Molecular patterns of response and treatment failure after frontline venetoclax combinations in older patients with AML.

The BCL-2 inhibitor venetoclax combined with hypomethylating agents or low-dose cytarabine represents an important new therapy for older or unfit patients with acute myeloid leukemia (AML). We analyzed 81 patients receiving these venetoclax-based combinations to identify molecular correlates of durable remission, response followed by relapse (adaptive resistance), or refractory disease (primary resistance). High response rates and durable remissions were typically associated with NPM1 or IDH2 mutations, with prolonged molecular remissions prevalent for NPM1 mutations. Primary and adaptive resistance to venetoclax-based combinations was most commonly characterized by acquisition or enrichment of clones activating signaling pathways such as FLT3 or RAS or biallelically perturbing TP53. Single-cell studies highlighted the polyclonal nature of intratumoral resistance mechanisms in some cases. Among cases that were primary refractory, we identified heterogeneous and sometimes divergent interval changes in leukemic clones within a single cycle of therapy, highlighting the dynamic and rapid occurrence of therapeutic selection in AML. In functional studies, FLT3 internal tandem duplication gain or TP53 loss conferred cross-resistance to both venetoclax and cytotoxic-based therapies. Collectively, we highlight molecular determinants of outcome with clinical relevance to patients with AML receiving venetoclax-based combination therapies.

"Reversible" myelodysplastic syndrome or ineffectual clonal haematopoiesis? - add(6p) myeloid neoplasm with a spontaneous cytogenetic remission.

Cytotoxic chemotherapy has inherent mutagenic potential and alters the bone marrow microenvironment after therapy. In some cases, this potentiates expansion of an aberrant clone and may lead to a therapy-related myeloid neoplasm if the clone overcomes selective pressure. We present the case of a 43-year-old woman diagnosed with an indolent, therapy-related myeloid neoplasm with an isolated chromosome 6p abnormality following treatment for de novo Acute Myeloid Leukaemia (AML), who manifest a sustained spontaneous cytogenetic remission two years later, possibly due to an ineffectual or non-dominant founding clone. This case reminds us to be mindful of the possibility that clonal haematopoiesis may not always equate to clinically relevant disease, even in the setting of an abnormal clonal karyotype.

Enhancing venetoclax activity in acute myeloid leukemia by co-targeting MCL1.

Targeted therapies are frequently combined with standard cytotoxic drugs to enhance clinical response. Targeting the B-cell lymphoma 2 (BCL-2) family of proteins is an attractive option to combat chemoresistance in leukemia. Preclinical and clinical studies indicate modest single-agent activity with selective BCL-2 inhibitors (for example, venetoclax). We show that venetoclax synergizes with cytarabine and idarubicin to increase antileukemic efficacy in a TP53-dependent manner. Although TP53 deficiency impaired sensitivity to combined venetoclax and chemotherapy, higher-dose idarubicin was able to suppress MCL1 and induce cell death independently of TP53. Consistent with an MCL1-specific effect, cell death from high-dose idarubicin was dependent on pro-apoptotic Bak. Combining higher-dose idarubicin with venetoclax was able to partially overcome resistance in Bak-deficient cells. Using inducible vectors and venetoclax to differentially target anti-apoptotic BCL-2 family members, BCL-2 and MCL1 emerged as critical and complementary proteins regulating cell survival in acute myeloid leukemia. Dual targeting of BCL-2 and MCL1, but not either alone, prolonged survival of leukemia-bearing mice. In conclusion, our findings support the further investigation of venetoclax in combination with standard chemotherapy, including intensified doses of idarubicin. Venetoclax should also be investigated in combination with direct inhibitors of MCL1 as a chemotherapy-free approach in the future.

Diagnosis and management of thrombotic thrombocytopenic purpura (TTP) in Australia: findings from the first 5 years of the Australian TTP/thrombotic microangiopathy registry.

BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening thrombotic microangiopathy (TMA). In 2009, the Australian TTP/TMA registry was established to collect data on patients presenting with TTP/TMA throughout Australia. AIM: To summarise information on the diagnosis and management of patients with TTP collected in the first 5 years (2009-2014) of the Australian TTP registry. METHODS: Registry data from June 2009 to October 2014 were reviewed. RESULTS: Fifty-seven patients were identified with TTP (defined as ADAMTS13 activity <10%), accounting for 72 clinical episodes. ADAMTS13 inhibitor testing was performed in nine out of 57 patients (16%), reflecting the limited availability of accredited testing facilities. Sixty-seven out of 72 episodes were treated with therapeutic plasma exchange (PEx) using cryodepleted plasma (40% of episodes), fresh frozen plasma (36%) or a mixture (22%). Median exposure to plasma products was 55.9 L. PEx was commenced ≥2 days from stated diagnosis in 15% of episodes. Adverse reactions to PEx were common with documented allergic reactions (including life threatening) in 21% of episodes. Adjunctive immunosuppression was documented in 76% of episodes (corticosteroid 71% and rituximab 39%). Platelet transfusion was administered in 15% of episodes. CONCLUSIONS: Data from the Australian TTP/TMA registry suggest a heterogenous approach to the diagnosis and management of TTP in Australia over the assessed period. These observations highlight areas for improvement and standardisation of practice, including comprehensive diagnostic testing, more immediate access to PEx and a more uniform approach to adjunctive immunosuppression and supportive care.

Does a dedicated nurse practitioner improve thromboprophylaxis use in acutely ill medical patients in Australia? The methodology for a multicentre VTE Task Force Audit.

AIM: To determine the extent to which a multifaceted venous thromboembolism (VTE) prophylaxis program, coordinated by a dedicated nurse practitioner, improves the level of appropriate prophylaxis in patients hospitalised with an acute medical illness. METHODS: A multicentre clinical audit was conducted in 16 hospitals across Australia. Approximately 9600 acutely ill medical patients over 18 years of age hospitalised for at least 3 days. A 4-month programme implemented by a VTE Nurse Educator to raise awareness of the risk of VTE, the importance of risk assessment and the appropriate prophylactic management of high-risk medical patients with local VTE prophylaxis audit result feedback. RESULTS: The effect of this programme on the proportion of high-risk medical patients receiving appropriate thromboprophylaxis according to current guidelines. CONCLUSIONS: The VTE Task Force Audit will be the first multicentre clinical audit in Australia to evaluate thromboprophylaxis use in acutely ill medical patients and the effects of employing a nurse educator. Based on published results from clinical audits conducted overseas, it is expected that thromboprophylaxis will be underutilised in these patients. It is hypothesised that an active multifaceted programme will improve the rate of thromboprophylaxis among eligible medical patients through the effective implementation of evidence-based guidelines.

Variations in endothelial function and arterial compliance during the menstrual cycle.

Female sex hormones have been implicated in the cardioprotection of premenopausal women. However, the cardiovascular actions of these hormones and the effects of their natural fluctuations during the menstrual cycle are not fully understood. We studied changes in vascular function during the menstrual cycle in 15 healthy premenopausal women. Four noninvasive procedures were performed during the early follicular (EF), late follicular (LF), early luteal (EL), and late luteal (LL) phases: flow-mediated dilatation (FMD) of the brachial artery during reactive hyperemia, laser Doppler velocimetry (LDV) with direct current iontophoresis of acetylcholine (ACh) and nitroprusside, whole body arterial compliance (WBAC), and pulse wave velocity. Hormone levels were consistent with predicted cycle phase and showed that all subjects ovulated during the cycle studied. FMD, LDV with ACh, and WBAC varied cyclically, with significant increases from the F to LF phase, sharp falls in the EL phase, and significant recoveries in the LL phase. These changes were most marked for FMD [EF, 8.8 +/- 0.6% (mean +/- SEM); LF, 10.0 +/- 0.7; EL, 4.2 +/- 0.6; LL, 8.6 +/- 0.9] and the LDV response to ACh (EF, 2.7 +/- 0.2 V/min; LF, 3.3 +/- 0.4; EL, 1.8 +/- 0.3; LL, 2.7 +/- 0.4). WBAC changed similarly (EF, 0.58 +/- 0.08 arbitrary units; LF, 0.84 +/- 0.06; EL, 0.65 +/- 0.05; LL, 0.68 +/- 0.06). Sodium nitroprusside-induced vasodilatation decreased significantly from EF to EL, with no other significant difference, and pulse wave velocity did not vary significantly over the four time points. Conductance and resistance artery endothelial reactivity and smooth muscle sensitivity to nitric oxide and arterial compliance are modulated significantly in response to the changing hormonal patterns of the menstrual cycle. These findings emphasize the importance of menstrual phase in the interpretation of data on endothelial function and may provide insights into the mechanisms underlying sex differences in cardiovascular risk and other disease processes in premenopausal women.

A review of reflex sympathetic dystrophy.

Reflex sympathetic dystrophy, or as it is now known, complex regional pain syndrome, Type 1, is an unusual complication of a variety of injuries whose development should be suspected in the presence of disproportionate pain coupled with autonomic disturbance. Early recognition and treatment with multimodality therapy offer a high probability of recovery.

Safety studies with the University of Melbourne multichannel electrotactile speech processor.

Results of safety investigations conducted as an integral part of the development of a multichannel electrotactile speech processor (Tickle Talker) are reported. Electrical parameters of the stimulus waveform, design of the electrode handset and cabling, and the electrical circuitry of the speech processor/stimulator and programming interface have been analyzed for potential risks. Constant current biphasic square pulses delivered to electrodes positioned on the skin surface over the digital nerve bundles were chosen to optimize the safety, comfort, and function of the electrotactile stimulus. The device was battery-powered, and the user circuit was isolated from earth-referenced sources. Each electrode was isolated by capacitive coupling, preventing DC leakage of current to the user circuit. Studies of finger temperature showed slight cooling of the skin on the fingers of both stimulated and unstimulated hands for individual subjects following electrotactile stimulation through the Tickle Talker. Subsequent analysis of finger and hand vascular circulation in five subjects showed slight reductions in hand blood flow in some individuals. The results did not demonstrate a significant mean decrease in hand or finger blood flow following electrotactile stimulation. No evidence of sympathetic involvement was found, nor were any changes in vascular structure of the hand such as those associated with Raynaud's disease found. Evidence suggests that the decrease in temperature found in the initial study may be due to a change in the ratio of blood flow between arteriovenous anastomoses and nutritive capillary beds. Studies of: 1) changes in mean threshold and comfortable pulse widths over time; and, 2) changes in tactual sensitivity as measured by hot/cold, sharp/dull, and two-point difference limen discrimination, did not detect any systematic change in peripheral nervous system function following electrotactile stimulation. Analysis of electroencephalogram (EEG) recordings taken during electrotactile stimulation, and after relatively long periods of experience with the device did not show any pathological changes which might be associated with epileptic foci. In summary, no contraindications to long-term use of the Tickle Talker were detected in the studies performed.

The effects of very low fat diets enriched with fish or kangaroo meat on cold-induced vasoconstriction and platelet function.

Eighteen healthy volunteers consumed very low fat diets (less than 7% of daily energy) enriched with different sources of long chain (C20 and C22) polyunsaturated fatty acids (PUFA). Three diets provided 500 g/day of fish caught in the tropical waters of Australia (rich in arachidonic acid and docosahexaenoic acid), fish caught in the southern waters of Australia (rich in docosahexaenoic acid), or kangaroo meat (rich in linoleic and arachidonic acids). The fourth diet was vegetarian, similarly low in fat but containing no 20- and 22-carbon PUFA. An increase in the percentage of a particular C20 or C22 PUFA in the plasma phospholipid fraction in subjects consuming these low fat diets corresponded to the dietary PUFA composition. This study examined the effect of dietary modification of the level of arachidonic acid in plasma phospholipids on both traditional measures of platelet function and on cold-induced vasoconstriction. The cold pressor response, measured by venous occlusion plethysmography, was depressed in diets which elevated the levels of arachidonic acid in plasma lipids (kangaroo and tropical fish), enhanced after subjects consumed a diet which increased the levels of docosahexaenoic acid and eicosapentaenoic acid (southern fish diet), and was unchanged by the low fat vegetarian diet. There was no effect on bleeding time or platelet responsiveness.

Hydrocortisone-induced hypertension in humans: pressor responsiveness and sympathetic function.

Oral hydrocortisone increases blood pressure and enhances pressor responsiveness in normal human subjects. We studied the effects of 1 week of oral hydrocortisone (200 mg/day) on blood pressure, cardiac output, total peripheral resistance, forearm vascular resistance, and norepinephrine spillover to plasma in eight healthy male volunteers. Although diastolic blood pressure remained unchanged, systolic blood pressure increased from 119 to 135 mm Hg (SED +/- 3.4, p less than 0.01), associated with an increased cardiac output (5.85-7.73 l/min, SED +/- 0.46, p less than 0.01). Total peripheral vascular resistance fell from 15.1 to 12.2 mm Hg/l/min (SED +/- 1.03, p less than 0.05). Resting forearm vascular resistance remained unchanged, but the reflex response to the cold pressor test was accentuated, the rise in resistance increasing from 10.5 mm Hg/ml/100 ml/min (R units) before treatment to 32.6 R units after treatment (SED +/- 6.4, p less than 0.025). The rise in forearm vascular resistance accompanying intra-arterial norepinephrine (25, 50, and 100 ng/min) was also significantly greater after hydrocortisone, increasing from an average of 14.9 +/- 2.4 R units before treatment to 35.1 +/- 5.5 R units after hydrocortisone (SED +/- 6.0, p less than 0.05). A shift to the left in the dose-response relation and fall in threshold suggested increased sensitivity to norepinephrine after treatment. Measurement of resting norepinephrine spillover rate to plasma and norepinephrine uptake indicated that overall resting sympathetic nervous system activity was not increased. The rise in resting blood pressure with hydrocortisone is associated with an increased cardiac output (presumably due to increased blood volume).(ABSTRACT TRUNCATED AT 250 WORDS)

Fate of the patient with chronic leg ischaemia. A review article.

Much has been published on the surgical treatment of leg ischaemia but relatively little is known about the incidence of claudication and the fate of the majority of patients presenting with chronic leg ischaemia who never come to surgery. A review of the available literature suggests the following conclusions: (1) about 1.5% of men under 49 and 5% of men over 50 will develop symptoms of intermittent claudication. The incidence of asymptomatic arterial disease is much higher; (2) the incidence of claudication in women is only slightly less, but the local disease follows a more benign course; (3) compared to the general population of comparable age the mortality of men presenting with chronic leg ischaemia is two to three times higher after 5 years; (4) about 50% of deaths will be due to myocardial ischaemia, 15% to stroke and 10% to vascular disease in the abdomen. In only 25% will the principal cause of death be unconnected with the circulation; (5) there is virtually no reliable information available at the moment on the incidence of non-fatal myocardial infarction or stroke in these patients.

Intermittent claudication. An update on management.

The mainstay of treatment for claudication is reversal of risk factors, especially smoking, and the use of antiplatelet drugs and possibly pentoxifylline. A major factor in the long term management is atherosclerotic involvement in other parts of the circulation resulting in a shortened life span. Treatment should be directed at the disease in general, rather than in the legs alone. Patients disabled by claudication may gain symptomatic relief with relatively low risk using balloon angioplasty or vascular reconstructive procedures.

The role of coronary artery disease in complications of abdominal aortic aneurysm surgery.

Coronary artery disease (CAD) is a major cause of morbidity and mortality after elective surgical repair of abdominal aortic aneurysm (AAA). The aim of this study was to determine the relationship between the extent of CAD observed in coronary angiograms (more than 50% stenosis) and the frequency of postoperative myocardial ischemic complications in a consecutive series of 84 patients who underwent elective AAA repair. Ninety-four percent of the patients with clinical evidence of CAD had significant disease as observed in coronary angiograms and eight patients had left main CAD. Seventy-two patients underwent AAA repair with a mortality rate of 1.4%; five patients had preliminary myocardial revascularization, and AAA surgery was not recommended for four patients because of severe cardiac disease. Postoperative myocardial ischemic complications occurred in 13.4% of the patients who had undergone surgery--almost exclusively in patients with clinical evidence of CAD. Both myocardial ischemia and preoperative intervention were more frequent in patients with double- or triple-vessel disease than in patients with less extensive disease. Patients with symptoms and with double- or triple-vessel CAD have a high risk of developing myocardial ischemia after AAA surgery. Preliminary myocardial revascularization may be beneficial in this group of patients.

The use of regional, low dose streptokinase in recently thrombosed arterial grafts.

Between August 1983 and January 1985, 20 patients aged 33-77 years, with occluded lower limb bypass grafts, were on 23 occasions treated with streptokinase via intra-arterial infusion. Streptokinase (5000 units/h) was effective in clearing occluded grafts in 15 patients on 16 occasions. The median duration of occlusion in these patients was 5 days and the median duration of streptokinase infusions was 24 h. Completion angiography following streptokinase thrombolysis revealed five graft stenoses and 12 outflow stenoses or occlusions. In two grafts no cause for graft failure could be identified. These results permitted the surgeon to make an accurate pre-operative assessment of the definitive therapy required to ensure graft patency.

The effect of desmethylimipramine on the metabolism of norepinephrine.

Eleven normal volunteers were given an acute and two chronic doses of desipramine (DMI). The plasma norepinephrine (NE), 3-methoxy-4-hydroxyphenylglycol (MHPG), and dihydroxyphenylglycol (DHPG) concentrations were measured before and during drug administration. DMI reduced plasma concentrations of MHPG by 13% and DHPG by 17%. After two weeks of drug administration, the MHPG/NE ratio was reduced, and there was a significant negative correlation with the concurrent drug concentration. These results suggest that DMI: (1) reduces the turnover of NE; and (2) diminishes the oxidative deamination of NE. In addition, the drug concentration response relationship indicates that the effects of uptake inhibition may not be maximal until concentrations in the apparent therapeutic range are achieved.

Measurement of total and organ-specific norepinephrine kinetics in humans.

A variety of biochemical tests, most notably measurement of the plasma concentration of norepinephrine, have been used to quantify overall sympathetic nervous system activity in humans. Plasma norepinephrine values provide a fallible index of sympathetic activity in that they are dependent in part on the rate of removal of norepinephrine from plasma. Measurement of the rate of release of norepinephrine to plasma is a better guide to overall sympathetic nervous tone because it avoids this confounding influence of norepinephrine plasma clearance. The overall norepinephrine spillover measurement, however, suffers from one major limitation: the sources of the released norepinephrine are not identified. Recently developed radiotracer techniques allow the estimation of regional sympathetic nervous activity from measurements of the organ-specific norepinephrine spillover rate. We find that the lungs are the main source of norepinephrine release to plasma, with mean pulmonary norepinephrine spillover of 159 ng/min constituting 40% of total norepinephrine release. Pulmonary norepinephrine release exceeded the combined norepinephrine spillover from the heart (3%), kidneys (17%), and hepatomesenteric circulation (8%).

Total, and organ-specific, noradrenaline plasma kinetics in essential hypertension.

We have developed radiotracer techniques, based on measurement of the rate of spillover of noradrenaline to plasma, to simultaneously estimate total, and organ-specific, sympathetic nervous activity in humans. In 27 unmedicated subjects without renal or liver disease, or cardiac failure, regional noradrenaline spillover rates were as follows: lungs 33% of total noradrenaline release to plasma, kidneys 22%, skeletal muscle 20%, hepatomesenteric 9%, skin 5%, and heart 3%. These findings have relevance to numerous previous studies on the importance of the sympathetic nervous system in the pathogenesis of human essential hypertension. The indices of overall sympathetic nervous tone which have been used, such as measurements of plasma noradrenaline concentration or total NA release to plasma, are seen to be not sufficiently specific, since the organs and regions thought to be central to hypertension pathogenesis (kidney, heart, splanchnic circulation) are responsible for no more than 35% of all noradrenaline released to plasma. Organ-specific noradrenaline spillover measurements are better suited to the elucidation of any sympathetic nervous system pathophysiology in human hypertension. Early results point to an increase in renal sympathetic tone in young patients with essential hypertension.