Comparing practice and outcome of laparoscopic liver resection between high-volume expert centres and nationwide low-to-medium volume centres.

BACKGROUND: Based on excellent outcomes from high-volume centres, laparoscopic liver resection is increasingly being adopted into nationwide practice which typically includes low-medium volume centres. It is unknown how the use and outcome of laparoscopic liver resection compare between high-volume centres and low-medium volume centres. This study aimed to compare use and outcome of laparoscopic liver resection in three leading European high-volume centres and nationwide practice in the Netherlands. METHOD: An international, retrospective multicentre cohort study including data from three European high-volume centres (Oslo, Southampton and Milan) and all 20 centres in the Netherlands performing laparoscopic liver resection (low-medium volume practice) from January 2011 to December 2016. A high-volume centre is defined as a centre performing >50 laparoscopic liver resections per year. Patients were retrospectively stratified into low, moderate- and high-risk Southampton difficulty score groups. RESULTS: A total of 2425 patients were included (1540 high-volume; 885 low-medium volume). The median annual proportion of laparoscopic liver resection was 42.9 per cent in high-volume centres and 7.2 per cent in low-medium volume centres. Patients in the high-volume centres had a lower conversion rate (7.4 versus 13.1 per cent; P < 0.001) with less intraoperative incidents (9.3 versus 14.6 per cent; P = 0.002) as compared to low-medium volume centres. Whereas postoperative morbidity and mortality rates were similar in the two groups, a lower reintervention rate (5.1 versus 7.2 per cent; P = 0.034) and a shorter postoperative hospital stay (3 versus 5 days; P < 0.001) were observed in the high-volume centres as compared to the low-medium volume centres. In each Southampton difficulty score group, the conversion rate was lower and hospital stay shorter in high-volume centres. The rate of intraoperative incidents did not differ in the low-risk group, whilst in the moderate-risk and high-risk groups this rate was lower in high-volume centres (absolute difference 6.7 and 14.2 per cent; all P < 0.004). CONCLUSION: High-volume expert centres had a sixfold higher use of laparoscopic liver resection, less conversions, and shorter hospital stay, as compared to a nationwide low-medium volume practice. Stratification into Southampton difficulty score risk groups identified some differences but largely outcomes appeared better for high-volume centres in each risk group.

Preoperative portal vein or portal and hepatic vein embolization: DRAGON collaborative group analysis.

BACKGROUND: The extent of liver resection for tumours is limited by the expected functional reserve of the future liver remnant (FRL), so hypertrophy may be induced by portal vein embolization (PVE), taking 6 weeks or longer for growth. This study assessed the hypothesis that simultaneous embolization of portal and hepatic veins (PVE/HVE) accelerates hypertrophy and improves resectability. METHODS: All centres of the international DRAGON trials study collaborative were asked to provide data on patients who had PVE/HVE or PVE on 2016-2019 (more than 5 PVE/HVE procedures was a requirement). Liver volumetry was performed using OsiriX MD software. Multivariable analysis was performed for the endpoints of resectability rate, FLR hypertrophy and major complications using receiver operating characteristic (ROC) statistics, regression, and Kaplan-Meier analysis. RESULTS: In total, 39 patients had undergone PVE/HVE and 160 had PVE alone. The PVE/HVE group had better hypertrophy than the PVE group (59 versus 48 per cent respectively; P = 0.020) and resectability (90 versus 68 per cent; P = 0.007). Major complications (26 versus 34 per cent; P = 0.550) and 90-day mortality (3 versus 16 per cent respectively, P = 0.065) were comparable. Multivariable analysis confirmed that these effects were independent of confounders. CONCLUSION: PVE/HVE achieved better FLR hypertrophy and resectability than PVE in this collaborative experience.

Surgical treatment options following chemotherapy plus cetuximab or bevacizumab in metastatic colorectal cancer-central evaluation of FIRE-3.

BACKGROUND: The FIRE-3 trial investigated combination chemotherapy plus either cetuximab or bevacizumab in patients with untreated metastatic colorectal cancer (mCRC) not scheduled for upfront surgery. We aimed to determine the number of patients who present with potentially resectable disease during systemic first-line therapy and to compare the findings with study reports concerning resections and outcome. PATIENTS AND METHODS: This evaluation of 448 patients was performed as central review blinded for treatment, other reviewers' evaluations and conducted interventions. Resectability was defined if at least 50% of the reviewers recommended surgical-based intervention. Overall survival was assessed by Kaplan-Meier method. RESULTS: Resectability increased from 22% (97/448) at baseline before treatment to 53% (238/448) at best response (P < 0.001), compared with an actual secondary resection rate for metastases of 16% (72/448). At baseline (23% versus 20%) and best response (53% versus 53%), potential resectability of metastases in this molecular unselected population was similar in cetuximab-treated patients versus bevacizumab-treated patients and not limited to patients with one-organ disease. The actual resection rate of metastases was significantly associated with treatment setting (P = 0.02; university hospital versus hospital/practice). Overall survival was 51.3 months (95% confidence interval [CI] 35.9-66.7) in patients with resectable disease who received surgery, 30.8 months (95% CI 26.6-34.9) in patients with resectable disease without surgery and 18.6 months (95% CI 15.8-21.3) in patients with unresectable disease (P < 0.001). CONCLUSIONS: Our findings illustrate the potential for conversion to resectability in mCRC, certain reluctance towards metastatic resections in clinical practice and the need for pre-planned and continuous evaluation for metastatic resection in high-volume centres. CLINICALTRIALS. GOV-IDENTIFIER: NCT00433927.

Tumor Necrosis Factor: Function, Release and Clearance.

Tumor Necrosis Factor (TNF) is a multifunctional cytokine. It plays an important role in the pathophysiology of several diseases. Recently, it has been discovered that TNF is circulating in two different forms, a bioactive form and an immunologically detectable form. These two forms of TNF show different clearance kinetics. The immunological form is supposed to be an inactivated TNF protein. For this inactivation, proteolytic degradation or TNF binding by inactivating proteins is necessary. In this review we have focused on TNF inactivation by TNF binding proteins. Recent data show that there are soluble TNF receptors circulating which can bind and inactivate TNF. These receptors are membrane-bound TNF receptors which have been proteolytically cleaved from the cell membrane. Two TNF receptors are circulating, the soluble TNF receptor of 55 kDa (P55) and the receptor of 75 kDa (P75). The receptors are held responsible not only for inactivation of the TNF, but also for the clearance of TNF. Recent data show that the kidney is the most important organ for TNF clearance, followed by the liver. All other organs are of less importance. In this review, function, release, and clearance of TNF are discussed.

Effects of postoperative morbidity on long-term outcome following surgery for colorectal liver metastases.

BACKGROUND: The impact of postoperative complications on long-term outcomes after surgery for colorectal liver metastases (CRLM) remains controversial. During the last decade, advances in surgical as well as non-surgical treatment have increased resectability and altered outcomes. We sought to determine the influence of postoperative morbidity on disease-free (DFS) and overall survival (OS). METHODS: All patients undergoing liver resection for CRLM for the first time between 2000 and 2011 were retrospectively identified from a prospective database. Postoperative morbidity was classified according to Dindo-Clavien grade. A Dindo-Clavien grade ≥ 3a was considered a major complication. Primary outcomes were DFS and OS depending on the presence or absence of postoperative morbidity. RESULTS: Of the 266 included patients, 97 patients (37 %) developed postoperative complications, of whom 61 (23 %) had major complications. Median DFS and OS (5-year) were 17 and 53 months (42 %). The occurrence of postoperative morbidity did not significantly shorten OS (p = 0.130) and DFS (p = 0.101). However, major morbidity reduced DFS significantly (p < 0.05). CONCLUSION: In the present study, the occurrence of major postoperative complications was associated with diminished DFS. However, the effect of (major) complications on OS did not reach statistical significance.

The introduction of a laparoscopic liver surgery programme: a cost analysis of initial experience in a university hospital.

BACKGROUND AND AIMS: In the era of expanding costs of healthcare, this study was conducted to perform a cost analysis of introducing a laparoscopic liver surgery programme for left sided liver lesions. MATERIALS AND METHODS: Consecutive patients treated by laparoscopic liver resections of left lateral segments were included. Controls were a group of 14 patients undergoing open resection for similar pathology. Primary outcomes were costs. Secondary outcomes were complications, conversions, blood loss, length of operation, and length of hospital stay. RESULTS: The laparoscopic approach for hepatic left lateral resection (bisegmentectomy 2 and 3) was performed in fourteen patients (group I, median age 54 [range 26-82] years). In the open group, fourteen patients from a prospectively collected database with the same type of resection were selected (group II, median age 64 [range 29-76] years). Costs of theatre usage in the laparoscopic group were significantly lower (p=0.031). No significant differences in costs of disposable instruments, ward stay and total costs were observed between the two groups. There were three complications in the laparoscopic group compared with two complications in the open group. In the laparoscopic group there were 2 conversions (14%). Median blood loss was significantly lower in the laparoscopic group (50 mls [range 0-750], (p=0.001) versus the open group (500 mls [range 150-750]). Furthermore, operation time was also significantly lower in the laparoscopic group (116 [range 85-261] minutes) versus the open group (165 [range 96-217] minutes, p=0.016). Median length of stay was 6 [range 4-11] days in group I versus 6 [range 5-13] days in group II (p=0.508). CONCLUSION: Costs of laparoscopic liver resections proved to be equivalent to open surgery. Furthermore, implementation of a laparoscopic liver resection programme seems feasible and safe with reduced blood loss and operation time and comparable morbidity and length of stay.

HIV care need not hamper maternity care: a descriptive analysis of integration of services in rural Malawi.

OBJECTIVE: To evaluate the use of reproductive health care and incidence of paediatric HIV infection during the expansion of antiretroviral therapy and services for the prevention of mother-to-child transmission in rural Malawi, and the influence of integration of these HIV-related services into general health services. DESIGN: Descriptive analysis. SETTING: Thyolo District, with a population of 600,000, an HIV prevalence of 21% and a total fertility rate of 5.7 in 2004. POPULATION: Women attending reproductive health services care in 2005 and 2010. METHODS: Review of facility records and databases for routine monitoring. MAIN OUTCOME MEASURES: Use of antenatal, intrapartum, postpartum, family planning and sexually transmitted infection services; incidence of HIV infection in infants born to mothers who received prevention of mother-to-child transmission care. RESULTS: There was a marked increase in the uptake of perinatal care: pregnant women in 2010 were 50% more likely to attend at least one antenatal visit (RR 1.50, 95% CI 1.48-1.51); were twice as likely to deliver at a healthcare facility (RR 2.05, 95% CI 2.01-2.08); and were more than four times as likely to present for postpartum care (RR 4.40, 95% CI 4.25-4.55). Family planning consultations increased by 40% and the number of women receiving treatment for sexually transmitted infections doubled. Between 2007 and 2010, the number of HIV-exposed infants who underwent testing for HIV went up from 421 to 1599/year, and the proportion testing positive decreased from 13.3 to 5.0%; infants were 62% less likely to test HIV positive (RR 0.38, 95% CI 0.27-0.52). CONCLUSIONS: During the expansion and integration of HIV care, the use of reproductive health services increased and the outcomes of infants born to HIV-infected mothers improved. HIV care may be successfully integrated into broader reproductive health services.

Reduced tuberculosis case notification associated with scaling up antiretroviral treatment in rural Malawi.

OBJECTIVE: To report on the trends in new and recurrent tuberculosis (TB) case notifications in a rural district of Malawi that has embarked on large-scale roll-out of antiretroviral treatment (ART). METHODS: Descriptive study analysing TB case notification and ART enrolment data between 2002 and 2009. RESULTS: There were a total of 10,070 new and 755 recurrent TB cases. ART scale-up started in 2003, and by 2007 an estimated 80% ART coverage had been achieved and was sustained thereafter. For new TB cases, an initial increase in case notifications in the first years after starting ART (2002-2005) was followed by a highly significant and sustained decline from 259 to 173 TB cases per 100,000 population (χ(2) for trend 261, P < 0.001, cumulative reduction for 2005-2009 = 33%, 95%CI 27-39). For recurrent TB, the initial increase was followed by a significant drop, from 20 to 15 cases/100,000 (χ(2) for linear trend = 8.3, P = 0.004, constituting a 25% (95%CI 9-49) cumulative reduction between 2006 and 2009. From 2005 to 2009, ART averted an estimated 1164 (95%CI 847-1480) new TB cases and 78 (95%CI 23-151) recurrent TB cases. CONCLUSIONS: High ART implementation coverage is associated with a very significant declining trend in new and recurrent TB case notifications at population level.

Development of a composite endpoint for randomized controlled trials in liver surgery.

BACKGROUND: The feasibility of randomized controlled trials (RCTs) in liver surgery using a single-component clinical endpoint is low as such endpoints require large sample sizes owing to their low incidence. A liver surgery-specific composite endpoint (CEP) could solve this problem. The aim of this study was to develop a liver surgery-specific CEP with well-defined components. METHODS: Components of a liver surgery-specific CEP were selected based on a systematic literature search and consensus among 28 international hepatopancreatobiliary (HPB) surgeons. As an example, two prospective cohorts of patients who had undergone liver surgery in high-volume HPB centres were used to assess the event rate and effect of implementing a liver surgery-specific CEP. RESULTS: Components selected for the liver surgery-specific CEP were ascites, postresectional liver failure, bile leakage, intra-abdominal haemorrhage, intra-abdominal abscess and operative mortality, all with a Clavien-Dindo grade of at least 3 and occurring within 90 days after initial surgery. The incidence of this liver surgery-specific CEP was 19.2 per cent in one cohort and 10.7 per cent in the other. These rates led to an approximately twofold reduction in the theoretical sample size required for an adequately powered RCT in liver surgery using the CEP as primary endpoint. CONCLUSION: The proposed liver surgery-specific CEP consists of ascites, postresectional liver failure, bile leakage, intra-abdominal haemorrhage, intra-abdominal abscess and operative mortality. It has a considerably higher event rate than any of its components. Its use as the primary endpoint will increase the feasibility and comparability of RCTs in liver surgery.

Initial experience with a multimodal enhanced recovery programme in patients undergoing liver resection.

BACKGROUND: Accelerated recovery from surgery has been achieved when patients are managed within a multimodal Enhanced Recovery After Surgery (ERAS) protocol. This study evaluated the benefit of an ERAS programme for patients undergoing liver resection. METHODS: The ERAS protocol of epidural analgesia, early oral intake and early mobilization was studied prospectively in a consecutive series of 61 patients. Outcomes were compared with those in a consecutive series of 100 patients who underwent liver resection before the start of the study. Endpoints were postoperative length of hospital stay, postoperative resumption of oral intake, readmissions, morbidity and mortality. RESULTS: Fifty-six patients (92 per cent) in the ERAS group tolerated fluids within 4 h of surgery and a normal diet on day 1 after surgery. Median hospital stay, including readmissions, was 6.0 days compared with 8.0 days in the control group (P < 0.001). There were no significant differences in rates of readmission (13 and 10.0 per cent respectively), morbidity (41 and 31.0 per cent) and mortality (0 and 2.0 per cent) between ERAS and control groups. CONCLUSION: The ERAS fast-track protocol is safe and effective for patients undergoing liver resection. It allows early oral intake, promotes faster postoperative recovery and reduces hospital stay.

TNF receptors in murine Candida albicans infection: evidence for an important role of TNF receptor p55 in antifungal defense.

TNF mediates multiple biologic activities through two distinct cell surface receptors, TNFR-p55 and TNFR-p75. TNF plays an important role in nonspecific resistance against the fungus Candida albicans. We used transgenic mice deficient for TNFR-p55 or TNFR-p75 to investigate the role of the TNFR in antifungal defense. Mice deficient for TNFR-p55 have highly impaired ability to clear infection with C. albicans and readily succumb to the infection. Also mice deficient for TNFR-p75 had a significant reduction in their ability to clear the fungus although lethality was not increased. These data demonstrate that TNFR-p55 in particular, but also TNFR-p75, plays a definite role in defense against infection with C. albicans. In NMRI mice, infection with C. albicans resulted in a significant systemic release of soluble (s)TNFR-p75. Cyclophosphamide-induced granulocytopenia led to a reduction of sTNFR-p75 release, whereas levels of bioactive TNF in response to fungal infection were increased. Release of sTNFR-p55 was not affected by induction of granulocytopenia. These observations suggest that granulocytes are a source of sTNFR-p75, possibly contributing to regulation of TNF activity during infection with C. albicans.

Increased concentrations of tumour necrosis factor (TNF) and soluble TNF receptors in biliary obstruction in mice; soluble TNF receptors as prognostic factors for mortality.

Systemic tumour necrosis factor (TNF) is present in jaundiced mice. Two soluble TNF receptors, sTNFr-P55 and sTNFr-P75 are reported to play a part in the natural defence against TNF. This study investigated the properties of circulating TNF and sTNFr in jaundiced mice. The data show that TNF in these mice is biologically inactive and that an increase of both sTNFr is seen (p < 0.001). Surgical trauma in jaundiced mice is known to be accompanied by a high mortality (36%) and increased TNF concentrations. This study shows that both systemic TNF and sTNFr concentrations are increased after surgical trauma in jaundiced mice and that sTNFr concentrations rather than TNF concentrations were found to be correlated with mortality. In line with this finding this study showed that lactulose pretreatment before a surgical trauma in these mice significantly reduces postoperative concentrations of sTNFr-P75 (p < 0.005) and mortality (0%; p < 0.05) without reducing TNF concentrations, while anti-TNF antibodies were ineffective. In conclusion, these data suggest that TNF in biliary obstruction is rapidly inactivated by increased concentrations of sTNFr. Furthermore, sTNFr concentrations rather than TNF concentrations show a good correlation with mortality after surgery in obstructive jaundice. The positive effect of lactulose on mortality could be caused by a decreased inflammatory status.

Tumor necrosis factor: function, release and clearance.

Tumor Necrosis Factor (TNF) is a multifunctional cytokine. It plays an important role in the pathophysiology of several diseases. Recently, it has been discovered that TNF is circulating in two different forms, a bioactive form and an immunologically detectable form. These two forms of TNF show different clearance kinetics. The immunological form is supposed to be an inactivated TNF protein. For this inactivation, proteolytic degradation or TNF binding by inactivating proteins is necessary. In this review we have focused on TNF inactivation by TNF binding proteins. Recent data show that there are soluble TNF receptors circulating which can bind and inactivate TNF. These receptors are membrane-bound TNF receptors which have been proteolytically cleaved from the cell membrane. Two TNF receptors are circulating, the soluble TNF receptor of 55 kDa (P55) and the receptor of 75 kDa (P75). The receptors are held responsible not only for inactivation of the TNF, but also for the clearance of TNF. Recent data show that the kidney is the most important organ for TNF clearance, followed by the liver. All other organs are of less importance. In this review, function, release, and clearance of TNF are discussed.

Differences in the shedding of soluble TNF receptors between endotoxin-sensitive and endotoxin-resistant mice in response to lipopolysaccharide or live bacterial challenge.

TNF-alpha plays a pivotal role in the pathogenesis of septic shock. It exerts its effects by binding two cell surface receptors, designated TNF-R I and II, also referred to as the p55 and p75 receptors, respectively. TNF-Rs are transmembrane proteins, which on cleavage of their extracellular domains, result in the release of soluble fragments (sTNF-R). sTNF-R levels increase markedly during infection, and may serve to modulate TNF-alpha bioactivity. The mechanisms regulating this process are uncertain. To investigate this, we measured sTNF-R release in endotoxin-sensitive C3H/HeN and endotoxin-resistant C3H/HeJ mice given LPS or live Gram-negative bacteria. In C3H/HeN mice, there was a rapid early response during the first 4 h, and a second peak at 8 h, particularly noticeable in the case of the p75 receptor. Prior administration of neutralizing Abs to TNF-alpha or IFN-gamma had no effect on receptor shedding. Surprisingly, C3H/HeJ mice also responded to both bacterial challenge and to LPS by shedding sTNF-R; the magnitude and duration of the early response was not substantially different from C3H/HeN mice, although the second peak was absent. Peritoneal macrophages from C3H/HeN mice responded promptly (5 h) when stimulated with LPS in vitro, and by 22 h levels had increased five- to 10-fold. In contrast, cells from C3H/HeJ mice demonstrated only a very modest response at 22 h following maximal stimulation. The data suggest that there may be at least two separately regulated pathways that control sTNF-R shedding in these mice.

Pharmacologic inhibitors of tumor necrosis factor production exert differential effects in lethal endotoxemia and in infection with live microorganisms in mice.

Tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) are principal mediators of septic shock; inhibition of TNF-alpha production may ameliorate outcome in severe infections. Pentoxifylline, chlorpromazine, and thalidomide inhibit TNF-alpha production. Their effects were tested in lethal endotoxemia in sensitized mice. Only chlorpromazine significantly improved survival. Chlorpromazine and pentoxifylline significantly reduced postendotoxin circulating TNF-alpha, by 89% and 76%, respectively. Chlorpromazine also significantly reduced IL-1 beta and soluble TNF receptor-P75. No drug improved survival in Klebsiella pneumoniae-infected mice despite significantly lower circulating TNF-alpha concentrations in chlorpromazine- or pentoxifylline-treated animals. The three compounds decreased circulating TNF-alpha in Candida albicans-infected mice, but survival was not influenced. In neutropenic mice, chlorpromazine had no influence on candida in organs, but in normal mice, Candida counts in kidneys were higher in chlorpromazine-treated mice. Thus, inhibition of TNF-alpha production was of no benefit in K. pneumoniae infection and worsened outcome in C. albicans infection.

Granulocytopenia reduces release of soluble TNF receptor p75 in endotoxin-stimulated mice: a possible mechanism of enhanced TNF activity.

This study demonstrates that granulocytopenia alters the TNF response to endotoxin. Significantly higher levels of bioactive TNF were observed in mice rendered granulocytopenic (< 0.05 x 10(9) granulocytes/litre) with cyclophosphamide than in normal mice. Levels of circulating soluble TNF receptor p75 (sTNFR-p75) in response to endotoxin were higher in normal mice than in granulocytopenic mice whereas no difference in levels of circulating soluble TNF receptor p55 (sTNFR-p55) was observed. To investigate further the role of both sTNFR in inactivation of TNF, murine recombinant (r) TNF or human rTNF was injected in to normal and granulocytopenic mice. Higher TNF bioactivity was recovered in granulocytopenic mice than in normal mice after administration of murine rTNF, whereas, no difference in recovered TNF bioactivity was observed after human rTNF. As murine TNFR-p75 does not bind to human TNF, this observation indicates that less sTNFR-p75 available for neutralization of TNF in the circulation in granulocytopenia results in enhanced TNF bioactivity. Furthermore, endotoxin-induced lethality was increased in granulocytopenic mice. In summary, this study shows that endotoxin-induced release of sTNFR-p75 is reduced and TNF bioactivity increased in granulocytopenia. Our data suggest that release of sTNFR-p75 from granulocytes is a mechanism in the regulation of TNF bioactivity.

Tissue distribution and clearance of soluble murine TNF receptors in mice.

In this study, clearance of sTNFR was investigated. The data show that bilateral nephrectomy results in an increase of the levels of both sTNFR after which a new steady state situation develops, suggesting that other organs, apart from the kidneys, are involved in clearing of sTNFR. Bilateral nephrectomy also leads to an increase in circulating TNF. This TNF was detected by ELISA and appeared to be not biologically active. To investigate whether the endotoxin induced increase in sTNFR is dependent of renal function, endotoxin was injected in nephrectomized mice. The data show that nephrectomy followed by endotoxin injection resulted in a further increase of the levels of both sTNFR. However, the endotoxin induced increase in nephrectomized mice was similar to the situation in normal mice after LPS indicating that the endotoxin induced increase is kidney independent in these mice. To investigate the relative participation of various organs in sTNFR clearance, 125I labelled sTNFR-P75 was injected. The data reveal that the majority of the sTNFR is removed from the circulation by the kidneys although indications for involvement of the liver and the lungs were also obtained. Calculation of the parametric clearance revealed that nephrectomy resulted in a 50% reduction of sTNFR-P75 clearance. Furthermore, the data presented strongly suggest that sTNFR release seems to be a continuous process, which is in balance with clearance of the sTNFR by the kidney, although other organs such as the liver and the lungs are involved.

In vivo T cell activation by anti-CD3 monoclonal antibody induces soluble TNF receptor release in mice. Effects of pentoxifylline, methylprednisolone, anti-TNF, and anti-IFN-gamma antibodies.

Injection of anti-CD3 is accompanied by an increase in systemic TNF, a mediator of the physiologic changes induced by anti-CD3 injection. Various mechanisms have been reported to be responsible for TNF inactivation and clearance. Recently, it has become evident that circulating soluble TNFRs (P55 and P75), which are known to increase in response to TNF inducers such as LPS, represent a natural protection mechanism against circulating TNF. Here we show that triggering the TCR by anti-CD3 injection results in a strong induction of both systemic TNF and soluble TNFR release. Maximal levels of TNF were reached after 2 h (10 ng/ml). Maximum levels of P55 (450 pg/ml) were reached between 0.5 and 8 h, whereas the highest levels of P75 were reached after 2 h (28 ng/ml). Because TNF and IFN-gamma are supposed to be involved in the pathophysiology of the anti-CD3 response, we investigated the influence of in vivo neutralization of TNF and IFN-gamma. Injection of mAb to TNF and IFN-gamma significantly reduced systemic TNF levels and both soluble TNFR levels. Two inhibitors of anti-CD3 induced TNF release; steroids and pentoxifylline both reduced TNF levels and P75 levels without affecting P55 levels. The results show that T cell activation induces both systemic TNF release and release of both soluble TNFRs. Although TNF and IFN-gamma are involved in this mechanism, their role does not seem to be crucial.