Enzymatic activities of circulating plasma proteasomes in newly diagnosed multiple myeloma patients treated with carfilzomib, lenalidomide and dexamethasone.

The proteasome inhibitor carfilzomib is highly effective in the treatment of multiple myeloma. It irreversibly binds the chymotrypsin-like active site in the ß5 subunit of the 20S proteasome. Despite impressive response rates when carfilzomib is used in combination with immunomodulatory agents in newly diagnosed multiple myeloma patients; no biomarker exists to accurately predict response and clinical outcomes. We prospectively assessed the activity in peripheral blood of the chymotrypsin-like (CHYM), caspase-like (CASP) and trypsin-like (TRYP) proteolytic sites in 45 newly diagnosed multiple myeloma patients treated with eight cycles of carfilzomib, lenalidomide and dexamethasone (CRd) (NCT01402284). Samples were collected per protocol and proteasome activity measured through a fluorogenic assay. Median CHYM levels after one dose of carfilzomib decreased by >70%. CHYM and CASP activity decreased throughout treatment reaching a minimum after eight cycles of treatment. Higher levels of proteasome activity associated with higher disease burden (r > 0.30; p < 0.05) and higher disease stage (0.10 < p <0.20). No association was found with the probability of achieving a complete response, minimal residual disease negativity or time to best response. Further studies evaluating proteasome activity in malignant plasma cells may help elucidate how proteasome activity can be used as a biomarker in multiple myeloma.

Prevalence of airflow obstruction and reduced forced vital capacity in an Aboriginal Australian population: The cross-sectional BOLD study.

BACKGROUND AND OBJECTIVE: Mortality and hospital separation data suggest a higher burden of chronic obstructive pulmonary disease (COPD) in indigenous than non-indigenous subpopulations of high-income countries. This study sought to accurately measure the true prevalence of post-bronchodilator airflow obstruction and forced vital capacity reduction in representative samples of Indigenous and non-Indigenous Australians. METHODS: This study applies cross-sectional population-based survey of Aboriginal and non-Indigenous residents of the Kimberley region of Western Australia aged 40 years or older, following the international Burden Of Lung Disease (BOLD) protocol. Quality-controlled spirometry was conducted before and after bronchodilator. COPD was defined as Global initiative for chronic Obstructive Lung Disease (GOLD) Stage 2 and above (post-bronchodilator forced expiratory volume in 1 s/forced vital capacity (FEV1 /FVC) ratio <0.7 and FEV1 < 80% predicted). RESULTS: Complete data were available for 704 participants. The prevalence of COPD, adjusted for age, gender and body weight in Aboriginal participants (7.2%, 95% confidence interval (CI) 3.9 to 10.4) was similar to that seen in non-Indigenous Kimberley participants (8.2%, 95% CI 5.7 to 10.7) and non-Indigenous residents of the remainder of Australia (7.1%, 95% CI 6.1 to 8.0). The prevalence of low FVC (<80% predicted) was substantially higher in Aboriginal compared with non-Indigenous participants (74.0%, 95% CI 69.1 to 78.8, vs 9.7%, 95% CI 7.1 to 12.4). CONCLUSIONS: Low FVC, rather than airflow obstruction, characterizes the impact of chronic lung disease previously attributed to COPD in this population subject to significant social and economic disadvantage. Environmental risk factors other than smoking as well as developmental factors must be considered. These findings require further investigation and have implications for future prevention of chronic lung disease in similar populations.

Metastatic pheochromocytoma: does the size and age matter?

BACKGROUND: Pheochromocytomas are tumours arising from chromaffin tissue located in the adrenal medulla associated with typical symptoms and signs which may occasionally develop metastases, which are defined as the presence of tumour cells at sites where these cells are not found. This retrospective analysis was focused on clinical, genetic and histopathologic characteristics of primary metastatic versus primary benign pheochromocytomas. MATERIALS AND METHODS: We identified 41 subjects with metastatic pheochromocytoma and 108 subjects with apparently benign pheochromocytoma. We assessed dimension and biochemical profile of the primary tumour, age at presentation and time to develop metastases. RESULTS: Subjects with metastatic pheochromocytoma presented at a significantly younger age (41·4 ± 14·7 vs. 50·2 ± 13·7 years; P < 0·001) with larger primary tumours (8·38 ± 3·27 vs. 6·18 ± 2·75 cm; P < 0·001) and secreted more frequently norepinephrine (95·1% vs. 83·3%; P = 0·046) compared to subjects with apparently benign pheochromocytomas. No significant differences were found in the incidence of genetic mutations in both groups of subjects (25·7% in the metastatic group and 14·7% in the benign group; P = 0·13). From available histopathologic markers of potential malignancy, only necrosis occurred more frequently in subjects with metastatic pheochromocytoma (27·6% vs. 0%; P < 0·001). The median time to develop metastases was 3·6 years with the longest interval 24 years. CONCLUSIONS: In conclusion, regardless of a genetic background, the size of a primary pheochromocytoma and age of its first presentation are two independent risk factors associated with the development of metastatic disease.

Sodium cromoglycate and eformoterol attenuate sensitivity and reactivity to inhaled mannitol in subjects with bronchiectasis.

BACKGROUND AND OBJECTIVE: Dry powder mannitol has the potential to be used to enhance clearance of mucus in subjects with bronchiectasis. A reduction in FEV1 has been recorded in some subjects with bronchiectasis after inhaling mannitol. The aim of this study was to investigate if pre-medicating with either sodium cromoglycate (SCG) or eformoterol could inhibit this reduction in FEV1. METHODS: A double-blind, placebo-controlled, randomized cross-over study was conducted. Lung function and airway response to mannitol was assessed on a control day and then re-assessed after pre-medication with placebo, SCG and eformoterol in nine subjects. Sensitivity to mannitol, expressed as the dose required to induce a 15% fall in FEV1 (PD15), and reactivity to mannitol, expressed as the % fall in FEV1 per mg of mannitol (response-dose ratio, RDR), are reported. RESULTS: Subjects had an FEV1 of 68 ± 14% predicted, FVC of 97 ± 15% predicted and FEV1 /FVC of 71 ± 8%. They were mildly hypoxemic and the SpO2 was 95 ± 2%.They had a PD15 to mannitol of 235 mg (95% CI: 150-368 mg) and a RDR of 0.057% fall in FEV1 per mg (95% CI: 0.038-0.085). After pre-medication with SCG, PD15 increased (773 mg, P < 0.05) and RDR was reduced (0.013, P < 0.05). Pre-medication with eformoterol also resulted in an increased PD15 (1141 mg, P < 0.01) and a reduced RDR (0.009, P < 0.01). A small but significant decrease in SpO2 from baseline was noted after mannitol in the presence of SCG (P < 0.05). CONCLUSIONS: Pre-medication with either SCG or eformoterol protects patients with bronchiectasis from developing a significant reduction in FEV1 after inhaling mannitol.

Anaesthesia in elderly patients with neurodegenerative disorders: special considerations.

Neurodegenerative diseases are increasingly common in elderly patients, who present a particular anaesthetic challenge. The majority of people over the age of 70 years have some degree of cerebral atrophy. The pathogenesis of neurodegenerative diseases is due to alterations in the transport, degradation and aggregation of proteins. Alterations in physiology that occur with advancing age affect both the pharmacokinetics and pharmacodynamics of drugs used in the elderly. Changes in pharmacokinetics result in either increased or reduced drug concentrations depending on the variable contributions of absorption, metabolism and elimination. The distribution of a drug depends on its protein binding, cardiac output and blood volume, which are all altered in the elderly. Metabolism and excretion of drugs are also affected due to changes in hepatic and renal mass and blood flow in the elderly. A number of drugs are used in neurodegenerative disorders including antidepressants, benzodiazepines, antipsychotics, acetylcholinesterase inhibitors and levodopa. Polypharmacy is a common problem, which can lead to adverse drug interactions and an exacerbation of dementia. Levodopa, bromocriptine and tricyclic antidepressants are known to cause orthostatic hypotension in patients with neurodegenerative disease. Elderly patients are liable to excessive sedation from benzodiazepines in both the pre- and postoperative period; therefore these drugs should be prescribed in low doses. For induction of general anaesthesia propofol is a suitable agent in patients with neurodegenerative disease due to its rapid metabolism, but may not be suitable in patients with Parkinson's disease as it can induce spontaneous involuntary movements. Volatile inhalational agents should be administered carefully in the elderly, as they are more sensitive to the depressant cerebral and cardiovascular effects. Levodopa should be avoided in conjunction with halothane, which sensitises the heart to catecholamines. Co-administration of monoamine oxidase inhibitors and opioids should be avoided as it can cause agitation, muscular rigidity, sweating and hyperpyrexia. If an anticholinergic agent is required, then glycopyrronium bromide is the drug of choice in this group of patients, as it does not cross the blood brain barrier. Patients should continue to take their usual medications in hospital and do not let the change in routine alter the times at which treatments are administered. This is particularly relevant to the timing of levodopa in Parkinson's disease, as missed treatment can be detrimental. Regional anaesthesia may, however, have significant advantages in patients with Parkinson's disease, who can continue to take oral levodopa preoperatively, during surgery, if required, and early in the postoperative period. Anti-emetic drugs such as phenothiazines, butyrophenones and metoclopramide should be used carefully in the postoperative period in these patients as their antidopaminergic effects may induce or exacerbate parkinsonian effects.

A feasibility study of dignity psychotherapy delivered via telemedicine.

OBJECTIVE: Dignity Psychotherapy has shown great promise as a value-affirming intervention for patients with advanced disease. We delivered the Dignity Psychotherapy intervention in a feasibility study of a series of eight cancer patients via videophone technology to deliver the therapy into their homes. METHODS: Once eligible patients were consented on this IRB-approved study, they completed baseline assessments and were scheduled to have the videophone placed in their homes. The Dignity Therapy sessions then encompassed a first session, which was transcribed and edited, followed by a second session to go over the edited transcript and allow the patient to make changes. Patients then filled out follow-up questionnaires and had the telemedicine equipment removed from their homes, and their legacy document delivered. RESULTS: Participants had a mean age of 56.32 years (range = 41-66, SD = 7.65) and were diagnosed with lung (n = 5, 62.5%), breast (n = 2, 25%), or colon cancer (n = 1, 12.5%). They reported overall benefit from the intervention along with a high level of satisfaction. We were able to deliver the intervention in a timely fashion, with minimal length between sessions and transcript delivery and few technical difficulties. SIGNIFICANCE OF RESULTS: Telemedicine can greatly extend the benefits of Dignity Psychotherapy by bringing it to patients who are dying at home. Our very preliminary work suggests that delivering the intervention to patients who are too ill to leave their homes or who are in rural locations may be a feasible way to help them.