Immune reconstitution and associated infections following axicabtagene ciloleucel in relapsed or refractory large B-cell lymphoma.

CD19 CAR T-cell therapy with axicabtagene ciloleucel (axi-cel) for relapsed or refractory (R/R) large B cell lymphoma (LBCL) may lead to durable remissions, however, prolonged cytopenias and infections may occur. In this single center retrospective study of 85 patients, we characterized immune reconstitution and infections for patients remaining in remission after axi-cel for LBCL. Prolonged cytopenias (those occurring at or after day 30 following infusion) were common with >= grade 3 neutropenia seen in 21/70 (30-0%) patients at day 30 and persisting in 3/31 (9-7%) patients at 1 year. B cells were undetectable in 30/34 (88-2%) patients at day 30, but were detected in 11/19 (57-9%) at 1 year. Median IgG levels reached a nadir at day 180. By contrast, CD4 T cells decreased from baseline and were persistently low with a median CD4 count of 155 cells/µl at 1 year after axi-cel (n=19, range 33 - 269). In total, 23/85 (27-1%) patients received IVIG after axi-cel, and 34/85 (40-0%) received G-CSF. Infections in the first 30 days occurred in 31/85 (36-5%) patients, of which 11/85 (12-9%) required intravenous antibiotics or hospitalization ("severe") and were associated with cytokine release syndrome (CRS), neurotoxicity, tocilizumab use, corticosteroid use, and bridging therapy on univariate analyses. After day 30, 7 severe infections occurred, with no late deaths due to infection. Prolonged cytopenias are common following axi-cel therapy for LBCL and typically recover with time. Most patients experience profound and prolonged CD4 T cell immunosuppression without severe infection.

Renal extramedullary plasmacytoma in a dog.

A 10-year-old, intact male Siberian husky dog was presented for a suspected left renal cyst. Computed tomography (CT) identified a large, left kidney mass with retroperitoneal hemorrhage. A left-sided nephrectomy was performed, and histopathology confirmed a renal plasmacytoma. Perioperative screening for multiple myeloma was negative. The dog was lost to follow-up and was euthanized 11 months after surgery. A necropsy was not performed. To the authors' knowledge, this is the first case of renal extramedullary plasmacytoma in a dog. Key clinical message: This report describes the clinical presentation, and laboratory, diagnostic imaging, and surgery findings of a case of renal extramedullary plasmacytoma in a dog.

Plasmocytome rénal extra-médullaire chez un chien. Un chien husky sibérien mâle intact de 10 ans a été présenté pour un kyste rénal gauche suspecté. La tomodensitométrie a identifié une grande masse rénale gauche avec une hémorragie rétropéritonéale. Une néphrectomie gauche a été réalisée et l'histopathologie a confirmé un plasmocytome rénal. Le dépistage péri-opératoire pour myélome multiple était négatif. Le chien n'a pas eu de suivi et a été euthanasié 11 mois après la chirurgie. Une autopsie n'a pas été réalisée. À la connaissance des auteurs, il s'agit du premier cas de plasmocytome rénal extra-médullaire chez un chien.Message clinique clé :Ce rapport décrit la présentation clinique et les résultats de laboratoire, d'imagerie diagnostique et de chirurgie d'un cas de plasmocytome rénal extra-médullaire chez un chien.(Traduit par Dr Serge Messier).

Lomustine (CCNU) and prednisone chemotherapy for high-grade completely excised canine mast cell tumors.

The efficacy and toxicity of lomustine and prednisone for treating high-grade completely excised mast cell tumors (MCTs) was evaluated in a retrospective study of 15 dogs. Dogs were treated with lomustine (CCNU) at 70 mg/m2 every 4 weeks and prednisone at 0.5 to 1 mg/kg body weight PO daily. Eight dogs had treatment failures due to recurrence at the site of the initial surgery (2/15), de novo cutaneous MCT (4/15), or metastatic disease (2/15). The median overall survival time was 904 days, with 9 dogs alive at 1 year and 6 dogs alive after 2 years. All but 2 of the dogs had toxicity throughout their treatment protocol, with neutropenia (67%) and elevations in ALT (60%) being the most common; however, no dogs required hospitalization. The protocol was overall well-tolerated and lomustine/prednisone should be considered in the adjunctive treatment of high-grade mast cell tumors.

Chimiothérapie avec lomustine (CCNU) et prednisone pour le traitement de tumeurs mastocytaires de grade élevé complètement excisées. L'efficacité et la toxicité de la lomustine et de la prednisone pour traiter des tumeurs mastocytaires (MCTs) de grade élevé complètement excisées furent évaluées dans une étude rétrospective de 15 chiens. Les chiens furent traités avec la lomustine (CCNU) à un dosage de 70 mg/m2 aux 4 semaines et avec de la prednisone à un dosage de 0,5 à 1 mg/kg de poids corporel PO quotidiennement. Un échec de traitement est survenu chez huit chiens étant donné la récurrence au site de la chirurgie initiale (2/15), une MCT cutanée de novo (4/15), ou une maladie métastasique (2/15). Globalement, la médiane du temps de survie était de 904 jours, avec neuf chiens toujours vivants après 1 an et 6 chiens toujours vivants après 2 ans. À l'exception de deux chiens, tous les chiens présentèrent des signes de toxicité durant toute la durée de leur protocole de traitement, la neutropénie (67 %) et une augmentation de l'ALT (60 %) étant les plus communes; toutefois, aucun chien ne nécessita d'être hospitalisé. Le protocole était généralement bien toléré et la combinaison lomustine/prednisone devrait être considérée dans le traitement complémentaire des tumeurs mastocytaires de grade élevé.(Traduit par Dr Serge Messier).

Yeast eIF4B binds to the head of the 40S ribosomal subunit and promotes mRNA recruitment through its N-terminal and internal repeat domains.

Eukaryotic translation initiation factor (eIF)4B stimulates recruitment of mRNA to the 43S ribosomal pre-initiation complex (PIC). Yeast eIF4B (yeIF4B), shown previously to bind single-stranded (ss) RNA, consists of an N-terminal domain (NTD), predicted to be unstructured in solution; an RNA-recognition motif (RRM); an unusual domain comprised of seven imperfect repeats of 26 amino acids; and a C-terminal domain. Although the mechanism of yeIF4B action has remained obscure, most models have suggested central roles for its RRM and ssRNA-binding activity. We have dissected the functions of yeIF4B's domains and show that the RRM and its ssRNA-binding activity are dispensable in vitro and in vivo. Instead, our data indicate that the 7-repeats and NTD are the most critical domains, which mediate binding of yeIF4B to the head of the 40S ribosomal subunit via interaction with Rps20. This interaction induces structural changes in the ribosome's mRNA entry channel that could facilitate mRNA loading. We also show that yeIF4B strongly promotes productive interaction of eIF4A with the 43S•mRNA PIC in a manner required for efficient mRNA recruitment.

Extramedullary plasmacytoma in the lung of a Doberman pinscher dog.

A 7-year-old Doberman pinscher dog was referred for evaluation of a radio-opaque thoracic mass. The left cranial lung lobe and associated mass were surgically resected and histopathology confirmed the presence of an extramedullary plasmacytoma (EMP). This is the first clinical description of an EMP in the lung of a veterinary patient.

Plasmocytome extramédullaire dans le poumon d'un chien Doberman pinscher. Un chien Doberman pinscher âgé de 7 ans a été recommandé pour l'évaluation d'une masse thoracique radio-opaque. Le lobe pulmonaire cranial gauche et la masse associée ont été retirés par chirurgie et l'histopathologie a confirmé la présence d'un plasmocytome extramédullaire (PEM). Il s'agit de la première description clinique d'un PEM dans le poumon d'un patient vétérinaire.(Traduit par Isabelle Vallières).

Composting post-anaerobic digestion for emerging contaminant biodegradation: Impacts of operating conditions.

Sustainable manure management technologies are needed, and combining anaerobic digestion (AD) for energy generation and aerobic composting (AC) to stabilize digestate and remove emerging contaminants (ECs), including veterinary pharmaceuticals and steroid hormones, is promising. This study identified post-AD, AC operating conditions that maximized degradation of study ECs, expected to be present in cattle manure digested using treated municipal wastewater as the water source. Study ECs included sulfamethoxazole (SMX), chlortetracycline (CTC), oxytetracycline (OTC), estrone (E1), and naproxen (NPX). Composting conditions were simulated in bench-scale reactors, with microorganisms from digestate produced in an AD system (25L scale), by varying temperatures, pH, and carbon source compositions (representing food waste/manure co-digestion with different residence times). Results indicate maximum SMX biodegradation occurred at 35°C, pH 7, and with high levels of easily degradable carbon (≥99%, 99%, and 98%), and maximum E1 biodegradation occurred at 35°C, and with low levels of easily degradable carbon (≥97% and 99%). Abiotic degradation was responsible for the nearly complete removal of tetracyclines under all conditions and for partial degradation of NPX (between 20% and 48%). Microorganisms originating from the AD system putatively capable of SMX and E1 biodegradation, or of contributing to biodegradation during the AC phase, were identified, including phylotypes previously shown to biodegrade SMX (Brevundimonas and Alcaligenes).

Combined transcranial direct current stimulation with virtual reality exposure for posttraumatic stress disorder: Feasibility and pilot results.

BACKGROUND: Facilitating neural activity using non-invasive brain stimulation may improve extinction-based treatments for posttraumatic stress disorder (PTSD). OBJECTIVE/HYPOTHESIS: Here, we examined the feasibility of simultaneous transcranial direct current stimulation (tDCS) application during virtual reality (VR) to reduce psychophysiological arousal and symptoms in Veterans with PTSD. METHODS: Twelve Veterans with PTSD received six combat-related VR exposure sessions during sham-controlled tDCS targeting ventromedial prefrontal cortex. Primary outcome measures were changes in skin conductance-based arousal and self-reported PTSD symptom severity. RESULTS: tDCS + VR components were combined without technical difficulty. We observed a significant interaction between reduction in arousal across sessions and tDCS group (p = .03), indicating that the decrease in physiological arousal was greater in the tDCS + VR versus sham group. We additionally observed a clinically meaningful reduction in PTSD symptom severity. CONCLUSIONS: This study demonstrates feasibility of applying tDCS during VR. Preliminary data suggest a reduction in psychophysiological arousal and PTSD symptomatology, supporting future studies.

Theta-Burst Transcranial Magnetic Stimulation for Posttraumatic Stress Disorder.

OBJECTIVE: Posttraumatic stress disorder (PTSD) is a highly prevalent psychiatric disorder associated with disruption in social and occupational function. Transcranial magnetic stimulation (TMS) represents a novel approach to PTSD, and intermittent theta-burst stimulation (iTBS) is a new, more rapid administration protocol with data supporting efficacy in depression. The authors conducted a sham-controlled study of iTBS for PTSD. METHODS: Fifty veterans with PTSD received 10 days of sham-controlled iTBS (1,800 pulses/day), followed by 10 unblinded sessions. Primary outcome measures included acceptability (retention rates), changes in PTSD symptoms (clinician- and self-rated), quality of life, social and occupational function, and depression, obtained at the end of 2 weeks; analysis of variance was used to compare active with sham stimulation. Secondary outcomes were evaluated 1 month after treatment, using mixed-model analyses. Resting-state functional MRI was acquired at pretreatment baseline on an eligible subset of participants (N=26) to identify response predictors. RESULTS: Retention was high, side effects were consistent with standard TMS, and blinding was successful. At 2 weeks, active iTBS was significantly associated with improved social and occupational function (Cohen's d=0.39); depression was improved with iTBS compared with the sham treatment (d=-0.45), but the difference fell short of significance, and moderate nonsignificant effect sizes were observed on self-reported PTSD symptoms (d=-0.34). One-month outcomes, which incorporated data from the unblinded phase of the study, indicated superiority of active iTBS on clinician- and self-rated PTSD symptoms (d=-0.74 and -0.63, respectively), depression (d=-0.47), and social and occupational function (d=0.93) (all significant). Neuroimaging indicated that clinical improvement was significantly predicted by stronger (greater positive) connectivity within the default mode network and by anticorrelated (greater negative) cross-network connectivity. CONCLUSIONS: iTBS appears to be a promising new treatment for PTSD. Most clinical improvements from stimulation occurred early, which suggests a need for further investigation of optimal iTBS time course and duration. Consistent with previous neuroimaging studies of TMS, default mode network connectivity played an important role in response prediction.

What is your diagnosis? Ventral neck mass in a dog.

: A 14-year-old male Labrador Retriever was presented for lethargy and collapse. On physical examination, numerous abnormalities were found, including a large ventral neck mass (100 cm(3)) in the area of the thyroid gland. Fine-needle aspirates revealed 2 apparent populations of cells: one suspected to be a well-differentiated thyroid carcinoma, and the other consisting of large pleomorphic to spindloid cells suggestive of sarcoma. Two days later, the dog died at home. A full necropsy was not performed, but examination of the head and neck revealed a well-encapsulated mass adjacent to the cranial trachea and larynx. A section of the mass was evaluated histologically and a diagnosis of anaplastic thyroid carcinoma was made. Immunohistochemical evaluation with antibodies to thyroglobulin, cytokeratin, and vimentin confirmed distinct populations of malignant epithelial and malignant mesenchymal cells, and the diagnosis was amended to thyroid carcinosarcoma. Thyroid carcinosarcoma is a rare neoplasm in dogs in which the cell type comprising the mesenchymal component can vary. Immunochemistry to demonstrate the 2 cell types may be necessary to differentiate thyroid carcinosarcoma from anaplastic thyroid carcinoma.

Clinical signs, treatments, and outcome in cats with transitional cell carcinoma of the urinary bladder: 20 cases (1990-2004).

OBJECTIVE: To characterize demographics and clinical signs and evaluate outcomes of treatments in cats with transitional cell carcinoma (TCC) of the urinary bladder. DESIGN: Retrospective case series. ANIMALS: 20 cats with TCC. PROCEDURES: Medical records of 20 cats with a bladder mass identified as a TCC that were examined at 2 veterinary institutions between 1990 and 2004 were evaluated. Signalment, treatments, and outcome were assessed. RESULTS: Breeds included domestic short hair (n=14), long hair (2), and medium hair (2) cats, Siamese (1), and Abyssinian (1). All cats had been neutered at an early age (< 1 year old; 13 neutered males and 7 spayed females). The median age at diagnosis of TCC was 15.2 years. The trigone region was affected in 9 cats. Treatments included piroxicam administration, chemotherapy, or surgery as single interventions or in combination; 6 cats were not treated. At the time of diagnosis, 3 cats had pulmonary metastasis and 1 cat had metastasis to local lymph nodes. Median survival time for all 20 cats was 261 days. Nearly all deaths were attributable to progressive disease in the urinary tract. Five cats were lost to follow-up. CONCLUSIONS AND CLINICAL RELEVANCE: In cats, TCC of the urinary bladder appears to be a rare and aggressive disease that is more prevalent in male cats and frequently develops at sites distant from the trigone (unlike TCC in dogs). Nevertheless, initial clinical signs of TCC in cats in this study were similar to those reported for affected dogs.

A comparative proteomic study of plasma in feline pancreatitis and pancreatic carcinoma using 2-dimensional gel electrophoresis to identify diagnostic biomarkers: A pilot study.

While pancreatitis is now recognized as a common ailment in cats, the diagnosis remains challenging due to discordant results and suboptimal sensitivity of ultrasound and specific feline pancreatic lipase (Spec fPL) assay. Pancreatitis also shares similar clinical features with pancreatic carcinoma, a rare but aggressive disease with a grave prognosis. The objective of this pilot study was to compare the plasma proteomes of normal healthy cats (n = 6), cats with pancreatitis (n = 6), and cats with pancreatic carcinoma (n = 6) in order to identify potential new biomarkers of feline pancreatic disease. After plasma protein separation by 2-dimensional gel electrophoresis, protein spots were detected by Coomassie Brilliant Blue G-250 staining and identified by mass spectrometry. Alpha-1-acid glycoprotein (AGP), apolipoprotein-A1 (Apo-A1), and apolipoprotein-A1 precursor (Pre Apo-A1) appeared to be differentially expressed, which suggests the presence of a systemic acute-phase response and alteration of lipid metabolism in cats with pancreatic disease. Future studies involving greater case numbers are needed in order to assess the utility of these proteins as potential biomarkers. More sensitive proteomic techniques may also be helpful in detecting significant but low-abundance proteins.

Bien que la pancréatite soit maintenant reconnue comme un problème peu fréquent chez les chats, le diagnostic demeure un défi étant donné les résultats discordants et la sensibilité sous-optimale de l'échographie et de l'épreuve spécifique de la lipase pancréatique féline (Spec fPL). La pancréatite partage également des similarités cliniques avec le carcinome pancréatique, une maladie rare mais agressive ayant un pronostic grave. L'objectif de cette étude pilote était de comparer les protéomes plasmatiques de chats normaux en santé (n = 6), de chats avec une pancréatite (n = 6), et de chats avec un carcinome pancréatique (n = 6) afin d'identifier de nouveaux biomarqueurs potentiels de maladie pancréatique féline. Après séparation des protéines plasmatiques par électrophorèse en gel en deux dimensions, les taches de protéines furent détectées par coloration avec du bleu brillant de Coomassie G-250 et identifiées par spectrométrie de masse. La glycoprotéine acide alpha-1 (AGP), l'apolipoprotéine A1 (Apo-A1), et le précurseur de l'apolipoprotéine A1 (Pre Apo-A1) apparaissent comme étant exprimées de manière différentielle, ce qui suggère la présence d'une réponse de phase-aiguë systémique et une altération du métabolisme des lipides chez les chats avec une maladie pancréatique. Des études additionnelles regroupant un plus grand nombre de cas sont nécessaires afin d'évaluer l'utilité de ces protéines comme biomarqueurs potentiels. Des techniques plus sensibles de protéomique pourraient également être utiles pour détecter des protéines significatives mais de faible abondance.(Traduit par Docteur Serge Messier).

Evaluation of lymph node aspirates at diagnosis and relapse in dogs with high-grade multicentric lymphoma and comparison with survival time.

BACKGROUND: Canine high-grade multicentric lymphoma, a common disease with variable response to chemotherapy, is often diagnosed using cytology. OBJECTIVES: The purpose of the study was to compare cytologic features of canine peripheral lymph node aspirates collected at diagnosis and at relapse, and evaluate their usefulness in predicting survival. METHODS: Cytologic scoring based on a rubric and nuclear morphometry analyses were performed on cytologic smears collected at diagnosis and at relapse. Scores at diagnosis and relapse were compared by paired t-test and evaluated in relation to time from diagnosis to remission, remission to relapse, relapse to death, and total survival time, using the Cox proportional-hazards regression model. RESULTS: Number of mitoses and total cytologic score were significantly higher at relapse compared to diagnosis (P < .05). None of the nuclear morphometry measures were significantly different between diagnosis and relapse. The presence of binucleated or multinucleated cells at diagnosis was associated with a shorter remission and decreased total survival (P < .05). Increased mean nucleoli at relapse was associated with longer remission and total survival (P < .05). Increased minimum nuclear radius and diameter at diagnosis were associated with a decreased time from relapse to death (P < .05). Several nuclear morphometry measures at relapse were associated with a shorter time from diagnosis to remission (P < .05). CONCLUSIONS: Number of mitoses and total score were higher at relapse than at diagnosis in canine lymphoma. The presence of binucleated or multinucleated cells at diagnosis may be useful as indicator of a poor prognosis. Further studies including a larger number of cases are required to reinforce the prognostic values of these cytologic features.