Breakthrough Cancer Pain: Preliminary Data of The Italian Oncologic Pain Multisetting Multicentric Survey (IOPS-MS)

Introduction

An ongoing national multicenter survey [Italian Oncologic Pain multiSetting Multicentric Survey (IOPS-MS)] is evaluating the characteristics of breakthrough cancer pain (BTP) in different clinical settings. Preliminary data from the first 1500 cancer patients with BTP enrolled in this study are presented here.

Methods

Thirty-two clinical centers are involved in the survey. A diagnosis of BTP was performed by a standard algorithm. Epidemiological data, Karnofsky index, stage of disease, presence and sites of metastases, ongoing oncologic treatment, and characteristics of background pain and BTP and their treatments were recorded. Background pain and BTP intensity were measured. Patients were also questioned about BTP predictability, BTP onset (≤10 or >10 min), BTP duration, background and BTP medications and their doses, time to meaningful pain relief after BTP medication, and satisfaction with BTP medication. The occurrence of adverse reactions was also assessed, as well as mucosal toxicity.

Results

Background pain was well controlled with opioid treatment (numerical rating scale 3.0 ± 1.1). Patients reported 2.5 ± 1.6 BTP episodes/day with a mean intensity of 7.5 ± 1.4 and duration of 43 ± 40 min; 977 patients (65.1%) reported non-predictable BTP, and 1076 patients (71.7%) reported a rapid onset of BTP (≤10 min). Higher patient satisfaction was reported by patients treated with fast onset opioids.

Conclusions

These preliminary data underline that the standard algorithm used is a valid tool for a proper diagnosis of BTP in cancer patients. Moreover, rapid relief of pain is crucial for patients’ satisfaction. The final IOPS-MS data are necessary to understand relationships between BTP characteristics and other clinical variables in oncologic patients.

Funding

Molteni Farmaceutici, Italy.

     

Poster 6: Traumatic brain injury as a relevant cause of growth hormone deficiency in adults. Experience from KIMS (pharmacia international metabolic database)

Objective: To compare baseline clinical characteristics and 1-year growth hormone (GH) replacement results in patients with adult onset growth hormone deficiency (GHD) caused by traumatic brain injury (TBI) versus nonfunctioning pituitary adenoma (NFPA). Design: Pharmacoepidemiologic survey of hypopituitary adults with GHD. Setting: Records were selected from the KIMS database, which contains information on >8500 patients with GHD, for 168 of whom TBI was identified as a cause. Participants: Both groups (NFPA group, n=207; TBI group, n=29) were age- (at pituitary disorder onset and entry into the KIMS database) and sex-matched (60% men, 40% women), previously not irradiated, and had not received GH. Interventions: Not applicable. Main Outcome Measures: Values given as mean ± SE. Results: The age at GHD diagnosis was 38.8±2.0 years for the TBI group and 41.5±0.5 years for the NFPA group. In both groups, the most frequent additional hypopituitary deficiency was luteinzing hormone/follicle-stimulating hormone, followed by adrenocorticotropic hormone and thyroid-stimulating hormone. The mean GH peak at diagnosis was 1.25±0.42ng/mL in the TBI group, which was significantly lower than that of the NFPA group (2.38±0.7ng/mL). There were no significant statistical differences in medical history, glucose level, lipids, waist circumference, or body composition measurements. Interestingly, patients with TBI were significantly shorter (168.2±1.5cm) than the NFPA patients (172.5±0.6cm). After 1 year of GH treatment, differences were shown in waist, lean mass, heart rate, glucose levels, quality of life as measured by the Quality of Life Assessment in Growth Hormone Deficient Adults and insulin-like growth factor I. Conclusions: Although hypopituitarism secondary to TBI was described more than 50 years ago, it is only now evident that a considerable number of patients experience severe GHD after TBI. It is suspected that a large number of patients after TBI have undiagnosed GHD. The present results confirm that clinical characteristics and GH treatment effects in GHD caused by TBI are indistinguishable from those in GHD caused by NFPA.     

Severe Hemoptysis Associated with Bacterial Pulmonary Infection: Clinical Features,Significance of Parenchymal Necrosis,and Outcome

Purpose

Severe hemoptysis (SH) associated with non-tuberculosis bacterial lower respiratory tract infection (LRTI) is poorly described, and the efficacy of the usual decision-making process is unknown. This study aimed at describing the clinical, radiological patterns, mechanism, and microbiological spectrum of SH related to bacterial LRTI, and assessing whether the severity of hemoptysis and the results of usual therapeutic strategy are influenced by the presence of parenchymal necrosis.

Methods

A single-center analysis of patients with SH related to bacterial LRTI from a prospective registry of consecutive patients with SH admitted to the intensive care unit of a tertiary referral center between November 1996 and May 2013.

Results

Of 1504 patients with SH during the study period, 65 (4.3%) had SH related to bacterial LRTI, including non-necrotizing infections (n = 31), necrotizing pneumonia (n = 23), pulmonary abscess (n = 10), and excavated nodule (n = 1). The presence of parenchymal necrosis (n = 34, 52%) was associated with a more abundant bleeding (volume: 200 ml [70–300] vs. 80 ml [30–170]; p = 0.01) and a more frequent need for endovascular procedure (26/34; 76% vs. 9/31; 29%; p < 0.001). Additionally, in case of parenchymal necrosis, the pulmonary artery vasculature was involved in 16 patients (47%), and the failure rate of endovascular treatment was up to 25% despite multiple procedures.

Conclusions

Bacterial LRTI is a rare cause of SH. The presence of parenchymal necrosis is more likely associated with bleeding severity, pulmonary vasculature involvement, and endovascular treatment failure.

     

Critical role of Aquaporin-1 and telocytes in infantile hemangioma response to propranolol beta blockade

Propranolol, a nonselective β-adrenergic receptor (ADRB) antagonist, is the first-line therapy for severe infantile hemangiomas (IH). Since the incidental discovery of propranolol efficacy in IH, preclinical and clinical investigations have shown evidence of adjuvant propranolol response in some malignant tumors. However, the mechanism for propranolol antitumor effect is still largely unknown, owing to the absence of a tumor model responsive to propranolol at nontoxic concentrations. Immunodeficient mice engrafted with different human tumor cell lines were treated with anti-VEGF bevacizumab to create a model sensitive to propranolol. Proteomics analysis was used to reveal propranolol-mediated protein alteration correlating with tumor growth inhibition, and Aquaporin-1 (AQP1), a water channel modulated in tumor cell migration and invasion, was identified. IH tissues and cells were then functionally investigated. Our functional protein association networks analysis and knockdown of ADRB2 and AQP1 indicated that propranolol treatment and AQP1 down-regulation trigger the same pathway, suggesting that AQP1 is a major driver of beta-blocker antitumor response. Examining AQP1 in human hemangioma samples, we found it exclusively in a perivascular layer, so far unrecognized in IH, made of telocytes (TCs). Functional in vitro studies showed that AQP1-positive TCs play a critical role in IH response to propranolol and that modulation of AQP1 in IH-TC by propranolol or shAQP1 decreases capillary-like tube formation in a Matrigel-based angiogenesis assay. We conclude that IH sensitivity to propranolol may rely, at least in part, on a cross talk between lesional vascular cells and stromal TCs.

Infantile hemangioma (IH), the most frequent tumor of infancy affecting 1 to 5 out of 100 newborns, is a noncongenital benign vascular tumor. Although most IHs are small, inconsequential, and regress spontaneously in many cases, medical treatment is needed in at least 15% of cases. The current first-line therapy for severe IH is systemic propranolol, a nonselective β-adrenergic receptor (ADRB) antagonist (1). Three subtypes of ADRBs (ADRB1, ADRB2, and ADRB3), which are coded by three distinct genes, belong to the superfamily of G protein–coupled receptors. They are characterized by a pocket containing binding sites for agonists (e.g., adrenaline and noradrenaline) and competitive antagonists (e.g., propranolol and timolol) (2). Although a role for ADRB in cancer progression was suggested long ago (3), our serendipitous observation of the efficacy of propranolol in treating IH (4) prompted many researchers to explore the anticancer properties of β-blockers.Although the therapeutic effect of propranolol is thought to be due to its ability to affect vasoconstriction, endothelial cell (EC) apoptosis, and/or inhibition of angiogenesis by modulating vascular endothelial growth factors (5, 6), the precise mechanism of its action is still under debate and largely unknown. Propranolol has been shown to have a growth inhibitory effect as a monotherapy on hemangioma cells in vitro (7–9). Nevertheless, growth inhibition was observed at doses 100- to 1,000-times higher than the plasmatic dose measured in treated IH patients (i.e., never above 0.5 µM) (10). It is then difficult to make the assumption that the effect of propranolol in IH can be mimicked and studied with such unrealistic doses. Indeed, the absence of an in vivo IH model that has shown a tumor growth inhibition induced by propranolol as well as difficulties in accessing IH patient samples before and after treatment have jointly hindered the quest to reveal its mechanism of action. Although several attempts have been made to create an in vivo IH model, a convincing antitumor effect of propranolol is still lacking (11–15). Of note, Lee et al. showed an effect of propranolol on vascular volume in a model of hemangioma cell–formed vessels in mice but without studying the effect on tumor growth (15). Considering this global effort and given the potential interest to identify a biomarker of malignant tumors sensitive to propranolol, we decided to explore the antitumor effect of propranolol in different tumor types in vivo. Retrospective clinical studies have shown that β-blocker use for hypertension is associated with improved cancer-specific survival compared with patients using other types of antihypertensive medications. For instance, a beneficial effect on survival was seen in breast cancer patients receiving the nonselective β-blocker propranolol but not with the β-1 antagonist atenolol (16). Additional studies showed a benefit of β-blocker use in patients with colorectal (17, 18) and pancreatic cancer (19). A prospective nonrandomized study of propranolol in the adjuvant setting for resected melanoma found an 80% reduction in melanoma recurrence (20). However, prospective clinical evidence supporting a role for propranolol in cancer treatment or prevention is limited. It is unlikely that beta blockade becomes an anticancer drug as a monotherapy, but combination therapy seems more promising (21). In this work, our hypothesis was that the antitumor effect of propranolol in malignant tumors was related to some common feature with the IH microenvironment. Since the increase of hypoxia-induced mediators has been shown in children with hemangioma (22, 23), we speculated that a hypoxic microenvironment could trigger the propranolol antitumor effect. We therefore chose a model of human malignant tumor cells xenografted in immunocompromised mice with continuous treatment of anti–vascular endothelial growth factor-(VEGF-A) bevacizumab (Avastin), hereafter abbreviated as Bev, in order to obtain a hypoxic tumor model (24). Tumor hypoxia induced by sunitinib and bevacizumab has already been used in mouse models in order to study specific drug sensitivity induced by up-regulation of HIF-1-α hypoxia (25). Sunitinib has also been used to assess propranolol antitumor efficacy in a melanoma model (26); nonetheless, bevacizumab is a more specific antiangiogenic drug than sunitinib.Using human malignant cell lines xenografted into immunodeficient mice as a model, we show in this study that propranolol induced the down-regulation of aquaporin-1 (AQP1), a transmembrane protein forming a channel for water and small solutes (27–30), and has a very pronounced effect on tumor growth in our mouse model (31–34). Looking for AQP1 expression in IH, we describe a special peripheral vascular layer made of dendritic cells named telocytes (TCs) with highly specific expression of AQP1, suggesting a key role in the exquisite sensitivity of IH to propranolol, which was verified in vitro with patients’ cells.     

Prevalence of comorbidities and management of gout in a tropical city in Australia

To examine the management of gout in general practice in Townsville, Australia, and to explore comorbid conditions in patients with gout. Study will also explore how closely guidelines are being followed in managing gout. Retrospective chart review was conducted from May to November 2014 in three general practices in Townsville. Registers for patients were established by searching “gout” and “gouty arthritis”. Three hundred and twenty-one patients were included in the study after excluding inactive patients, patients below age of 18 and patients with cancer. Main outcome measures were prevalence of comorbidities in gout patients, gout medications and adequate serum urate control (≤0.36 mmol/l). Multivariate logistic regression was used to study the relationship between serum urate level, comorbid conditions and lifestyle factors. Hypertension was the most common comorbid condition with 60.8 % of patients followed by obesity and dyslipidaemia. In terms of medication, 46.7 % of patients were on allopurinol, 12.8 % on indomethacin and 13.4 % on diuretics. Eighty-six percentage of patients had serum urate level (sUA) recorded in the previous year. Of these, 32.2 % had a serum urate level below or equal to 0.36 mmol/l. Moreover, 17.4 % of patients had lifestyle advice documented in chart. Male gender was the most influential factor in having poor uric acid control (p < 0.01), followed by not being on allopurinol (p < 0.01) and patients older than 50 years (p = 0.02). Management of gout in this study sample was not entirely concordant with guidelines. The study also suggests a need for possible tighter monitoring and allopurinol dosing regime in older, male patients.     

Ketorolac pharmacokinetics in experimental cirrhosis by bile duct ligation in the rat

The purpose of the present work was to study the pharmacokinetics of ketorolac, a poorly metabolized drug, in experimental cirrhosis. Cirrhosis was induced by bile duct ligation (BDL) for four weeks in male Wistar rats. Ketorolac was given intravenously (1 mg/kg ) or orally (3.2 mg/kg) to control (sham-operated) and BDL-rats. Determination of ketorolac in plasma was carried out by HPLC and estimation of pharmacokinetic parameters was performed by non-compartmental analysis. Indicators of liver damage and liver fibrosis were significantly increased (p < 0.05) in BDL compared to control rats. Experimental cirrhosis did not induce any significant alteration in intravenous ketorolac pharmacokinetics. Volume of distribution, clearance, AUC and t1/2 were similar in BDL and control animals. Notwithstanding, oral ketorolac bioavailability was significantly altered in BDL rats. AUC and Cmax were reduced, while tmax was prolonged, suggesting that both, the extent and the rate of ketorolac absorption were decreased. Results show that liver cirrhosis may result in significant pharmacokinetic alterations, even for poorly bio-transformed drugs, but that alterations may vary with the route of administration. In conclusion, uncritical generalizations on the effect of liver damage on drug kinetics should be avoided and systematic studies for every drug and every route of administration are thus recommended.