Immune-related encephalitis after immune checkpoint inhibitor therapy.

BACKGROUND: Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment but can trigger immune-related encephalitis. We report one of the largest case series of patients with immune-related encephalitis and review of the literature. METHODS: Retrospective series of patients with immune-related encephalitis and literature review. RESULTS: Fourteen patients with cancer treated with ICI (50% combination therapy) developed immune-related encephalitis. Diagnostic testing revealed cerebral spinal fluid (CSF) lymphocytic pleocytosis (85%) and elevated protein (69%), abnormal brain magnetic resonance imaging(MRI) (33%) or brain FDG-PET (25%), electroencephalogram (EEG) abnormalities (30%), and autoantibodies (31%). Encephalitis treatment included: corticosteroids (86%), intravenous immunoglobulin (IVIg) (36%), plasmapheresis (7%), and rituximab (29%). There were no deaths and 12 patients had significant recovery, although long-term complications were observed. All patients discontinued ICI. Longitudinal follow-up demonstrated anti-cancer response to ICI at 3 months (85%) and 6 months post-ICI initiation (77%). A literature review identified 132 patients with immune-related encephalitis. Most were treated with PD-1 inhibitors (18% combination). Common abnormalities included elevated CSF protein (84%) or pleocytosis (77%), abnormal brain MRI (65%), or autoantibodies (47%). Nearly all were treated with corticosteroids, many required additional therapy with IVIg (26%) or rituximab (12%). Most patients had clinical improvement (81%) but a minority (10%) had a clinical relapse after completing corticosteroid taper. ICIs were resumed in 7 patients (5%), with relapse in 3. CONCLUSIONS AND RELEVANCE: Immune-related encephalitis is treatable and improves with corticosteroids in most cases but may require additional immunosuppression. Re-emergence of encephalitis is rare and does not typically result in adverse outcomes, and this should be considered in neurological immune-related adverse event management guidelines.

CNTF Gene Therapy Confers Lifelong Neuroprotection in a Mouse Model of Human Retinitis Pigmentosa.

The long-term outcome of neuroprotection as a therapeutic strategy for preventing cell death in neurodegenerative disorders remains unknown, primarily due to slow disease progression and the inherent difficulty of assessing neuronal survival in vivo. Employing a murine model of retinal disease, we demonstrate that ciliary neurotrophic factor (CNTF) confers life-long protection against photoreceptor degeneration. Repetitive retinal imaging allowed the survival of intrinsically fluorescent cone photoreceptors to be quantified in vivo. Imaging of the visual cortex and assessment of visually-evoked behavioral responses demonstrated that surviving cones retain function and signal correctly to the brain. The mechanisms underlying CNTF-mediated neuroprotection were explored through transcriptome analysis, revealing widespread upregulation of proteolysis inhibitors, which may prevent cellular/extracellular matrix degradation and complement activation in neurodegenerative diseases. These findings provide insights into potential novel therapeutic avenues for diseases such as retinitis pigmentosa and amyotrophic lateral sclerosis, for which CNTF has been evaluated unsuccessfully in clinical trials.

MEASUREMENT OF RETINAL DISPLACEMENT AND METAMORPHOPSIA AFTER EPIRETINAL MEMBRANE OR MACULAR HOLE SURGERY.

PURPOSE: To quantify retinal displacement and metamorphopsia after surgery for epiretinal membrane (ERM) or full-thickness macular hole (FTMH). METHODS: Fundus autofluorescence imaging was analyzed for evidence of retinal displacement. Displacement was quantified using a novel standardized approach with measures of vertical interarcade distance, fovea to disk margin, and perimacular area. The vertical disk diameter and normal fellow eyes served as controls. Metamorphopsia was quantified using the Morphision test. RESULTS: Thirty-three eyes of 33 consecutive patients underwent vitrectomy (21 for ERM; 12 for FTMH). After surgery for ERM, the macula expanded (perimacular area: +10.14%, P < 0.0001; intraarcade distance: +6.10%, P < 0.0001; fovea to disk margin: +4.80%, P = 0.0042). Conversely, after surgery for FTMH the macula parameters showed evidence of constriction (interarcade distance: -2.11%, P = 0.0047; perimacular area: -2.95%, P = 0.0197; fovea to disk margin: -4.69%, P = 0.0010). The degree of change in intraarcade distance and perimacular area was greater for the ERM compared with the FTMH (P < 0.0001). The vertical disk diameter was not altered by surgery for either the ERM or the FTMH. The average change in any measurements between visits in control eyes was just 0.61%, representing high test-retest reliability. Preoperative morphision distortion scores were worse with FTMH (57.3%) than ERM (38%, P = 0.0636) and improved overall after surgery (43.6-21.3%, P = 0.0019). CONCLUSION: Serial fundus autofluorescence imaging, with the measurement parameters used here, is a reliable means of monitoring retinal blood vessel movement over time. Significant retinal displacement occurs after vitrectomy for FTMH and ERM with the retina expanding after ERM removal and contracting after FTMH closure, with associated improvements in measured metamorphopsia.

Characteristics of rhegmatogenous retinal detachment and their relationship to success rates of surgery.

PURPOSE: To determine features of rhegmatogenous retinal detachment predictive of anatomical success with surgical procedure. METHODS: All patients undergoing surgery at a tertiary referral practice had contemporaneous data collection in an electronic database. Overall, 847 eyes from 847 patients undergoing surgical procedure for rhegmatogenous retinal detachment were included in this study. RESULTS: Mean age was 62.2 years with 60% male subjects and 56% right eyes. Mean postoperative follow-up was 9.6 months (range, 6 weeks to 10 years). With univariate analysis, the presence of superotemporal breaks was associated with a reduction in the chance of failed primary surgery (P = 0.005); detached inferonasal breaks (P = 0.002), proliferative vitreoretinopathy (PVR) (P < 0.0001), breaks in detached inferior retina (P < 0.0001), fovea off (P = 0.001), and 4-quadrant rhegmatogenous retinal detachment (P < 0.0001) increased the risk of failure. After multivariate analysis PVR, detached inferior breaks, increased number of breaks, and 4-quadrant detachment remained associated with an increased risk of failure, and superotemporal detached breaks with the reduced risk of failure (r(2) = 0.08). For patients without PVR, only inferonasal detached breaks and 3 to 4 quadrants of detachment remained predictive of failure (r(2) = 0.04). For patients with PVR (n = 120), multivariate analysis showed that PVR C4-12 and posterior breaks increased the failure risk and detached superotemporal breaks reduced the risk of failure (r(2) = 0.22). CONCLUSION: Number of breaks, inferior positioning of breaks, the extent of rhegmatogenous retinal detachment, and PVR are associated with failed primary surgery.

A randomised controlled trial to compare patient satisfaction with two different types of local anaesthesia in ptosis surgery.

BACKGROUND: Ptosis surgery is performed under local anaesthetic to allow intra-operative assessment of lid positioning. Most commonly the anaesthetic is administered as a subcutaneous infiltration at the surgical site. Ptosis surgery using a regional nerve block has also been described, with reported advantages for minimising levator paralysis and disruption of the surgical landmarks. This study was designed to compare patient satisfaction with the two techniques of local anaesthetic administration. METHODS: 32 patients undergoing ptosis surgery were enrolled into a randomised controlled trial to receive local anaesthetic either by subcutaneous infiltration or by regional nerve block. Patient satisfaction was measured postoperatively with a self-administered vertical response column questionnaire, the Iowa Satisfaction with Anaesthesia Scale (ISAS). RESULTS: Of the 32 patients who were recruited 3 patients were excluded from analysis due to incomplete questionnaires or deviation from the trial protocol. Patient groups were well matched in terms of age, sex, time on waiting list, anaesthetic risk score, and operating grade of surgeon. Comparison of ISAS scores with the Mann Whitney test demonstrated an equal level of patient satisfaction with the two techniques. CONCLUSION: This randomised controlled trial found regional nerve blocks to be associated with equal levels of patient satisfaction as the more standard technique of diffuse infiltration of local anaesthetic along the upper eyelid. This result supports the use of regional nerve blocks as a valid alternative for anaesthesia in ptosis surgery.

Biliary Obstruction Promotes Multilineage Differentiation of Hepatic Stem Cells.

Because of their high regenerative potential, stem cells are an ideal resource for development of therapies that replace injured tissue mass and restore function in patients with end-stage liver diseases. Using a rat model of bile duct ligation (BDL) and biliary fibrosis, we investigated cell engraftment, liver repopulation, and ectopic tissue formation after intrasplenic transplantation of epithelial stem/progenitor cells. Fetal liver cells were infused into the spleens of Fisher 344 rats with progressing biliary fibrosis induced by common BDL or rats without BDL. Cell delivery was well tolerated. After migration to the liver, donor-derived stem/progenitor cells engrafted, differentiated into hepatocytes and cholangiocytes, and formed large cell clusters at 2 months in BDL rats but not controls. Substantial numbers of donor cells were also detected at the splenic injection site where they generated hepatic and nonhepatic tissue. Transplanted cells differentiated into phenotypes other than hepato/cholangiocytic cells only in rats that underwent BDL. Quantitative reverse-transcription polymerase chain reaction analyses demonstrated marked up-regulation of tissue-specific genes of nonhepatic endodermal lineages (e.g., caudal type homeobox 2 [Cdx2], pancreatic and duodenal homeobox 1 [Pdx1], keratin 13 [CK-13]), confirmed by immunohistochemistry. Conclusion: BDL and its induced fibrosis promote liver repopulation by ectopically transplanted fetal liver-derived cells. These cell fractions contain multipotent stem cells that colonize the spleen of BDL rats and differentiate into multiple gastrointestinal tissues, including liver, pancreas, intestine, and esophagus. The splenic microenvironment, therefore, represents an ideal niche to assess the differentiation of these stem cells, while BDL provides a stimulus that induces their differentiation.

Scheimpflug imaging to determine intraocular lens power in vivo.

PURPOSE: To assess the feasibility of determining intraocular lens (IOL) power by measurement of the central optic thickness using clinically available Scheimpflug imaging (Pentacam, Oculus). SETTING: King's College Hospital Ophthalmology Department, London, United Kingdom. METHODS: Sixty-seven eyes were assessed 1 month after uneventful phacoemulsification with in-the-bag implantation of AcrySof MA60AC IOLs (Alcon). The correlation between IOL thickness measurement and IOL power was calculated. Repeatability of central optic thickness measurement was determined from 10 successive scans of 4 patients. RESULTS: Within-subject standard deviation increased with the subject mean. The coefficient of variability was 1.4%. Measured lens thickness was highly correlated with lens power (R(2) = 0.94, P<.001). Over the measured range, 95% confidence intervals varied between +/-0.83 diopters (D) and +/-0.92 D. CONCLUSIONS: Central IOL thickness measurements with the Pentacam Scheimpflug camera were highly repeatable and closely correlated with the known IOL power. The IOL power, calculated from a regression equation, is likely to be less than +/-1.00 D away from the actual power. Approximate in vivo IOL power determination is feasible with clinically available Scheimpflug imaging. This could be applied clinically in cases of unexplained postoperative refractive error.

Postremission therapy with low-dose interleukin 2 with or without intermediate pulse dose interleukin 2 therapy is well tolerated in elderly patients with acute myeloid leukemia: Cancer and Leukemia Group B study 9420.

PURPOSE: The purpose of the study is to investigate the tolerability of interleukin 2 (IL-2) after intensive chemotherapy in elderly acute myeloid leukemia (AML) patients in first complete remission (CR). EXPERIMENTAL DESIGN: AML patients > or =60 years in CR after induction and consolidation chemotherapy on Cancer and Leukemia Group B study 9420 were eligible if they had neutrophils > or =1 x 10(9)/liters and platelets > or =75 x 10(9)/liters. Patients received low-dose IL-2 (1 x 10(6) IU/m(2)/day s.c. for 90 days) or low-dose IL-2 with intermediate pulse doses (6-12 x 10(6) IU/m(2)/day s.c. for 3 days) every 14 days (maximum five pulses). In a subset of patients, we investigated the expression of NKG2D ligands by leukemic cells because they are likely important mediators of natural killer cytotoxicity. RESULTS: Of 35 CR patients receiving IL-2, 34 were evaluable for toxicity. Median age was 67 (range, 60-76) years. Thirteen of 16 patients receiving low-dose IL-2 completed the planned therapy, and 11 of 18 who also received intermediate pulse dose IL-2 therapy completed all five pulses. The spectrum of toxicity in both groups was similar, with predominantly grade 1-2 fatigue, fever, injection site reactions, nausea, anemia, and thrombocytopenia. Grade 3-4 hematological and nonhematological toxicity were more frequent in patients also receiving intermediate pulse dose IL-2 therapy. Grade 3-4 fatigue and hematological toxicity, although uncommon, were the major causes for discontinuing or attenuating therapy. In 8 cases, mRNA for one or more NKG2D ligands was detected in leukemic cells obtained at diagnosis before treatment. CONCLUSIONS: Low-dose IL-2, with or without intermediate pulse dose therapy, given immediately after chemotherapy in first CR to elderly AML patients is well tolerated. Expression of NKG2D ligands by leukemic cells was detected in the majority of cases tested and should be assessed for correlation with response to IL-2 in future studies.

AAV-mediated gene transfer of human X-linked inhibitor of apoptosis protects against oxidative cell death in human RPE cells.

PURPOSE: To determine whether human X-linked inhibitor of apoptosis (XIAP) enhances the survival of cultured human retinal pigment epithelial cells exposed to H(2)O(2). METHODS: ARPE-19 cells were exposed to H(2)O(2) to induce oxidative cell death. Intracellular reactive oxygen species (ROS) were measured using 2',7'-dichlorofluorescein diacetate. MTT assay was performed to quantify mitochondrial stress. Cell apoptosis was determined by TUNEL assay. Human XIAP was delivered with bicistronic expression of green fluorescent protein (GFP), using recombinant adeno-associated virus (AAV-XIAP-GFP). The null vector, containing identical sequences but without XIAP, was used as a control (AAV-NULL-GFP). Transduced cells underwent fluorescence-activated cell sorting. XIAP overexpression was examined by immunostaining and Western blot analysis. RESULTS: ARPE-19 cells exposed to 0.25 mM H(2)O(2) for 1 hour showed increased TUNEL staining compared with nonstressed cells (17 ± 1.4 vs. 1.8 ± 0.4 cells per 20 × field; P = 0.000006), accompanied by a significant increase in intracellular ROS (207 ± 46% vs. 100 ± 9.5%; P = 0.0002). The AAV-XIAP-GFP transduced cells had 11-fold higher XIAP expression than the AAV-NULL-GFP controls (1300 ± 126% vs. 120 ± 10%; P = 0.0006). XIAP over-expression significantly reduced the number of apoptotic cells after stress compared with the AAV-NULL-GFP controls (3.2 ± 0.6 vs. 18 ± 1.6 cells per 20 × field; P = 0.00003). Mitochondrial stress was reduced by AAV-XIAP-GFP, but did not reach a statistical significance (68 ± 3.5% vs. 74 ± 3.8%; P = 0.24). CONCLUSIONS: Overexpression of human XIAP protects ARPE-19 cells against H(2)O(2)-induced oxidative cell death by acting downstream on the apoptotic pathway. XIAP gene therapy using AAV may provide a means of reducing the effect of oxidative stress to RPE cells in age-related macular degeneration.

Late-Onset Cystoid Macular Edema Associated With Small-Incision Cataract Surgery and Inadvertent Entry of Chloramphenicol Ointment into the Anterior Chamber.

The authors report the long-term outcome of a 78-year-old man who experienced inadvertent entry of chloramphenicol ointment into the anterior chamber following small-incision sutureless cataract surgery. The chloramphenicol initially formed a single spherical mass on the interior aspect of the corneal section with no discernable effect on visual acuity. However, in the following 6 years the vision deteriorated with the development of multiple fine droplets within the anterior chamber and cystoid macular edema. An anterior chamber washout and removal of the ointment was performed with a subsequent improvement in vision. The authors discuss risks associated with unsutured corneal wounds and the use of ocular ointments.

Levator function revisited: a two-phase assessment of lid movement to better identify levator-superior rectus synkinesis.

AIM: To assess a two-phase method of recording levator function in order to facilitate the identification of patients with ptosis who have a synkinesis between the levator and superior rectus muscles. METHODS: 40 consecutive patients who attended oculoplastic clinics with ptosis and 22 patients with normal lid function were recruited. In each subject, levator function was recorded by the conventional method, measuring total upper eyelid excursion between the extremes of down-gaze and up-gaze. Levator function was also assessed using our novel two-phase approach in which upper-eyelid excursion is measured separately between down-gaze and primary position (Phase 1), and between primary position and up-gaze (Phase 2). RESULTS: In normal patients and most of the patients with ptosis, the majority of lid movement and hence levator function occurs between down-gaze and the primary position (Phase1). In those patients with ptosis and levator-superior rectus synkinesis, a higher proportion of lid movement occurred on up-gaze (Phase2). CONCLUSION: The two-phase measurement of lid movement highlights levator function in differing gaze positions and facilitates the identification of those patients with levator-superior rectus synkinesis.

A new instrument to aid the lateral tarsal sling procedure.

We describe a new surgical instrument and its use in the lateral tarsal sling procedure. We reviewed the charts of 23 cases of such surgery over 5 years and found its use to be an effective means of correcting horizontal eyelid laxity, with a low rate of complications. This approach provides a safe and effective alternative to the lateral tarsal strip procedure.

A cyclophilin functions in pre-mRNA splicing.

We report that the cyclophilin USA-CyP is part of distinct complexes with two spliceosomal proteins and is involved in both steps of pre-mRNA splicing. The splicing factors hPrp18 and hPrp4 have a short region of homology that defines a high affinity binding site for USA-CyP in each protein. USA-CyP forms separate, stable complexes with hPrp18 and hPrp4 in which the active site of the cyclophilin is exposed. The cyclophilin inhibitor cyclosporin A slows pre-mRNA splicing in vitro, and we show that its inhibition of the second step of splicing is caused by blocking the action of USA-CyP within its complex with hPrp18. Cyclosporin A also slows splicing in vivo, and we show that this slowing results specifically from inhibition of USA-CyP. Our results lead to a model in which USA-CyP is carried into the spliceosome in complexes with hPrp4 and hPrp18, and USA-CyP acts during splicing within these complexes. These results provide an example of the function of a cyclophilin in a complex process and provide insight into the mechanisms of action of cyclophilins.

Intensive chemotherapy with and without cranial radiation for Burkitt leukemia and lymphoma: final results of Cancer and Leukemia Group B Study 9251.

BACKGROUND: The objective of the current study was to evaluate the efficacy of intensive chemotherapy with and without cranial radiation for central nervous system (CNS) prophylaxis in adults with Burkitt leukemia or lymphoma. METHODS: Patients received 18 weeks of therapy. Prophylactic cranial radiation (2400 centigrays) and 12 doses of triple intrathecal chemotherapy were administered to the first cohort of patients. A subsequent cohort received the same therapy, with the exceptions that intrathecal therapy was reduced to six doses and radiotherapy was administered only to high-risk individuals. RESULTS: The median follow-up durations were 6.8 years in Cohort 1 and 4.1 years in Cohort 2. Three occurrences of transverse myelitis, 2 severe neuropathies, 3 cases of aphasia, and 1 case of blindness were documented in the first cohort of 52 patients (Cohort 1). In the subsequent cohort of 40 patients (Cohort 2), none of these occurrences were observed, and patients experienced less neurologic toxicity overall (61% vs. 26%; P=0.001). Responses were similar, and the 3-year event-free survival rate was 0.52 (95% confidence interval, 0.38-0.65) for Cohort 1 and 0.45 (0.29-0.60) for Cohort 2. CONCLUSIONS: Intensive, short-duration chemotherapy with less intensive CNS prophylaxis led to control at this sanctuary site with little neurotoxicity and may be curative for adults with Burkitt leukemia or lymphoma.

Differences in prognostic factors and outcomes in African Americans and whites with acute myeloid leukemia.

Whites have a more favorable prognosis than African Americans for a number of cancers. The relationship between race and outcome is less clear in acute myeloid leukemia (AML). Using data from 7 Cancer and Leukemia Group B studies initiated from 1985 to 1997, we conducted a retrospective cross-sectional analysis of 2570 patients (270 African American and 2300 white) with de novo AML who received induction chemotherapy. African Americans were younger than whites (48 versus 54 years, P <.001). African Americans also had different cytogenetic risk group distributions than whites (P <.001): they were more commonly classified in the favorable (23% versus 14%) and unfavorable (31% versus 23%) groups, and less commonly classified in the intermediate group (47% versus 63%). African American men had a lower complete remission (CR) rate (54%, compared with 64% for white men, 65% for white women, and 70% for African American women, P =.001) and a worse overall survival compared with all other patients (P =.004), when known risk factors are taken into account. African Americans and whites with AML differ with respect to important prognostic factors. African American men have worse CR rates and overall survival than whites and African American women, and should be considered a poor-risk group.