Integrated safety profile of single-agent carfilzomib: experience from 526 patients enrolled in 4 phase II clinical studies

Carfilzomib, a selective proteasome inhibitor, was approved in 2012 for the treatment of relapsed and refractory multiple myeloma. Safety data for single-agent carfilzomib have been analyzed for 526 patients with advanced multiple myeloma who took part in one of 4 phase II studies (PX-171-003-A0, PX-171-003-A1, PX-171-004, and PX-171-005). Overall analyses of adverse events and treatment modifications are presented, as well as specific analyses of adverse events by organ system. Overall, the most common adverse events of any grade included fatigue (55.5%), anemia (46.8%), and nausea (44.9%). In the grouped analyses, any grade adverse events were reported in 22.1% for any cardiac (7.2% cardiac failure), 69.0% for any respiratory (42.2% dyspnea), and 33.1% for any grouped renal impairment adverse event (24.1% increased serum creatinine). The most common non-hematologic adverse events were generally Grade 1 or 2 in severity, while Grade 3/4 adverse events were primarily hematologic and mostly reversible. There was no evidence of cumulative bone marrow suppression, either neutropenia or thrombocytopenia, and febrile neutropenia occurred infrequently (1.1%). Notably, the incidence of peripheral neuropathy was low overall (13.9%), including patients with baseline peripheral neuropathy (12.7%). Additionally, the incidence of discontinuations or dose reductions attributable to adverse events was low. These data demonstrate that single-agent carfilzomib has an acceptable safety profile in heavily pre-treated patients with relapsed/refractory multiple myeloma. The tolerable safety profile allows for administration of full-dose carfilzomib, both for extended periods and in a wide spectrum of patients with advanced multiple myeloma, including those with pre-existing comorbidities.     

Pepsin and Bile Acid Concentrations in Sputum of Mustard Gas Exposed Patients

Background/Aim:

Gastro-esophageal reflux has been suggested to be associated with several pulmonary complications such as asthma, and post-transplant bronchiolitis obliterans (BO). Pepsin or bile salts in the sputum is shown to be an optimal molecular marker of gastric contents macro/micro aspiration. In this study, we investigated sputum pepsin as a marker of micro-aspiration in sulfur mustard (SM) exposed cases compared to healthy controls.

Materials and Methods:

In a case controlled study, 26 cases with BO and 12 matched healthy controls were recruited and all cases were symptomatic and their exposure to SM was previously documented during Iran-Iraq conflict. Pepsin levels in sputum and total bile acids were measured using enzymatic assay. The severity of respiratory disorder was categorized based upon the spirometric values.

Result:

The average concentration of pepsin in sputum was higher in the case group (0.29 ± 0.23) compared with healthy subjects (0.13 ± 0.07; P ± 0.003). Moreover, the average concentration of bile acids in the sputum cases was not significantly different in comparison to the controls (P = 0.5).

Conclusion:

Higher pepsin concentrations in sputum of SM exposed patients compared with healthy control subjects indicate the occurrence of significantly more gastric micro-aspiration in SM exposed patients.     

Characteristics and early and long-term outcome in patients with acute ischemic stroke and low ejection fraction

Objectives

We assessed the clinical characteristics of patients with acute ischemic stroke (AIS) with left ventricular ejection fraction (EF) ≤ 35% and investigated the association of low EF with early and long-term outcome.

Methods

A total of 2439 patients of the Acute Stroke Registry and Analysis of Lausanne (ASTRAL) were selected. Demographics, risk factors, pre-stroke treatment, and clinical, radiological and metabolic variables in patients with and without low EF were compared. Functional independence (modified Rankin Score ≤ 2) and mortality were recorded 1 week up to 12 months from admission.

Results

Low EF patients (n = 119) were more commonly men, older, had higher rates of coronary artery disease and atrial fibrillation (AF), and more frequent pretreatment with anticoagulants, antiplatelets and antihypertensive agents. On admission, they presented with higher stroke severity and had lower values of systolic blood pressure, higher heart rate, and worse estimated glomerular filtration rate. Stroke-related disability and death rates were higher in low EF patients during follow-up (19.5% vs. 7.8% at 1 week, and 36.1% vs. 16.5% at 12 months). Increasing age, stroke severity, and AF were independent predictors of one-year mortality in these patients while prior use of statins had a favorable effect on early mortality.

Conclusions

AIS in patients with low EF is associated with older age, cardiac comorbidities, and more severe clinical presentation. Low EF can identify a subset of AIS patients at high risk of early and long-term functional disability and mortality.     

Pharmacologically preconditioned skeletal myoblasts are resistant to oxidative stress and promote angiomyogenesis via release of paracrine factors in the infarcted heart

Strategies to enhance skeletal myoblast (SkM) survival after transplantation in the ischemic heart have achieved little success. We posit that preconditioned (PC) SkMs show improved survival and promote repair of the infarcted myocardium via paracrine signaling after transplantation. SkMs from male Fischer-344 rats (rSkMs) were PC for 30 minutes with 200 micromol/L diazoxide. Treatment of PC rSkMs with 100 micromol/L H(2)O(2) for 2 hours resulted in significantly reduced cell injury, as shown by lactate dehydrogenase-release assay, and prevented apoptosis, as demonstrated by cytochrome c translocation, TUNEL, annexin V staining, and preservation of mitochondrial membrane potential. PC rSkMs expressed elevated phospho-Akt (1.85-fold), basic fibroblast growth factor (1.44-fold), hepatocyte growth factor (2.26-fold), and cyclooxygenase-2 (1.33-fold) as compared with non-PC rSkMs. For in vivo studies, female Fischer-344 rats after permanent coronary artery ligation were grouped (n=12/group) to receive 80 microL of basal medium without rSkMs (group 1) or containing 1.5 x 10(6) non-PC (group 2) or PC (group 3) rSkMs. Real-time PCR for sry gene 4 days after transplantation (n=4/group) showed 1.93-fold higher survival of rSkMs in group 3 as compared with group 2. Four weeks later, echocardiography revealed improved indices of left ventricular function, including ejection fraction and fractional shortening in group 3 (P<0.02) as compared with groups 1 and 2. Blood vessel count per surface area (at x400 magnification) was highest in scar and periscar areas in group 3 as compared with the other groups (P<0.05). We conclude that activation of signaling pathways of preconditioning in SkMs promoted their survival by release of paracrine factors to promote angiomyogenesis in the infarcted heart. Transplantation of PC SkMs for heart cell therapy is an innovative approach in the clinical perspective.     

Roles of the C-terminal tyrosine residues of LAT in GPVI-induced platelet activation: insights into the mechanism of PLC gamma 2 activation

Linker for activation of T cells (LAT) is an adaptor protein required for organization of the signaling machinery downstream of the platelet collagen receptor, the glycoprotein VI (GPVI). Here, we investigated the effect of LAT mutations on specific signaling pathways and on platelet functions in response to GPVI triggering by convulxin (Cvx). Using mice containing tyrosine to phenylalanine mutations of the adaptor, we show the crucial role played by the tyrosine residues at positions 175, 195, and 235 in the phosphorylation of LAT and in the whole pattern of protein tyrosine phosphorylation in response to Cvx. These 3 C-terminal tyrosine residues are important to recruit the tyrosine kinase Fyn, which may be involved in LAT phosphorylation. Efficient phosphoinositide 3-kinase (PI3K) activation requires the 3 C-terminal tyrosine residues of LAT but not its tyrosine 136. Interestingly, single mutation of the tyrosine 136 results in the loss of phospholipase C gamma2 (PLCgamma2) activation without affecting its PI3K-dependent membrane association, and is sufficient to impair platelet responses to Cvx. Thus, activation of PLCgamma2 via GPVI is dependent on 2 complementary events: its interaction with the tyrosine 136 of LAT and its membrane location, which itself requires events mediated by the 3 C-terminal tyrosines of LAT.     

Prevalence of renal cysts in a Middle-Eastern population: an evaluation of characteristics and risk factors

OBJECTIVE

To assess the prevalence of renal cysts in a large Middle‐Eastern population presenting for a health‐screening programme, evaluating cyst characteristics and risk factors for their development.

PATIENTS AND METHODS

The reported prevalence of renal cysts detected by ultrasonography (US) in the general population is 5.0–20.8%, and their development has been linked to several factors. The electronic charts of 8551 patients (from eight nations, predominantly Egypt and Yemen) presenting for the ‘check‐up’ programme at the author’s institution during 2005 were retrospectively reviewed. The presence and characteristics of renal cysts on abdominal US were noted, as were any associated renal pathologies. Various risk factors were evaluated for renal cyst development, i.e. age, gender, hypertension, diabetes mellitus and serum creatinine levels, and hyperlipidaemia and a history of bilharziasis were also assessed.

RESULTS

The prevalence of renal cysts was 4.2%, ranging from 0.6% for patients in their third decade, to a third of those aged >80 years. Cysts were detected in 4.8% of men and 2.8% of women (P < 0.001). The mean serum creatinine level was 1.02 mg/dL in those with cysts and 0.88 mg/dL in those without (P < 0.001). On univariate analysis, hypertension, diabetes and hyperlipidaemia had a significant influence on the occurrence of renal cysts, but not in the multivariate model. Of the 361 patients with renal cysts, 58 (16.1%) had bilateral and 26 (7.2%) had multiple unilateral cysts, with a mean (range) size of 26 (4–104) mm. The vast majority of cysts were classified as Bosniak I simple cysts; seven were Bosniak II and there was one Bosniak IV cyst. Associated renal pathologies included renal stones in 39 patients, hydronephrosis in nine, increased parenchymal echogenicity in 18, small atrophic kidneys in three, haematuria (not associated with other imaging abnormalities) in six, and a renal mass in one patient.

CONCLUSIONS

The prevalence of renal cysts detected by US in a health‐screened population from the Middle East was 4.2%. Increasing age, male gender and a higher serum creatinine level were significant independent risk factors for cyst development. There was also a relatively high prevalence of associated renal pathologies (increased parenchymal echogenicity and stones).     

Granular cell tumour of the common bile duct

Granular cell tumors (GCTs) are rare soft tissue neoplasms and occur in different parts of the body. We report a case of granular cell tumour of common bile duct (CBD) in a 39 years old lady, presenting with obstructive jaundice. Magnetic resonance cholangiopancreatography (MRCP) showed it as a benign looking mass in CBD. Complete surgical excision of the tumour was done. Histopathology was confirmatory. No histological evidence of malignancy was found.     

Sirolimus for visceral and cutaneous Kaposi's sarcoma in a renal-transplant recipient

The incidence of Kaposi's sarcoma among recipients of solid organs is about 500 times the rate in the general population, suggesting a role for immunosuppression in its development. On the basis of these findings, we investigated the impact of sirolimus on cutaneous and disseminated visceral Kaposi's sarcoma in a renal-transplant recipient. The introduction of sirolimus in this patient allowed complete regression of Kaposi's sarcoma (cutaneous and visceral) with preservation of excellent renal function. Meanwhile, in view of the available observational reports, we think that sirolimus should be included in the standard treatment for Kaposi's sarcoma after transplantation, to permit remission of the sarcoma (both cutaneous and visceral) while preserving the renal function.     

Opioid saving strategy: bilateral single-site thoracic paravertebral block in right lobe donor hepatectomy

BACKGROUND AND OBJECTIVES: Postoperative analgesia after hepatectomy remains a challenge, mainly because of limited therapeutic index of the conventional opioids. The aim of this study is to evaluate the efficacy of bilateral single-site thoracic paravertebral block for the management of postoperative pain following right lobe donor hepatectomy (RLDH) using a prospective, randomized and controlled study design. METHODS: Twenty four adult patients, aged 18-50 years, ASA-I-II, of both sexes scheduled for right lobe donor hepatic resection, were enrolled in this study. Patients were randomly allocated into 2 equal groups of 12 patients each. Before induction of general anesthesia, all patients received bilateral single-site thoracic paravertebral injection at the level of T7-8 in the sitting position. Patients of Group B were injected with 25 mL of bupivacaine 0.25% with epinephrine 1:200.000 on each side. Patients of Group P were injected with 25 mL of 0.9% NaCl (placebo). General anesthesia was standardized in all patients. Postoperative pain score, analgesic requirements and the incidence of postoperative nausea and vomiting were recorded. RESULTS: Bilateral single-site thoracic paravertebral block significantly decrease the pain visual analogue score parameters. Total morphine consumption in the first 24 hours postoperatively was decreased by more than 50% in Group B (21.76 +/- 6.8 mg compared to 44.12 +/- 9.2 mg in Group P). There was significant prolongation in time to rescue analgesia (104.08 +/- 2.04 min in Group B, and 31.5 +/- 6.14 min in Group P). Postoperative nausea and vomiting was significantly less in the active Group B when compared to the controlled Group P. CONCLUSION: Bilateral single-site thoracic paravertebral block is easy, safe and efficient technique for postoperative pain management in patients undergoing right lobe donor hepatectomy.