Tailoring Therapy in Older Adults With Hematologic Malignancies.

Hematologic malignancies most often present in the sixth or seventh decade of life. Even so, many older adults may be unable to tolerate standard chemotherapy or require supplementary care or dose adjustments to do so. Both in community and academic centers, geriatric assessment (GA) can be used to improve the care of older adults with blood cancers. For example, hematologic oncologists can use GA to guide treatment selection, adjusting for patient frailty and goals, as well as prompt initiation of enhanced supportive care. After initial therapy, GA can improve the identification of older adults with aggressive myeloid malignancies who would benefit from hematopoietic cell transplantation (HCT), inform shared decision making, as well as allow transplanters to tailor conditioning regimen, donor selection, graft-versus-host disease prophylaxis, and pre- and post-HCT treatments. As in HCT, GA can improve the care of older patients with relapsed lymphoma or multiple myeloma eligible for chimeric antigen receptor-T therapy, identifying patients at higher risk for toxicity and providing a baseline for subsequent neurocognitive testing. Here, we review the data supporting GA for the care of older adults with blood cancers, from the community to the academic center. In addition, we explore future directions to optimize outcomes for older adults with hematologic malignancies.

Venetoclax in combination with hypomethylating agents or low dose cytarabine for relapsed and refractory acute myeloid leukemia.

Limited treatment options exist for patients with relapsed/refractory (R/R) acute myeloid leukemia (AML). Venetoclax (VEN) in combination with a hypomethylating agent (HMA) or low-dose cytarabine (LDAC) has been recently approved for treatment-naïve patients unfit for intensive induction. Limited data are available to characterize the efficacy of VEN combinations in R/R AML. We retrospectively analyzed 77 patients with a median of 1 prior therapy (range 0-5) treated with VEN combinations for R/R AML or AML secondary to myelodysplastic syndrome (MDS) progressing after HMA monotherapy. The median overall survival (OS) was 13.1 months (95% CI 9.2-15.1). The median progression-free survival (PFS) was 12 months (95% CI 8.2-15.4) with a median duration of response of 8.9 months (95% CI 5.7-13.9). Overall response rate (ORR) was 68% with a composite complete response (CR) and CR with incomplete hematologic recovery (CRi) rate of 53%. VEN combination therapy is efficacious in R/R AML and further prospective studies are warranted.

Evolving insights into the mechanisms of toxicity associated with immune checkpoint inhibitor therapy.

Immune checkpoint inhibitors have emerged as a revolutionary treatment option for patients with various types of malignancy. Although these agents afford a significant improvement in outcomes for melanoma and other previously untreatable malignancies, their novel mechanism of action may predispose patients to immune-related adverse effects (irAEs). In the tumour neoantigen environment, these irAEs are due to the activation of the immune system by the blockade of suppressive checkpoints, leading to increases in T-cell activation and proliferation. IrAEs have been reported in almost any organ and at any point in time, even months to years after discontinuation of therapy. Certain populations with distinct physiological changes, genetic risk factors, and specific antigen exposures may be more highly predisposed to develop irAEs. This review discusses the incidence and mechanisms of irAEs and the relationship between host factors and irAE occurrence.

New-onset post-transplant diabetes mellitus after haploidentical hematopoietic cell transplant with post-transplant cyclophosphamide.

Haploidentical hematopoietic cell transplant (haplo-HCT) with post-transplant cyclophosphamide (PTCY) is utilized for patients with hematological disorders but without conventional donors. The effects of new-onset post-transplant diabetes mellitus (PTDM) following haplo-HCT are unknown. We examined PTDM incidence and outcomes after haplo-HCT with PTCY. Patients without diabetes receiving haplo-HCT (n=64) were analyzed for PTDM diagnosis (defined as blood glucose≥ 200 mg/dL). By day 100, 14 (22%) patients developed PTDM (median, 18 days). Hyperglycemia (blood glucose ≥ 200 mg/dL) preceded corticosteroids in 11 (79%) individuals. PTDM patients had increased death/relapse (p=0.029). PTDM occurs frequently, precedes corticosteroids, and leads to inferior outcomes following haplo-HCT. PTDM prophylaxis/treatment may improve HCT survival.

Ophthalmic abnormalities secondary to periocular or ocular snakebite (pit vipers) in dogs--11 cases (2012-2014).

OBJECTIVE: To describe ophthalmic abnormalities secondary to periocular and ocular snakebite in dogs. ANIMAL STUDIED: Retrospective review of medical records from dogs presenting to the Small Animal Hospital at University of Florida following snakebites to the face (2012-2014). Two groups were identified: periocular bites (PB) and ocular bites (OB). RESULTS: Records from eleven dogs matched the search criteria and were included in the study (PB=9, 81.8%; OB=2, 18.2%). Both OB cases involved the cornea. Facial edema, blepharospasm, chemosis, and conjunctival hyperemia occurred in all cases (100%). Hemorrhage from the eyelids occurred in eight cases (72.7%; PB=7, OB=1). Subconjunctival hemorrhage occurred in seven cases (63.6%; PB=6, OB=1). Third eyelid laceration and nictitans gland prolapse occurred in 1 case each (9%; PB=1). Lagophthalmia was present in three cases (27.3%; PB=3), with secondary corneal ulcer in two cases (18.2%; PB=2). Corneal ulcer due to direct corneal bite occurred in two cases (18.2%-partial thickness with melting (1) and full thickness (1) ). Uveitis was present in 6 cases (54.5%; PB=4, OB=2), with flare and miosis in 4 cases (36.4%; PB=2, OB=2). Hyphema, fibrin in anterior chamber, and cataract occurred in one case (9%; OB=1). Vision loss occurred in two cases (18.2%; PB=2), secondary to retinal degeneration (PB=1) and amaurosis (PB=1). Mean follow-up time was 7 weeks (range: 3 days-11 months). Most clinical signs had resolved by last examination. CONCLUSIONS: Periocular symptoms were more commonly observed than ocular alterations, regardless of bite location. Appropriate supportive therapy should be instituted according to clinical signs.

Equine deep stromal abscesses (51 cases - 2004-2009)--Part 2: the histopathology and immunohistochemical aspect with attention to the histopathologic diagnosis, vascular response, and infectious agents.

PURPOSE: To investigate histopathologic and immunohistochemical aspects of equine deep stromal abscesses (DSA) with a focus on the histopathologic diagnosis, presumptive etiology, and the immunohistochemical expression of three angiogenesis-related factors: vascular endothelial growth factor-A (VEGF-A), pigment epithelium-derived factor (PEDF), and interleukin-1 receptor antagonist (IL-1ra). SAMPLE POPULATION: Paraffin-embedded biopsy samples from 51 DSA. The biopsies were collected from full-thickness penetrating keratoplasty or split-thickness lamellar keratoplasty surgeries at the University of Florida Veterinary Medical Center in the period from 2004 to 2009. PROCEDURE: The histopathologic and immunohistochemical findings were tested for association between each other. Prevalence calculation and test for association with qualitative data analysis was used for data evaluation. RESULTS: Fungal hyphae were found histologically in 47.1% (n = 24) of the DSA cases. Histopathologically, most fungal DSA showed suppurative keratitis (n = 34; 66.7%) and little to no stromal vascularization infiltrating the abscess (negative association, P = 0.005). All three angiogenesis-related factors were expressed to some degree in DSA tissue. A negative association between VEGF-A and PEDF when compared to the presence of fungal hyphae (P < 0.001, P = 0.023) indicated that cases positive for these two factors will most probably not have fungal hyphae present. CONCLUSION: Abnormally decreased VEGF-A expression is suggested as the reason for the slow vascularization and delayed resolution of fungal DSA, whereas PEDF and IL-ra did not seem to have any influence on the vascularization process. Clinical and histopathologic characteristics of DSA make it possible to suggest an etiology for an equine DSA with an unknown etiology.

Equine deep stromal abscesses (51 cases - 2004-2009)--Part 1: the clinical aspects with attention to the duration of the corneal disease, treatment history, clinical appearance, and microbiology results.

OBJECTIVE: To study the equine deep stromal abscesses (DSA) with focus on the duration of the corneal disease, medical treatment, season of presentation, clinical appearance, and the degree of corneal vascularization. MATERIAL AND METHODS: Equine DSA diagnosed, biopsied, and surgically treated at the University of Florida Veterinary Medical Center (UFVMC) from 2004 to 2009 were identified. The medical record, clinical photographic images, and microbiology results for each case were evaluated. Frequency and prevalence calculation as well as qualitative data analysis was performed for clinical and microbiological data. RESULTS: Fifty-one equine DSA were included in the study. Spring (March, April, May; 33.4%) and winter (December, January, February; 31.4%) were the most common seasons for DSA presentation. The 51 cases were divided into four categories of focal opacity from their clinical appearance: focal yellow (45.2%), focal white (23.5%), diffuse yellow/white (23.5%), and focal pink (7.8%). 5.9% of the DSA (n = 3) were culture positive for fungal growth, whereas 17.6% were positive for bacterial growth (n = 9). No association between short-/long-term systemically administered NSAID treatment and the corneal vascular response to the corneal lesion could be appreciated. CONCLUSION: Equine DSA most often present in the spring and winter in the subtropical environment of the state of Florida (USA). The clinical appearance may have a connection with the etiology and pathogenesis of the equine DSA. No connection between short- or long-term systemically administered NSAID and the degree of corneal vascularization of the DSA was noted.

Equine subepithelial keratomycosis.

OBJECTIVE: To describe clinical findings in equine subepithelial keratomycosis (SEK). DESIGN: Retrospective medical records study. ANIMALS STUDIED: Medical records of horses that had subepithelial keratomycosis (SEK) at the University of Florida Veterinary Medical Center from 2007 to 2011 were reviewed. PROCEDURES: Data collected from the medical records included signalment, clinical descriptions of ocular lesions, diagnostic techniques, and therapeutic outcomes. RESULTS: Twenty-one horses, consisting of three Quarter horse geldings, two Morgan geldings, one Morgan mare, two Arabian mares, three Arabian geldings, two warm blood mares, two warm blood geldings, two Thoroughbred geldings, one Thoroughbred mare, one Appaloosa mare, one Holsteiner gelding, and one Holsteiner mare with SEK were identified. Multifocal punctate and/or geographic patterns of subepithelial opacification were present in all eyes. Intermittent phases of weak fluorescein and/or rose Bengal dye were found in 16 eyes. Clinical signs of iridocyclitis were absent in all eyes. Cytologic confirmation of fungi was found in ten cases, Candida was cultured from one eye, and Aspergillus cultured in three eyes. Nineteen of 21 eyes with SEK resolved when topical antifungal therapy was initiated. Two of the 19 responding eyes recurred and required additional therapy, and two other eyes progressed to ulcerative keratomycosis. CONCLUSIONS: This is the first clinical report of a subtle form of keratomycosis in the horse. Subepithelial keratomycosis may be a distinct clinical entity or represent a continuum in the described forms of equine keratomycosis.

Light microscopic evaluation and scanning electron microscopic analysis of horse eyes following deep anterior lamellar keratectomy.

OBJECTIVE To describe the technique of deep anterior lamellar keratoplasty (DALK) with Descemet's membrane (DM) exposure in horse eyes. Also, to compare the efficacy and safety of viscodissection and big-bubble techniques for DALK. ANIMALS STUDIED Thirty-four ex vivo horse eyes. PROCEDURE Deep anterior lamellar keratoplasty was performed in 34 ex vivo horse eyes. Two groups (Group V--viscodissection--2% sodium hyaluronate; Group A--air--big-bubble) of 17 eyes were studied. Other than the substance used, the surgical technique was similar for both groups. Nonperforated eyes were submitted for light microscopic histologic evaluation and scanning electron microscopic (SEM) analysis. RESULTS Group V--Perforations occurred in 18% of the eyes during surgery. Light microscopy revealed exposure of DM in 28% of the eyes with mean thickness of the remaining stroma being 70.4 µm. Group A--Perforations occurred in 42% of the eyes. Light microscopy revealed exposure of DM in 60% of the eyes with mean thickness of the remaining stroma being 23.3 µm. No significant differences in safety, efficacy and thickness of the remaining stroma (including all eyes or excluding those with DM exposure) were observed. SEM of the surgical site revealed a more even surface in those eyes with DM exposure compared to eyes with thicker remaining stroma in both groups. CONCLUSIONs We describe two DALK techniques (viscodissection and big-bubble) for use in horses. No significant differences in safety, efficacy and thickness of the remaining stroma were observed. However, a nonsignificant trend toward the big-bubble technique being more efficacious but less safe was observed.

Equine Multiple Congenital Ocular Anomalies (MCOA) syndrome in PMEL17 (Silver) mutant ponies: five cases.

OBJECTIVE: To describe the clinical phenotype and genetics of equine Multiple Congenital Ocular Anomalies (MCOA) syndrome in PMEL17 (Silver) mutant ponies. ANIMALS STUDIED: Five presumably unrelated ponies. PROCEDURES: The ponies were examined under field conditions in their barn by slit lamp biomicroscopy, indirect ophthalmoscopy, and applanation tonometry. Blood was collected and genomic DNA extracted for MCOA genotyping using the PMEL17ex11 marker. RESULTS: One pony solely presented with temporal ciliary body cysts, suggestive of the less severe Cyst phenotype of MCOA; the animal was heterozygous at the MCOA locus. Multiple bilateral anterior segment anomalies were identified in four ponies, consistent with the more severe MCOA phenotype characterized by cornea globosa, iris hypoplasia, encircling granula iridica along the pupillary ruff, and cataracts. These animals were homozygous for the mutant MCOA allele. Four of the ponies had a silver dapple or chocolate coat color with white or flaxen manes and tails. Silver dappling was masked by the palomino coloring of a 5th pony that was homozygous at the MCOA locus. CONCLUSIONS: The MCOA syndrome can be seen in ponies. The results of both clinical evaluation and genotyping resembled the previously described MCOA of both Rocky Mountain and Kentucky Mountain Saddle horses.

Bilateral nasolacrimal duct atresia in a cria.

A 2-month-old, male alpaca had a 1-month history of mucoid ocular discharge from the left eye. Signalment, history and clinical findings were suggestive of a congenital nasolacrimal outflow obstruction. A dacryocystorhinogram confirmed bilateral nasolacrimal duct atresia, which involved the distal half of both nasolacrimal ducts. In order to establish alternative outflow, a conjunctivomaxillosinusotomy and conjunctivorhinostomy were performed on the right and left eye, respectively. The surgical openings remain patent after 11 months, and there have been no clinical signs of nasolacrimal disease.

Microvessel loss, vascular damage and glutamate redistribution in the retinas of dogs with primary glaucoma.

OBJECTIVE: Vascular damage and ischemia-like changes in glutamate distribution occur in primary glaucoma (PG) in dogs. We measured the microvessel density in PG retinas to determine whether microvessel loss may induce ischemia and glutamate redistribution. ANIMALS STUDIED: Sections from 12 control and 33 glaucomatous dog retinas. PROCEDURES: Vessels in retinas were identified by staining with Griffonia simplicifolia isolectin B4 or immunohistochemical staining for laminin or glutamate. Damage to regions of the inner nuclear layer (INL) was classified as mild (< 10% damaged neurons), moderate (> or = 10% damaged neurons, INL > or = 2 cells thick) or severe (INL < 2 cells thick). RESULTS: Glutamate redistribution was found in some mildly damaged regions and increased as damage increased. Regions with increased glutamate redistribution and increased damage had lower densities of microvessels in plastic sections. However, neuronal damage and glutamate redistribution were seen even in areas adjacent to the remaining microvessels. Microvessel loss in damaged regions was confirmed in paraffin sections with lectin staining and immunohistochemical localization of laminin. The density of larger vessels was not decreased in PG, but larger vessels often had thickened walls, cuffing with leukocytes, and leakage of albumin. CONCLUSIONS: Microvessel loss may occur in regions of glutamate redistribution and neuronal damage in PG retinas. Larger vessels were often damaged. The redistribution of glutamate is associated with a loss of microvessels, even in mildly damaged regions. However, neuronal damage and glutamate redistribution may occur close to remaining microvessels, suggesting microvessel loss was not the sole factor inducing these changes.

Retinal pigment epithelial damage, breakdown of the blood-retinal barrier, and retinal inflammation in dogs with primary glaucoma.

OBJECTIVE: This paper aims to determine if abnormalities of the retinal pigment epithelium (RPE) and retinal inflammation occur in primary glaucoma. PROCEDURE: Twenty-three canine globes with primary glaucoma, goniodysgenesis, and elevated intraocular pressure were evaluated. Sections from 6 control and 23 glaucomatous canine globes were stained with hematoxylin and eosin, Griffonia simplicifolia isolectin B4, or immunohistochemically stained for CD3 or albumin. The retinal sections were evaluated with light microscopy for morphological and immunohistochemical evidence of pigmentary changes and inflammation. RESULTS: Abnormal pigmented cells including displaced RPE cells and macrophages (identified by lectin binding) were found in the neuroretinas and vitreous bodies of glaucomatous eyes. Other abnormalities included hypertrophy of RPE cells and loss of RPE continuity. Regions of neuroretina with more displaced pigment had fewer remaining neurons. Signs of retinal inflammation found in glaucomatous eyes included infiltration with leukocytes, retinal swelling, and albumin leakage from vessels. Accumulation of perivascular CD3-positive T lymphocytes also occurred in glaucomatous retinas. Chronic glaucomatous retinas had increased pigmentary changes, fewer neutrophils, and less swelling than acute glaucomatous retinas. CONCLUSIONS: Disruption of the RPE, increased permeability of the vascular endothelium, accumulation of inflammatory cells, and retinal swelling or thinning occur in canine primary glaucoma. The displacement of pigment and accumulation of inflammatory cells in the neuroretina suggests that inflammation may be an important contributor to retinal damage.