Adverse event management in patients with relapsed and refractory multiple myeloma taking pomalidomide plus low-dose dexamethasone: A pooled analysis.

OBJECTIVES: Heavily pretreated patients with relapsed and refractory multiple myeloma are susceptible to treatment-related adverse events (AEs). Managing AEs are important to ensure patients continue therapy long enough to receive the best clinical benefit. Data from the MM-002, MM-003, and MM-010 trials were pooled to further characterize the safety profile of pomalidomide plus low-dose dexamethasone and AE management. METHODS: This analysis included 1088 patients who received ≥ 2 prior therapies, including lenalidomide and bortezomib, and progressed ≤ 60 days of last therapy. Patients received 28-day cycles of pomalidomide 4 mg/day on days 1-21 and low-dose dexamethasone 40 mg (20 mg if aged > 75 years) weekly until disease progression or unacceptable toxicity. Thromboprophylaxis was required. RESULTS: The most common grade 3/4 AEs were neutropenia (56.2%), anemia (32.3%), and thrombocytopenia (25.8%), which occurred within the first few cycles of treatment. Grade 3/4 infections occurred in 33.7% patients, of whom 13.9% had pneumonia, and 40.3% had neutropenia. Pomalidomide dose reductions or interruptions were reported in 24.2% and 66.0% of patients, respectively. AEs were managed by dose modifications and/or supportive care. CONCLUSIONS: Pomalidomide plus low-dose dexamethasone showed an acceptable safety profile, and AEs were well managed according to study protocols and established guidelines.

Safety and efficacy of pomalidomide plus low-dose dexamethasone in STRATUS (MM-010): a phase 3b study in refractory multiple myeloma.

Patients with relapsed and/or refractory multiple myeloma (RRMM) have poor prognosis. The STRATUS study assessed safety and efficacy of pomalidomide plus low-dose dexamethasone in the largest cohort to date of patients with RRMM. Patients who failed treatment with bortezomib and lenalidomide and had adequate prior alkylator therapy were eligible. Pomalidomide 4 mg was given on days 1-21 of 28-day cycles with low-dose dexamethasone 40 mg (20 mg for patients aged >75 years) on days 1, 8, 15, and 22 until progressive disease or unacceptable toxicity. Safety was the primary end point; secondary end points included overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Among 682 patients enrolled, median age was 66 years, and median time since diagnosis was 5.3 years. Median number of prior regimens was 5. Most patients were refractory to both lenalidomide and bortezomib (80.2%). Median follow-up was 16.8 months; median duration of treatment was 4.9 months. Most frequent grade 3/4 treatment-emergent adverse events were hematologic (neutropenia [49.7%], anemia [33.0%], and thrombocytopenia [24.1%]). Most common grade 3/4 nonhematologic toxicities were pneumonia (10.9%) and fatigue (5.9%). Grade 3/4 venous thromboembolism and peripheral neuropathy were rare (1.6% each). The ORR was 32.6%, and the median DOR was 7.4 months. Median PFS and OS were 4.6 months and 11.9 months, respectively. We present the largest trial to date evaluating pomalidomide plus low-dose dexamethasone in patients with RRMM, further confirming that this regimen offers clinically meaningful benefit and is generally well tolerated. www.Clinicaltrials.gov identifier NCT01712789.

A novel placement technique for nasogastric and nasoesophageal tubes.

BACKGROUND: Early enteral nutrition in dogs and cats can have significant benefit in the therapeutic management of critical illness. Blind placement of nasogastric or nasoesophageal feeding tubes to accomplish this goal has become standard practice. However, complications from tube misdirection into the tracheobronchial tree can lead to significant patient morbidity and mortality. Safe and consistent alternatives are desirable to minimize these risks. KEY CONCEPTS: A modified method for placement of nasoenteric tubes is described. The main variation from standard procedure involves a second tube measurement, with the distal tip of the tube positioned at the thoracic inlet and measured to the nostril. The tube is advanced to this level and tested for negative pressure using a 12 mL syringe attached to the end of the feeding tube. This improves confidence in esophageal positioning before complete advancement of the tube to its distal endpoint. SIGNIFICANCE: This procedural adaptation to feeding tube placement has the potential to reduce bronchopulmonary trauma from intratracheal misdirection by providing an early safety check to identify malpositioning. Prospective validation studies are needed to support its advantages over standard tube placement techniques.

Iron metabolism following intravenous transfusion with stored versus fresh autologous erythrocyte concentrate in healthy dogs.

OBJECTIVE To determine effects of IV transfusion with fresh (3-day-old) or stored (35-day-old) autologous erythrocyte concentrate on serum labile iron concentration, iron-binding capacity, and protein interaction with iron in dogs. ANIMALS 10 random-source healthy dogs. PROCEDURES Dogs were randomly assigned to receive autologous erythrocyte concentrate stored for 3 days (n = 5) or 35 days (5). One unit of whole blood was collected from each dog, and erythrocyte concentrates were prepared and stored as assigned. After erythrocyte storage, IV transfusion was performed, with dogs receiving their own erythrocyte concentrate. Blood samples were collected from each dog before and 5, 9, 24, 48, and 72 hours after transfusion. Serum was harvested for measurement of total iron, labile iron, transferrin, ferritin, hemoglobin, and haptoglobin concentrations. RESULTS For dogs that received fresh erythrocytes, serum concentrations of the various analytes largely remained unchanged after transfusion. For dogs that received stored erythrocytes, serum concentrations of total iron, labile iron, hemoglobin, and ferritin increased markedly and serum concentrations of transferrin and haptoglobin decreased after transfusion. CONCLUSIONS AND CLINICAL RELEVANCE Transfusion with autologous erythrocyte concentrate stored for 35 days resulted in evidence of intravascular hemolysis in healthy dogs. The associated marked increases in circulating concentrations of free iron and hemoglobin have the potential to adversely affect transfusion recipients.

Intravenous lipid emulsion therapy in three cases of canine naproxen overdose.

OBJECTIVE: To report a case series of canine naproxen overdoses successfully treated with intravenous lipid emulsion therapy (IVLE). SERIES SUMMARY: Three dogs were presented for acute ingestion of naproxen and were treated with IVLE. Baseline and post treatment serum naproxen concentrations were measured. The first exposure involved ingestion of 61 mg/kg of an over-the-counter naproxen formulation in a 7-month-old male intact Labrador Retriever. Pre-IVLE toxin concentration assessed by high performance liquid chromatography (HPLC) was 73 µg/mL with a one-hour post-IVLE concentration decreasing to 30 µg/mL. The second and third exposures were 3-year-old female spayed Pembroke Welsh Corgi dogs from the same family, presented for potential ingestion of up to 207 mg/kg of a prescription strength naproxen formulation. Pre-IVLE naproxen concentration by HPLC for case 2 was 30 µg/mL with a reduction to 12 µg/mL and 7.2 µg/mL 1 and 3 hours post-IVLE treatment, respectively. For case 3, pre-IVLE naproxen concentration by HPLC was 86 µg/mL with post concentrations at 21 µg/mL one hour and 10 µg/mL 3 hours post-IVLE administration. NEW OR UNIQUE INFORMATION PROVIDED: Naproxen is a nonsteroidal anti-inflammatory drug with a long half-life and narrow margin of safety in dogs. Ingestion of > 5 mg/kg has been associated with adverse gastrointestinal effects, including ulceration. At doses > 10-25 mg/kg, acute kidney failure has been reported, and at doses > 50 mg/kg, neurologic abnormalities occur. This is the first reported use of IVLE for treatment of naproxen overdose with documented decrease in serum toxin concentrations shortly after administration. No long-standing gastrointestinal, renal, or neurologic effects occurred in these dogs.

Procoagulant phospholipid concentration in canine erythrocyte concentrates stored with or without prestorage leukoreduction.

OBJECTIVE: To evaluate canine erythrocyte concentrates (ECs) for the presence of procoagulant phospholipid (PPL), determine whether PPL concentration changes during the course of storage of ECs, and ascertain whether prestorage leukoreduction (removal of leukocytes via gravity filtration) reduces the development of PPL. SAMPLE: 10 whole blood units (420 g each) collected from 10 random-source, clinically normal dogs (1 U/dog). PROCEDURES: The dogs were randomized to 1 of 2 groups. Of the 10 whole blood units collected, 5 were processed through a standard method, and 5 underwent leukoreduction. Whole blood units were processed to generate ECs, from which aliquots were aseptically collected from each unit weekly for 5 weeks. Supernatants from the concentrates were evaluated for procoagulant activity, which was converted to PPL concentration, by use of an automated assay and by measurement of real-time thrombin generation. RESULTS: Supernatants from stored canine ECs contained procoagulant activity as measured by both assays. In general, the PPL concentration gradually increased during the storage period, but leukoreduction reduced the development of increased procoagulant activity over time. CONCLUSIONS AND CLINICAL RELEVANCE: The presence of PPL in canine ECs may be associated with procoagulant and proinflammatory effects in vivo, which could have adverse consequences for dogs treated with ECs.

Contrast-enhanced multidetector computed tomography to diagnose pulmonary thromboembolism in an awake dog with pyothorax.

OBJECTIVES: To (1) describe the use of contrast-enhanced multidetector computed tomography (CE-MDCT) for identifying pulmonary thromboembolism (PTE) in an awake dog with pyothorax, (2) report the first documented case of PTE associated with pyothorax in veterinary medicine, and (3) review diagnostic imaging modalities and therapeutic options for PTE. CASE SUMMARY: A 5-year, 4-month-old female neutered Labrador Retriever was presented for respiratory distress secondary to a pyothorax. The dog underwent thoracic exploratory surgery in which no underlying etiology was identified. Aerobic bacterial culture grew Streptococcus canis. The patient remained hypoxemic despite thoracocentesis and surgery. CE-MDCT was performed without general anesthesia and showed luminal-filling defects in the right cranial and right and left caudal lobar primary pulmonary arteries consistent with PTE. Anticoagulant therapy using unfractionated heparin was initiated. The dog responded well and was discharged 3 days postoperatively. NEW OR UNIQUE INFORMATION PROVIDED: To the authors' knowledge, this is the first reported case of PTE diagnosed in a dog with pyothorax using CE-MDCT.

Follicular and estradiol parameters that improve success with natural cycle in vitro fertilization.

OBJECTIVE: To describe clinical thresholds for follicle size and estradiol levels to optimize success with natural cycle in vitro fertilization (NCIVF). STUDY DESIGN: Descriptive cohort of candidates for stimulated IVF, < 43 years old, with regular menstrual cycles, regardless of ovarian reserve or fertility treatment history. Patients underwent NCIVF, defined as oocyte retrieval, fertilization and embryo transfer after human chorionic gonadotropin (hCG) trigger without luteinizing hormone (LH) suppression or ovarian stimulation medications. RESULTS: A total of 422 patients underwent 821 NCIVF cycles. Clinical pregnancy rates per cycle start, retrieval, and transfer were 13%, 17%, and 32%, respectively, for all patients and 19%, 25%, and 49% for patients < 30 years old. The threshold estradiol level on day of hCG was 101 pg/mL; below that level no clinical pregnancies occurred. Likewise, a mean follicular diameter > 15 mm was the optimal threshold for hCG trigger. Anti-Müllerian hormone and follicle-stimulating hormone levels did not predict success in NCIVF, and no statistical difference in clinical pregnancy rates between day 3 or day 5 embryo transfer was observed. CONCLUSION: NCIVF is an effective therapy for infertile patients regardless of their ovarian reserve. Cycle cancellation due to a premature LH surge can be reduced, without sacrificing success, by triggering smaller follicles above a threshold level of estradiol.

Cytokine concentration in stored canine erythrocyte concentrates.

OBJECTIVE: To evaluate the effect of leukoreduction (LR) as compared to standard nonleukoreduced (NLR) units on cytokine concentrations in canine erythrocyte concentrates during regular storage time. DESIGN: Randomized, experimental study. SETTING: University teaching hospital. ANIMALS: Ten random-source research dogs. INTERVENTIONS: One unit of whole blood was collected from each dog and randomized to standard processing (NLR, n = 5) or prestorage LR (n = 5). All units were stored at 4°C. Samples were aseptically collected from each unit weekly for 5 weeks. On day 35, 1 mL of blood was collected from each unit and submitted for aerobic culture. MEASUREMENT AND MAIN RESULTS: An ELISA assay was used to analyze the concentrations of IL-1ß, IL-8, TNF-α, and IL-10. There were no significant effects of either group or storage time for IL-1ß, IL-10, or TNF-α. IL-8 concentration was significantly increased over the storage period in NLR units, and was significantly higher compared to LR units on days 28 and 35. Aerobic culture was negative on all units. CONCLUSIONS: This study demonstrated a marked, storage time-dependent accumulation of IL-8 in canine erythrocyte concentrates. Prestorage LR attenuated the accumulation of IL-8. This chemokine may contribute to the proinflammatory effects of transfusion of stored erythrocyte concentrates.

Retention of structure and function of the cat germinal vesicle after air-drying and storage at suprazero temperature.

The study explored a novel approach for preserving the maternal genome without the entire oocyte by air-drying the cat germinal vesicle (GV) in the presence of the disaccharide trehalose. Specifically, we examined GV structure and function after desiccation, storage at 4 °C (up to 32 wk), and rehydration including the ability to resume meiosis after injection into a fresh, conspecific cytoplast. In experiment 1, DNA integrity was similar to fresh controls after 1 and 4 wk storage in the presence of trehalose, but was more fragmented at later time points (especially after 32 wk). Nuclear envelope integrity was sustained in >90% of oocytes stored for 0, 4, or 16 wk regardless of protective treatment. In experiment 2, compacted, air-dried GVs were stored for 2 or 4 wk, rehydrated, and injected into fresh cytoplasts. After culture for 24 h in vitro, up to 73% of oocytes reconstructed with desiccated GVs preserved in trehalose resumed meiosis compared to 30% of those dried in the absence of the disaccharide. At each storage time point, trehalose presence during air-drying was advantageous for resumption of meiosis, with >20% of oocytes completing nuclear maturation to metaphase II. This demonstrates a potential for preserving the female genome using the GV alone and for multiple weeks after desiccation. Trehalose enhanced the process by retaining the ability of a dried and rehydrated GV to resume communication with the surrounding cytoplasm of the recipient oocyte to permit reaching metaphase II and likely sustain subsequent embryo development.

Microparticles in stored canine RBC concentrates.

BACKGROUND: Transfusion of RBC concentrates may cause adverse effects in the recipient, particularly when stored > 2 weeks. Prestorage removal of WBCs and platelets (leukoreduction, LR) improves clinical outcome in the human recipient. As blood ages during storage, progressive alterations in the structure and function of the cells occur. Changes in cell membranes may lead to formation of microparticles (MPs) in stored blood. OBJECTIVES: The aim of the study was to quantify MP concentration in supernatants from canine RBC concentrates from 11 clinically healthy dogs. METHODS: Whole blood units (n = 11) were collected and randomized either to be stored without LR (n = 5), or to be subject to prestorage LR (n = 6). Whole blood was processed for the generation of RBC concentrates, from which aliquots were aseptically collected weekly for 5 weeks. Supernatants from the concentrates were evaluated for phosphatidylserine-expressing MPs by flow cytometry using staining with Annexin-V-phycoerythrin. RESULTS: Microparticle counts were similar between non-LR and LR units on storage days 0 and 7, but were significantly higher in non-LR units on days 14, 21, 28, and 35. MPs increased during the 35-day storage by a mean (SD) of 1.8 (1.4)-fold in LR units and 5.5 (3.1)-fold in non-LR units. CONCLUSIONS: There was marked formation of phosphatidylserine-expressing MPs during storage beyond 7 days in canine RBC concentrates. Prestorage LR attenuated the generation of MPs.

Diagnostic approach to small animal bleeding disorders.

A well-designed and executed diagnostic approach to patients with bleeding disorders is critical to determine disease etiology and guide therapeutic measures. This systematic process begins with a comprehensive history and physical examination, followed by laboratory tests of primary hemostasis (platelet enumeration, platelet function testing, and von Willebrand factor assays), secondary hemostasis (prothrombin time, activated partial thromboplastin time, activated clotting time, and individual factor deficiencies), and fibrinolysis (fibrinogen activity, thrombin time, fibrin degradation products, D-dimers), dependent on the clinical picture. Equally valuable are proper specimen collection, handling, and storage methods, which provide reliable and reproducible result interpretation. This review will emphasize the common diagnostic tools and blood sampling techniques important to the workup of hemostatic diseases as well as provide an overview of advanced clinical and research methods and equipment available to assist our bleeding veterinary patients, including thromboelastography/thromboelastometry, calibrated automated thrombogram, and the thrombin-antithrombin assay.

RECOVER evidence and knowledge gap analysis on veterinary CPR. Part 2: Preparedness and prevention.

OBJECTIVE: To systematically examine the evidence on the effect of prevention and preparedness measures on outcomes in veterinary cardiopulmonary resuscitation and to determine knowledge gaps. DESIGN: Standardized, systematic evaluation of the literature, categorization of relevant articles according to level of evidence and quality, and development of consensus on conclusions for application of the concepts to clinical practice. Relevant questions were answered on a worksheet template and reviewed by the Reassessment Campaign on Veterinary Resuscitation (RECOVER) prevention and preparedness domain members, by the RECOVER committee, and opened for comments by veterinary professionals for 3 months. SETTING: Academia, referral practice, and general practice. RESULTS: Nine worksheets were prepared to determine the extent to which preparation of the environment (charts, visual aids, etc) and personnel (training, debriefing, etc) are beneficial in improving return of spontaneous circulation. CONCLUSIONS: Of the questions evaluated, only the association between anesthesia-related cardiopulmonary arrest and better outcomes was supported by strong evidence. There is some evidence from the human literature that the use of cognitive aids, standardized didactic, and hands-on training with high-fidelity simulators, team and leadership training, and post-cardiac arrest debriefing improve adherence to cardiopulmonary resuscitation guidelines and, in some cases, patient outcomes. Veterinary studies investigating these issues are lacking, and development of initial guidelines is a crucial first step.

Siltuximab, a novel anti-interleukin-6 monoclonal antibody, for Castleman's disease.

PURPOSE: Interleukin-6 (IL-6) has emerged as a key factor in the pathogenesis of the atypical lymphoproliferative disorder Castleman's disease (CD). Siltuximab is a new anti-IL-6, chimeric monoclonal antibody with potential therapeutic benefit in patients with CD. METHODS: We report interim results from an open-label, dose-finding, seven-cohort, phase I study in which patients with symptomatic, multicentric or unresectable, unicentric CD received siltuximab at 1-, 2-, or 3-week intervals. The main efficacy end point of clinical benefit response (CBR) was defined as a composite of clinical and laboratory measures relevant to the management of CD. In addition, radiologic response was independently assessed by using modified Cheson criteria. RESULTS: Eighteen (78%) of 23 patients (95% CI, 56% to 93%) achieved CBR, and 12 patients (52%) demonstrated objective tumor response. All 11 patients (95% CI, 72% to 100%) treated with the highest dose of 12 mg/kg achieved CBR, and eight patients (73%) achieved objective tumor response. Overall objective-response duration ranged from 44 to > or = 889 days, and one patient had complete response for > or = 318 days. Hemoglobin increased markedly in 19 patients (median increase, 2.1 g/dL; range, 0.2 to 4.7 g/dL) in the absence of transfusion or erythropoiesis-stimulating agents. No dose-limiting toxicity was reported, and only three patients had grade 3 or higher adverse events after a median exposure of 331 days (range, 1 to 1,148 days). CONCLUSION: These interim results strongly suggest that siltuximab is an effective treatment with favorable safety for the management of CD. An additional study is planned to fully evaluate safety and efficacy at the recommended dose of 12 mg/kg every 3 weeks.

Blastocyst rate and live births from vitrification and slow-cooled two-cell mouse embryos.

OBJECTIVE: The purpose of this study was to develop a closed vitrification system, compare vitrification to a slow-cooled cryopreservation method, and compare the pup rate between both methods using two-cell mouse embryos. DESIGN: Randomized, prospective animal study. SETTING: Hospital-based IVF practice. ANIMAL(S): B6C3F1 mouse embryos. INTERVENTION(S): Two-cell mouse embryos were cryopreserved using a slow-cooled or vitrification method and then thawed at a later date. The embryos were cultured and transferred to recipient females. MAIN OUTCOME MEASURE(S): Embryos were observed for blastocyst rate and pups were observed for phenotypic anomalies and weighed at 30, 60, and 90 days after birth. RESULT(S): Neither the blastocyst rate, pup rate, nor pup weights were significantly different when the two cryopreservation methods were compared. CONCLUSION(S): Because there were no differences in blastocyst rates, pup rates, or pup weights, we plan to further investigate the potential effects of vitrification on genotypic damage via the Comet Assay.