Need for standardization of cytokine profiling in CAR T cell therapy.

With expansion of chimeric antigen receptor (CAR) T cell therapy and broader utilization of anti-cytokine directed therapeutics for toxicity mitigation, the routine assessment of cytokines may enhance understanding of toxicity profiles, guide therapeutic interventions, and facilitate cross-trial comparisons. As specific cytokine elevations can correlate with and provide insights into CAR T cell toxicity, mitigation strategies, and response, we explored the reporting of cytokine detection methods and assessed for the correlation of cytokines to cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) across clinical trials. In this analysis, we reviewed 21 clinical trials across 60 manuscripts that featured a US Food and Drug Administration-approved CAR T cell construct or one of its predecessors. We highlight substantial variability and limited reporting of cytokine measurement platforms and panels used across CAR T cell clinical trials. Specifically, across 60 publications, 28 (46.7%) did not report any cytokine data, representing 6 of 21 (28.6%) clinical trials. In the 15 trials reporting cytokine data, at least 4 different platforms were used. Furthermore, correlation of cytokines with ICANS, CRS, and CRS severity was limited. Considering the fundamental role of cytokines in CAR T cell toxicity, our manuscript supports the need to establish standardization of cytokine measurements as a key biomarker essential to improving outcomes of CAR T cell therapy.

Factors affecting perioperative pulmonary function in acute respiratory failure.

To determine the magnitude, duration, and associated factors of perioperative changes in pulmonary function, we retrospectively reviewed the medical records of 145 patients who required preoperative mechanical ventilation for acute respiratory failure before undergoing 200 surgical procedures. Patients were grouped into five pulmonary diagnostic categories: (1) adult respiratory distress syndrome (ARDS) (n = 49); (2) pneumonia (n = 20); (3) atelectasis (n = 65); (4) congestive heart failure (n = 11); and (5) acute ventilatory failure (n = 55). Sixty patients underwent intra-abdominal surgery, 135 patients required surgery on the periphery, and five patients had a thoracotomy. For all patients, PaO2/FIO2 declined significantly from 321 mm Hg (mean) preoperatively to 258 mm Hg intraoperatively, and shunt fraction (Qs/QT) increased from 0.16 to 0.23 without a significant change in PaCO2. The magnitude of the increase in Qs/QT did not differ among pulmonary diagnostic groups. Preoperatively, patients undergoing laparotomy had lower PaO2/FIO2 (278 vs 340) and higher Qs/QT (0.19 vs 0.14) than patients requiring surgery on the periphery. Intraoperatively, Qs/QT increased more during abdominal procedures than during peripheral procedures. Intraoperative hypoxemia (PaO2/FIO2 less than 80 mm Hg) occurred during 13 procedures. Hypoxemic patients had a mean increase in Qs/QT of 0.20 (0.25 preoperatively to 0.45 intraoperatively), and a significant increase in PaCO2 from 38 mm Hg to 45 mm Hg intraoperatively). In general, these patients had ARDS (n = 10), sepsis (n = 10), a laparotomy (n = 9), and intraoperative mechanical ventilation via the Ohio Anesthesia ventilator (n = 8), a commonly used operating room ventilator. Their preoperative peak airway pressure (54 cm H2O) and minute ventilation (20 L/min) requirements exceeded the capabilities of the Ohio Anesthesia ventilator and likely contributed to impaired gas exchange intraoperatively. Within the first several hours postoperatively, PaO2/FIO2 recovered to preoperative levels in all patients, even in those who had severe intraoperative hypoxemia develop and who underwent laparotomy. We conclude that most patients with acute respiratory failure receiving preoperative mechanical ventilation experienced mild-to-moderate deterioration in intraoperative pulmonary oxygen exchange that rapidly returned to preoperative levels after surgery. We recommend that necessary surgery not be postponed by concern that pulmonary function will be worsened by surgery and anesthesia.

Angioplasty-induced vasospasm in rabbit model. Mechanisms and treatment.

Angioplasty of the distal iliac and proximal femoral arteries in rabbits resulted in focal and diffuse vasospasm similar to that seen in humans. The focal vasospasm occurred in all experiments immediately distal to the site of angioplasty. Occasional diffuse vasospasm was preceded by intravascular thrombosis or extravasation. Heparin reduced the incidence of diffuse vasospasm and reduced the severity of focal vasospasm. Verapamil and Dazoxiben reversed focal vasospasm, but only Verapamil in the presence of heparin prevented vasospasm. Prazocin had no effect on vasospasm.

Intrathecal dextrose to prevent seizures after metrizamide myelography in dogs.

Seizures are possible complications of metrizamide myelography. The protective effect (as measured by reduction in seizure incidence) of dextrose in solution with metrizamide was studied by conducting a double-blind trail. Fourteen dogs each had two myelograms at five- to 16-day intervals in a crossover study, while ten additional dogs each had a single myelogram. Metrizamide alone and metrizamide in dextrose were used for the myelograms. No significant protective effect of dextrose was found.

MR of brain radiation injury: experimental studies in cats.

Two of six cats receiving small-field, single-dose, brain irradiation of 35 Gy with 6 MeV photons developed brain abnormalities in the irradiated area on MR images at 6 and 8 months, respectively, after treatment. The lesions were of high intensity on T2-weighted images and did not enhance after IV administration of gadolinium-DTPA. An additional lesion in one of these cats displayed high signal on T2-weighted images and enhanced on T1-weighted images after IV gadolinium-DTPA. Pathologic correlation revealed that the nonenhancing T2-weighted lesions consisted of edema or demyelinated regions without inflammation while the gadolinium-enhanced lesion demonstrated necrosis with inflammatory infiltrate. Focal brain irradiation may produce noninflammatory demyelination and necrosis. These histologic entities may be potentially distinguished on MR with IV gadolinium-DTPA.

Ureterocolonic anastomosis in clinically normal dogs.

Ureterocolonic anastomosis was evaluated in 13 clinically normal dogs. Urinary continence was maintained after surgery, and the procedure was completed without technique errors in all but 2 dogs. Three dogs died within 5 weeks (2 of undetermined causes and 1 of aspiration pneumonia and neurologic disease), and 1 dog was euthanatized 4 months after surgery because of neurologic signs. Two healthy dogs were euthanatized 3 months after surgery for light microscopic evaluation of their kidneys. Five dogs were euthanatized 6 months after surgery for light microscopic evaluation of their kidneys. Gastrointestinal and neurologic disturbances developed in 4 dogs at various postoperative intervals. Plasma ammonia concentration measured in 2 dogs with neurologic signs was increased. Plasma ammonia concentration measured in 5 dogs without neurologic signs was within normal limits. All 5 dogs, in which metabolic acidosis was diagnosed, had high normal or above normal serum chloride concentration. Serum urea nitrogen values were increased after surgery because of colonic absorption of urea. Serum creatinine concentration was increased in 1 dog 6 months after surgery. Individual kidney glomerular filtration rate was reduced in 38% (3/8) of the kidneys from 4 other dogs at 6 months after surgery. Of 5 dogs euthanatized at 3 to 4 months after surgery, 4 had bilateral pyelitis, and 1 had unilateral pyelonephritis. Six months after surgery, pyelonephritis was diagnosed in 40% (4/10) of the kidneys from 5 dogs. The ureterocolonic anastomosis procedure is a salvage procedure that should allow complete cystectomy. However, variable degrees of metabolic acidosis, hyperammonemia, and neurologic disease may result.

Coxofemoral joint laxity from distraction radiography and its contemporaneous and prospective correlation with laxity, subjective score, and evidence of degenerative joint disease from conventional hip-extended radiography in dogs.

A 3-year prospective study of large-breed dogs (4 months to 3 years of age) was conducted to evaluate the influence of radiographic positioning and age on coxofemoral joint (hip) laxity, subjective hip score, and development of degenerative joint disease (DJD). The dogs (n = 142) were breeder- or client-owned and represented 14 breeds. With dogs under heavy sedation, hips were radiographed in the standard hip-extended position and in the new compression/distraction position at 4, 6, 12, 24, and 36 months of age. The standard hip-extended radiographic view was evaluated by 3 methods: subjective evaluation by a board-certified veterinary radiologist (WHR), according to the standard 7-point Orthopedic Foundation for Animals (OFA) scoring scheme (OFA/WHR); joint laxity quantitation, using the Norberg angle (NA) method; and subjective scoring by a veterinary orthopedic surgeon for radiographic evidence of DJD. The hips in the distraction radiographic view were evaluated for passive hip laxity, as measured by use of a unitless distraction index (DI). Results of the study indicated that at a specific age (4, 6, 12, 24, or 36 months), all methods of hip evaluation correlated with each other at a moderate level (P < 0.05). The strength of contemporaneous correlation tended to increase with age of evaluation. Longitudinally, the between-method correlations were usually significant (P < 0.05), but not at a sufficiently high level to permit reliable between-method prediction. Prospective intraclass (within-method) statistical analysis of the various hip-scoring methods indicated that DI was superior to NA and OFA/WHR in comparability of score over time. The intraclass correlation coefficient ranged from 0.55 to 0.91 for DI in contrast to 0.40 to 0.78 for NA, and 0.06 to 0.39 for OFA/WHR over the age intervals of the study. For reference, the highest Kappa of 0.39 for the subjective OFA/WHR scoring reflected a maximal level of agreement between time intervals, only slightly better than chance. The associated large error questions the predictive use of the 7-point, subjective hip-scoring scheme, particularly prior to the age of 2 years.

Effects of dietary electrolyte balance on subluxation of the femoral head in growing dogs.

Effects of increased dietary chloride and reduced sodium and potassium ion concentrations on coxofemoral joint conformation, as assessed by radiography, were examined in growing dogs. Dietary electrolyte balance was quantified by dietary anion gap (DAG), defined as Na+ + K+ - Cl- in milli-equivalents per 100 g of food. Diets had anion gap ranging from 8 to 41 mEq/100 g of food. One hundred sixty-seven pups from 27 litters representing 5 breeds were studied during the period of rapid growth. The extent of subluxation of the femoral head was measured on radiographs, using the method of Norberg. On average, less subluxation of the femoral head (P < 0.05) was observed when diets with lower DAG were fed. Differences in DAG balance did not result in different rates of weight gain; therefore, the reduction in coxofemoral joint subluxation attributable to low DAG was unrelated to weight gain. Norberg angles measured at 30 weeks of age were highly correlated with coxofemoral joint status at 2 years of age, as measured by the Swedish diagnostic system and the scoring system of the Orthopedic Foundation for Animals (lrl > or = 0.70, P < 0.0002, n = 24). This diet-related improvement in coxofemoral joint subluxation would be expected, on average, to delay or mitigate the characteristic clinical and radiographic signs of hip dysplasia in growing dogs.

Diabetes insipidus and hyperadrenocorticism associated with high plasma adrenocorticotropin concentration and a hypothalamic/pituitary mass in a dog.

Central diabetes insipidus was diagnosed in association with a dexamethasone-insuppressible adrenocorticotropin-secreting tumor in a dog. Over the 3 years before the dog's death, the combination of specific pituitary function tests, peptide hormone radioimmunoassays, and visualization of the tumor by use of x-ray computed tomography of the skull, allowed an etiologic diagnosis. Because initial signs of glucocorticoid excess were questionable and adrenolytic therapy was not allowed by the owners, treatment consisted only of administration of synthetic vasopressin, which was successful in the management of the diabetes insipidus.

Bone sarcomas associated with multifocal medullary bone infarction in dogs.

Nine dogs with primary osteosarcoma also had concurrent bone infarctions. The median weight of the 9 dogs was less than 12 kg, and the median age was 10 years. Radiographically and histologically, bone infarctions were apparent in the limb bones and the cranium. Radiographically, there were multiple, irregular intramedullary densities, particularly in the limb bones. Histologically, there was widespread necrosis of the medullary soft tissue and bone, with proliferative new bone formation on medullary trabeculae. Collagen deposition throughout the vessel walls leading to occlusion was seen only in the intramedullary arteries.

Ectopic ureters in a male cat.

A 16-week-old male cat with urinary incontinence was initially diagnosed as having a right ectopic ureter. Other abnormalities of the urinary system included phimosis, hydronephrosis, and localized right megaloureter. Surgical removal of the right kidney and right ureter was partially successful in stopping the urinary incontinence. Further radiographic studies and retrospective examination of initial radiographs revealed that the left ureter was also ectopic.

Malignant tumor formation at the site of previously irradiated acanthomatous epulides in four dogs.

The radiation response of acanthomatous epulis in 32 dogs was good, with an estimated median survival time of 21 months. Of the 32 patients, 14 have died. In 4 of those 14, malignant tumors developed at the site of the acanthomatous epulis. The tumors were of epithelial origin in 3 patients and of mesenchymal origin in 1 patient. Possibilities explaining the appearance of the malignancies included spontaneous malignant transformation, radiation induction of neoplasms, and radiation induction of malignant transformation. This uncommon complication was not considered contradictory to radiotherapy of acanthomatous epulides, because of their excellent response to irradiation and the long latent period between irradiation and appearance of the malignant tumor.

New concepts of coxofemoral joint stability and the development of a clinical stress-radiographic method for quantitating hip joint laxity in the dog.

From mechanical principles and postmortem observations of coxofemoral joints of dogs, a hydrostatic mechanism influencing hip joint stability was discovered. This discovery led to the development of a stress-radiographic positioning method to quantitate hip joint laxity in dogs. The method incorporated 2 views with the dog in supine position and hips at neutral flexion/extension angle: a compression view, with the femoral heads fully seated in the acetabula; and a distraction view, with the femoral heads at maximal lateral displacement. An index measurement method was formulated to quantitate the relative degree of joint laxity appearing in either the compression or distraction view. Clinical evaluation of 6 dogs was done to compare the compression/distraction method with the standard hip-extended radiographic method. Also, the stress-radiographic method was performed on 16-week-old Borzoi and German Shepherd Dogs to compare the characteristics of inherent hip joint laxity in these breeds. In all dogs tested, hip joint laxity was masked by the standard hip-extended view as indicated by a 2.5-fold improvement in sensitivity to hip joint laxity of the new method (P less than 0.00001). Moreover, the mean hip joint laxity of 16-week-old German Shepherd Dogs exceeded the mean hip joint laxity of Borzois by 79% (P less than 0.00001). Reports in the literature document the incontrovertible association of hip joint laxity to the development of hip dysplasia in dogs. We believe the ability to accurately quantitate hip joint laxity will provide key diagnostic and prognostic criteria for the selection of pet dogs, and more importantly, breeding stock.

Trigonal-colonic anastomosis: a urinary diversion procedure in dogs.

Trigonal-colonic anastomosis for diversion of urine into the colon was performed in 12 clinically normal dogs and in 10 incontinent dogs with diseases of the urinary bladder or urethra. Dogs were studied from 1 to 30 months after surgery. The surgical procedure was technically satisfactory. Fifteen of 22 dogs were studied with intravenous urography, and only 1 case of hydronephrosis was found. Pyelitis was a common histopathologic finding in both groups of dogs. Pyelonephritis developed in 30% of dogs, regardless of duration of anastomosis. Glomerular filtration rate was reduced in all dogs studied, but renal failure was infrequent. Values for blood urea nitrogen and serum inorganic phosphorus were elevated due to intestinal recycling of nitrogenous products and phosphate. Electrolyte imbalances were not a problem, but gastrointestinal disturbances developed in 3 of the 10 diseased dogs. Six of 10 diseased dogs survived from 9 months to more than 3 years. Trigonal-colonic anastomosis appears to be a satisfactory salvage procedure for incontinent dogs with diseases of the urinary bladder or urethra that do not respond to other forms of therapy.

Five-year longitudinal study on limited food consumption and development of osteoarthritis in coxofemoral joints of dogs.

OBJECTIVE: To examine the effects of limited food intake on frequency and severity of osteoarthritis in coxofemoral joints of labrador Retrievers. DESIGN: Dogs were paired according to gender and body weight, within each litter at 8 weeks of age. One dog of each pair was fed ad libitum. The limit-fed pairmate was fed 75% of the amount eaten the previous day by the ad libitum-fed counterpart. ANIMALS: 48 Labrador Retrievers. PROCEDURE: All dogs received the same diet. Radiographic evaluation of coxofemoral joints for frequency and severity of osteoarthritis were made when dogs were 4 and 6 months and 1, 2, 3, and 5 years old. RESULTS: Radiographic evaluation for osteoarthritis indicated greater frequency and more severity of osteoarthritis in the ad libitum-fed group of dogs. CLINICAL IMPLICATIONS: Analysis of data suggested that limit feeding of dogs over a 5-year period minimizes development of osteoarthritis in the coxofemoral joints.

Effects of limited food consumption on the incidence of hip dysplasia in growing dogs.

Forty-eight 8-week-old Labrador Retrievers were allotted to 2 groups of 24 dogs each; 1 group was fed ad libitum and the other group was given 25% less of the same feed until the dogs were 2 years old. Radiography of the hip joints was done when the dogs were 30, 42, 54, 78, and 104 weeks old. Subluxation was measured by the Norberg angle on radiographs made with the dog in the standard (extended limb) position. Independent of age at which the radiography was done, there was less subluxation of the femoral heads in the limit-fed dogs. Using the Swedish method of hip joint evaluation on the same radiographs, it was found that fewer dogs on limited food intake had signs of hip dysplasia. Radiographs done when dogs were 2 years old, for all the methods used (Norberg angle in standard and frog-limb position, the Orthopedic Foundation for Animals [OFA] score, and the Swedish score), revealed less hip dysplasia (less joint subluxation and less degenerative joint disease) in the limit-fed dogs. Using the OFA method, 7 of the 24 limit-fed dogs and 16 of the 24 ad libitum-fed dogs were diagnosed as having hip dysplasia. Similarly, using the Swedish method, 5 of the 24 limit-fed dogs and 18 of the 24 ad libitum-fed dogs were diagnosed as having hip dysplasia. The food-intake-related differences were significant both for the OFA score and for the Swedish score.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of the effect of limited food consumption on radiographic evidence of osteoarthritis in dogs.

OBJECTIVE: To determine prevalence of radiographic evidence of osteoarthritis in 4 diarthrodial joints of dogs with restricted feed intake, compared with dogs without restricted feed intake. DESIGN: Paired feeding study. ANIMALS: 48 Labrador Retrievers. PROCEDURE: Dogs in litters from 7 dams and 2 sires were paired by sex and weight within litters and randomly assigned to a control-fed group or a limit-fed group that received 25% less food than the control-fed group. Radiographic evaluation of prevalence and severity of osteoarthritis in the hip, shoulder, elbow, and stifle joints was performed when dogs were 8 years of age. RESULTS: Radiographic evidence of osteoarthritis that affected multiple joints was significantly more common in the control-fed group than in the limit-fed group. Prevalence of lesions in the hip joint was 15/22 in the control-fed group and 3/21 in the limit-fed group. Prevalence of lesions in the shoulder joint was 19/22 in the control-fed group and 12/21 in the limit-fed group; lesions in this joint were generally mild. Severity, but not prevalence, of osteoarthritis in the elbow joint was greater in the control-fed group than in the limit-fed group. CONCLUSIONS AND CLINICAL RELEVANCE: Prevalence and severity of osteoarthritis in several joints was less in dogs with long-term reduced food intake, compared with control dogs. Food intake is an environmental factor that may have a profound effect on development of osteoarthritis in dogs.

Contrast studies of the urogenital system.

Traditional contrast radiographic techniques for evaluation of the urogenital system are reviewed. Specific procedural protocols are suggested. The indications, limitations, and interpretation of the studies are discussed.

Endoscopic retrograde cholangiopancreatography: what role does it have in primary care?

Endoscopic retrograde cholangiopancreatography (ERCP) is a unique specialty tool used for the diagnosis and treatment of biliary and pancreatic disease. The procedure is much more available now and can be used in place of surgery or in conjunction with surgery. This article reviews the indications, applications, and personal experiences with the procedure in a rural referral hospital. Discussion includes the risks and complications of ERCP. Also included are explanations of therapeutic interventions. After reading this article, primary care physicians should have greater familiarity with the utility of this endoscopic tool.