CAR T in patients with large B-cell lymphoma not fit for autologous transplant.

Large B-cell lymphoma (LBCL) patients with comorbidities and/or advanced age are increasingly considered for treatment with CD19 CAR T, but data on the clinical benefit of CAR T in the less fit patient population are still limited. We analysed outcomes of consecutive patients approved for treatment with axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) by the UK National CAR T Clinical Panel, according to fitness for autologous stem cell transplant (ASCT). 81/404 (20%) of approved patients were deemed unfit for ASCT. Unfit patients were more likely to receive tisa-cel versus axi-cel (52% vs. 48%) compared to 20% versus 80% in ASCT-fit patients; p < 0.0001. The drop-out rate from approval to infusion was significantly higher in the ASCT-unfit group (34.6% vs. 23.5%; p = 0.042). Among infused patients, response rate, progression-free and overall survival were similar in both cohorts. CAR T was well-tolerated in ASCT-unfit patients with an incidence of grade ≥3 cytokine release syndrome and neurotoxicity of 2% and 11%, respectively. Results from this multicentre real-world cohort demonstrate that CD19 CAR T can be safely delivered in carefully selected older patients and patients with comorbidities who are not deemed suitable for transplant.

Feasibility of aqueous shunts for reduction of intraocular pressure in horses.

REASONS FOR PERFORMING STUDY: Based on the current literature, neither medical, surgical nor combination therapy adequately controls equine glaucoma for many horses. Aqueous shunts have been useful in other species to control glaucoma. OBJECTIVES: To determine whether aqueous shunts in normal equine eyes significantly reduce intraocular pressure (IOP) without causing vision threatening complications. STUDY DESIGN: Prospective experimental trial. METHODS: Aqueous shunts were placed in 7 normal eyes of 4 horses. The shunts were placed dorsotemporally. Examinations were initially performed daily for 7 days and after that every 3 days through 4 weeks after implantation. Horses were then subjected to euthanasia and globes enucleated for routine histological examination. The IOPs for each day post operatively were compared to the preoperative value (Day -1) using a Wilcoxon signed ranks test. Significance was set at P<0.05. RESULTS: The mean IOP preoperatively (20.7 ± 3.0 mmHg) was significantly higher than on any post operative day (P values ranged from 0.018 to 0.048). The aqueous shunts remained in situ for the entire study. Two eyes developed corneal ulcers that resolved. Shallow anterior chambers were noted in 2 eyes after shunt placement, which normalised after placement of full eye cup masks. Histologically, 7/7 eyes had fibrosis surrounding the implant. Minimal peripheral neovascularisation and neutrophilic keratitis were noted in 5/7 eyes. Corneal damage was scored as none in 3/7, mild in 2/7, moderate in 1/7 and marked in 1/7 eyes. CONCLUSIONS: After placement of aqueous shunts, a significant decrease in IOP was noted from preoperatively (Day -1) to Day 28 despite fibrosis surrounding the implants. No vision threatening complications were noted. POTENTIAL RELEVANCE: Aqueous shunts may represent a feasible therapeutic option for equine glaucoma. The results of this study suggest that further studies in glaucomatous horses would be warranted.

A pilot study on the corneal curvatures and ocular dimensions of horses less than one year of age.

Intraocular lenses (IOLs) have been implanted in adult equine eyes after cataract surgery. Foals and weanlings comprise a large proportion of those horses undergoing cataract surgery. Due to potential differences in the size and corneal curvature of the juvenile eye, it is not currently known whether implantation of adult IOLs is appropriate in foals and weanlings. The objective of the study was to measure the anterior chamber depth (ACD), central lens thickness (CLT), vitreous chamber depth (VCD), axial globe length (AGL) and corneal curvature of horses less than one year of age. The axial dimensions from one eye of 10 foals were measured using simultaneous A and B scan ultrasonography. The corneal curvature from one eye of 7 weanlings was determined using a modified photokeratometer. Ultrasonography revealed a mean ACD of 4.94 mm, mean CLT of 9.38 mm, mean VCD of 18.96 mm and mean AGL of 33.32 mm for the foals. The mean corneal curvature was 15.4 diopters (D). The mean ACD, CLT, VCD and AGL of the foals were less than the measurements reported in the literature for adult horses. The mean corneal curvature was similar to the values reported by some authors for adult horses. Due to the differences in axial dimensions between adult and juvenile eyes, an IOL that corrects vision in an adult horse might not adequately correct vision in a horse less than one year of age.

Phacoemulsification and implantation of foldable +14 diopter intraocular lenses in five mature horses.

Presently, intraocular lenses (IOLs) are not routinely implanted after equine cataract surgery. Subsequently, horses are visual but markedly farsighted (hyperopic). This report describes the surgical results and visual status after phacoemulsification and implantation of IOLs in mature horses with spontaneous cataracts. Six eyes of 5 mature horses underwent phacoemulsification and implantation of a +14 diopter (D) foldable IOL. Recheck ocular examinations were performed at 1, 4 and 24 weeks post operatively. Refractive error was recorded at 4 weeks post operatively. Visual status, refractive error and anterior chamber depth were recorded 24 weeks post operatively: 5 of 6 operated eyes remained visual and the average refractive error was +0.4 ± 1.1D. There was a significant difference between the 24 week post operative refractive error and the population mean of +10D (P<0.0001) for aphakic horses. The average post operative anterior chamber depth was 7.89 ± 1.55 mm. One globe was enucleated 2 months post operatively. Phacoemulsification with IOL implantation resulted in a significant reduction in post operative refractive error and restored vision to within 0.4D of emmetropia in 5 of 6 operated eyes. Implantation of a +14D IOL ameliorated the hyperopia documented in aphakic horses and improved the post operative visual acuity.

Pathological changes in horses dying with equine influenza in Australia, 2007.

Analysis of pathology results from the 2007 equine influenza (EI) outbreak in Australia indicate that young foals in naïve horse populations are prone to developing broncho-interstitial pneumonia, and that this can be a rare manifestation of EI virus infection in mature horses. All horses may develop secondary bacterial bronchopneumonia, with mature horses more likely to die. EI outbreaks among heavily pregnant mares can result in increased neonatal losses because of premature placental separation and dystocia causing fetal hypoxia.

Responding to the equine influenza outbreak: challenges from a laboratory perspective.

The unique challenges that laboratories in Queensland and New South Wales faced during the response to the 2007 equine influenza outbreak and how these were managed are described.

Central corneal thickness and intraocular pressure in Puerto Rican glaucoma patients

OBJECTIVE: To compare the variations in central corneal thickness and intraocular pressure measurements according to race, gender, and age. METHODS: A non-concurrent prospective study of 372 (744 eyes) glaucoma patients was conducted. Central corneal thickness was measured with ultrasound pachymeter and intraocular pressure with Goldmann tonometer. The relationship between CCT, race, gender, and age was evaluated using both descriptive and statistical analysis. RESULTS: The population age was 64 +/- 19.52 years. The mean central corneal thickness was 546 +/- 43.84 microm. The mean corrected intraocular pressure was 17 +/- 5.26 mm Hg. Central corneal thickness of male patients (549 +/- 43.43 pm) was thicker than that of female patients (546 +/- 41.83 microm). The mean corrected intraocular pressure in male patients (16 +/- 5.41 mm Hg) was less than that of female patients (17 +/- 5.18 mm Hg). The mean central corneal thickness in patients 0 to 9 years-of-age was 548 +/- 36.08 microm; 10 to 19 years-of-age was 606 +/- 82.30 microm; 20 to 29 years-of-age was 564 +/- 29.23 microm; 30 to 39 years-of-age was 579 +/- 15.32 microm; 40 to 49 years-of-age was 546 +/- 48.29 microm; 50 to 59 years-of-age was 550 +/- 38.12 mirom; 60 to 69 years-of-age was 545 +/- 40.22 microm; 70 to 79 years-of-age was 541 +/- 34.71 microm; 80 to 89 years-of-age was 541 +/- 34.05 microm; older than 90 years-of-age was 527 +/- 46.90 microm. CONCLUSIONS: Central corneal thickness of glaucoma patients in Puerto Rico was similar to that of Hispanics in the continental United States. However, the intraocular pressure and corrected intraocular pressure of glaucoma patients in Puerto Rico were statistically higher than that of Hispanics with glaucoma in the continental United States. In our study population, central corneal thickness and intraocular pressure were not affected by gender or age.

Eye diseases in Puerto Rico

OBJECTIVE: To report on the major causes of eye diseases leading to visual impairment and blindness in a sub-urban population in Puerto Rico. DESIGN: A population-based study of eye diseases in Puerto Ricans living in the San Juan metropolitan area of Puerto Rico. PARTICIPANTS: Nine thousand two hundred ninety-eight patients aged from 40 to 79 years-of-age from the San Juan metropolitan area. METHODS: A chart review of 9,298 patients was done. Patients carrying diagnosis such as cataracts, glaucoma, age-related macular degeneration (ARMD), and diabetic retinopathy were evaluated. Descriptive statistics and chi square analysis were used to evaluate findings. RESULTS: 2,056 patients out of 9,298 had cataracts (22.1); 3,963 patients (42.6) had glaucoma; 199 patients had ARMD (2.1); and 700 patients (7.5) had diabetic retinopathy. The prevalence of cataracts was higher in the population study than in the Hispanic population of the Los Angeles Latino Eye Study (LALES) (p<0.001). The prevalence of glaucoma was higher in our patients than in Hispanic population studied by the LALES (p<0.0001). The prevalence of ARMD and the prevalence of diabetic retinopathy was lower than expected when compared to Hispanic population of LALES study (p<0.0001 in both instances). CONCLUSIONS: In this population-based study, the prevalence of cataracts and glaucoma was higher than the results found in the Hispanic populations reported in the LALES. However, in our study, we found a lower prevalence of ARMD and diabetic retinopathy. Various factors may lead to this significant difference in the prevalence of eye diseases between the PR population and Hispanic population in the continental USA. Further studies are needed to evaluate the prevalence of eye diseases in Puerto Rico.

Color vision in patients with the Hermansky-Pudlak syndrome

PURPOSE: To study color vision in patients with oculocutaneous albinism (OCA) METHODS: We evaluated color vision in 42 patients with OCA using the HRR color plates. Sixty seven percent of the patients had the Hermansky-Pudlak syndrome (HPS), diagnosed genetically or clinically. The remaining patients had unknown mutations leading to OCA. RESULTS: 47.6 of patients of OCA of all types included had a color vision defect. Of these, 55 were female and 45 were male patients. 50 of patients with the HPS (all types) had a color vision deficit. 42.9 of patients with OCA of unknown type had color weakness. 57.1 had normal color vision. CONCLUSIONS: Results suggest that many patients with OCA and the HPS have a mild red-green color perception deficiency that is not a sex linked trait. The prevalence of color vision deficits in our study population increased with decreasing visual acuity

Teacher's guide: management of wastes from health - care activities

It provides teaching materials and recommendations for a three day training course, designed mainly for managers of health -care establishments, public health professionals and policy makers. Document in Word and pdf format; for pdf, Acrobat Reader is required.

Tumor metastasis biopsy as a surrogate marker of response to melanoma immunotherapy.

In patients undergoing immunotherapy for metastatic melanoma, the clinical response in immunotherapeutic trials may be partial or difficult to detect. Tumor metastasis biopsy allows direct characterisation of an anti-tumor immunological response. During a phase I/II trial of granulocyte macrophage colony stimulating factor (GM-CSF) transduced autologous melanoma immunotherapy, the cellular response was examined by immunohistochemical analysis in a limited number of tumor biopsies taken from patients who either responded or progressed. Clinical response was associated with tumor infiltration by CD4+ and CD8+ T-cells, macrophages and differentiated dendritic cells (DC), and expression of HLA-DR by the tumor cells. This tumor infiltration was associated with increased melanoma-specific peripheral blood precursor cytotoxic T-lymphocyte (pCTL) and the ability to obtain tumor-infiltrating lymphocytes in vitro. In contrast, progression or a lack of clinical response was associated with a lack of T-cell and DC infiltration into the tumor tissue in all such biopsies. Macrophages and eosinophils infiltrated these tumors, while T-cells and DC were present at some distance from the tumor. These preliminary data strongly suggest that the location and extent of T-cell and DC infiltration, as well as the expression of HLA-DR by tumor cells are associated with a clinical response in this form of melanoma immunotherapy.

Unsedated transnasal EGD: an alternative approach to conventional esophagogastroduodenoscopy for documenting Helicobacter pylori eradication.

BACKGROUND: The aim of this study was to assess the yield of antral biopsies performed via unsedated transnasal esophagogastroduodenoscopy, a technique that does not require conscious sedation with its concomitant costs and complications, for documentation of Helicobacter pylori eradication. METHODS: Nineteen patients who were previously CLO test positive on conventional esophagogastroduodenoscopy and subsequently treated for H pylori infection were enrolled. The subjects had not received antibiotic therapy in the prior month and had no prior gastric surgery. By using a GIF-N30 fiberoptic endoscope and a tiny cup biopsy forceps (1.8 mm diameter), unsedated transnasal endoscopy was performed and antral biopsy specimens were taken for a CLO test, histologic analysis (Dieterle stain), and tissue culture. On the same day, the subjects underwent a carbon 13-labeled area urea breath test. All subjects completed a visual analog scale, rating the acceptability of the unsedated transnasal examination and the previous sedated conventional esophagogastroduodenoscopy. RESULTS: There was no statistically significant difference between the results of the CLO tests (5/19 positive) versus the 13C-urea breath test (4/19 positive) (p = 0.96), the CLO tests versus histologic findings (5/19 positive) (p = 0.71), or the 13C-urea breath test versus histologic findings (p = 0.96). All tissue culture results were negative. The overall acceptability of unsedated transnasal esophagogastroduodenoscopy was similar to that of sedated conventional esophagogastroduodenoscopy. CONCLUSION: Unsedated transnasal esophagogastroduodenoscopy, a technique that eliminates the costs and complications associated with conscious sedation, is a feasible and accurate alternative to conventional esophagogastroduodenoscopy when documentation of H pylori eradication and confirmation of gastric ulcer healing are both indicated.

Nuclear localization of RelB is associated with effective antigen-presenting cell function.

Dendritic cells (DC) are potent APCs that enter resting tissues as precursors and, after Ag exposure, differentiate and migrate to draining lymph nodes. The phenotype of RelB knockout mice implicates this member of the NF kappa B/Rel family in DC differentiation. To further elucidate the role of RelB in DC differentiation, mRNA, intracellular protein expression, and DNA binding activity of RelB were examined in immature and differentiated human DC, as well as other PB mononuclear cell populations. RelB protein and mRNA were detected constitutively in lymphocytes and in activated monocytes, differentiated DC, and monocyte-derived DC. Immunohistochemical staining demonstrated RelB within the differentiated lymph node interdigitating DC and follicular DC, but not undifferentiated DC in normal skin. Active nuclear RelB was detected by supershift assay only in differentiated DC derived from either PB precursors or monocytes and in activated B cells. These RelB+ APC were potent stimulators of the MLR. The data indicate that RelB expression is regulated both transcriptionally and post-translationally in myeloid cells. Within the nucleus, RelB may specifically transactivate genes that are critical for APC function.

Langerhans cells in the development of skin cancer: a qualitative and quantitative comparison of cell markers in normal, acanthotic and neoplastic ovine skin.

The distribution of Langerhans cells in normal, acanthotic and neoplastic ovine epithelium was examined using the enzyme marker Acetylcholinesterase (AchE) and monoclonal antibodies (MoAb) to CD1 (20.27) and MHC Class II (49.1 and 28.1) molecules. In normal skin, where Langerhans cells were regularly spaced within the basal layer, qualitative observations and direct pairwise testing showed that AChE was superior to the MoAb in detecting these cells. Significantly more (P < 0.01) dendritic cells were also detected with MoAb 49.1 than MoAb 20.27 or 28.1, suggesting differential expression of MHC Class II subsets and the presence of CD1- MHC Class II+ granule- dendritic cells in sheep analogous to indeterminate cells of man. In acanthotic skin, compared to normal skin, Langerhans cells were less numerous, irregular and more suprabasal in distribution and their morphology was occasionally swollen and indistinct. No difference was seen in the ability of AChE and MoAb in detecting Langerhans cells, however pairwise testing of markers did demonstrate that significantly more (P < 0.05) cells without dendritic processes were stained with MoAb 49.1 than with 20.27 or 28.1. In all squamous cell carcinomas examined dendritic cells that stained for AChE, CD1 or MHC Class II antigens were concentrated at the peripheral areas of neoplastic epithelium. Many dendritic cells were detected with MoAb to MHC Class II antigens, whereas CD1 and AChE positive dendritic cells were rare in tumor bearing tissue. The quantitative differences in the immunohistochemical staining of Langerhans cells between normal, acanthotic and neoplastic epithelium were consistent with ultrastructural studies. When compared with those of a newborn lamb, which had had very little exposure to antigens or ultraviolet radiation (UVR), the Langerhans cells of the aged sheep were deformed and contained far fewer Birbeck granules. The abnormalities were progressively more severe in acanthotic and neoplastic skin. These observed changes may have resulted from UVR induced damage and may be indicative of impaired function involved in the development of skin cancer.

Evaluation of dyspepsia and functional gastrointestinal disorders: a cost-benefit analysis of different approaches.

OBJECTIVE: To establish a decision rule for diagnostic testing in patients with dyspepsia. DESIGN: Medical decision analysis using a decision-tree model. METHODS: Costs and benefits associated with two alternative strategies are compared. In the first strategy, empirical therapy alone is provided. The second strategy also includes tests to diagnose the cause of dyspepsia. RESULTS: It is more beneficial to test than to employ empirical treatment alone if the a-priori probability P of an organic disease is larger than the ratio of the costs T of testing to the costs C of a missed diagnosis: P > T/C. In most clinical situations, the costs of a missed diagnosis outweigh the costs of testing by a factor of 5-10, for which the cost ratio is 10-20%. CONCLUSION: Diagnostic tests should be performed in patients with dyspepsia, whenever the probability of finding organic disease exceeds the ratio of the cost of testing to the cost of missing this diagnosis.

Costs of duodenal ulcer therapy with antibiotics.

BACKGROUND: Intermittent or maintenance therapy with histamine2 antagonists, highly selective vagotomy, or antibiotic therapy to eradicate Helicobacter pylori all represent distinct, viable options to manage duodenal ulcer disease. Comparing the costs associated with these four approaches could help in deciding among them. METHODS: The decision model of a Markov chain was used to compare the costs of the four approaches and their influence on the natural course of duodenal ulcers. Direct costs were calculated from the average wholesale prices of drugs and from charges for medical services submitted to and allowed by the Health Care Financing Administration. Average annual income was used to estimate indirect costs. RESULTS: The model predicted that after antibiotic therapy, 99.7% of patient time is spent free of duodenal ulcer. The corresponding percentages were 96.6% for maintenance therapy, 94.4% for vagotomy, 89.4% for intermittent therapy, and 82.8% without therapy. For an individual patient after 15 years, the expected total costs of a treatment approach involving antibiotics are $995, compared with $10,350 for intermittent therapy with histamine2 antagonists, $11,186 for maintenance therapy with histamine2 antagonists, and $17,661 after vagotomy. Incorporating upper gastrointestinal tract endoscopy to verify eradication of H pylori raises the costs of the antibiotic therapy option to $2426. Increasing the annual infection rate of H pylori from baseline 1% to 10% raises the expected costs after 15 years to $3431. Decreasing the H pylori eradication rate from baseline 80% to 50% raises the costs to $2679. CONCLUSIONS: Compared with other options, antibiotics to eradicate H pylori are the cheapest therapy for duodenal ulcer and provide the least time spent with an active ulcer. From an economic perspective, antibiotics represent the treatment of choice.

Major histocompatibility complex antigens in normal, acanthotic and neoplastic ovine skin: an association been tumor invasiveness and low level MHC class I expression.

The distribution and density of ovine MHC class I and class II antigens in normal, acanthotic and malignantly transformed ovine skin was investigated using monoclonal antibodies and an immunoperoxidase technique. The subjects were sheep that had been exposed to high levels of sunlight for more than 6 years. The expression of MHC class II antigens in the plasma membrane of cells within the normal epidermis was restricted to basally located dendritic and mononuclear cells. Normal keratinocytes did not express MHC class II antigens. However, we observed low levels of intracellular MHC class II expression in both acanthotic and neoplastic keratinocytes. Expression of MHC class I antigens was variable in normal and acanthotic epithelium; it was usually present, but of low intensity in very early ovine squamous cell carcinoma and was increased in small, but morphologically typical, tumors. Tumors originating on the nose, which are more invasive than those on the ear, were found to express significantly less MHC class I (P < 0.05). Thus, an association between tumor invasiveness and low level expression of MHC class I was apparent. This may have diagnostic value and highlights a mechanism by which neoplastic cells may evade immune surveillance by T cells.