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In this report the concomitant infection with canine parvovirus type 2 (CPV-2), Hepatozoon canis and Ehrlichia canis in two puppy dogs from Southern Italy is described. Dogs were referred to a veterinary university hospital for the acute onset of lethargy and gastrointestinal signs. A complete clinical and clinicopathological evaluation was carried out and the multiple infection was confirmed by microscopic detection of inclusion bodies in peripheral blood smear, rapid immunoenzymatic tests, indirect fluorescent antibody tests, and molecular assays. Sequence analysis revealed that the CPV-2 identified belonged to the 2c variant and had amino acid residues in the predicted VP2 protein typical of "Asian-like" strains widespread in Asia and occasionally reported in Romania, Nigeria and Italy, particularly in the region of Sicily. Numerous monocytes were infected by both H. canis gamonts and E. canis morulae, suggesting that this co-infection is not accidental and that E. canis preferably infects those cells parasitized by H. canis . The clinical presentation of these animals was severe but supportive cares associated with early etiological therapy allowed a good prognosis. Movement of puppies from geographic areas where vector-borne pathogens are endemic must be carefully evaluated and core vaccinations and ectoparasite prevention treatments must be rigorously adopted., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Urbani, Tirolo, Balboni, Troia, Dondi and Battilani.)

A 2 mo old domestic shorthair kitten was presented for acute respiratory distress and severe ambulatory difficulties. Thoracic radiography revealed hyperinflation of the left cranial lung lobe and a mass with soft-tissue/gas opacity in the caudal mediastinum, leading to the suspicion of congenital lung lobe emphysema and hiatal hernia. Decreased bone radiopacity and suspected pathological fractures were also present. Complete clinicopathological analyses showed significant ionized hypocalcemia and suspicion of secondary hyperparathyroidism related to an inadequate diet. Lung lobectomy and reduction of the hiatal hernia following a median sternotomy and a cranial laparotomy were performed. IV and oral supplementation of calcium led to a full recovery and improvement in the kitten's walking. A histopathological analysis revealed pulmonary emphysema associated with hypoplastic and irregular bronchial cartilage. Congenital lobar emphysema is a rare disease in both humans and animals. This is the first veterinary report describing a kitten affected by congenital lobar emphysema combined with a hiatal hernia and additionally complicated by secondary nutritional hyperparathyroidism with a good long-term outcome., (© 2022 by American Animal Hospital Association.)

Canine parvovirus type 2 (CPV-2) is one of the most relevant pathogens associated with enteritis in dogs and is frequently reported in association with the detection of other pathogens in faeces. In this study the concomitant presence of Canine circovirus (CanineCV) and Canine adenovirus (CAdV) DNA in faecal or intestine samples of 95 dogs with parvovirus enteritis sampled in Italy (1995-2017) was investigated and the viruses identified were genetically characterised. Potential correlations with the antigenic variant of CPV-2 and with signalment data and outcome were evaluated. Twenty-eight of 95 (29.5%) CPV-2 infected dogs tested positive to other viruses: 7/28 were also positive to CanineCV, 1/28 to CAdV-1, 18/28 to CAdV-2, 1/28 to CanineCV and CAdV-2, and 1/28 to CAdV-1 and CAdV-2. The frequency of CAdV DNA detection and coinfections was significantly higher in purebred dogs compared to mixed breed ones (P = 0.002 and 0.009, respectively). The presence of coinfection was not associated with any other relevant data available, including CPV-2 variant and final outcome. The detection of CanineCV in a dog sampled in 2009 allowed to backdating its circulation in dogs. The eight CanineCV completely sequenced were phylogenetically related to the CanineCV identified in dogs, wolves and a badger from Europe, USA, Argentina and China. Nine CAdV were partially sequenced and phylogenetic analysis showed a separate branch for the oldest CAdV-2 identified (1995). From the results obtained in this study population, CanineCV and CAdV coinfections in dogs with parvoviral enteritis did not result in more severe disease., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

The electrochemical oxidation of small organic molecules (SOMs) such as methanol and glucose is a critical process and has relevant applications in fuel cells and sensors. A key challenge in SOM oxidation is the poisoning of the surface by carbon monoxide (CO) and other partially oxidized intermediates, which is attributed to the presence of Pt-Pt pair sites. A promising pathway for overcoming this challenge is to develop catalysts that selectively oxidize SOMs via "direct" pathways that do not form CO as a primary intermediate. In this report, we utilize an ambient, template-based approach to prepare PtAu alloy nanowires with tunable compositions. X-ray photoelectron spectroscopy measurements reveal that the surface composition matches that of the bulk composition after synthesis. Monte Carlo method simulations of the surface structure of PtAu alloys with varying coverage of oxygen adsorbates and varying degrees of oxygen adsorption strength reveal that oxygen adsorption under electrochemical conditions enriches the surface with Pt and a large fraction of Pt-Pt sites remain on the surface even with the Au content of up to 50%. Electrochemical properties and the catalytic performance measurements of the PtAu nanowires for the oxidation of methanol and glucose reveal that the mechanistic pathways that produce CO are suppressed by the addition of relatively small quantities of Au (∼10%), and CO formation can be completely suppressed by 50% Au. The suppression of CO formation with small quantities of Au suggests that the presence of Pt-Au pair sites may be more important in determining the mechanism of SOM oxidation rather than Pt-Pt pair site density.

Purpose: To address the role of consolidation treatment for newly diagnosed, transplant eligible patients with multiple myeloma in a controlled clinical trial., Patients and Methods: The EMN02/HOVON95 trial compared consolidation treatment with two cycles of bortezomib, lenalidomide, and dexamethasone (VRD) or no consolidation after induction and intensification therapy, followed by continuous lenalidomide maintenance. Primary study end point was progression-free survival (PFS)., Results: Eight hundred seventy-eight eligible patients were randomly assigned to receive VRD consolidation (451 patients) or no consolidation (427 patients). At a median follow-up of 74.8 months, median PFS with adjustment for pretreatment was prolonged in patients randomly assigned to VRD consolidation (59.3 v 42.9 months, hazard ratio [HR] = 0.81; 95% CI, 0.68 to 0.96; P = .016). The PFS benefit was observed across most predefined subgroups, including revised International Staging System (ISS) stage, cytogenetics, and prior treatment. Revised ISS3 stage (HR, 2.00; 95% CI, 1.41 to 2.86) and ampl1q (HR, 1.67; 95% CI, 1.37 to 2.04) were significant adverse prognostic factors. The median duration of maintenance was 33 months (interquartile range 13-86 months). Response ≥ complete response (CR) after consolidation versus no consolidation before start of maintenance was 34% versus 18%, respectively ( P < .001). Response ≥ CR on protocol including maintenance was 59% with consolidation and 46% without ( P < .001). Minimal residual disease analysis by flow cytometry in a subgroup of 226 patients with CR or stringent complete response or very good partial response before start of maintenance demonstrated a 74% minimal residual disease-negativity rate in VRD-treated patients. Toxicity from VRD was acceptable and manageable., Conclusion: Consolidation treatment with VRD followed by lenalidomide maintenance improves PFS and depth of response in newly diagnosed patients with multiple myeloma as compared to maintenance alone., Competing Interests: Pieter SonneveldConsulting or Advisory Role: Celgene, Janssen, Amgen, Karyopharm Therapeutics, CARsgen TherapeuticsResearch Funding: Janssen, Amgen, Skyline Diagnostics Meletios A. DimopoulosHonoraria: Amgen, Takeda, Janssen-Cilag, Bristol Myers Squibb, BeigeneConsulting or Advisory Role: Amgen, Janssen-Cilag, Takeda, Bristol Myers Squibb, Beigene Meral BeksacConsulting or Advisory Role: Amgen, Janssen, Sanofi, Oncopeptides, TakedaTravel, Accommodations, Expenses: Amgen, Janssen, Takeda, Sanofi Meral BeksacConsulting or Advisory Role: Celgene, Janssen-Cilag, Amgen, Takeda, Sanofi Pasteur, OncopeptidesSpeakers' Bureau: Amgen, Celgene, Janssen-Cilag, Sanofi Pasteur Heinz LudwigConsulting or Advisory Role: Amgen, Janssen-Cilag, Sanofi, Seattle GeneticsSpeakers' Bureau: Celgene, Bristol Myers Squibb, Janssen-Cilag, Amgen, TakedaResearch Funding: Takeda, Amgen Sonja ZweegmanConsulting or Advisory Role: Janssen-Cilag, Takeda, Celgene, Sanofi, OncopeptidesResearch Funding: Janssen-Cilag, Takeda, CelgeneTravel, Accommodations, Expenses: Janssen-Cilag, Takeda, Celgene Elena ZamagniHonoraria: Janssen-Cilag, Celgene, Amgen, Bristol Myers Squibb, Takeda, GlaxoSmithKline, Oncopeptides, SanofiConsulting or Advisory Role: Celgene, Janssen-Cilag, Amgen, SanofiTravel, Accommodations, Expenses: Janssen-Cilag, Celgene, Amgen Ruth WesterHonoraria: Sanofi Roman HajekConsulting or Advisory Role: Takeda, Amgen, Celgene, AbbVie, BMS, PharmaMar, Janssen-Cilag, NovartisSpeakers' Bureau: Takeda, AmgenResearch Funding: Novartis, BMS, Amgen, Celgene, Takeda Lucia PantaniHonoraria: Celgene, Janssen, Takeda, Amgen Francesca GayHonoraria: Amgen, Bristol Myers Squibb, Celgene, Takeda, AbbVie, Janssen, GlaxoSmithKlineConsulting or Advisory Role: AbbVie, Adaptive Biotechnologies, Amgen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Oncopeptides, Roche, Takeda, Janssen, Bluebird bio Stefania OlivaHonoraria: Amgen, Celgene/Bristol Myers Squibb, JanssenConsulting or Advisory Role: Adaptive Biotechnologies, Janssen, Amgen, Takeda Vincent van de VeldenResearch Funding: BD Biosciences, Pfizer, Janssen, Novartis/Navigate, Agilent/DAKOPatents, Royalties, Other Intellectual Property: Patent EuroFlow MRD antibody tubes. No financial relationship KaLung WuConsulting or Advisory Role: Janssen Oncology Gerard BosEmployment: CiMaasLeadership: CiMaasStock and Other Ownership Interests: CIMaasHonoraria: CiMaas Mark-David LevinHonoraria: AbbVie, Celgene, Janssen, TakedaTravel, Accommodations, Expenses: Takeda, Janssen Annemiek BroijlHonoraria: Amgen, Sanofi, Celgene, Bristol Myers Squibb/Celgene, JanssenTravel, Accommodations, Expenses: Bristol Myers Squibb/Celgene Monique MinnemaConsulting or Advisory Role: Janssen-Cilag, Alnylam, Gilead SciencesSpeakers' Bureau: Celgene/Bristol Myers SquibbTravel, Accommodations, Expenses: Celgene Anders WaageHonoraria: Janssen OncologySpeakers' Bureau: Janssen Oncology Cecilie BlimarkHonoraria: Bristol Myers Squibb/Celgene, Janssen, Takeda, AmgenConsulting or Advisory Role: Adaptive Biotechnologies, Janssen, GlaxoSmithKline Niels W. C. J. van de DonkConsulting or Advisory Role: Janssen, Celgene, Bristol Myers Squibb, Novartis, Amgen, Servier, Takeda, BayerSpeakers' Bureau: Janssen Research & Development, Celgene, Amgen, Bristol Myers SquibbResearch Funding: Janssen, Celgene, Amgen, Novartis, Bristol Myers Squibb, Cellectis Massimo OffidaniHonoraria: BMS, Janssen, CelgeneConsulting or Advisory Role: Janssen Giuseppe A. PalumboConsulting or Advisory Role: Novartis, Janssen Oncology, AOP Orphan Pharmaceuticals, AbbVie, AstraZeneca, Celgene/Bristol Myers SquibbSpeakers' Bureau: Novartis, Celgene/Bristol Myers Squibb, AbbVieTravel, Accommodations, Expenses: Takeda, Novartis Andrew SpencerHonoraria: Janssen-Cilag, BMSConsulting or Advisory Role: Janssen-Cilag, BMSSpeakers' Bureau: Janssen-CilagResearch Funding: Janssen-Cilag Mario BoccadoroHonoraria: Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol Myers Squibb, AbbVieConsulting or Advisory Role: Janssen, GlaxoSmithKlineResearch Funding: Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol Myers Squibb, Mundipharma Michele CavoHonoraria: Janssen, Bristol Myers Squibb, Celgene, Sanofi, GlaxoSmithKline, Takeda, Amgen, Oncopeptides, AbbVie, Karyopharm Therapeutics, Adaptive BiotechnologiesConsulting or Advisory Role: Janssen, Bristol Myers Squibb, Celgene, Sanofi, GlaxoSmithKline, Takeda, Amgen, Oncopeptides, AbbVie, Karyopharm Therapeutics, Adaptive BiotechnologiesSpeakers' Bureau: Janssen, CelgeneNo other potential conflicts of interest were reported.

Reduced genioglossus muscle tone is considered one of the major causes for obstructive sleep apnea (OSA). Hypoglossal nerve stimulation (HNS) keeps the upper airway patent by increasing the muscle tone of the genioglossus muscle being the major airway opener. According to the German S3-Guideline on Sleep Disordered Breathing this treatment is indicated in patients with OSA failing or rejecting positive airway pressure, showing an AHI between 15 and 65, in particular when anatomy is normal and the BMI below 35. In 2021 it has been made available for regular patient care in Germany. However, breathing synchronized, continuous, and bilateral HNS differ in parts relevantly regarding their patient selection criteria, technical features, surgical technique, therapy setting and programming, and daily use for the patient. There are many publications showing the safety, efficacy, and patient satisfaction of breathing synchronized HNS. Less but promising data are available for continuous and the most recent bilateral HNS., Competing Interests: Erklärung zu finanziellen Interessen Forschungsförderung erhalten: ja, von einer anderen Institution (Pharma- oder Medizintechnikfirma usw.); Honorar/geldwerten Vorteil für Referententätigkeit erhalten: ja, von einer anderen Institution (Pharma- oder Medizintechnikfirma usw.); Bezahlter Berater/interner Schulungsreferent/Gehaltsempfänger: ja, von einer anderen Institution (Pharma- oder Medizintechnikfirma usw.); Patent/Geschäftsanteile/Aktien (Autor/Partner, Ehepartner, Kinder) an im Bereich der Medizin aktiven Firma: nein; Patent/Geschäftsanteile/Aktien (Autor/Partner, Ehepartner, Kinder) an zu Sponsoren dieser Fortbildung bzw. durch die Fortbildung in ihren Geschäftsinteressen berührten Firma: nein Erklärung zu nichtfinanziellen Interessen > Finanzielle Interessen Revent Medical: Honorar für Tätigkeit als Operationstutor und Referent, Reisekostenerstattung, klinische Studien, Drittmittelkonten Inspire Medical: Honorar für Vortragstätigkeit, Reisekostenerstattung, klinische Studien, Drittmittelkonten ImThera/LivaNova: Honorar für Vortragstätigkeit, Reisekostenerstattung, klinische Studien, Drittmittelkonten Nyxoah: klinische Studien, Drittmittelkonten, Honorar für Vortragstätigkeit, Reisekostenerstattung, Beratertätigkeit MedEl: Forschungsvorhaben, Reisekostenerstattungen, klinische Studien, Drittmittelkonten Neuwirth Medical Products: Honorar für Vortragstätigkeit, Reisekostenerstattung XM Consult: Honorar für Vortragstätigkeit, Reisekostenerstattung Gramann Veranstaltungsorganisation: Honorar für Vortragstätigkeit, Reisekostenerstattung Pura Vida: Beratungstätigkeit RG Gesellschaft für Information und Organisation: Honorar für Vortragstätigkeit, Reisekostenerstattung Akadamie für Schlafmedizin: Honorar für Vortragstätigkeit, Reisekostenerstattung Deutsche Gesellschaft für Schlafforschung und Schlafmedizin: Reisekostenerstattungen, Erlass der Teilnahmegebühren für Referenten Ärztekammer Westfalen-Lippe: Honorar für Vortragstätigkeit/Kursmaterialien Dresden International University: Honorar für Lehrauftrag, Reisekostenerstattung Forum Otorhinolaryngologicum: Honorar für Vortragstätigkeit, Reisekostenerstattung Fortbildungsgemeinschaft des Berufsverbands der HNO-Ärzte: Honorar für Vortragstätigkeit, Reisekostenerstattung Continentale Versicherung: Honorar für Vortragstätigkeit, Reisekostenerstattung Nicht-finanzielle Interessen Verband der Somnologen Baden-Württemberg (Vorsitzender), Arbeitsgemeinschaft Schlafmedizin der DGHNO (Stellvertretender Vorsitzender), European Academy of Sleep Medicine (Stellvertretender Vorsitzender) Mitglied in: Deutsche Gesellschaft für Schlafforschung und Schlafmedizin (DGSM), Deutsche Gesellschaft für Hals-Nasen-Ohren-Heilkunde, Kopf- und Halschirurgie (DGHNO-KHC), Deutscher Berufsverband der Hals-Nasen-Ohren-Ärzte, Französische HNO-Gesellschaft (SFORL), Deutsche Gesellschaft für Endoskopie und Bildgebende Verfahren (DGEBV), Arbeitsgemeinschaft „Chirurgische Therapieformen in der Schlafmedizin“ der DGSM, (Thieme. All rights reserved.)

Background: Three different phenotypes of septic shock based on changes in blood pressure and lactate are recognized in people. Dysoxic shock, representing the combination of fluid-refractory hypotension and hyperlactatemia, is characterized by greater disease severity and mortality compared to cryptic shock (hyperlactatemia alone) and vasoplegic shock (hypotension with normal blood lactate). Little is known about septic shock and specifically its phenotypes in cats. Objective: To analyze the characteristics and prognostic implications of three septic shock phenotypes in cats with sepsis. Methods: Cats with septic shock were prospectively included. Septic shock was defined by the presence of hypotension (mean blood pressure <60 mmHg) requiring vasopressor support and/or persistent hyperlactatemia (>4 mmol/L) and classified in three subgroups: dysoxic shock, vasoplegic shock and cryptic shock . Clinical and clinicopathological variables including APPLE fast and APPLE full scores, occurrence of multi-organ dysfunction syndrome (MODS; presence of at least two dysfunctional organs simultaneously) and outcome were compared among subgroups. Cats with sepsis showing normal blood pressure and lactate concentrations hospitalized during the study period were included as uncomplicated sepsis , and compared to cats with septic shock for selected variables. Length of hospital stay and mortality were evaluated in the whole study population. Odds ratios for mortality were calculated using logistic regression analysis. Significance was set at P < 0.05. Results: The study enrolled 48 cats with uncomplicated sepsis and 37 cats with septic shock (dysoxic shock n = 17; vasoplegic shock n = 11; cryptic shock n = 7). Cats with dysoxic shock had significantly higher APPLE fast and APPLE full scores compared to vasoplegic and cryptic shock. Mortality rates were not significantly different among cryptic (57%), dysoxic (65%) and vasoplegic shock (91%), while MODS occurrence was significantly lower in cats with cryptic shock (57%) compared to patients affected by dysoxic (94%) and vasoplegic (100%) shock. Cats with septic shock had higher frequency of MODS and greater mortality rate than cats with uncomplicated sepsis. Conclusion: Despite similar in-hospital mortality, cats with dysoxic and vasoplegic shock are characterized by having higher occurrence of multi- organ dysfunction compared to cats affected by cryptic shock. Results from this study suggest novel means of identifying high-risk subgroups of septic cats., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Troia, Buzzurra, Ciuffoli, Mascalzoni, Foglia, Magagnoli, Dondi and Giunti.)

Minimal residual disease (MRD) by multiparameter flow cytometry (MFC) is the most effective tool to define a deep response in multiple myeloma (MM). We conducted an MRD correlative study of the EMN02/HO95 MM phase III trial in newly diagnosed MM patients achieving a suspected complete response before maintenance and every 6 months during maintenance. Patients received high-dose melphalan (HDM) versus bortezomib-melphalan-prednisone (VMP) intensification, followed by bortezomib-lenalidomide-dexamethasone (VRd) versus no consolidation, and lenalidomide maintenance. Bone marrow (BM) samples were processed in three European laboratories, applying EuroFlow-based MFC protocols (eight colors, two tubes) with 10 -4 -10 -5 sensitivity. At enrollment in the MRD correlative study, 76% (244/321) of patients were MRD-negative. In the intention-to-treat analysis, after a median follow-up of 75 months, 5-year progression-free survival was 66% in MRD-negative versus 31% in MRD-positive patients (HR 0.39; p < 0.001), 5-year overall survival was 86% versus 69%, respectively (HR 0.41; p < 0.001). MRD negativity was associated with reduced risk of progression or death in all subgroups, including ISS-III (HR 0.37) and high-risk fluorescence in situ hybridization (FISH) patients (HR 0.38;). In the 1-year maintenance MRD population, 42% of MRD-positive patients at pre-maintenance became MRD-negative after lenalidomide exposure. In conclusion, MRD by MFC is a strong prognostic factor. Lenalidomide maintenance further improved MRD-negativity rate.

We analyzed variations in terms of chromosomal abnormalities (CA) by fluorescence in situ hybridization (FISH) analysis on purified bone marrow plasma cells throughout the progression from monoclonal gammopathy of undetermined significance/smoldering multiple myeloma (MGUS/SMM) to newly diagnosed MM/plasma cell leukemia (NDMM/PCL) at diagnosis and from diagnostic samples to progressive disease. High risk was defined by the presence of at least del(17p), t(4;14), and/or t(14;16). 1p/1q detection (in the standard FISH panel from 2012 onward) was not available for all patients. We analyzed 139 MM/PCL diagnostic samples from 144 patients, with a median follow-up of 71 months: high-risk CA at diagnosis (MGUS/SMM or NDMM) was present in 28% of samples, whereas 37-39% showed high-risk CA at relapse. In 115 patients with NDMM who evolved to relapsed/refractory MM, we identified 3 different populations: (1) 31/115 patients (27%) with gain of new CA (del13, del17p, t(4;14), t(14;16) or 1q CA when available); (2) 10/115 (9%) patients with loss of a previously identified CA; and (3) 74 patients with no changes. The CA gain group showed a median overall survival of 66 months vs. 84 months in the third group (HR 0.56, 95% CI 0.34-0.92, p = 0.023). Clonal evolution occurs as disease progresses after different chemotherapy lines. Patients who acquired high-risk CA had the poorest prognosis. Our findings highlight the importance of performing FISH analysis both at diagnosis and at relapse.

Background: Pyothorax in cats is routinely managed, at least initially, with thoracic tube placement associated with systemic antimicrobial administration. Traditionally, large-bore trocar-type thoracostomy tubes have preferentially been used for the drainage of thick material from the pleural space. In recent years, the use of small-bore wire-guided thoracic drains has increased in both small animals and in humans. Few studies have highlighted the efficacy of small-bore wire-guided thoracostomy tubes., Aim: The purpose of this study was to describe the use of small-bore wire-guided thoracostomy tubes in feline pyothorax in terms of efficacy, safety, and outcome., Methods: Cats with pyothorax managed with small-bore thoracostomy tubes (SBTTs) (2015-2018) were retrospectively studied. The number of drains inserted, the need for anesthesia and analgesia for chest tube placement and maintenance, and related major and minor complications were reviewed. Clinical data, diagnostic results, treatment, and outcome were recorded., Results: Ten cats were enrolled. Thoracostomy tube placement was unilateral in 7/10 cats, despite the presence of bilateral effusion in 9/10 cats, and required sedation (8/10) or anesthesia (2/10). Three cats experienced minor complications during the chest tube insertion, including self-limiting pneumothorax (1/3) and malpositioning (2/3). One cat had a major complication (non-functional malposition) requiring reposition of the drain. Pain management was adequately achieved using opioids (8/10) or opioids plus nonsteroidal anti-inflammatory drugs (2/10). Partial chest tube occlusion occurred in three cases and it was resolved with lavage. In one case, the occlusion was complete, requiring drain removal. Three out of 10 cats were treated medically, combining thoracostomy tubes and antibiotics, while 7/10 cats underwent surgery. All the cats survived., Conclusion: SBTTs represent a safe and effective option for the initial management of feline pyothorax. In fact, mainly minor complications were reported during insertion and usage. The SBTTs were well tolerated by the cats with a satisfactory performance in terms of exudate drainage in most cases. The combined use of a small-bore thoracostomy drain together with the common practice of surgical treatment might have resulted in the successful management of the cases presented., Competing Interests: The authors declare that there is no conflict of interest. The authors received no financial support for the research, authorship, and/or publication of this article.

Large amount of nitric oxide (NO) can be released in patients with sepsis. Methemoglobin is formed from the interaction between NO and hemoglobin. Mild methemoglobinemia reflecting NO overproduction has been reported in septic people, and occasionally associated to septic shock and organ dysfunction. The aim of this retrospective study was to evaluate circulating methemoglobin fraction in dogs with sepsis and to assess its prognostic value. Methemoglobin reference interval (RI) was calculated in 41 healthy dogs and was set at 0-2.2%. A total of 131 dogs with sepsis were included in the study; 24/131 had a circulating methemoglobin ≥2.2%. The median methemoglobin fraction was significantly higher in dogs with sepsis compared to healthy ones (1.7%, 0.4-3.5% vs. 1.0, 0.3-2.2%, P = 0.0005). No significant difference was observed between dogs with uncomplicated sepsis ( n = 98) vs. dogs with septic shock ( n = 33) (1.8%, 0.4-2.8% vs. 1.5%, 0.4-3.5%, P = 0.74), between dogs with and without multi-organ dysfunction ( n = 38 and n = 93, respectively) (1.7%, 0.4-3.5% vs. 1.7%, 0.5-2.8%, P = 0.27), and between survivors ( n = 77) vs. non survivors ( n = 54) (1.5%, 0.4-2.8% vs. 1.8%, 0.4-3.5%, P = 0.05). Dogs with methemoglobin fraction above or equal to the upper limit of the RI had a significantly higher frequency of death compared to dogs with methemoglobin levels <2.2% (60.0% vs. 36.8%, P = 0.04). In conclusion, mild methemoglobinemia is detected in dogs with sepsis, and methemoglobin values above the RI might be associated with a worse outcome., (Copyright © 2020 Troia, Ciuffoli, Vasylyeva, Foglia, Dondi and Giunti.)

Background: The emergence of highly active novel agents has led some to question the role of autologous haematopoietic stem-cell transplantation (HSCT) and subsequent consolidation therapy in newly diagnosed multiple myeloma. We therefore compared autologous HSCT with bortezomib-melphalan-prednisone (VMP) as intensification therapy, and bortezomib-lenalidomide-dexamethasone (VRD) consolidation therapy with no consolidation., Methods: In this randomised, open-label, phase 3 study we recruited previously untreated patients with multiple myeloma at 172 academic and community practice centres of the European Myeloma Network. Eligible patients were aged 18-65 years, had symptomatic multiple myeloma stage 1-3 according to the International Staging System (ISS), measurable disease (serum M protein >10 g/L or urine M protein >200 mg in 24 h or abnormal free light chain [FLC] ratio with involved FLC >100 mg/L, or proven plasmacytoma by biopsy), and WHO performance status grade 0-2 (grade 3 was allowed if secondary to myeloma). Patients were first randomly assigned (1:1) to receive either four 42-day cycles of bortezomib (1·3 mg/m 2 administered intravenously or subcutaneously on days 1, 4, 8, 11, 22, 25, 29, and 32) combined with melphalan (9 mg/m 2 administered orally on days 1-4) and prednisone (60 mg/m 2 administered orally on days 1-4) or autologous HSCT after high-dose melphalan (200 mg/m 2 ), stratified by site and ISS disease stage. In centres with a double HSCT policy, the first randomisation (1:1:1) was to VMP or single or double HSCT. Afterwards, a second randomisation assigned patients to receive two 28-day cycles of consolidation therapy with bortezomib (1·3 mg/m 2 either intravenously or subcutaneously on days 1, 4, 8, and 11), lenalidomide (25 mg orally on days 1-21), and dexamethasone (20 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12) or no consolidation; both groups received lenalidomide maintenance therapy (10 mg orally on days 1-21 of a 28-day cycle). The primary outcomes were progression-free survival from the first and second randomisations, analysed in the intention-to-treat population, which included all patients who underwent each randomisation. All patients who received at least one dose of study drugs were included in the safety analyses. This study is registered with the EU Clinical Trials Register (EudraCT 2009-017903-28) and ClinicalTrials.gov (NCT01208766), and has completed recruitment., Findings: Between Feb 25, 2011, and April 3, 2014, 1503 patients were enrolled. 1197 patients were eligible for the first randomisation, of whom 702 were assigned to autologous HSCT and 495 to VMP; 877 patients who were eligible for the first randomisation underwent the second randomisation to VRD consolidation (n=449) or no consolidation (n=428). The data cutoff date for the current analysis was Nov 26, 2018. At a median follow-up of 60·3 months (IQR 52·2-67·6), median progression-free survival was significantly improved with autologous HSCT compared with VMP (56·7 months [95% CI 49·3-64·5] vs 41·9 months [37·5-46·9]; hazard ratio [HR] 0·73, 0·62-0·85; p=0·0001). For the second randomisation, the number of events of progression or death at data cutoff was lower than that preplanned for the final analysis; therefore, the results from the second protocol-specified interim analysis, when 66% of events were reached, are reported (data cutoff Jan 18, 2018). At a median follow-up of 42·1 months (IQR 32·3-49·2), consolidation therapy with VRD significantly improved median progression-free survival compared with no consolidation (58·9 months [54·0-not estimable] vs 45·5 months [39·5-58·4]; HR 0·77, 0·63-0·95; p=0·014). The most common grade ≥3 adverse events in the autologous HSCT group compared to the VMP group included neutropenia (513 [79%] of 652 patients vs 137 [29%] of 472 patients), thrombocytopenia (541 [83%] vs 74 [16%]), gastrointestinal disorders (80 [12%] vs 25 [5%]), and infections (192 [30%] vs 18 [4%]). 239 (34%) of 702 patients in the autologous HSCT group and 135 (27%) of 495 in the VMP group had at least one serious adverse event. Infection was the most common serious adverse event in each of the treatment groups (206 [56%] of 368 and 70 [37%] of 189). 38 (12%) of 311 deaths from first randomisation were likely to be treatment related: 26 (68%) in the autologous HSCT group and 12 (32%) in the VMP group, most frequently due to infections (eight [21%]), cardiac events (six [16%]), and second primary malignancies (20 [53%])., Interpretation: This study supports the use of autologous HSCT as intensification therapy and the use of consolidation therapy in patients with newly diagnosed multiple myeloma, even in the era of novel agents. The role of high-dose chemotherapy needs to be reassessed in future studies, in particular in patients with undetectable minimal residual disease after four-drug induction regimens including a monoclonal antiboby combined with an immunomodulatory agent and a proteasome inhibitor plus dexamethasone., Funding: Janssen and Celgene., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Sepsis is a life-threatening condition associated with an exacerbated production of both pro- and anti-inflammatory cytokines that can promote a hyperactive response to infection or induce immunoparalysis. Data regarding the immune response to sepsis in cats are scarce. Establishing the profiles of cytokines and chemokines in feline sepsis to characterize the nature of the immune responses to sepsis might enable individualized treatments to be developed and targeted. Objective: To evaluate the cytokine and chemokine network in cats with sepsis and septic shock, and to investigate the associations of these analytes with disease severity and outcome. Methods: Blood samples prospectively collected at presentation of cats with sepsis and septic shock to two veterinary teaching hospitals were analyzed. Forty healthy cats were included as controls. A 19-plex feline cytokine/chemokine magnetic bead assay system was used to measure analytes in citrated plasma samples. Cytokine concentrations were compared between groups using the Kruskal-Wallis test with Dunn's post-hoc correction for multiple comparisons. Cytokine concentrations were compared between survivors and non-survivors with the Mann-Whitney U test. Odds ratios were calculated using logistic regression. A multivariable logistic regression model for prediction of septic shock was constructed. Results: The study enrolled 35 septic cats. Many cytokines were undetectable in both sick and healthy control cats and were excluded from subsequent analyses. Comparisons of cytokine concentrations among healthy controls, cats with sepsis ( n = 12) and cats with septic shock ( n = 23) revealed that sick cats (sepsis or septic shock) had significantly higher plasma concentrations of IL-6, IL-8, KC-like, and RANTES compared to healthy controls. The combination of MCP-1, Flt-3L, and IL-12 was predictive of septic shock. None of the cytokines analyzed was predictive of outcome in this study population. Conclusion: Plasma concentrations of IL-6, IL-8, KC-like, and RANTES are increased in cats with sepsis and may play important roles in pathogenesis. Multivariable modeling suggested that analysis of cytokines might aid differentiation of septic shock from sepsis. None of the cytokines analyzed was predictive of outcome. Measurement of these cytokines might enable future studies to better diagnose and characterize feline sepsis and septic shock., (Copyright © 2020 Troia, Mascalzoni, Agnoli, Lalonde-Paul, Giunti and Goggs.)

Polytrauma is a common emergency condition in small animals and is frequently associated with higher morbidity and mortality rates compared to minor trauma. Multiple Organ Dysfunction Syndrome (MODS) is a major complication of extensive traumatic injury, carrying a high risk of death despite intensive care treatment. Little is known about the prevalence and the prognostic impact of MODS in feline polytrauma. The current study aimed to prospectively evaluate the occurrence and the prognostic significance of organ dysfunction at admission in a population of polytraumatized cats. Cats with polytrauma requiring intensive care unit hospitalization were included and categorized according to outcome (survivors/non-survivors). Clinical and clinicopathological data, including scores of disease severity [Animal Trauma Triage Score (ATTS), APPLE fast , and APPLE full ], selected organ dysfunction and presence of MODS were evaluated upon admission, and analyzed with respect to mortality. Non-parametric statistics was performed and P < 0.05 was considered significant. Thirty-eight cats met the inclusion criteria: 8/38 (21%) had penetrating trauma, while 30/38 (79%) had blunt trauma. The overall in-hospital mortality was 37% (14/38). Cats with evidence of MODS upon admission had significantly higher frequency of death compared to cats without MODS (9/14 vs. 2/24 P = 0.0004). Hemostatic dysfunction, respiratory dysfunction, and MODS upon admission were significantly associated with mortality in the univariate logistic regression analysis ( P = 0.005, P = 0.001, P = 0.001, respectively). The values of APPLE fast , APPLE full , and ATTS were independently associated with a higher risk of death and positively correlated with the number of dysfunctional organs ( P = 0.025, P = 0.004, P = 0.003, r = 0.57, P = 0.0002; r = 0.59, P = 0.0001; r = 0.55, P = 0.0003, respectively). Multiple Organ Dysfunction Syndrome is a common complication of feline polytrauma and its development is associated with increased disease severity and worse outcomes. The presence of hemostatic dysfunction and respiratory dysfunction upon admission is associated with a higher risk of death. The ATTS and the APPLE scores are useful prognostic tools for the assessment of cats with polytrauma.

Background: Minimal residual disease (MRD) is one of the most relevant prognostic factors in patients with multiple myeloma (MM); however, the impact of maintenance therapy on MRD levels remains unclear. Among patients with newly diagnosed MM (NDMM) who received lenalidomide maintenance until they developed disease progression, the role of MRD status as a predictor of progression-free survival (PFS) was evaluated by multiparameter flow cytometry (MFC) and allelic-specific oligonucleotide real-time quantitative polymerase chain reaction (ASO-RQ-PCR) analysis., Methods: Seventy-three patients with NDMM enrolled in the RV-MM-EMN-441 (clinical trials.gov identifier, NCT01091831) and RV-MM-COOP-0556 (clinicaltrials.gov identifier, NCT01208766; European Myeloma Network EMN02/HO95 MM Trial) phase 3 trials who achieved at least a very good partial response after intensification/consolidation were included. The median patient age was 57 years (interquartile range, 53-61 years), and all patients received lenalidomide maintenance until they developed progression. MRD was evaluated on bone marrow after intensification/consolidation, after 6 courses of maintenance, and every 6 months thereafter until clinical relapse using both ASO-RQ-PCR (sensitivity, 10 -5 ) and MFC (sensitivity, from 10 -4 to 10 -5 )., Results: After intensification/consolidation, 33 of 72 patients (46%) achieved a molecular complete response (m-CR), and 44 of 70 (63%) achieved a flow complete response (flow-CR). Almost 27% of patients who were MRD-positive after consolidation became MRD-negative during maintenance. After a median follow-up of 38 months, PFS was prolonged in patients who achieved negative MRD status during maintenance according to results from both ASO-RQ-PCR analysis (hazard ratio, 0.29; 95% confidence interval, 0.14-0.62; P = .0013) and MFC (hazard ratio, 0.19; 95% confidence interval, 0.09-0.41; P < .001). The impact of negative MRD status on PFS was similar in all subgroups (ASCT and no-ASCT; International Staging System stages I, II, and III; high-risk and standard-risk cytogenetics), and the two techniques were highly correlated., Conclusions: MRD status is a stronger predictor of PFS than standard risk factors, and lenalidomide maintenance further increases the rate of negative MRD results., (© 2018 American Cancer Society.)

In the biology of multiple myeloma (MM), immune dysregulation has emerged as a critical component for novel therapeutic strategies. This dysfunction is due to a reduced antigen presentation, a reduced effector cell ability and a loss of reactive T cells against myeloma, together with a bone marrow microenvironment that favors immune escape. The Programmed Death-1 (PD-1) pathway is associated with the regulation of T cell activation and with the apoptotic pathways of effector memory T cells. Specifically, the binding with PD-1 ligand (PD-L1) on the surface of tumor plasma cells down-regulates T cell-proliferation, thus contributing to the immune escape of tumor cells. In relapsed and/or refractory MM (RRMM) patients, PD-1/PD-L1 blockade was analyzed by using nivolumab, pembrolizumab, and durvalumab. Outcomes with single agents were unsatisfactory, whereas combination strategies with backbone immunomodulatory drugs (IMiDs) suggested a synergistic action in such a complex immunological landscape, even in patients previously refractory to these drugs. Nevertheless, these combinations were also associated with an increased incidence of adverse events. This review aims to analyze the available preclinical and clinical data on the role of PD-1/PD-L1 inhibitors in MM therapy, focusing on available preliminary efficacy and safety data and offering insights for future investigation.

We report on the unusual presentation of a schwannoma. Aside from the aberrant dorsolateral anatomical presentation, ultrasonography revealed not only peripheral vascularity but also internal vascularity. Internal vascularity often suggests a malignant process as opposed to a benign one; however, in the presented case, the diagnosis of a benign lesion was confirmed with S100 immunohistochemical staining. In this study, we review the literature on this pathology and present an uncommon presentation of a benign nerve tumor., (Copyright ©2018 by the American Podiatric Medical Association.)

Sepsis, the life-threatening organ dysfunction caused by a dysregulated host response to infection, is difficult to identify and to prognosticate for. In people with sepsis, procalcitonin (PCT) measurement aids diagnosis, enables therapeutic monitoring and improves prognostic accuracy. This study used a commercial canine PCT assay to measure plasma PCT concentrations in dogs with gastric dilatation volvulus (GDV) syndrome and in dogs with sepsis. It was hypothesised that dogs with GDV syndrome and with sepsis have greater plasma PCT concentrations than healthy dogs and that dogs with sepsis have greater PCT concentrations than dogs with GDV syndrome. Before analysing canine plasma samples, the ability of the assay to identify canine PCT, in addition to assay imprecision and the lower limit of detection were established. The assay had low imprecision with coefficients of variation ≤4.5 per cent. The lower limit of detection was 3.4 pg/ml. Plasma PCT concentrations were measured in 20 dogs with sepsis, in 32 dogs with GDV syndrome and in 52 healthy dogs. Median (IQR) PCT concentration in dogs with sepsis 78.7 pg/ml (39.1-164.7) was significantly greater than in healthy dogs 49.8 pg/ml (36.2-63.7) (P=0.019), but there were no significant differences between PCT concentrations in dogs with GDV syndrome and controls (P=0.072) or between dogs with sepsis and GDV syndrome (P=1.000). Dogs with sepsis have significantly increased plasma PCT concentrations compared with healthy dogs, although considerable overlap between these populations was identified. Future investigations should confirm this finding in other populations and evaluate the diagnostic and prognostic value of PCT in dogs with sepsis., Competing Interests: Competing interests: None declared.

Canine gastric dilatation-volvulus (GDV) is a life-threatening disease characterized by extensive tissue ischemia, tissue hypoperfusion, and systemic inflammation. Biomarkers that better reflect the severity of gastric necrosis and systemic inflammation would aid clinicians in the management of these patients. This study aimed to investigate the prognostic significance of cell-free DNA (cfDNA), high-mobility group box-1 (HMGB1), and procalcitonin (PCT) in dogs with GDV. Concentrations of cfDNA, HMGB1, and PCT were measured in citrated plasma samples collected from 29 dogs with GDV at hospital admission. Additional data collected included baseline lactate concentrations, APPLE fast score, evidence of gastric necrosis, occurrence of postoperative complications, and outcome. Twenty-four healthy dogs were sampled as controls. Continuous variables between groups were compared with the Mann-Whitney U and correlations between continuous variables were assessed by calculation of Spearman's correlation coefficient. Alpha was set at 0.05. Dogs with GDV had significantly greater concentrations of cfDNA, HMGB1, and PCT compared to controls ( P  = 0.0009, P  = 0.004, and P  = 0.009, respectively). PCT concentrations were significantly higher in non-survivors compared to survivors ( P  = 0.008). Dogs with gastric necrosis had significantly greater lactate concentrations compared to dogs without gastric necrosis ( P  = 0.0005). The APPLE fast score was not prognostic. Lactate and PCT concentrations were moderately, positively correlated ( r s 0.51, P  = 0.0005). Concentrations of the inflammatory biomarkers cfDNA, HMGB1, and PCT are increased in canine GDV. Only lactate and PCT concentrations were prognostic in this population of GDV dogs and were predictive of the presence of gastric necrosis and of non-survival to hospital discharge, respectively.

Background: Procalcitonin (PCT) is a valuable prognostic biomarker in human sepsis that is predictive of organ dysfunction, septic shock and mortality. Data on PCT in dogs is limited. This study aimed to investigate the prognostic value of baseline and serial PCT measurements in dogs with sepsis and to determine the association between PCT and sepsis severity and the presence of organ dysfunction. PCT concentrations were measured in citrated plasma samples collected from 53 dogs with sepsis at the time of admission (T0, n = 53) and at 24 h (T1, n = 35) and 48 h (T2, n = 30) post-admission using a commercial ELISA. Dogs were classified by sepsis severity (sepsis without organ dysfunction; severe sepsis; septic shock) and outcome (survivors; non-survivors). Organ dysfunctions were recorded at T0 and during hospitalization, and the APPLE fast score calculated at T0. Healthy dogs (n = 12) were used as controls., Results: There were 18 septic dogs without organ dysfunction, 24 dogs with severe sepsis and 11 with septic shock. Baseline PCT concentrations were significantly greater in dogs with sepsis compared to healthy controls (P < 0.0001), and in dogs with septic shock compared to dogs without cardiovascular compromise (P = 0.01). Baseline PCT was significantly correlated with organ dysfunction (P = 0.003). Declining PCT concentrations were documented in survivors at T1 and T2 compared to PCT at T0 (P = 0.0006), and PCT clearance at 24 h was significantly higher in survivors (n = 38) compared to non-survivors (n = 15) (P = 0.037). Canine APPLE fast score was not predictive of sepsis severity, the development of MODS or outcome., Conclusion: In dogs with sepsis, PCT concentrations at hospital admissions are predictive of organ dysfunction and septic shock. Serial procalcitonin monitoring may offer valuable prognostic information in canine sepsis, wherein early decreases in PCT concentrations are associated with survival.

Introduction: multiple myeloma (MM) is a plasma cell disorder that represents the second most frequent hematologic cancer. Although MM is still an incurable disease, prognosis has improved in the last decades thanks to the introduction of novel agents such as proteasome inhibitors (PIs), immunomodulatory drugs, monoclonal antibodies, and histone deacetylase inhibitors. Areas covered: ixazomib is the first oral PI recently approved by Food and Drug Administration (FDA) and European Medicine Agency (EMA) in combination with lenalidomide and dexamethasone as salvage therapy in MM patients. In this paper, we focus on its pharmacokinetics features, as well as its safety and efficacy in clinical studies. Expert opinion: ixazomib can be considered an oral analogue of bortezomib, with 9.5-day half-life, 58% of oral bioavailability, and a large distribution volume of 543L. These features make it a versatile molecule, potentially useful both in combination and as single agent. Oral route of administration and good efficacy/safety profile are its winning characteristics, providing the rationale for a future role also in the maintenance setting.

Critical illness can be associated with transient alterations in circulating thyroid hormone concentrations, indicating the presence of non-thyroidal illness (NTI). NTI is well described in humans, but there are few reports on its occurrence and prognostic significance in dogs. This retrospective study assessed the occurrence of NTI in a population of dogs with systemic inflammatory response syndrome (SIRS) and investigated its association with disease severity (APPLE fast scores). A total of 41 SIRS dogs were included and were divided by SIRS origin (non-septic SIRS, n = 10; septic SIRS, n = 41) and final outcome (survivors, n = 37; non-survivors, n = 4). Healthy, age-matched dogs (n = 15) were included as controls. Serum thyroid hormone levels including total T3, free T3, total T4, and reverse T3 were measured upon admission. Compared to controls, there were significant changes in serum thyroid hormone concentrations in SIRS dogs, suggesting the presence of NTI. Septic SIRS dogs had higher APPLE fast scores and lower serum thyroid hormones concentrations than those in non-septic SIRS and control dogs. In conclusion, NTI was frequent in dogs with SIRS and may be associated with the presence of sepsis or high illness severity.

Introduction: Multiple myeloma (MM) is an incurable disease characterized by clonal plasma cell proliferation and overproduction of monoclonal paraprotein, hypercalcemia, renal failure, anemia, osteolytic bone lesions, and infections. Melphalan, a nitrogen mustard, is an alkylating agent synthesized in 1953, and it has been used in multiple myeloma therapy for fifty years. Although novel agents have been introduced in the past few decades improving prognosis of the disease, melphalan still maintains a crucial role in the treatment of MM acting both as cytotoxic agent through damage to DNA, and as immunostimulatory drug by inhibiting Interleukin-6, as well as interaction with dendritic cells, and immunogenic effects in tumor microenvironment. Areas covered: This review focuses on available data about melphalan pharmacology and its role in clinical practice. Expert opinion: Melphalan remains crucial in therapy of multiple myeloma because of its good manageability, safety profile, efficacy, and economic sustainability. These characteristics make it pivotal also for new regimens in combination with novel agents.

Objective: There is no strong evidence to guide therapeutic approach to multiple myeloma (MM) patients who experience first relapse. The treatment choice can be difficult since currently all patients are exposed to novel agents as thalidomide, bortezomib and lenalidomide., Methods: In this retrospective analysis, we evaluated the best therapeutic sequence, the role of retreatment, and the most beneficial cutoff of first remission in order to choose retreatment, analyzing 476 patients relapsed after first-line therapy., Results: Bortezomib-based regimens upfront followed by lenalidomide-based regimens at first relapse resulted in significantly better second progression-free survival (2ndPFS), PFS2, and overall survival (OS) compared to the opposite sequence. Changing therapy resulted in significantly better 2ndPFS in the whole population, whereas PFS2 was significantly longer only in patients who underwent maintenance therapy. Moreover, until PFS1 was shorter than 27 months, changing therapy at first relapse significantly extended 2ndPFS and PFS2 compared to retreatment, whereas similar outcomes were observed between the two strategies, when PFS1 was longer than 27 months., Conclusion: Lacking randomized trials, our study could help to choose the most appropriate therapy algorithm in patients with MM., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To investigate the prognostic value of the acute patient physiologic and laboratory evaluation (APPLE) score and relevant clinicopathological markers in dogs with systemic inflammatory response syndrome (SIRS)., Design: Prospective observational cohort study., Setting: Veterinary teaching hospital., Animals: Thirty-three dogs with SIRS admitted to the intensive care unit (ICU) were compared to 35 healthy control dogs. Dogs with SIRS were divided into septic (n = 20) and nonseptic (n = 13) etiologies and as survivors (alive to discharge, n = 22) and nonsurvivors (n = 11: died, n = 6, or humanely euthanized, n = 5)., Measurements and Main Results: For all dogs, physiological and laboratory parameters were prospectively collected for the calculation of the APPLE fast score. No difference between septic and nonseptic SIRS dogs was detected for any parameter evaluated. Survivors had significantly higher total protein, albumin concentrations, antithrombin activity (ATA), and base excess (BE), as well as significantly lower lactate, urea, creatinine concentrations, urinary protein to creatinine ratio and APPLE fast score compared to nonsurvivors. Higher values of creatinine, lactate, anion gap, alanine transaminase (ALT), and APPLE fast score were significantly associated with an increased risk of death in SIRS dogs, while higher values of total protein, albumin, ATA, and BE were associated with a significantly reduced risk of mortality. When a multivariate binary logistic regression analysis was performed, the APPLE fast score was the only significant parameter retained., Conclusions: The determination of the APPLE fast score in clinical setting, as well as the measurement of APP, ATA, lactate, BE, anion gap, ALT, urinary proteins, and electrolytes may be beneficial for a better assessment of dogs with SIRS. Identified parameters were significantly related with the presence of SIRS and their evaluation should be considered for the assessment of disease severity, and guidance of the decision-making process in critically ill dogs., (© Veterinary Emergency and Critical Care Society 2014.)

Introduction: The introduction and exploration of novel agents has significantly improved patient outcome in the treatment of multiple myeloma (MM). One such compound, bortezomib, was the first proteasome inhibitor (PI) to be approved as a MM therapeutic. The efficacy and safety data provided by bortezomib usage has provided the basis for the development of a second generation of PIs., Areas Covered: This review focuses on PIs that are currently under evaluation in Phase II clinical trials for the treatment of MM. Furthermore, the article summarizes the currently understood mechanisms of action and the available clinical data for its use in MM., Expert Opinion: Second generation PIs have demonstrated promising activity in patients with advanced-stage myeloma, including those refractory to bortezomib. It should be noted, however, that their efficacy in upfront settings is currently under investigation. Future PI development should include schedule optimization and the investigation of PIs potential synergistic activity with other anti-myeloma agents.

Introduction: Despite the introduction of novel agents, such as thalidomide, lenalidomide and bortezomib, multiple myeloma (MM) remains an incurable disease and new therapies are needed. mAbs are a new promising anticancer treatment option., Areas Covered: This review will focus on mAbs that are currently under evaluation in Phase II and III clinical trials, as single agent and in combination with established treatment options., Expert Opinion: mAbs are a new strategy against MM, and they have demonstrated encouraging results in preclinical models. mAbs have a relatively benign side-effect profile and work synergistically with traditional chemotherapies and with immunomodulatory drugs and proteasome inhibitors.

Introduction: The 26S proteasome has many important roles in the biological functions of the cells, and proteasome inhibitors have multiple and complex activities on cells. These compounds can be natural or synthesized. Most synthetic derivatives have been rationally designed, synthesized and optimized to obtain the best selectivity and increase the activity. The design of chemical entities with desired molecular identification, which plays an important role in biological systems, is provided by pharmacophore modeling. Indeed, pharmacophore models can be established either in a ligand-based manner or in a receptor-based manner., Areas Covered: The authors discuss the application of pharmacophore modeling techniques to proteasome inhibitors development. Furthermore, the article reviews the classification of the currently discovered proteasome inhibitors where the principal mechanism of action and clinical application are represented., Expert Opinion: In the era of new drug development, database of compounds should be thoroughly evaluated with a combination of methods that consider both pharmacophore- and ligand-based virtual screening. The concept of pharmacophore helps to discover new active compounds and to evaluate their activity. The nature of proteasome inhibitor pharmacophore affects the secondary active-site specificity; indeed, increasing specificity decreases the cytotoxicity of the proteasome inhibitors. It is hypothesized that the balanced simultaneous modulation of a few druggable targets may have superior efficacy and fewer side effects than single-target or combination therapies for the treatment of human cancers. The discovery of new compounds should aim to find more active compounds that improve the compliance of patients.

Introduction: Multiple myeloma (MM) patients who relapse, or become refractory to currently available novel agents, have limited treatment options with poor outcomes. The introductions of the newer proteasome inhibitor carfilzomib and the immunomodulatory agent pomalidomide have provided new treatment strategies within the relapse setting. Pomalidomide, a novel 4-amino derived from thalidomide, was recently introduced for the treatment of MM. In addition to being immune-adjuvant with anti-inflammatory properties, pomalidomide has shown several biological activities that directly and indirectly inhibit MM cells., Areas Covered: Herein, the authors review the chemistry, the mechanism of action and the pharmacokinetic properties of pomalidomide. The data reviewed within this article based on the relevant literature pertaining to pomalidomide's Phase I, II and III clinical trials., Expert Opinion: Pomalidomide has shown to be a safe and active agent, both alone and in combination with dexamethasone, in heavily pretreated patients. Furthermore, pomalidomide represents an effective treatment option for relapsed/refractory patients. Results from the ongoing trials evaluating the synergistic activity of pomalidomide combined with conventional chemotherapy or novel agents look promising and may prove to be viable treatment options in the future.