K. Dhital

[18F]Fluorodeoxyglucose positron emission tomography and its prognostic value in lung cancer

OBJECTIVE Positron emission tomography (PET) is being increasingly used as an accurate and non-invasive modality in diagnosis, staging and post-therapy assessment in patients with lung cancer. In this study, we examine whether the uptake of [(18)F]fluorodeoxyglucose (FDG), a marker of increased glucose metabolism in neoplastic cells, is of prognostic value in patients with primary lung cancer. METHODS We have retrospectively analyzed 77 patients (mean age, 63. 0 years; male/female ratio, 53:24) with primary lung cancers who underwent whole body and localized thoracic PET as part of their diagnostic and staging procedures prior to consideration of surgical resection. The standardized uptake value (SUV) of injected FDG for each primary lesion was correlated with tumour histology and the patients clinical outcome. RESULTS A SUV of 20 or greater was found to be of significant prognostic value. The chance of survival (with 95% confidence intervals (CI)) at 12 months post-surgery for the various SUV groups was as follows: 75.2% (59.6-85.5) for SUV<10; 67.5% (29.0-88.2) for SUV 10-<12; 63.6% (29.7-84.5) for SUV 12-<15; 66.7% (19.5-90.4) for SUV 15-<20; 16.7% (0.01-0.52) for SUV>20. A SUV of 20 or more is associated with a 4.66 times increase in hazard, compared with lower levels of SUV. We found no significant correlation between tumour histology and SUV. CONCLUSION We have previously reported on the significant advantages of PET in the staging and surgical care of patients with lung cancer. The present study adds further support for an additional prognostic role for PET in the management of thoracic malignancy as determined by the amount of labelled-FDG taken up by the primary lesion.

Adult heart transplantation with distant procurement and ex-vivo preservation of donor hearts after circulatory death: a case series

BACKGROUND Orthotopic heart transplantation is the gold-standard long-term treatment for medically refractive end-stage heart failure. However, suitable cardiac donors are scarce. Although donation after circulatory death has been used for kidney, liver, and lung transplantation, it is not used for heart transplantation. We report a case series of heart transplantations from donors after circulatory death. METHODS The recipients were patients at St Vincents Hospital, Sydney, Australia. They received Maastricht category III controlled hearts donated after circulatory death from people younger than 40 years and with a maximum warm ischaemic time of 30 min. We retrieved four hearts through initial myocardial protection with supplemented cardioplegia and transferred to an Organ Care System (Transmedics) for preservation, resuscitation, and transportation to the recipient hospital. FINDINGS Three recipients (two men, one woman; mean age 52 years) with low transpulmonary gradients (<8 mm Hg) and without previous cardiac surgery received the transplants. Donor heart warm ischaemic times were 28 min, 25 min, and 22 min, with ex-vivo Organ Care System perfusion times of 257 min, 260 min, and 245 min. Arteriovenous lactate values at the start of perfusion were 8·3-8·1 mmol/L for patient 1, 6·79-6·48 mmol/L for patient 2, and 7·6-7·4 mmol/L for patient 3. End of perfusion lactate values were 3·6-3·6 mmol/L, 2·8-2·3 mmol/L, and 2·69-2·54 mmol/L, respectively, showing favourable lactate uptake. Two patients needed temporary mechanical support. All three recipients had normal cardiac function within a week of transplantation and are making a good recovery at 176, 91, and 77 days after transplantation. INTERPRETATION Strict limitations on donor eligibility, optimised myocardial protection, and use of a portable ex-vivo organ perfusion platform can enable successful, distantly procured orthotopic transplantation of hearts donated after circulatory death. FUNDING NHMRC, John T Reid Charitable Trust, EVOS Trust Fund, Harry Windsor Trust Fund.

The nerves to blood vessels supplying blood to nerves: the innervation of vasa nervorum

Noradrenergic, serotoninergic and peptidergic nerves have been demonstrated in perivascular plexuses of vasa nervorum of sympathetic, parasympathetic and somatic nerve trunks. 5-Hydroxytryptamine-, vasoactive intestinal polypeptide- and substance P-containing fibers were found by immunohistochemistry to variable extents in whole mounts of the epineurium of sciatic, vagus and paravertebral sympathetic chains of rabbits. Innervation increased with age. This suggests an hitherto unsuspected role for these vasoactive substances in normal blood flow to nerves and in the genesis of experimental and human neuropathies.

The Papworth Experience With the Levitronix CentriMag Ventricular Assist Device

OBJECTIVES The Levitronix CentriMag ventricular assist device (VAD) is a centrifugal pump designed for short-term extracorporeal support in cardiogenic shock. The aim of this study is to report our clinical experience with the Levitronix CentriMag for uni- and biventricular support. METHODS Between July 2004 and December 2006, 27 patients were supported using the Levitronix CentriMag device. Nineteen were male. Mean age was 47.9 (range 19 to 72) years. Indications for support at implantation were cardiogenic shock that included: end-stage heart failure and too ill to undergo transplantation, with questionable neurologic status (9 subjects); right ventricular failure after left VAD (LVAD) implantation (5 subjects); post-cardiotomy status (7 subjects); and acute donor graft failure after heart transplantation (6 subjects). RESULTS Post-VAD 30-day survival was 30% (8 patients). Mean support time was 11 days for all patients (range 1 to 51 days). Mean support time for 14 Levitronix biventricular VADs was 11 (range 1 to 51) days. Mean support time for 7 Levitronix LVADs was 13.7 (range 1 to 30) days. The highest survival rates after Levitronix support were after donor graft failure (50%) and after cardiotomy (42%). Levitronix right VAD (RVAD) support after long-term LVAD insertion incurred 100% hospital mortality. Of those who survived, 8 patients were discharged home after VAD support and remain alive to date. Two patients were bridged to primary and another bridged to repeat heart transplantation. Five patients were weaned to recovery. Re-operation for bleeding occurred in 8 patients, clinical evidence of cerebral thromboembolism in 3, overwhelming sepsis in 1, and aortic thrombus formation in 1. Clot formation in the tubing was observed in 1 patient, necessitating emergent replacement at bedside, which was successful. CONCLUSIONS The Levitronix CentriMag system is a reliable and facile temporary circulatory support system as a bridge to decision in patients with refractory acute cardiogenic shock.

An increase in the expression of neuropeptidergic vasodilator but not vasoconstrictor cerebrovascular nerves in aging rats

Perivascular nerve fibres containing noradrenaline (NA), serotonin (5-HT), substance P (SP), vasoactive intestinal polypeptide (VIP), neuropeptide Y (NPY) and calcitonin gene-related peptide (CGRP) were localized in whole-mount stretch preparations of the arteries of the rat circle of Willis using fluorescence and immunohistochemical techniques. Changes in the pattern and density of these perivascular nerves were studied from birth to 27 months of age. All perivascular nerve types reached a peak density of innervation at 1 month of age. This was followed by a general fall in the density of fluorescent nerve fibres. However, with aging, there was a decrease in the expression of vasoconstrictor neurotransmitters (NA and 5-HT) in cerebrovascular nerves, whereas the expression of vasodilator neurotransmitter (VIP and CGRP) in perivascular nerve fibres supplying the rat cerebral arteries was strikingly increased in old age. The density of NPY- and SP-containing nerve fibres was not significantly altered in old age. These changes are discussed in relation to the increased incidence of cerebrovascular disorders in the elderly.

Increased density of perivascular nerves to the major cerebral vessels of the spontaneously hypertensive rat: differential changes in noradrenaline and neuropeptide Y during development.

Fluorescence and immunohistochemical techniques were used to study the pattern and density of perivascular nerves containing noradrenaline (NA) and neuropeptide Y (NPY) supplying the major cerebral arteries of 4-, 6-, 8- and 12-week-old spontaneously hypertensive rats (SHR) and normotensive Wistar (WIS) controls. Levels of NA and NPY in the superior cervical ganglia were measured. The density of nerves containing NA and NPY was greater in the hypertensive animals at all ages studied. However, the developmental changes in the density of innervation showed similar trends in both SHR and WIS groups. With few exceptions, there was a significant increase in the density of nerves containing NA from 4 to 6 weeks and from 8 to 12 weeks of age. This was in contrast to a low expression, and in some vessels a significant decrease in the number of NPY-containing nerves from 4 to 6 weeks. The density of nerve fibres containing NPY increased significantly in almost all vessels between 6 and 8 weeks of age and then stabilized. Thus there is a differential time course for the appearance of NA and NPY during development. Furthermore, the hyperinnervation of cerebral vessels in SHR by nerves containing NA and NPY precedes the onset of hypertension and associated medial hypertrophy. High-performance liquid chromatography and enzyme-linked immunosorbant assays show that the NA and NPY contents of the superior cervical ganglion do not reflect the changes in innervation pattern seen in the terminal fibres in the cerebral arteries. This tends to support the view that a local neurovascular mechanism is involved in the maintenance of hypertension. The possibility that increase in NPY as well as NA in cerebral perivascular nerves of hypertensive animals is involved in the protection of the blood-brain barrier against oedema and cerebral haemorrhage is raised.

Primary Graft Failure after Heart Transplantation

Primary graft failure (PGF) is a devastating complication that occurs in the immediate postoperative period following heart transplantation. It manifests as severe ventricular dysfunction of the donor graft and carries significant mortality and morbidity. In the last decade, advances in pharmacological treatment and mechanical circulatory support have improved the outlook for heart transplant recipients who develop this complication. Despite these advances in treatment, PGF is still the leading cause of death in the first 30 days after transplantation. In todays climate of significant organ shortages and growing waiting lists, transplant units worldwide have increasingly utilised “marginal donors” to try and bridge the gap between “supply and demand.” One of the costs of this strategy has been an increased incidence of PGF. As the threat of PGF increases, the challenges of predicting and preventing its occurrence, as well as the identification of more effective treatment modalities, are vital areas of active research and development.

Adrenergic innervation of vasa and nervi nervorum of optic, sciatic, vagus and sympathetic nerve trunks in normal and streptozotocin-diabetic rats.

Adrenergic nerves were studied in nervi nervorum and perivascular nerve plexus of vasa nervorum in whole-mount nerve sheath preparations of optic, sciatic and vagus nerves and in the paravertebral sympathetic chain in normal and streptozotocin-treated diabetic rats. A substantial or complete loss of fluorescent adrenergic fibres around blood vessels in the optic nerves was observed 8 weeks after induction of diabetes. This was in marked contrast to the increase in perivascular adrenergic fibres in the sciatic, vagus and sympathetic chain nerve trunks of the same animals at the same time. Assays of noradrenaline levels in whole nerve segments also showed that they were not biochemically detectable in the optic nerves but were significantly higher in the vagus of diabetic animals (P less than 0.05). There was also an increase in numbers of mast cells in the vicinity of vasa nervorum of diabetic nerves.

Cardiac recovery in a human non-heart-beating donor after extracorporeal perfusion: source for human heart donation?

Successful renal, liver and more recently lung transplantation using organs from non-heart-beating donors (NHBDs) has been reported. Regarding the heart, it has generally been assumed that warm ischemic insult would result in overwhelming and irreversible myocardial damage. We report recovery of cardiac function in a human NHBD by using extracorporeal perfusion 23 minutes after cardiorespiratory arrest. Successful cardiac resuscitation in the NHBD represents a potential source of increased donor organ supply for clinical heart transplantation.

Increasing the Tolerance of DCD Hearts to Warm Ischemia by Pharmacological Postconditioning

Donation after circulatory death (DCD) offers a potential additional source of cardiac allografts. We used a porcine asphyxia model to evaluate viability of DCD hearts subjected to warm ischemic times (WIT) of 20–40 min prior to flushing with Celsior (C) solution. We then assessed potential benefits of supplementing C with erythropoietin, glyceryl trinitrate and zoniporide (Cs), a combination that we have shown previously to activate ischemic postconditioning pathways. Hearts flushed with C/Cs were assessed for functional, biochemical and metabolic recovery on an ex vivo working heart apparatus. Hearts exposed to 20‐min WIT showed full recovery of functional and metabolic profiles compared with control hearts (no WIT). Hearts subjected to 30‐ or 40‐min WIT prior to C solution showed partial and no recovery, respectively. Hearts exposed to 30‐min WIT and Cs solution displayed complete recovery, while hearts exposed to 40‐min WIT and Cs solution demonstrated partial recovery. We conclude that DCD hearts flushed with C solution demonstrate complete recovery up to 20‐min WIT after which there is rapid loss of viability. Cs extends the limit of WIT tolerability to 30 min. DCD hearts with ≤30‐min WIT may be suitable for transplantation and warrant assessment in a transplant model.