flow, with figures approaching statistical significance (P = 0.06-0.07). The proposal of UW as a universal storage medium prompted this study, and its results suggest the need for a clinical comparison of renal preservation using UW and PBS140 in a prospective randomized trial.

Changes in human natural killer activity early and late ater renal transplantation using conventional immunosuppression.

The natural killer (NK) cell activity of human peripheral blood lymphocytes falls following major surgical procedures including renal transplantation but in non-immunosuppressed individuals returns to normal levels within the first 72 hr after operation. In renal allograft recipients, if this early postoperative fall is excluded from the analysis, NK cell function appears to follow changes in allograft function, suggesting that in vivo, as has been reported in vitro, NK activity is generated during activation of the alloreactive process. In an additional group of patients whose grafts were functioning for between 3 and 102 months after cadaveric renal transplantation using conventional immunosuppression, NK function was depressed in comparison with that of control subjects. However, some patients who were more than 48 months post-transplant had normal NK cell activity. Collectively, these results suggest that NK cell function may recover despite the continued administration of conventional immunosuppressive agents.

Ranolazine--a new drug with beneficial effects on renal preservation.

Ranolazine is a new drug with a novel mode of action as a metabolic modulator and membrane stabilizer. In this prospective randomized double-blind trial, a porcine model of renal autotransplantation was used to assess the effects of this drug during preservation and reperfusion of kidneys cold-stored for 24 hr in phosphate-buffered sucrose (PBS140). Three groups of 10 animals were compared: a Placebo group (placebo given intravenously to the animal before nephrectomy, added to the preservation solution, and given again to the animal during reperfusion); a Storage group (Ranolazine before and during storage, placebo during reperfusion); and a Reperfusion group (placebo before and during storage, Ranolazine during reperfusion). Detailed analysis of posttransplant renal function was carried out over a 14-day follow-up period. There were 7 deaths with primary nonfunction: 2 Placebo, 1 Storage, 4 Reperfusion. Analysis of the whole group and separate analysis of the survivors demonstrated significantly improved glomerular (P less than 0.05), tubular (P less than 0.05), and loop of Henle (P less than 0.05) function in the Storage group. The results of this study clearly demonstrate the beneficial effects of Ranolazine during the storage phase of porcine renal preservation, and further investigation of this drug is warranted.

Improved 72-hour renal preservation with phosphate-buffered sucrose.

The result of this study shows that a simple phosphate buffered sucrose solution (PBS) is better than hyperosmolar citrate (HOC) solution in the flush perfusion and hypothermic storage of canine kidneys for 72 hr prior to autotransplantation with immediate contralateral nephrectomy. The peroperative measurement of postreperfusion renal blood flow revealed a significant reduction after 60 min in kidneys preserved with HOC solution. All grafts and animals in the PBS group (5/5) survived with primary renal function compared with one in the HOC group (1/5), which functioned after a period of oliguria. The early serum creatinine and urea levels were significantly lower in the PBS group, with a return to normal range within two weeks. This is reflected in higher inulin clearances and a more rapid recovery of proximal tubular function in the PBS animals, which also demonstrated a more rapid return of loop function and the ability to concentrate urine.

The response to interferon of NK and K cells from conventionally immunosuppressed and cyclosporine-treated renal allograft recipients.

Interferon is a potent stimulator of natural killer (NK) and killer (K) cell activity in human beings, both these cytotoxic functions representing host defense mechanisms against viral infections and lymphoid malignancy. Both NK and K cell functions are markedly impaired in conventionally immunosuppressed allograft recipients but coincubation of lymphocytes from these patients with purified human lymphoblastoid interferon considerably augments both these activities. Cyclosporine immunosuppression causes only a moderate, but significant, impairment of NK activity--but K cell activity appears to be normal. Again IFN increases NK activity of the lymphocytes of these patients but produces a fall or only moderate increases in K cell activity. We conclude that these data support the functional distinction between NK and K cells and suggest that immunosuppressive agents act at the pre-NK/K cell stage of maturation, though possibly via different mechanisms.

Inappropriate use of metronidazole in gastrointestinal surgery.

Pharmacokinetic data suggest that current treatment regimens of metronidazole in abdominal surgery are not always appropriate. We have examined antibiotic concentrations during emergency and elective surgery using a specific and sensitive high pressure liquid chromatography assay. Serum and tissue concentrations were measured after intravenous infusion during intra-abdominal surgery and after suppositories given before appendicectomy. After intravenous dosage, bactericidal concentrations were reached in serum (13.6 +/- 7.8 micrograms/ml), bowel (9.0 +/- 6.6 micrograms/g), tumour (9.9 +/- 7.1 micrograms/g) and subcutaneous fat (4.9 +/- 3.2 micrograms/g). After suppositories the concentrations were: serum 4.6 +/- 2.7 micrograms/ml, appendix 1.1 +/- 0.6 micrograms/g, fat 1.5 +/- 0.9 micrograms/g and peritoneal fluid 4.7 +/- 4.3 micrograms/g. These values were obtained at a mean interval of 86.9 +/- 27.5 min following administration of the drug. Serum concentrations were measured during post-surgical infusion of 500 mg i.v. 8 or 12 hourly. Mean concentrations after 8 hourly doses were 16.3 +/- 4.85 micrograms/ml pre-dose and 28.7 +/- 6.76 micrograms/ml post-dose, with evidence of drug accumulation by detection of metabolites. Twelve hourly infusions gave pre-dose levels of 7.4 +/- 3.86 micrograms/ml and post-dose levels of 17.1 +/- 3.69 micrograms/ml. Metronidazole (500 mg) intravenously at induction of anaesthetic gives effective prophylactic concentrations in all tissues including tumour, but a metronidazole 1 g suppository before appendicectomy does not provide reliable tissue concentrations. Metronidazole (500 mg) i.v. 12 hourly gives effective bactericidal concentrations of the drug and is more economical.

A comparison of methods of removing inhibitors to the chromogenic Limulus assay in normal and jaundiced blood.

A comparative study was performed of methods of removing inhibitors to the quantitative chromogenic method of Limulus assay for endotoxin in normal and jaundiced plasma. Chloroform treatment failed to remove inhibitors in normal and jaundiced plasma and did not prevent inhibition of colorimetry by bilirubin. Perchloracetic acid (PCA) treatment decolourised jaundiced samples but gave unreliable results due to poor pH control. Boiling and dilution gave reliable results in jaundiced and normal plasma without significant loss of sensitivity and is the method of choice.

The relationship between plasma pharmacokinetics and tissue metabolites of 5-fluorouracil (5-FU) in patients with colorectal cancer.

To assess the relationship between the plasma pharmacokinetics of 5-Fluorouracil (5-FU) and the levels of intracellular 5-FU metabolites, we have studied eight patients presenting with primary carcinomas of the colon and rectum. Serum 5-FU levels and fluorinated metabolites within normal and malignant tissue were estimated using chromatographic methods. An analysis of the total fluorinated products against plasma halflife, plasma clearance and maximum plasma concentration failed to demonstrate any significant correlation. Furthermore the differing levels of 5-FU metabolites in normal and malignant tissue could not be correlated with the pharmacokinetic parameters studied. It is concluded that the cellular levels of active 5-FU metabolites reflect local cellular activity rather than the handling of the drug in vivo.

Sequential changes in NK and ADCC effector cell function after organ transplantation in man.

Antibody-dependent cellular (K cell) cytotoxicity (ADCC) and cellular cytotoxicity against natural killer (NK) targets exerted by the same cells were both measured sequentially in ten patients after renal transplantation using conventional immunosuppression. Cytotoxicity against NK targets appeared to correlate more closely with rejection episodes than did assays of ADCC activity during the same period. An apparent rise in NK activity was frequently accompanied by a fall in ADCC activity. Collectively these data suggest that the previously reported increase in NK activity during rejection episodes may represent a manifestation of the appearance of non-clonally activated T-cells in peripheral blood during rejection.

Urinary aluminium excretion following renal transplantation and the effect of pulse steroid therapy.

Urinary aluminium was measured in 48 patients with primary graft function for 14 days following renal transplantation. The plasma aluminium prior to transplantation was greater in those prescribed aluminium-containing phosphate binders (1.7 +/- 0.2 vs 0.6 +/- 0.2 mumol/L, P less than 0.05) and correlated with the duration of dialysis therapy (r = 0.42, P less than 0.008). After an initial reduction the plasma aluminium returned to pre-transplant values by the fifth day. The 24 h urinary aluminium excretion, aluminium clearance and fractional aluminium excretion all increased during the first week to a maximum around the sixth postoperative day, thereafter returning to values obtained during the first postoperative days, suggesting an early 'wash-out' of a readily accessible aluminium pool followed by a lower steady state determined by the rate of release of aluminium from tissue stores. For the whole group, aluminium excretion, at this steady state, was five times that of urinary aluminium excretion in normal subjects. Acute allograft rejection was diagnosed in 25 patients, who were treated with pulsed methyl prednisolone. Apart from improving graft function, no additional effect was observed on aluminium excretion, suggesting that the readily accessible aluminium pool does not come from lysosomal release, but probably from aluminium bound to small molecular weight protein.

Reproducibility of Doppler ultrasound measurement of resistance index in renal allografts.

In recent years measurements of arterial blood flow in the renal allograft have been studied in an attempt to provide a non-invasive method of diagnosing and monitoring post-transplant renal dysfunction. Many studies have involved measurement of the resistance index (RI) of arterial blood flow. Although the reproducibility of the technique has been studied in other areas of application, no such studies have been performed on the renal allograft. In this study we attempted to evaluate the reproducibility of the measurement of the RI of the interlobar artery in the renal allograft. 18 renal allograft recipients with stable functioning grafts were studied twice by each of two experienced sonographers using a colour-coded duplex Doppler ultrasound scanner, in order to determine the intraobserver and interobserver variability in the measurement of RI of the interlobar arteries in the allograft. Variability was small and although interobserver variability exceeded intraobserver variability, both were within repeatability limits adopted by the British Standards Institution. The results suggest that measurement of the RI of the interlobar artery of renal allografts is repeatable and reproducible when performed by experienced operators.

Hepatic perfusion index and the evolution of liver metastases.

A total of 150 patients with primary carcinoma of the gastrointestinal tract had first-pass technetium colloid scintigraphy to estimate the hepatic perfusion index (HPI). Postoperative follow-up over 2-4 years shows that the HPI remains a sensitive method of detecting hepatic metastases, even in patients whose liver appeared normal at laparotomy. HPI was elevated in 94% of patients with liver metastases found at laparotomy; 87% of patients with occult metastases which became overt within 3 years of surgery had elevated HPI; and 91% of all patients who have to date developed hepatic metastases had elevated HPI at presentation. Of all patients with elevated HPI, 82% had metastases which were either apparent at surgery or became detectable by other means within 3 years.

Initial clinical experience with degradable starch microspheres.

Four patients with advanced hepatic malignancy have been investigated with a view to intra-arterial treatment with degradable starch microspheres (DSM) and mitomycin-C (MMC). Computer-assisted interpretation of data gathered during the administration of technetium-labelled albumin allows the degree of arteriovenous shunting within the liver to be measured. In a similar way, the effectiveness of DSM in blocking hepatic arterial flow is determined. Two patients showed unacceptably high levels of shunting (75% and 100%) and were excluded from further study. One patient with hepatocellular carcinoma shunted only 24% of the macroaggregated albumin, and flow through the liver was reduced to 48% by DSM therapy. This patient has undergone four courses of MMC without significant toxic complications. The last patient had 25% shunting. The DSM titration and the first MMC administration had to be abandoned because of severe abdominal pain and nausea related to a fracture of the intra-arterial catheter. Complications directly associated with the procedures have been acceptable. The relationship between flow reduction and the amount of DSM administered is non-linear, and the appropriate dose of DSM for each treatment must be titrated against both the patient's symptoms and the computer-generated flow indices.

Recurrent pyogenic cholangiohepatitis.

Three cases of complicated oriental cholangiohepatitis are described in patients of Asian origin. The development of high biliary strictures in two patients required liver resection; in the third patient the process was complicated by a presumed bile duct malignancy. Oriental cholangiohepatitis may be expected in UK surgical practice given the increased frequency of migration from Asia.

Monitoring of renal allografts by Doppler ultrasound.

Cyclosporin (CyA) associated renal dysfunction may be due to an arteriolopathy which reduces graft perfusion. We have prospectively monitored 27 renal allograft recipients, within 30 days of transplantation, by continuous wave Doppler ultrasound. Changes in the frequency shift waveform should indicate alterations in renal blood flow. Objective analysis was made in 112 waveforms by determining the ratio of the area under the frequency shift/time curve of the first half and the second half of the cardiac cycle (AUC 1/2 ratio). The AUC of the first half of the cycle indicates systolic blood flow plus the first part of diastolic flow, whereas the AUC of the second half indicates the remainder of diastolic flow. The AUC 1/2 ratio during ATN was not significantly different from that during stable renal function. However the ratio was significantly higher during acute rejection episodes and CyA nephrotoxicity. Although a statistical difference was demonstrated between acute rejection and CyA nephrotoxicity, the AUC 1/2 ratio alone does not differentiate these 2 conditions. These preliminary findings suggest CyA nephrotoxicity does reduce renal allograft blood flow and that this non-invasive technique may have a useful role to play in monitoring of patients immunosuppressed with CyA.

Evaluation of CEA in patients with known residual disease after resection of colonic cancer.

Serial carcinoembryonic antigen (CEA) levels were measured in 43 patients following incomplete excision of colorectal cancer. Twenty-seven patients received chemotherapy. In the majority the subsequent elevation of CEA could be related to clinical progression, but some patients receiving chemotherapy may have a suppressed rate of CEA rise and may have a more prolonged survival.The clinical application of serial CEA estimations remains of dubious value. However, one area which may be worthy of study is to determine whether suppression of the CEA slope by chemotherapy is attended by clinical control and an improved survival.

[Combination of cancer markers in the detection and prognosis of digestive system tumors]. / Combinação de marcadores de câncer na detecção e prognóstico de tumores do aparelho digestivo.

The role of carcinoembryonic antigen (CEA), gamma glutamyl transpeptidase (gamma GT), phosphohexose isomerase (PHI), pseudouridine (PSD) and acute phase reactant proteins (C-reactive protein (C-RP], alpha 1-acid glycoprotein (alpha 1-AGP) and alpha 1-antichymotrypsin (alpha 1-ACT) in distinguishing benign from malignant conditions of the digestive tract and their value in assessing the prognosis of gastrointestinal neoplasms was evaluated. For each marker it has been possible to produce a simple scoring index derived from the values found in the control population. This work suggests that pre-operative levels of certain cancer markers may be useful in tumor detection and may also give prognostic information additional to pathological staging.