Venous thromboembolism (VTE) is a frequent complication of long-term access using central venous catheters, with the highest frequency in hemato-oncology diseases, and is one of the leading
causes of death in oncology patients.1Cohort studies of surgical
patients have shown that the incidence of VTE is markedly higher
in patients with cancer than in patients without cancer.2
Post-mortem studies have also demonstrated a higher incidence of VTE
in patients with cancer.3The association between cancer and VTE
arises both as a direct consequence of tumor growth and host inflammatory responses and indirectly as a consequence of cancer treatment, venous stasis, and direct vessel trauma.4It is well known
that the risk for developing VTE in cancer patients is significantly increased during chemotherapy and as a result of long-term cen-tral venous catheter (CVC) placement. Many cancer patients require long-term central venous access for the safe deliverance of chemotherapeutic agents, nutrients and fluids, and transfusion of blood and blood products, as well as for the withdrawal of blood samples from the central circulation. Long-term CVCs may remain in position for months or years, and their role in facilitat-ing patient care is clear. Nevertheless, they are associated with a
number of early and late complications, including catheter-related deep vein thrombosis (CVC-related DVT), which represents the
second cause for catheter loss, after infection.5Though scientific
evidences and clinical experience are steadily increasing, many uncertainties still exist about several aspects concerning etiology, pathogenesis , diagnosis, management, and prevention of this com-mon complication of central venous long-term access. The inci-dence of this complication has been investigated in several studies, but major differences and inconsistencies in study design, patient populations, techniques of catheter insertion, and accuracy of tests used to diagnose thrombosis have hampered an accurate
estima-tion. In a recently performed systematic review,6the incidence of
symptomatic CVC-related DVT in adult varied between 0.3% and 28.3%, whereas the incidence of venography-assessed cases (mostly asymptomatic) ranged from 27% to 66%. Pulmonary embolism has been reported to occur in 15% to 25% of patient with CVC-related DVT. Although the thrombosis rate is high, only a third of the thrombosed CVCs become symptomatic. Nonethe-less, CVC thrombosis can result in clinical symptoms, the loss of catheter function, a higher rate of infection, postphlebitic syndrome of the upper extremity, pulmonary embolus, and greater costs.
Considering the lack of official and widely accepted guide-lines on this subject, the Italian Study Group for Long Term Central Venous Access (GAVeCeLT) decided to develop a nationwide Consensus. Adopted methodology and results of this work are the subject of this article.
Catheter-Related Central Venous
Thrombosis: The Development of a
Nationwide Consensus Paper in Italy
Costantino Campisi, MD, Roberto Biffi, MD, and Mauro Pittiruti, MD
on behalf of the GAVeCeLT Committee for the Consensus
Abstract
Catheter-related central venous thrombosis is a serious complication in patients who need long-term venous access. Though sci-entific data and clinical experience are steadily increasing, many uncertainties still exist about several aspects of this complication, including etiology, pathogenesis, diagnosis, management, and prevention of this complication. The GAVeCeLT (the Italian Study Group for Long Term Central Venous Access) promoted a nationwide consensus, and 12 experts reviewed systematically all the avail-able literature. A preliminary document was presented and discussed during a specific Consensus Meeting, in front of a panel of more than 80 experts (representing different health professions and disciplines). This led to a prefinal document, which was presented to more than 800 health professionals. After peer review by an external board of experts, the final document was prepared. In this article, methodology and results of the consensus are presented.
Correspondence concerning this article should be addressed to roberto.biffi@ieo.it
DOI: 10.2309/java.12-1-10
CE T
est
Material
Methods
The methodology was planned and carried out according to the principles of evidence-based medicine (EBM), with special attention to the recommendations of the Italian National Health
Institute (ie, Standards for Planning National Guidelines).7The
guidelines have been developed by using methods that maximize their validity, such as:
• Identification of evidence by systematic review; • Development by a multidisciplinary group; and
• Use of explicit links between evidence and recommenda-tions, defining the strength of the recommendation
accord-ing to accepted standards as follows:8
Level Evidence
I Randomized clinical trial of high statistical value
or meta-analysis of randomized, clinical trials (RCTs).
II RCT of lower statistical value.
III Case-control study, historical study, nonrandom.
IV Clinical series and retrospective analysis.
V Case reports and anecdotal data.
Category Strength of recommendation
A Level I evidence
B Level II evidence
C Level III, IV, or V evidence
A committee of 12 experts examined systematically the liter-ature and defined 8 questions to be answered:
1. By what mechanisms may a catheter cause a venous
thrombosis?
2. Is there an ideal insertion technique for minimizing the risk?
3. Is there any device or material that may intrinsically reduce the risk?
4. What are the patient's risk factors?
5. What is the role of tip position?
6. If thrombosis occurs, when should the catheter be
removed?
7. What is the ideal pharmacological management?
8. Can CVC-related DVT be prevented?
A preliminary document was presented and discussed during a specific consensus meeting, in front of an enlarged panel of more than 80 experts (representing different health professions and different disciplines). This led to a prefinal document, which was presented during a GAVeCeLT Congress in Milan, Italy, to an external board of experts (including international European referees), a final document was prepared.
Results
1. By What Mechanisms May a Catheter Cause Venous Throm-bosis?
Soon after the insertion of almost all catheters, a fibrin sheath forms around the catheter. Data from several studies have shown that the sheath develops within 24 hours of catheter
insertion.9In an autopsy study of patients with CVCs, all 55
patients examined developed this sleeve, and, in phlebographic
studies, 45 of 57 (78%) patients had a fibrin sheath.9-10A
veno-graphic study showed that 83 of 95 (87%) patients had these
sheaths.11Furthermore, detailed studies by quantitative electron
microscopy and by quantitative microbiologic testing of these fibrin sheaths over time have shown that they are always colo-nized by cocci.12,13
The presence of these sheaths does not predict subsequent DVT of the vessel in which the catheter is placed. In one study, only 1 of 16 patients with a fibrin sheath developed thrombosis
over a median of 12.5 months.14
Conclusions of the Consensus
There are multiple mechanisms, always including an acute and/or chronic endothelial damage to the vein wall, produced by a foreign intravascular body. Although mechanisms of fibrin sheath formation are well known, their relationship with the thrombotic event is not yet clear.
Recommendation for Clinical Practice Cannot Be Proposed. 2. Is There an Ideal Insertion Technique for Minimizing the Risk?
New techniques have been developed to access central veins with different imaging aides (ie, ultrasound, eco-color-Doppler, digital venography, etc.). The only procedure that is associated with valid scientific data, retrieved in clinical, randomized, con-trolled studies15and elaborated in a meta-analysis16is the
ultra-sound (US)-guided placement of central venous access. This meta-analysis, taking into account 8 randomized studies, showed that US-guided placement is useful in reducing compli-cations in percutaneous accesses performed with the standard “landmarks” technique, should the operator have little experi-ence. In fact, in such studies, the control arm (unguided percu-taneous access) often had an unusually high complication and failure rate (over 40%). Most studies do not exhibit a sufficient follow up, thus leading to an underestimation of costs; it is also well known that a number of late complications (thrombosis
included) could arise months after implantation.17
More recently, other articles have addressed this issue with a randomized or prospective approach in the intensive care unit
(ICU) setting18 and in oncology,19 pediatric,20 and dialysis
patients,21leading to the conclusion that US guidance improved
the success rate of internal jugular vein cannulation, reducing the number of attempts and the failure rate, as well as reduced the incidence of thrombotic complication. The National Institute for
Clinical Excellence-UK (Nice-UK)22made the following
rec-ommendations in 2002:
1. 2-D imaging US guidance should be the preferred method
when inserting a CVC into the internal jugular vein in adults and children in elective situations.
2. 2-D imaging US guidance should be considered in most
clinical situations where CVC insertion is necessary, whether the situation is elective or an emergency.
3. Everyone who uses 2-D imaging US guidance to insert
CVCs should have appropriate training to ensure they are competent to use the technique.
With respect to the vein chosen, in one randomized trial, catheter-related thrombosis occurred in 21.5% of the patients with femoral venous catheters and in 1.9% of those with subclavian
venous catheters.23In an observational study, the risk of
thrombo-sis associated with internal jugular vein insertion was approxi-mately four times the risk associated with subclavian insertion, thus reinforcing the idea that subclavian vein catheterization
car-ries the lowest risk of catheter-related thrombosis.24It should be
emphasized that these data were obtained in critically ill patient populations; a trial of oncology patients undergoing long-term cannulation has not been published to date, although an objective need of such a trial is clear. The present state of central venous long-term cannulation, especially for CVCs and ports used in oncology, is confusing. These procedures differ from center to center, and the majority of operators tends to rely on personal experience and professional formation when choosing an approach, the most important factor being their personal confi-dence with the various possible techniques. Looking at prospec-tive, nonrandomized studies, percutaneous technique and surgical
cutdown seem to have the same rate of thrombotic complication.25
Conclusions of the Consensus
• To date, to our knowledge, no randomized trials have inves-tigated the relationships between insertion techniques in the long-term setting (eg, percutaneous vs venous cut-down, US-guided vs anatomic landmark techniques) and central venous thrombosis rate.
• Prospective, not randomized, studies have suggested a rela-tionship between minimal insertion damage to vein wall, as obtained with US guidance, and low rate of subsequent thrombotic events.
Strength C Recommendation.
3. Is There Any Device or Material That May Intrinsically Reduce the Risk?
Currently, a wide variety of CVCs are used in medicine. Major design efforts have been undertaken to develop catheters that minimize trauma to blood vessels and are less thrombo-genic. The catheter type and materials have undergone major design changes and continue to evolve. Randomized trials and prospective observations have indicated an inherent superiority of silicone and 2nd-3rd-generation polyurethane over more rigid materials, like polyvinilchloride (PVC), tetrafluoroethylen, and
polyethylen.26-32Pure silicone, valved catheters exhibited a lower
rate of thrombosis compared with barium-added, open-ended
sil-icone ones in a randomized trial.33The number of catheter
lumens is a major predictor of catheter thrombosis. In one study, triple-lumen, tunneled catheters failed at three times the rate of
double-lumen catheters.34
Conclusions of the Consensus
• Silicone and 2nd-3rd-generation, polyurethane catheters are less thrombogenic than polyethylene or PVC ones.
• A lower-diameter catheter and a single lumen might be pro-tective against the risk of central venous thrombosis. When
the number of therapies demands a multiple-lumen catheter, the number of lumens used should be minimized.
Strength B Recommendation. 4. What Are the Patient's Risk Factors?
The patient risk factors related to CVC thrombosis are many,
and most have been studied primarily in oncology patients.35-38As
previously discussed, the presence of malignancy generally results in a higher rate of thrombosis; some types of malignancy (eg, ade-nocarcinoma of the lung or the pancreas) may be associated with higher rates of thrombosis. In a prospective study, 45% of patients with lung cancer developed symptomatic CVC thrombosis,
whereas only 9% of those with head and neck cancer did.39This
may be related to the activation of the coagulation system in these different malignancies, tumor-related changes in blood flow, or levels of tissue factor or tissue-factor-pathway inhibitor.
Inherited thrombophilia has been investigated as possible pre-dictor of CVC thrombosis. One study reported that low antithrom-bin III levels were associated with a greater risk for thrombosis.40
Another study found that 32% of patients who had CVC throm-boses had diagnoses of a hypercoagulable state; most had elevated anticardiolipin antibody levels, but there was no greater incidence of prothrombin 20210A mutation, Factor V Leiden, protein C
deficiency, or protein S deficiency.41A case-control study showed
that Factor V Leiden carriers with locally advanced or metastatic breast cancer have an increased risk of developing catheter-related
DVT during chemotherapy.42Last, fibrinogen level and platelet
count have been measured in patients with CVC thromboses, but the data are conflicting and most cases are not related to elevations in fibrinogen or platelet count.43-44
Conclusions of the Consensus
• Neoplastic disease and chemotherapy are recognized risk fac-tors for development of central venous thrombosis in patients with a CVC. Pathophysiology is known: It includes direct release of thrombogenic factors by neoplastic cells, decrease of antithrombotic natural factors induced by the tumor, and the procoagulant activity of many antitumor drugs. • In nonrandomized studies, mutations of Factor V Leiden
and/or the prothrombin gene and low antithrombin III levels have been found to be related to a higher incidence of cen-tral venous thrombosis in cancer patients with a CVC. Hereditary screening procedures for thrombophilia are not presumably cost effective.
Recommendation for clinical practice cannot be proposed. 5. What Is the Role of Tip Position?
The position of the catheter in the vascular system is a major determinant of CVC-related thrombosis, and tip position has been shown to be the main independent prognostic factor for malfunc-tion and reduced duramalfunc-tion of the device. Placement of the catheter tip high in the superior vena cava (SVC) results in a higher inci-dence of thrombosis than when the catheter tip is placed low in the
SVC or at atrio-caval junction.45-48Therefore, at least in oncology
patients, the atrial-caval junction is apparently the optimal position; hemodialysis could require a full atrial positioning of the catheter
tip, at least for cuffed devices.49The side of the body where the
catheter is inserted has been investigated, with conflicting results; most reports indicate that catheters inserted from the left
subcla-vian vein clotted more commonly.50-51
Conclusions of the Consensus
• In many prospective studies, tip position emerged as the main independent prognostic factor for malfunction, throm-bosis, and reduced duration of the device. In oncology patients, the atrial-caval junction appears to be the optimal position of the catheter tip, as it minimizes the risk of cen-tral venous thrombotic events.
Strength B Recommendation.
6. If Thrombosis Occurs, When Should the Catheter Be Removed?
The majority of clinical reports about pharmacology treatment of catheter-related DVT have focused on clinically overt and imaging-diagnosed thromboses. These studies have not always indicated the fate of the catheter.52-56Only 7 retrospective articles
that indicated this problem could be retrieved;57-63and those 7
articles reported a rate of successful catheter preservation rang-ing from 45.5% to 96% (N = 235). No clear advantages could be obtained by catheter removal after the thrombosis was estab-lished, and the clinical outcome did not seem influenced by this measure. In addition, local thrombolitic treatment may require the presence of the catheter and a poor peripheral vein status could represent a major limiting factor for most therapies, after the catheter has been removed.
A risk of embolization during or immediately after catheter removal has been clinically confirmed by many anecdotal
reports.64-67The mandatory indications to catheter removal in case
of thrombosis include infected thrombus, malposition of the tip (primary or secondary to migration), and irreversible occlusion of the lumen.
Conclusions of the Consensus
• Catheter removal or maintenance does not influence the out-come.
• Although local thrombolitic treatment may require the pres-ence of the catheter, a poor peripheral vein status could rep-resent a major limiting factor for most therapies, if the catheter has been removed.
• In case of clinically overt or imaging-diagnosed DVT , a risk of embolization during or immediately after catheter removal has been clinically confirmed.
• Catheter should be removed in case of: Infected thrombus;
Malposition of the tip (radiologic reposition of the tip often fails, as a consequence of the inability to reach it inside the thrombus); or
Irreversible occlusion of the lumen.
Strength B Recommendation. 7. What Is the Ideal Pharmacological Management?
This topic has been investigated exclusively by retrospective studies and a small clinical series of monocentric experiences.52-63
In general, thrombolytic drugs showed higher efficacy when used in acute symptomatic cases (diagnosis made less than 24 hours after the first symptoms arising). The efficacy of systemic versus local thrombolysis is still matter of debate; the latter may require the availability of an interventional radiology suite and specific expertise when a second, smaller catheter is directed percuta-neously into a large thrombus to deliver locally a thrombolitic
agent.68Catheter-directed, low-dose infusion of a thrombolytic
agent for a defined period of time is safely done on the nursing units and often in alternative-care settings such as ambulatory infusion clinics.
Another unresolved issue is the long-term treatment of patients who experienced symptomatic catheter-related DVT. Most insti-tutions and authorities prescribe warfarin therapy as long as can-cer is active; nevertheless, the effectiveness of warfarin in preventing VTE recurrence is lower in patients with cancer than without cancer, whereas the risk of bleeding may be higher in
patients with malignancy.69-70Warfarin carries the additional
dis-advantage of having substantial inter- and intraindividual vari-ability in dose requirement and the need for frequent dose monitoring. Several low-molecular-weight heparins (LMWHs) have demonstrated superior efficacy to warfarin in the prevention of recurrent VTE. Specifically, dalteparin demonstrated superior efficacy to warfarin in a large trial of patients with cancer and
VTE without increasing the risk of bleeding.71 Thus, compared
with warfarin, the LMWHs exhibit a superior safety profile and more predictable antithrombotic effects and can usually be given once daily, without the need for dose monitoring. It is important that possible antineoplastic effects of LMWHs may alter the nat-ural history of malignant disease.72-74
Conclusions of the Consensus
• Thrombolytic drugs should be used in acute symptomatic cases (diagnosis <24 hours after the first symptoms). Effi-cacy of systemic versus local thrombolysis is still matter of debate, especially for large thrombi.
• Chronic symptomatic cases should be treated with a combi-nation of LMWH and then oral anticoagulants, or LMWH long term alone, depending on the clinical setting. Com-pared with warfarin, the LMWHs exhibit a superior safety profile and more predictable antithrombotic effects and can usually be given once daily in a unit dose without the need for dose monitoring
Strength C Recommendation.
8. Can We Prevent Catheter-Related Central Venous Thrombosis?
The benefit of systemic prophylaxis with LMWHs or warfarin has not been well established. Although many older studies sup-port the use of low-dose warfarin and LMWHs, most recent
stud-ies do not. In a 1990 randomized, open, prospective study of oncology patients, Bern et al compared the administration of 1
mg/day of warfarin with no warfarin for 90 days.75All patients
underwent a venogram at the time of thrombotic symptoms or at 90 days. Total thrombosis rates determined by venographic meth-ods were 37.5% (15/40) for patients without warfarin and 9.5% (4/42) for patients given warfarin. Symptomatic thrombi occurred in 13 of 40 (32.5%) patients without warfarin and in 4 of 42 (9.5%) patients given warfarin (p = 0.001). Boraks et al obtained similar results in a nonrandomized study in which patients received 1 mg/day warfarin prophylactically and were assessed
for venographically verified thrombi.76In those patients treated
with minidoses of warfarin, symptomatic thrombi occurred in 5 of 108 (5%) patients compared with 15 of 115 (13%) patients in a historical control group that did not receive warfarin (p = 0.03). Furthermore, the time to thrombosis was a median of 72 days in those who received warfarin but was 16 days in those who did not receive warfarin.
Since the studies discussed above, a number of other studies have been performed to assess the utility of low-dose warfarin prophylaxis. Three have shown a probable benefit of low-dose warfarin, which was of borderline statistical significance given
the small number of patients studied.77-79Three more recent
stud-ies did not show any benefit of low-dose warfarin. In a nonran-domized study of 160 patients with melanoma or renal cell cancer being treated with interleukin-2, 1 mg/day warfarin did
not reduce the CVC thrombosis rate.80Heaton et al randomized
88 patients with double-lumen, subclavian, tunneled catheters to
receive either 1 mg/day warfarin or no therapy.81After 90 days,
there was no difference in the rates of clinically significant thrombi between those treated with warfarin and those not treated: 8 of 45 (18%) patients treated with warfarin and 5 of 43 (12%) patients not treated had clinically evident thrombi. Couban et al randomized 255 cancer patients to receive warfarin
1 mg daily or placebo.82The overall incidence of symptomatic
CVC-related DVT was 4.3%: 6 of 130 patients (4.6%) in the warfarin group and 5 of 125 patients (4.0%) in the placebo group. Moreover, the incidence of serious bleeding was 2% in the warfarin group and 0 in the placebo-treated group.
This discrepancy in the results probably reflects the inade-quate number of patients in the old clinical trials but may also be due to better catheter care, superior catheter design, and more attention to implantation technique.
Similar trends were observed for LMWH-based prophylaxis. In an early, randomized, open-label, prospective study by Mon-real et al, oncology patients with Port-a-Cath (Smiths Medical, Saint Paul, MN) catheters received 2500 units/day dalteparin or no therapy and underwent a venogram at the time of symptoms
or at 90 days.83Of the 16 patients who received dalteparin, only
1 developed a thrombosis, and this thrombosis was symptomatic. Of the 13 patients who received no treatment, 8 (62%) devel-oped thromboses, and of those, 7 were symptomatic. Because of the highly statistically significant difference in outcome (p = 0.002), the study was closed early to accrual.
Similar studies done with larger numbers of patients failed to show any difference in CVC thrombosis rates. Pucheu et al prospectively compared patients given 2500 anti-Xa U/day
dal-teparin subcutaneously with untreated historical controls using
US done at Months 1, 3, and 12 to screen for thrombosis.84
Doc-umented thrombi occurred in 3 of 46 (6.5%) patients who received dalteparin, and all were without symptoms. In the his-torical control group, 11 of 72 (15%) patients developed docu-mented clots, not a statistically significant difference. Two recent, large, randomized, blinded, placebo-controlled studies failed to demonstrate a benefit from prophylactic use of LMWHs in can-cer patients. In the first,84194 patients received placebo injections
and 294 received 5000 IU/day dalteparin subcutaneously for 16
weeks.85Clinical thrombosis occurred in 5.3% of placebo-treated
and 5.8% of dalteparin-treated patients, not a statistically signifi-cant difference. There was no difference in infection rates. In the
second study,86385 patients were randomly assigned to receive
the LMWH enoxaparin, 40 mg daily for 42 days, or placebo. The primary endpoints were CVC-related DVT of the upper limbs screened by venography or clinically overt pulmonary embolism, confirmed by objective testing. Venography was performed at 6 weeks or earlier in case of clinical suspicion of thrombosis. CVC-related thrombosis was found in 22 (14.1%) of the 155 patients in the enoxaparin group and 28 (18%) of the placebo group, cor-responding to a 22% (not statistically significant) risk reduction in the rate of CVC-related DVT (p = 0.35).
Conclusions of the Consensus
• Although some open-label, early trials suggested a benefit of oral, low-dose daily warfarin or daily subcutaneous dose of LMWHs, more recent randomized, double-blind, placebo-controlled, and sufficiently powered trials did not find any advantages for either of these prevention strategies. • The choice to start a prophylaxis of venous thromboembolic
events in all oncology patients bearing a CVC, either with LMWHs or with minidose warfarin, remains unsupported by evidence-based medicine.
• GAVeCeLT suggests considering prophylaxis with a daily single dose of LMWH 100 IU/kg only in high-risk popula-tion (including those who have a family history or previ-ously suffered from idiopathic venous thrombotic events of the upper or lower vena cava district).
Strength C Recommendation.
Final Remarks
On a population basis, CVC-related thrombosis is associated with considerable morbidity and expense. When CVC-related DVT occurs, it seriously complicates the clinical management of the patient because of the need for anticoagulant treatment and the occasional need to start another central line. DVT may be particu-larly troublesome in a patient who already has compromised venous access because of multiple courses of chemotherapy.
Two important areas of investigation deserve additional, sub-stantive efforts: prevention and treatment. Future prevention studies should also focus on achieving a better understanding of the risk factors for CVC thrombosis, contributing to a better def-inition of risk patient population. Certain patient groups, includ-ing those with a hematological malignancy undergoinclud-ing intensive chemotherapy as well as those with a hereditary thrombophilia
or with a prior history of unprovoked thrombosis, may have an elevated risk of developing this complication, making them potential candidates for prophylaxis. Future trials evaluating antithrombotic prophylaxis in these special patient groups should concentrate on the potential reduction in risk of bacterial colo-nization and catheter-related infection.
Current available prophylactic agents are not optimal for the prevention of thrombosis, especially in the cancer patient. Cer-tainly, larger, placebo-controlled studies of LMWHs or low-dose warfarin prophylaxis in patients with CVCs could be useful overcoming the intrinsic limits of previous studies, but it may be more appropriate to consider instead the use of newer factor-Xa
inhibitors, such as pentasaccharide,87-90 or direct thrombin
inhibitors, such as ximelegatran,91-95which, at the present time,
are available for investigational use only. The former appears from early trials to be a more effective prophylactic agent of venous thromboembolism and is associated with less bleeding than LMWH. The latter may be a more stable oral anticoagulant than warfarin by not being affected by diet or antibiotics. Clearly, such agents would first have to undergo evaluation in large Phase III trials in this clinical setting.
Last, the timing of onset and the type and duration of pro-phylaxis have not been yet fully investigated. Given that fibrin sheaths and occlusive or nonocclusive thrombi seem to occur soon after catheter placement, early prophylaxis is probably war-ranted, but the duration of therapy has not been studied.
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Acknowledgment
Presented in part as an oral abstract at the 20th Annual Meet-ing of the Association for Vascular Access, Indianapolis, IN, September 9-12, 2006.
Costantino Campisi, MD, is Professor of Surgical Pathophys-iology at the University of Chieti-School of Medicine. He is Researcher of the Italian National Council of Research at the Institute of Biomedical Engineering and works at the San Pietro-Fatebenefratelli Hospital in Rome. Dr. Campisi has coauthored about 200 papers, including 12 books or book chapters. He is a founding member of the GAVeCeLT.
Roberto Biffi, MD, is the Deputy Director of the Division of General Surgery at the European Institute of Oncology in Milan. He serves as Director of the new Division of Abdomino-Pelvic Surgery. Dr. Biffi has coauthored 90 papers, 54 books or book chapters, and 127 abstracts or congress proceedings. He is a founding member of the GAVeCeLT.
Mauro Pittiruti, MD, is Researcher of the Italian National Council of Researches at the Department of Surgery-Catholic University in Rome. He has coauthored more than 400 papers, including journal articles, books or book chapters, and congress proceedings. He is a founding member of the GAVeCeLT.
