Challenges in chemotherapy delivery: comparison of standard chemotherapy delivery to locoregional vascular mass fluid transfer.

Standard intravenous chemotherapy delivery to neoplasms relies on simple diffusion gradients from the intravascular to the interstitial space. Systemic perfusion creates untoward effects on normal tissue limiting both concentration and exposure times. Regional intra-arterial therapy is limited by drug recirculation and vascular isolation repeatability and does not address the interstitial microenvironment. Barriers to delivery relate to chaotic vascular architecture, heterogeneous fluid flux, increased interstitial and variable solid tumor pressure and ischemia. To address these difficulties, a delivery system was developed allowing mass fluid transfer of chemotherapeutic agents into the interstitium. This implantable, reusable system is comprised of multiple independently steerable balloons and catheters capable of controlling the locoregional hydraulic and oncotic forces across the vascular endothelium.

Safety and Feasibility of Repeatable Hepatic Vascular Isolation Chemotherapy: A Pilot Study.

BACKGROUND: The authors herein describe a novel method of repeatable hepatic isolation using an implantable access system allowing simultaneous control of hepatic arterial and portal flows by multiple endovascular catheters. PURPOSE: The aim of this study was to assess the feasibility and safety of the system and to compress standard intravenous chemotherapy into 4 weeks of targeted intra-arterial delivery. METHODS: An arterial access system was implanted to the axillary artery via an anastomosis. Infusions of oxaliplatin were performed biweekly for 4 weeks, using balloon catheters to achieve hepatic isolation and segmental selectivity for 20-25 min. Fifty-seven treatments under general anesthetic were performed in ten patients with inoperable chemotherapy-refractory metastatic colorectal cancer. Systemic, intrahepatic, and hepatic venous pressures were recorded to assess vascular isolation, and platinum levels were measured to assess chemotherapy distribution. RESULTS: Pressure verified, multiple day-only hepatic vascular isolation infusions were achieved in nine of ten patients, with a single patient receiving multiple hepatic arterial infusions. Positron emission tomography-computed tomography (PET-CT) imaging confirmed partial response in three of ten patients and stable disease in three of ten patients. Systemic toxicity was minimal as all treatment-related gastrointestinal and neuropathic symptoms reported throughout the 4 weeks were grades 1-2. CONCLUSIONS: Intra-arterial chemotherapy infusions with hepatic vascular isolation can be achieved repeatedly with targeted selectivity and minimal complications using an implantable multicatheter access system. Oxaliplatin infusions over a 4-week period may achieve tumor response in selected patients in the salvage setting. The technique should be further assessed in a phase Ib/II study.

Hypertensive extracorporeal limb perfusion for critical limb ischemia.

OBJECTIVE: This article reports the early results in humans of hypertensive extracorporeal limb perfusion (HELP) technology in the prevention of major limb amputation due to ischemia. The short-term aim was to dilate pre-existing collateral channels, and the long-term aim was to stimulate remodeling and new collateral development by increasing endothelial shear stress and wall tension. METHODS: This study evaluated 20 patients with critical limb ischemia who were treated with HELP. These patients had no other option but major amputation, as determined by at least two vascular surgeons. The arterial circulation to the ischemic limb was isolated from the systemic circulation by the use of an endoluminal balloon catheter in seven patients and by an implantable, inflatable, occlusive cuff in 13. The limbs were hyperperfused through the peripheral access system with an extracorporeal pump, producing a minimally pulsatile waveform at 200% to 300% of the mean arterial pressure. This was performed repeatedly in sessions of 24 to 36 hours, up to a maximum of 74 hours. The primary end point was avoidance of major amputation. The secondary end points were the clinical improvements in rest pain, ulcer healing, and claudication distance. Patients were analyzed and reviewed using infrared thermography and ultrasound imaging parameters of the limb. RESULTS: Given adequate arterial access, 39 of 40 connections developed flows four to eight times those supplied to the limb by the normal cardiac output. A progressive decrease was noted in peripheral resistance. All patients developed a pain-free, warm foot or hand while on the pump in the short-term. In the longer term at a mean of 22 months (range, 12-54 months), eight of 20 patients (40%) had avoided major amputation and four more had a delay in amputation of an average of 4 months. The ankle-brachial index changed from 0.04 ± 0.07 (range, 0.00-0.94) to 0.63 ± 0.39 (t-test, P < .05). Bleeding, infection, premature cessation of the treatment, and poor patient selection resulted in the failures. There were two short-term unrelated deaths that occurred at 1 and 3 months follow-up. CONCLUSIONS: The collateral circulation of ischemic limbs can be augmented and regulated by a connection to an extracorporeal centrifugal pump, with isolation from the systemic circulation provided by balloons and with an access system providing repeatable pump connections. Major amputation may be avoided in selected cases.

An arterial access system for targeted chemotherapy delivery and arterial-arterial extracorporeal recirculation for 'end stage' peripheral vascular disease.

BACKGROUND: Vascular access via a single arterial catheter for targeted chemotherapy delivery has difficulties with concentration, dilution, drug retention, plasma binding, and lack of control of the tumour microcirculation. An implantable arterial access system to accommodate multi-catheter access was developed address these problems. The system was also adapted for isolated arterial-to-arterial extracorporeal suprasystolic perfusion for end stage peripheral vascular disease. The arterial-to-arterial logistics were compared with standard venovenous and arteriovenous fistulae access employed in haemodialysis. METHODS: Targeted chemotherapy delivery was addressed in a pilot study of vascular liver isolation. Ten patients with secondary colorectal cancer, were treated with multiple infusions employing up to five individually steered catheters. The arterial-to-arterial extracorporeal access system was also used to treat end stage peripheral vascular disease in 20 patients where amputation was the only option. The trial was named Hypertensive Extracorporeal Limb Perfusion (HELP). RESULTS: Multiple day only infusions produced a partial response or stable disease in six out of the ten patients in an 'end stage' setting. The mean survival was 11.2 months. Of the twenty patients facing amputation 40% had avoided amputation at follow-up 22 months and 20% had delay of 4 months. CONCLUSION: The access system allows repeatable steerable multi-catheter arterial access for chemotherapy delivery to address difficulties of concentration, dilution, plasma binding and microvascular control. The access system supports multiple repeatable suprasystolic extracorporeal arterial to arterial access. It is cardiac independent generating flows of greater than 1 L/min with zero flow in between treatments. The device logistics compares favourably with arteriovenous and venovenous access systems.

Hypertensive extracorporeal limb perfusion (HELP): a new technique for managing critical lower limb ischemia.

OBJECTIVE: The concept of repeatedly connecting an extracorporeal blood pump to produce pancycle suprasystolic inflow pressures to ischemic limbs is introduced. Balloon catheters allow for limb isolation from the systemic circulation. In the acute phase, it is assumed that pressure is proportion to flow (Poiseuille's Law) and in the chronic phase that collateral growth is related to endothelial shear stress and wall tension. The primary objective was to establish that increased flow could be achieved through collateral circulation in animals and in man with extracorporeal limb hyperperfusion. The second objective was to develop and test an arterial access system capable of intermittent regional hyperperfusion similar in concept to intermittent hemodialysis. Finally, to demonstrate the translocation of these concepts into humans facing major limb amputation where all standard treatment options had been exhausted. METHODS: Twelve sheep (6 hyperperfusion and 6 controls) were attached to a cardiac vortex pump and perfused at 200 mm Hg pancycle with the superficial femoral artery doubly ligated and isolated from the systemic circulation with a balloon catheter. Pressure transducers measured carotid and distal femoral pressures and the carotid-femoral index was calculated. To allow hyperperfusion to be repeated transcutaneously, a peripheral access system (PAS [Allvascular, St Leonards, New South Wales, Australia]) was constructed. This device was implanted in the common carotid artery in 8 sheep and opened approximately 3 days a week for continuous arterial access up to 37 days for 67 openings. To demonstrate these principles in humans, 3 patients with critically ischemic limbs were hyperperfused intermittently. Digital thermography compared the other limb as controls and provided objective evidence of the vascular changes. RESULTS: The mean carotid-femoral index was 0.6 +/- 0.01 for controls compared with 1.1 +/- 0.28 for the hyperperfusion group (P < .001). The collateral flow was superior to normal flow (ie, with the superficial femoral not occluded). Continuous access to the carotid arterial tree via the access device was 25.3 +/- 8.8 days with 5 of 8 devices open for the entire observational period (maximum 37 days). The human ischemic limbs were hyperperfused at 2-4 times the mean arterial pressure producing 3-6 times an increase in pump flow measurements intermittently for 53 +/- 16 hours. The clinical findings of rest pain, paresthesia, capillary return, and movement showed dramatic improvement as did thermographic emissions. Major amputation was avoided in the cases presented. CONCLUSION: Blood flow through collaterals can be very significantly augmented by connection to an extracorporeal pump with isolation from the systemic circulation. The pancycle hyperperfusion can be safely repeated by implantation of an arterial access device. In the longer term, there is evidence of collateral development. When amputation is the only alternative, hypertensive extracorporeal limb perfusion should be considered.

Long-term comparison of external valvular stenting and stripping of varicose veins.

BACKGROUND: The recurrence rate following stripping of the long saphenous vein is unacceptable. Repair of the terminal valve of the long saphenous vein is a physiological alternative. The aim of the present study was to prospectively compare the long-term recurrence rates in patients having had reparative and ablative procedures at the same time. METHODS: Patients were grouped first into those receiving high ligation and stripping of the long saphenous vein in one limb and valve repair on the contralateral side. The second group consisted of those patients who received short saphenous vein removal and valve repair of the ipsilateral long saphenous system. Finally, the effect of pregnancy on patients who received valve repairs was also studied. All patients were examined postoperatively clinically and with duplex ultrasound. RESULTS: Cumulative and absolute recurrence rates for both procedures were analysed. Over the 13-year follow-up period, external valvular stenting produced a superior outcome. The effect of pregnancy on the venous valve repair cases resulted in recurrences in 23% of cases but there was no evidence of incompetence at the site of the valve repair. CONCLUSION: If a valve repair is possible at the saphenofemoral junction, then it should be the preferred treatment option.

The effect of pregnancy on venous valve repair to the sapheno-femoral junction for varicose veins.

OBJECTIVES: Pregnancy represents a special situation where both the mechanical and hormonal instigating factors of varicose veins are reversible with the venous valve cusps preserved. Exostent venous valve repairs are a physiological alternative which minimises stimulus to collateral growth (recurrence). The study purpose was to assess the effect of pregnancy on the durability of valve repairs. METHODS: In a prospective study of 36 limbs, 20 young females (30 ± 4.7 years) had an exostent implanted to the terminal valve of the saphenofemoral junction for varicose veins. At routine long-term follow up (9.7 ± 3.8 years), 38 pregnancies were completed (mean: 1.8, range: 1-4). The controls were a non-pregnant group of limbs (n = 386). RESULTS: At 9.7 years, the internal diameter of the greater saphenous vein (GSV) changed from 7.8 ± 2.8 mm preoperatively to 4.5 ± 1.4 mm post-operatively. Recurrence was associated with reflux, preoperative deep system and ovarian vein involvement. Pregnancy induced 33.3% recurrences compared with non-pregnant controls (4.7%) similarly treated or 22.8% compared with non-pregnant ablative controls. At 9.7 years, symptomatic improvement continued with significantly better CEAP status (described later) (31CSEAP preoperative to 6CSEAP) with no further truncal ablation (strip, laser) required. CONCLUSIONS: Venous valve repairs can withstand the special stresses of pregnancy. There is no need to ablate the GSV. This approach is contrary to the traditional dictum; the treatment of varicose veins should be delayed until the family is completed.

Popliteal vein compression syndrome pathophysiology and correlation with popliteal compartment pressures.

OBJECTIVE: The link between obesity and popliteal vein compression syndrome (PVCS) has been documented, but the pathophysiological mechanism is unclear. The aim of this study is to understand the pathogenesis of PVCS by assessing popliteal compartment pressures (PCP). METHODS: Twenty-three limbs (15 patients) were included. Eleven limbs were ultrasonically diagnosed with PVCS and underwent popliteal vein decompression. The control group consisted of 12 limbs with functional popliteal artery entrapment. Perioperatively, PCP measurements were obtained. The body mass index (BMI) was calculated and the clinical symptoms were documented (CEAP). RESULTS: The median BMI for the PVCS group was 32 (range, 26-45.8) compared with 28 (range, 19-31) for the control group (P = .05). In PVCS, the popliteal vein internal diameter was 9.4 mm (range, 8.0-20.0 mm) upon knee flexion, compared with 0 mm (range, 0.0-0.1 mm) upon knee extension. Upon knee flexion, there was no difference in pressure (PVCS 10.0 [range, 4-20] vs control 11.5 [range, 3-22]; P = .95). Upon knee extension, the median PCP in the PVCS group was 53 cm H2O (range, 38-76 cm H2O) compared with 26 cm H2O (range, 17-43 cm H2O) in the control group (P < .001). CONCLUSIONS: PVCS is associated with high popliteal compartment pressures compared with controls. The pathophysiology of popliteal obstruction, in the absence of anatomical abnormalities, is related to an increase in popliteal compartment pressure while standing due an increase of the popliteal fat pad, related to high BMI.