John Broom

Minimal access surgery for cholelithiasis induces an attenuated acute phase response

BACKGROUNDnSome benefits of laparoscopic (LC) and minilaparotomy (MC) cholecystectomy may reflect attenuation of the acute phase response. The authors examined components of this response.nnnMETHODSnPatients were randomized to LC (n = 11) or MC (n = 11). C-reactive protein (CRP), alpha-1-antitrypsin (AAT), retinol-binding protein (RBP), transferrin, and albumin were measured preoperatively and on postoperative days 1, 2, 4, and 7. Interleukin-1 receptor antagonist (IL-1ra), IL-6, and tumor necrosis factor (TNF-alpha) were measured more frequently perioperatively. Peak expiratory flow rate, forced expiratory volume in 1 second, and forced vital capacity were measured daily.nnnRESULTSnThe IL-6 increase was more persistent and marked in the MC patients from hour 8 to day 7 postoperatively (P < 0.05). Alterations in CRP, AAT, and albumin were similar. Postoperative deficits of respiratory function correlated with the magnitude of acute phase protein alteration.nnnCONCLUSIONSnMinimal access surgery induces an acute phase response that is less prominent after a laparoscopic technique.

Acute phase proteins and recombinant IL‐2 therapy: prediction of response and survival in patients with colorectal cancer

Twenty‐four patients with metastatic colorectal cancer were treated with recombinant IL‐2 (rIL‐2) by continuous intravenous infusion for 5 days (18 · 106 U/m2 per 24 h), followed by three injections of 5‐fluorouracil (600 mg/m2) and folinic acid (25mg/m2) at weekly intervals. The response to treatment was assessed using standard UICC criteria (partial or complete response, stasis or progression of disease). The serum concentrations of the acute phase proteins; C‐reactive protein (CRP), retinol binding protein (RBP), α1‐antitrypsin (α1‐AT), transferrin (TF) and albumin were measured. A response to therapy occurred in the tumours of seven (29%) of the 24 patients (two complete and five partial responses). All patients who demonstrated a response to treatment had a serum albumin level of > 37 g/l and a CRP level of · 10 mg/l. In contrast, of the 17 patients who did not respond to therapy, 12 (71%) had a serum albumin of less than 37 g/dl and a CRP of greater than 10 mg/l. Examination of the survival times of the 12 patients who had a pretreatment serum albumin level of less than 37 g/l revealed that all had died within 12 months of cessation of therapy. However, 58% of patients with pretreatment serum albumin levels of greater than 37 g/l survived for longer than 12 months. These results have shown that (i) patients who respond to rIL‐2‐based therapy and (ii) those patients who have prolonged survival times, can be identified by pretreatment measurement of serum levels of acute phase proteins.

Correlation of serum cytokine and acute phase reactant levels with alterations in weight and serum albumin in patients receiving immunotherapy with recombinant IL‐2

Recombinani IL‐2 (rlL‐2) has been used alone or in combination wiih other chemotherapeutic agents to enhance hosl defences against caneer. Prolonged administration of high doses, required for clinical efficacy, may precipitate serious dose‐limiting loxicity. rlL‐2‐induccd ‘vascular leak syndrome’ leads lo hypotension, renal insufficiency, respiratory disturbances and other organ dysfunctions. Serial measurements ofserunicylokincs and the acute phase protein C‐rcactivc protein (CRP) were performed on nine palienls who received high‐dose i.v. continuous therapy with rIL‐2. The infiuence of these immunological parameters upon alleralions in patients weight and serum albumin, as indicators of toxicity, was assessed. All patients experienced weight increases during the cycle (3‐11% of total body weight). The serum levels of tumour necrosis factor (TNF‐a) and CRP were highly predictive of aileralions in patients weight (both P<0.001), while no correlation was found with lL‐6 and weight change. Serum albumin tell linearly throughout the infusion cycle, but this showed no correlation with variations in serum levels of IL‐6, TNF‐α, or CRP. The complement components C3 and C4 were significantly reduced at thccndofthc infusion, suggesting a possible role for this cascade system in mediating ihesc clinical changes. The strong association between serum TNF‐α and weight change, not previously documented, further supports the hypothesis that TNF‐α is a key mediator in the pathogenesis of the ‘vascular leak syndrome’.

In vivo cytokine production and recombinant interleukin 2 immunotherapy : an insight into the possible mechanisms underlying clinical responses

Recombinant interleukin 2 (rIL-2), when given to patients with advanced malignant disease, induces a limited beneficial effect, with only 20-30% of patients with solid tumours responding. This present study has identified those patients with advanced colorectal cancer most likely to respond to rIL-2 therapy, by analysis of serum cytokine levels, prior to and during rIL-2 treatment, documented in responders and non-responders. Responders were found to have significantly lower pretreatment serum IL-6 and soluble IL-2 receptor levels (sIL-2R) than non-responders (P < 0.01 and P < 0.05 respectively). During rIL-2 infusion, responders developed high circulating levels of IL-6 and had low constant levels of prostaglandin E2 (PGE2). Non-responders failed to produce IL-6 and demonstrated elevated serum concentrations of PGE2, during infusions of rIL-2. Thus, an enhanced ongoing IL-6 and sIL-2R response, prior to therapy, was detrimental to subsequent treatment with rIL-2. Differential production and/or release of cytokines and prostaglandins, during therapy, further determined the likelihood of response to rIL-2.

Interleukin 2 therapy in cancer: identification of responders.

C-reactive protein (CRP) levels in serum were measured in fifteen patients with metastatic colorectal carcinoma, prior to and during treatment with a continuous intravenous infusion of rIL.2. Patients were subsequently classified as responders or non-responders to this therapy. Baseline serum CRP levels, prior to treatment, were significantly lower in the responders (range < 2-8 mg l-1) when compared with the non-responders (range 7.5-116 mg l-1), P = 0.004. Furthermore, the responding patients demonstrated significantly and grossly elevated CRP stimulation indices (SI) compared with non-responders at different time intervals during the rIL2 infusion. At the cessation of rIL2 therapy, the CRP stimulation index was 31.3 +/- 9.3 in the responders, and only 1.6 +/- 0.3 in the non-responders (means +/- s.e.m, P = 0.014). These findings suggest that it is possible to predict those cancer patients who are most likely to respond to and benefit from rIL2 therapy, either prior to the commencement of or during the first course of rIL2.

Lithium Clearance Measurements During Recombinant Interleukin 2 Treatment: Tubular Dysfunction in Man

Renal tubular function was evaluated in nine patients undergoing recombinant interleukin 2 (rIL2) treatment for metastatic colorectal carcinoma. A lithium clearance technique was used and the activities of the lysosomal enzyme N N-acetyl-beta-D-glucosaminidase were also measured in the patients urine, before treatment, during treatment, and then 2 days and 23 days after rIL2 therapy had finished. Significant reductions in clearances of creatinine, sodium, and lithium were observed. The fractional excretions of sodium and lithium were also reduced. Twenty-three days following cessation of rIL2 treatment, there was still a significant reduction in creatinine clearance compared with pretreatment values (p < .01). The clearances of sodium and lithium were also reduced compared with pretreatment values although this did not achieve significance. The fractional reabsorption of sodium and water by the proximal nephron increased during rIL2 treatment, from 0.707 +/- 0.030 (pretreatment) to 0.793 +/- 0.043. This increased reabsorption of sodium and water persisted, rising to 0.849 +/- 0.029, 2 days following cessation of treatment (p < .001, means +/- SEM). Twenty-three days later this had returned toward the pretreatment value, being 0.781 +/- 0.036. The fractional reabsorption of sodium by the distal nephron was also significantly elevated, both during and 2 days after completing rIL2 treatment. Twenty-three days after cessation of rIL2, this value had returned to the pretreatment value. However, in contrast, the fractional reabsorption of water by the distal nephron demonstrated no change during rIL2 treatment, but 2 days posttreatment was significantly reduced and remained low for a further 3 weeks.

Whole Blood and Red Cell ATP Content in Patients With Peripheral Vascular Disease: The Effect of Cigarette Smoking and Oxpentifylline

The relationship between erythrocyte ATP content and the presence of atherosclerotic peripheral occlusive vascular disease was investigated. In 20 elderly patients with severe peripheral vascular insufficiency (10 male, 10 female; age 68.8 ± 12.5 years; Mean ± SD) the mean erythrocyte ATP content was 1.57 ± 0.16 mmol/litre. In a sex and age matched group (69.1 ± 9.6 years) with no signs or symptoms of peripheral or myocardial ischaemia, erythrocyte ATP content did not differ significantly (1.49 ± 0.29 mmol/litre). In young healthy volunteers, there was no difference in erythrocyte ATP content between males and females or between cigarette smokers and non-smokers, nor were the values for the young group different from those obtained from the elderly patients. The effect of oxpentifylline administration on erythrocyte ATP levels in patients with peripheral vascular disease was also studied. Administration of oxpentifylline (1.6 g per day in divided doses) over 7 days had no effect on erythrocyte ATP content in 10 patients (5 male, 5 female) with ischaemic lower limbs. These results suggest that measurement of erythrocyte ATP content is unlikely to be a useful index in the assessment of peripheral vascular disease.

Reply to the letter from Blay et al: Pretreatment serum CRP and response to interleukin 2

SirWe read with interest the letter from Blay et al. confirming our initial findings in patients with metastatic colorectal cancer that pretreatment measurement of serum C-reactive protein (CRP) levels could predict which patients with metastatic renal cancer would respond to rIL-2-based therapy. Our preliminary data have also indicated that there are differences in other acute-phase proteins (albumin, transferrin, retinol-binding protein and transferrin) between patients who do or do not respond to rIL-2 treatments. Furthermore, we have also found that these measurements not only predict tumour response (in terms of reduction in tumour volume) but also predict the survival of these patients following treatment. The reasons for this are unclear, but Blay et al. have suggested that CRP, which has well-documented immunosuppressive effects, may be inhibiting some of the biological mechanisms responsible for the anti-neoplastic effect of rIL-2 in vivo. However, CRP has also been documented to activate complement, stimulate macrophage phagocytosis and enhance lymphocyte proliferation and cytotoxicity (Vetter et al., 1983) and therefore the situation in vivo may be more complex. Furthermore, in our study patients who responded to rIL-2 treatment demonstrated rising levels of CRP during the rIL-2 infusion, whereas those who failed to respond had no change in the levels of CRP during the infusion. However, we agree that these findings have important implications in the selection of patients for rIL-2 therapy and that evaluation of the functions of CRP may allow further understanding of the complex relationship between acutephase reactants and the cytokine system. Yours etc.

Glomerulotubular Function in Patients Undergoing Moderate Surgical Stress

Glomerular function and renal tubular function assessed by measurements of creatinine clearance rates (CCR), lithium clearance rates (CLi, and N-acetyl-beta-D-glucosaminidase (NAG) enzymuria were measured immediately prior to and within 24 h of operation (average operative time 150 min) in 16 patients undergoing a moderate surgical stress. Although serum creatinine concentrations and CCR were similar pre- and postsurgery at 105 +/- 21 and 108 +/- 21 mumol/L and 108 +/- 67 and 110 +/- 59 mL/min/100 kg body weight (mean +/- SD), respectively, both CLi and NAG were significantly increased following the surgical insult. CLi was increased from 19.7 +/- 6.1 to 31.7 +/- 16.7 mL/min/100 kg (p less than 0.01) and NAG from 71 +/- 58 to 164 +/- 10 U/mmol urinary creatinine (p less than 0.001). In addition, the absolute distal tubular reabsorption of sodium and water increased from 18.3 +/- 5.9 and 15.8 +/- 9.7 to 30.6 +/- 16.4 and 27.6 +/- 12.2 mL/min/100 kg body weight (both p less than 0.05), respectively. These results indicate early postoperative renal tubular dysfunction following a moderate surgical stress, undetected by conventional screening.