Cognitive impairment in asymptomatic carotid artery stenosis is associated with abnormal segments in the Circle of Willis.

OBJECTIVE: Our group has previously demonstrated that patients with asymptomatic carotid artery stenosis (ACAS) demonstrate cognitive impairment. One proposed mechanism for cognitive impairment in patients with ACAS is cerebral hypoperfusion due to flow-restriction. We tested whether the combination of a high-grade carotid stenosis and inadequate cross-collateralization in the Circle of Willis (CoW) resulted in worsened cognitive impairment. METHODS: Twenty-four patients with high-grade (≥70% diameter-reducing) ACAS underwent carotid duplex ultrasound, cognitive assessment, and 3D time-of-flight magnetic resonance angiography. The cognitive battery consisted of nine neuropsychological tests assessing four cognitive domains: learning and recall, attention and working memory, motor and processing speed, and executive function. Raw cognitive scores were converted into standardized T-scores. A structured interpretation of the magnetic resonance angiography images was performed with each segment of the CoW categorized as being either normal or abnormal. Abnormal segments of the CoW were defined as segments characterized as narrowed or occluded due to congenital aplasia or hypoplasia, or acquired atherosclerotic stenosis or occlusion. Linear regression was used to estimate the association between the number of abnormal segments in the CoW, and individual cognitive domain scores. Significance was set to P < .05. RESULTS: The mean age of the patients was 66.1 ± 9.6 years, and 79.2% (n = 19) were male. A significant negative association was found between the number of abnormal segments in the CoW and cognitive scores in the learning and recall (ß = -6.5; P = .01), and attention and working memory (ß = -7.0; P = .02) domains. There was a trend suggesting a negative association in the motor and processing speed (ß = -2.4; P = .35) and executive function (ß = -4.5; P = .06) domains that did not reach significance. CONCLUSIONS: In patients with high-grade ACAS, the concomitant presence of increasing occlusive disease in the CoW correlates with worse cognitive function. This association was significant in the learning and recall and attention and working memory domains. Although motor and processing speed and executive function also declined numerically with increasing abnormal segments in the CoW, the relationship was not significant. Since flow restriction at a carotid stenosis compounded by inadequate collateral compensation across a diseased CoW worsens cerebral perfusion, our findings support the hypothesis that cerebral hypoperfusion underlies the observed cognitive impairment in patients with ACAS.

Reconstruction of Broad Lower Lip Defects Using Karapandzic-Type Flaps.

BACKGROUND: Reconstruction of lower lip defects is challenging because of the functional and aesthetic demands of the lower face. We review the functional and aesthetic outcomes of the Karapandzic-type flaps for reconstructing lower lip defects. METHODS: A retrospective review of patients who underwent repair using Karapandzic-type flaps. RESULTS: Fifty patients with lower lip defects ranging from 20% to 95% (mean 59.2% ± 20%) were included. Eighteen patients (36%) were repaired using a bilateral flap, and 32 (64%) were reconstructed using a unilateral flap design. All patients had preservation of oral competency and a satisfactory aesthetic result. No patient complained of microstomia. A complication rate of 8% was noted ( n = 4) with postoperative wound infection and small areas of dehiscence. There was no statistically significant difference in complication rates in patients older than 75 years, in patients with a history of head/neck radiation, or in defects greater than 70% of lower lip breadth. CONCLUSION: Karapandzic-type flaps are versatile and reliable for the reconstruction of a broad range of lower lip defects. This one-stage procedure can produce superior functional and aesthetic results as compared with other local and distant flaps with minimal risk of functional microstomia.

Targeting intracellular WT1 in AML with a novel RMF-peptide-MHC-specific T-cell bispecific antibody.

Antibody-based immunotherapy is a promising strategy for targeting chemoresistant leukemic cells. However, classical antibody-based approaches are restricted to targeting lineage-specific cell surface antigens. By targeting intracellular antigens, a large number of other leukemia-associated targets would become accessible. In this study, we evaluated a novel T-cell bispecific (TCB) antibody, generated by using CrossMAb and knob-into-holes technology, containing a bivalent T-cell receptor-like binding domain that recognizes the RMFPNAPYL peptide derived from the intracellular tumor antigen Wilms tumor protein (WT1) in the context of HLA-A*02. Binding to CD3ε recruits T cells irrespective of their T-cell receptor specificity. WT1-TCB elicited antibody-mediated T-cell cytotoxicity against AML cell lines in a WT1- and HLA-restricted manner. Specific lysis of primary acute myeloid leukemia (AML) cells was mediated in ex vivo long-term cocultures by using allogeneic (mean ± standard error of the mean [SEM] specific lysis, 67 ± 6% after 13-14 days; n = 18) or autologous, patient-derived T cells (mean ± SEM specific lysis, 54 ± 12% after 11-14 days; n = 8). WT1-TCB-treated T cells exhibited higher cytotoxicity against primary AML cells than an HLA-A*02 RMF-specific T-cell clone. Combining WT1-TCB with the immunomodulatory drug lenalidomide further enhanced antibody-mediated T-cell cytotoxicity against primary AML cells (mean ± SEM specific lysis on days 3-4, 45.4 ± 9.0% vs 70.8 ± 8.3%; P = .015; n = 9-10). In vivo, WT1-TCB-treated humanized mice bearing SKM-1 tumors exhibited a significant and dose-dependent reduction in tumor growth. In summary, we show that WT1-TCB facilitates potent in vitro, ex vivo, and in vivo killing of AML cell lines and primary AML cells; these results led to the initiation of a phase 1 trial in patients with relapsed/refractory AML (#NCT04580121).

Surgery Alone (Without Adjuvant Radiation) Adequately Treats Histologic Perineural Basal Cell Carcinomas: A Systematic Review With Meta-Analysis.

BACKGROUND: Histologic perineural invasion (PNI) in basal cell carcinomas (BCC) lacks evidence-based treatment guidelines. OBJECTIVE: Systematically review and analyze treatment outcomes of BCC with histologic PNI (PNBCC). MATERIALS AND METHODS: PubMed, Embase, and Cochrane Reviews were searched through June 25, 2021. Thirteen eligible cohort studies were meta-analyzed. RESULTS: 502 of 713 PNBCC were treated with Mohs Surgery (MMS), wide local excision (WLE), or surgery (MMS or WLE) with adjuvant radiation (Surg + RT). Overall 5-year local control (LC) was 97.2% and cancer-specific survival (CSS) was 99.6%. Surg and Surg + RT did not differ in recurrence (2.1% vs 4.7%; p-value 0.56; RR 1.51 [0.37, 6.20]), LC (97.9% vs 96.2%; p-value 0.19; RR 0.98 [0.96, 1.01]) or CSS (100% vs 99.1%; p-value 0.40; RR 0.99 [0.95, 1.02]). LIMITATIONS: No randomized controlled trials were found. Outcome data were often lacking. CONCLUSION: Overall LC and CSS were high at median 5-year follow-up for surgery alone and Surg + RT. Surgery alone and Surg + RT demonstrated statistically equivalent outcomes. We do not recommend adjuvant radiation therapy for solely histologic PNBCC if clear margins are achieved.

The Use of a Dehydrated Complete Human Placental Membrane Allograft for Mohs Surgical Defects of the Nose.

BACKGROUND: Repair options for Mohs surgical defects include primary closure, flap or graft, or healing by second intention. These options may not be optimal in all cases. A dehydrated complete human placental membrane (dCHPM) allograft may serve as an alternative repair option. OBJECTIVE: To assess the aesthetic and functional outcomes of an alternative repair technique for Mohs surgical defects of the nose. METHODS: Twenty patients with Mohs surgical defects of the nose repaired with a dCHPM allograft were retrospectively identified. Photographs were used to demonstrate surgical technique and outcomes. Two blinded observers evaluated final outcomes using the Patient and Observer Scar Assessment Scale. RESULTS: Observers rated the scar outcome a combined mean score of 8.4 ± 3.2 (scale 5-50). Patients rated their outcomes a mean of 12.6 ± 7.4 (scale 6-60). The mean "Overall Opinion score" was 2.5 ± 1.8 by patients and 1.9 ± 1.3 by observers (scale 1-10). LIMITATIONS: This was a single institution study with a small sample size. CONCLUSION: Our study demonstrates that dCHPM allografts are a viable alternative repair option for Mohs surgical defects of the nose.

Computed tomography angiographic biomarkers help identify vulnerable carotid artery plaque.

OBJECTIVE: The current risk assessment for patients with carotid atherosclerosis relies primarily on measuring the degree of stenosis. More reliable risk stratification could improve patient selection for targeted treatment. We have developed and validated a model to predict for major adverse neurologic events (MANE; stroke, transient ischemic attack, amaurosis fugax) that incorporates a combination of plaque morphology, patient demographics, and patient clinical information. METHODS: We enrolled 221 patients with asymptomatic carotid stenosis of any severity who had undergone computed tomography angiography at baseline and ≥6 months later. The images were analyzed for carotid plaque morphology (plaque geometry and tissue composition). The data were partitioned into training and validation cohorts. Of the 221 patients, 190 had complete records available and were included in the present analysis. The training cohort was used to develop the best model for predicting MANE, incorporating the patient and plaque features. First, single-variable correlation and unsupervised clustering were performed. Next, several multivariable models were implemented for the response variable of MANE. The best model was selected by optimizing the area under the receiver operating characteristic curve (AUC) and Cohen's kappa statistic. The model was validated using the sequestered data to demonstrate generalizability. RESULTS: A total of 62 patients had experienced a MANE during follow-up. Unsupervised clustering of the patient and plaque features identified single-variable predictors of MANE. Multivariable predictive modeling showed that a combination of the plaque features at baseline (matrix, intraplaque hemorrhage [IPH], wall thickness, plaque burden) with the clinical features (age, body mass index, lipid levels) best predicted for MANE (AUC, 0.79), In contrast, the percent diameter stenosis performed the worst (AUC, 0.55). The strongest single variable for discriminating between patients with and without MANE was IPH, and the most predictive model was produced when IPH was considered with wall remodeling. The selected model also performed well for the validation dataset (AUC, 0.64) and maintained superiority compared with percent diameter stenosis (AUC, 0.49). CONCLUSIONS: A composite of plaque geometry, plaque tissue composition, patient demographics, and clinical information predicted for MANE better than did the traditionally used degree of stenosis alone for those with carotid atherosclerosis. Implementing this predictive model in the clinical setting could help identify patients at high risk of MANE.

High-Throughput Identification of MHC Class I Binding Peptides Using an Ultradense Peptide Array.

Rational vaccine development and evaluation requires identifying and measuring the magnitude of epitope-specific CD8 T cell responses. However, conventional CD8 T cell epitope discovery methods are labor intensive and do not scale well. In this study, we accelerate this process by using an ultradense peptide array as a high-throughput tool for screening peptides to identify putative novel epitopes. In a single experiment, we directly assess the binding of four common Indian rhesus macaque MHC class I molecules (Mamu-A1*001, -A1*002, -B*008, and -B*017) to ∼61,000 8-mer, 9-mer, and 10-mer peptides derived from the full proteomes of 82 SIV and simian HIV isolates. Many epitope-specific CD8 T cell responses restricted by these four MHC molecules have already been identified in SIVmac239, providing an ideal dataset for validating the array; up to 64% of these known epitopes are found in the top 192 SIVmac239 peptides with the most intense MHC binding signals in our experiment. To assess whether the peptide array identified putative novel CD8 T cell epitopes, we validated the method by IFN-γ ELISPOT assay and found three novel peptides that induced CD8 T cell responses in at least two Mamu-A1*001-positive animals; two of these were validated by ex vivo tetramer staining. This high-throughput identification of peptides that bind class I MHC will enable more efficient CD8 T cell response profiling for vaccine development, particularly for pathogens with complex proteomes for which few epitope-specific responses have been defined.

Efficacy of topical tranexamic acid in epistaxis: A systematic review and meta-analysis.

INTRODUCTION: Epistaxis is a very common presentation in the emergency department (ED), accounting for approximately 1 in 200 ED visits in the United States. Currently, standard practice includes the initial use of topical anesthetics and vasoconstrictors, followed by more invasive treatments such as nasal packing, cauterization or surgical ligation for refractory cases. Over the years several studies have investigated the potential use of topical Tranexamic Acid (TXA) in the management of epistaxis. We have conducted a meta-analysis to assess the efficacy of topical TXA versus other standard practices or placebo in the management of epistaxis. METHODS: PubMed and Scopus databases were searched from inception to April 2021. We included randomized controlled trials and observational studies investigating the efficacy of TXA in bleeding cessation in epistaxis in adults. The primary outcome measured was the prevalence of bleeding cessation after treatment at first assessment. Other outcomes were bleeding reoccurrence between 24 and 72 h and at 7-8 days. A random-effects model was used to estimate odds ratio (OR) for outcomes. RESULTS: A total of eight studies were included in the analysis, including seven randomized trials and one retrospective study. We included a total of 1299 patients, 596 (46%) received TXA while 703 (54%) received control treatment (placebo, lidocaine plus vasoconstrictors or local anesthetics). Patients who were treated with TXA were 3.5 times (OR 3.5, 95% CI 1.3-9.7) more likely to achieve bleeding cessation at the first assessment. Patients treated with TXA had 63% (OR 0.37, 95% CI 0.20-0.66) less likelihood of returning due to rebleeding at 24-72 h. CONCLUSION: Topical TXA is associated with better bleeding cessation rates after treatment compared to the standard practices.

PD-1 inhibitors for cutaneous squamous cell carcinoma: A meta-analysis.

PD-1 inhibitors are immunotherapeutic agents used in the treatment of advanced cutaneous squamous cell carcinoma (cSCC). This study aimed to determine the pooled objective response and disease control rates of patients with advanced cSCC treated with PD-1 inhibitors. Pubmed, Cochrane Library and EMBASE databases were searched up to 1 January 2021 to include eligible articles. Objective response rate (ORR) and disease control rate (DCR) were pooled and analysed. Subgroup analysis of the odds ratio (OR) for ORR for patients by PD-L1 tumour proportion score (TPS) was performed. Seven articles including a total of 453 patients were identified and included. Pooled estimate of ORR was 44% (95% CI: 39-49%, I2 = 23.7%) and of DCR was 66% (95% CI: 57-74%, I2 = 68.2%). Pooled odds ratio of ORR for patients by PD-L1 TPS was 2.81 (95% CI: 1.22-6.51, I2 = 0.0%). These results were derived from single-arm studies, some of which were retrospective. No head-to-head trials comparing PD-1 inhibitors have been reported. We present aggregate estimates of ORR and DCR for patients with advanced cSCC treated with PD-1 inhibitors, as well as subgroup analysis for ORR for patients by PD-L1 TPS.

Valproic Acid Overdose: Case Report and Literature Review.

BACKGROUND: Valproic acid (VPA) is a common antiepileptic drug that is also used routinely for various psychiatric disorders. VPA toxicity typically manifests as central nervous system depression, while hyperammonemic encephalopathy and hepatotoxicity are potentially life-threatening complications. CASE REPORT: We describe the case of a 56-year-old man who presented to the emergency department after an intentional VPA overdose, was found to have hyperammonemia, and was treated with L-carnitine exclusively. He was subsequently admitted to the hospital for monitoring and serial laboratory testing. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Although VPA toxicity has conventionally been managed by gastric decontamination, L-carnitine, and, in severe and refractory cases, extracorporeal removal, recent literature supports the use of carbapenem antibiotics, particularly meropenem. Thus, we report the details of current treatment modalities for VPA toxicity by reviewing current literature.

Epitope-Specific Antibody Responses to a Plasmodium falciparum Subunit Vaccine Target in a Malaria-Endemic Population.

Circumsporozoite protein (CSP) coats the Plasmodium falciparum sporozoite surface and is a major malaria subunit vaccine target. We measured epitope-specific reactivity to field-derived CSP haplotypes in serum samples from Malian adults and children on a custom peptide microarray. Compared to children, adults showed greater antibody responses and responses to more variants in regions proximal to and within the central repeat region. Children acquired short-lived immunity to an epitope proximal to the central repeat region but not to the central repeat region itself. This approach has the potential to differentiate immunodominant from protective epitope-specific responses when combined with longitudinal infection data.

Correlation of the Position of the Anal Dimple with the Caudal Termination of the Striated Muscle Complex in Patients with Anorectal Malformations.

Background: In children with anorectal malformations (ARM), the vertical fibres of the striated muscle complex (SMC) are believed to be located within the limits of the anal dimple (AD). Methods: Forty five cases of ARM underwent posterior sagittal anorectoplasty (PSARP), median age 8.5 months. During PSARP the anterior, posterior limits and midpoint of the AD and SMC were marked. The location of AD was correlated with SMC. Results: A 'well developed' AD and SMC was seen in 80 % and 86.7 % patients respectively. The mean width of the AD and SMC was more in females than in males (20.96 vs. 18.98 mm and 14.24mm vs. 13.45mm respectively). In 36 cases (80 %), across the spectrum of ARM, the SMC was posterior in relation to the AD. In 7 cases (15.5 %) it correlated in position with the AD and in 2 cases (4.44 %), it was anterior to the AD. Conclusions: In the majority of cases AD and SMC were 'well developed' and the location of the SMC does not correlate with that of the AD. This has significant practical value in the important step of optimizing the placement of the rectum through the center of the SMC during repair.

Asymptomatic carotid artery stenosis is associated with cerebral hypoperfusion.

OBJECTIVE: We have shown that almost 50% of patients with asymptomatic carotid stenosis (ACS) will demonstrate cognitive impairment. Recent evidence has suggested that cerebral hypoperfusion is an important cause of cognitive impairment. Carotid stenosis can restrict blood flow to the brain, with consequent cerebral hypoperfusion. In contrast, cross-hemispheric collateral compensation through the Circle of Willis, and cerebrovascular vasodilation can also mitigate the effects of flow restriction. It is, therefore, critical to develop a clinically relevant measure of net brain perfusion in patients with ACS that could help in risk stratification and in determining the appropriate treatment. To determine whether ACS results in cerebral hypoperfusion, we developed a novel approach to quantify interhemispheric cerebral perfusion differences, measured as the time to peak (TTP) and mean transit time (MTT) delays using perfusion-weighted magnetic resonance imaging (PWI) of the whole brain. To evaluate the utility of using clinical duplex ultrasonography (DUS) to infer brain perfusion, we also assessed the relationship between the PWI findings and ultrasound-based peak systolic velocity (PSV). METHODS: Structural and PWI of the brain and magnetic resonance angiography of the carotid arteries were performed in 20 patients with ≥70% ACS. DUS provided the PSV, and magnetic resonance angiography provided plaque geometric measures at the stenosis. Volumetric perfusion maps of the entire brain from PWI were analyzed to obtain the mean interhemispheric differences for the TTP and MTT delays. In addition, the proportion of brain volume that demonstrated a delay in TTP and MTT was also measured. These proportions were measured for increasing severity of perfusion delays (0.5, 1.0, and 2.0 seconds). Finally, perfusion asymmetries on PWI were correlated with the PSV and stenosis features on DUS using Pearson's correlation coefficients. RESULTS: Of the 20 patients, 18 had unilateral stenosis (8 right and 10 left) and 2 had bilateral stenoses. The interhemispheric (left-right) TTP delays measured for the whole brain volume identified impaired perfusion in the hemisphere ipsilateral to the stenosis in 16 of the 18 patients. More than 45% of the patients had had ischemia in at least one half of their brain volume, with a TTP delay >0.5 second. The TTP and MTT delays showed strong correlations with PSV. In contrast, the correlations with the percentage of stenosis were weaker. The correlations for the PSV were strongest with the perfusion deficits (TTP and MTT delays) measured for the whole brain using our proposed algorithm (r = 0.80 and r = 0.74, respectively) rather than when measured on a single magnetic resonance angiography slice as performed in current clinical protocols (r = 0.31 and r = 0.58, respectively). CONCLUSIONS: Interhemispheric TTP and MTT delay measured for the whole brain using PWI has provided a new tool for assessing cerebral perfusion deficits in patients with ACS. Carotid stenosis was associated with a detectable reduction in ipsilateral brain perfusion compared with the opposite hemisphere in >80% of patients. The PSV measured at the carotid stenosis using ultrasonography correlated with TTP and MTT delays and might serve as a clinically useful surrogate to brain hypoperfusion in these patients.

Treatment of advanced cutaneous squamous cell carcinoma: a Mohs surgery and dermatologic oncology perspective.

Locally advanced or metastatic cutaneous squamous cell carcinoma no longer amenable to surgical resection or primary radiation therapy requires an alternative approach to treatment. Until 2018, management consisted of limited systemic chemotherapies, which carried marginal clinical benefit. The introduction of immunotherapy with anti-PD-1 antibodies resulted in alternative treatment options for advanced cutaneous squamous cell carcinoma with substantial antitumor activity, durable response and acceptable safety profile. The field of immunotherapeutics continues to expand with adjuvant, neoadjuvant and intralesional studies currently in progress. Herein, the authors discuss their approach for the treatment of advanced cutaneous squamous cell carcinoma from the perspective of a Mohs surgeon and a dermatologic oncologist.

Efficacy of uncovered colonic stents for extrinsic versus intrinsic malignant large bowel obstruction.

BACKGROUND: Previous studies evaluating self-expandable metal stents (SEMS) for management of malignant extrinsic colon obstruction have yielded conflicting results. We evaluated the efficacy of uncovered SEMS for extrinsic colon malignancy (ECM) versus intrinsic colon malignancy (ICM). METHODS: Retrospective review of all patients referred for colonic SEMS at a tertiary cancer center between 2007 and 2018 was performed. Primary outcome measures were technical success, clinical success, intervention rate, and overall survival. RESULTS: 138 patients with ECM and 119 patients with ICM underwent attempted stent placement. The rectum and/or sigmoid colon was the most common stricture site. Technical success was lower in the ECM group [86% vs 96% (p = .009)]. Clinical success was lower in the ECM group both at 7 days [82% vs 95% (p = .004)] and at 90 days [60% vs 86% (p < .001)]. Subsequent intervention was required more frequently [44% vs 35%; p = .23] and earlier [median 9 vs 132 days; p < .001] in the ECM group. Median overall survival in the ECM group was 92 vs 167 days. Among predictive variables analyzed, the ECM group had a higher frequency of peritoneal metastasis (87% vs 32%; p < .001), multifocal strictures with requirement for multiple stents (20% vs 6%; p = .002), sharp angulated strictures (39% vs 25%; p = .04) , and radiation therapy (21% vs 10%; p = .02). CONCLUSIONS: Colonic SEMS for ECM is associated with lower technical and clinical success with earlier intervention rates compared with ICM. Our findings can be used to better inform patients and referring providers as well as guide new stent design to enhance efficacy in this population.

Contribution of non-HLA incompatibility between donor and recipient to kidney allograft survival: genome-wide analysis in a prospective cohort.

BACKGROUND: The introduction of HLA matching of donors and recipients was a breakthrough in kidney transplantation. However, half of all transplanted kidneys still fail within 15 years after transplantation. Epidemiological data suggest a fundamental role of non-HLA alloimmunity. METHODS: We genotyped 477 pairs of deceased donors and first kidney transplant recipients with stable graft function at three months that were transplanted between Dec 1, 2005, and April 30, 2015. Genome-wide genetic mismatches in non-synonymous single nucleotide polymorphisms (nsSNPs) were calculated to identify incompatibilities in transmembrane and secreted proteins. We estimated the association between nsSNP mismatch and graft loss in a Cox proportional hazard model, adjusting for HLA mismatch and clinical covariates. Customised peptide arrays were generated to screen for antibodies against genotype-derived mismatched epitopes in 25 patients with biopsy-confirmed chronic antibody-mediated rejection. FINDINGS: 59 268 nsSNPs affecting a transmembrane or secreted protein were analysed. The median number of nsSNP mismatches in immune-accessible transmembrane and secreted proteins between donors and recipients was 1892 (IQR 1850-1936). The degree of nsSNP mismatch was independently associated with graft loss in a multivariable model adjusted for HLA eplet mismatch (HLA-A, HLA-B, HLA-C, HLA-DP, HLA-DQ, and HLA-DR). Each increase by a unit of one IQR had an HR of 1·68 (95% CI 1·17-2·41, p=0·005). 5-year death censored graft survival was 98% in the quartile with the lowest mismatch, 91% in the second quartile, 89% in the third quartile, and 82% in the highest quartile (p=0·003, log-rank test). Customised peptide arrays verified a donor-specific alloimmune response to genetically predicted mismatched epitopes. INTERPRETATION: Genetic mismatch of non-HLA haplotypes coding for transmembrane or secreted proteins is associated with an increased risk of functional graft loss independently of HLA incompatibility. As in HLA alloimmunity, donor-specific alloantibodies can be identified against genotype derived non-HLA epitopes. FUNDING: Austrian Science Fund, WWTF (Vienna Science and Technology Fund), and Ministry of Health of the Czech Republic.

Resolution of Pembrolizumab-Associated Steroid-Refractory Lichenoid Dermatitis with Cyclosporine.

Checkpoint inhibitors such as pembrolizumab, an anti-PD-1 monoclonal antibody, are a promising new category of oncological therapeutics, associated with a higher risk of immune-related adverse events including dermatological, autoimmune and endocrine sequelae. Here, we present a case of a woman 76 years of age with stage IV lung adenocarcinoma who developed a severe and steroid-refractory lichenoid dermatitis associated with pruritus on pembrolizumab. This eruption resolved completely with a short course of oral cyclosporine. Cyclosporine is a promising and effective treatment option for checkpoint inhibitor-related severe cutaneous eruptions.

Quantitative assessment of carotid plaque morphology (geometry and tissue composition) using computed tomography angiography.

OBJECTIVE: Quantification of carotid plaque morphology (geometry and tissue composition) may help stratify risk for future stroke and assess plaque progression or regression in response to medical risk factor modification. We assessed the feasibility and reliability of morphologic measurements of carotid plaques using computed tomography angiography (CTA) and determined the minimum detectable change in plaque features by this approach. METHODS: CTA images of both carotid arteries in 50 patients were analyzed by two observers using a semiautomatic image analysis program, yielding 93 observations per user (seven arteries were excluded because of prior stenting). One observer repeated the analyses 4 weeks later. Measurements included total plaque volume; percentage stenosis (by diameter and area); and tissue composition for calcium, lipid-rich necrotic core (LRNC), and intraplaque hemorrhage (IPH). Reliability of measurements was assessed by intraclass and interclass correlation and Bland-Altman plots. Dice similarity coefficient (DSC) and modified Hausdorff distance (MHD) assessed reliability of geometric shape measurements. We additionally computed the minimum amount of change in these features detectable by our approach. RESULTS: The cohort was 51% male (mean age, 70.1 years), and 56% had a prior stroke. The mean (± standard deviation) plaque volume was 837.3 ± 431.3 mm3, stenosis diameter was 44.5% ± 25.6%, and stenosis area was 58.1% ± 29.0%. These measurements showed high reliability. Intraclass correlation coefficients for plaque volume, percentage stenosis by diameter, and percentage stenosis by area were 0.96, 0.87, and 0.83, respectively; interclass correlation coefficients were 0.88, 0.84, and 0.78. Intraclass correlations for tissue composition were 0.99, 0.96, and 0.86 (calcium, LRNC, and IPH, respectively), and interclass correlations were 0.99, 0.92, and 0.92. Shape measurements showed high intraobserver (DSC, 0.95 ± 0.04; MHD, 0.16 ± 0.10 mm) and interobserver (DSC, 0.94 ± 0.05; MHD, 0.19 ± 0.12 mm) luminal agreement. This approach can detect a change of at least 3.9% in total plaque volume, 1.2 mm3 in calcium, 4.3 mm3 in LRNC, and 8.6 mm3 in IPH with the same observer repeating measurements and 9.9% in plaque volume, 1.9 mm3 in calcium, 7.9 mm3 in LRNC, and 6.8 mm3 in IPH for two different observers. CONCLUSIONS: Carotid plaque geometry (total volume, diameter stenosis, and area stenosis) and tissue composition (calcium, LRNC, and IPH) are measured reliably from clinical CTA images using a semiautomatic image analysis program. The minimum change in plaque volume detectable is ∼4% if the same observer makes both measurements and ∼10% for different observers. Small changes in plaque composition can also be detected reliably. This approach can facilitate longitudinal studies for identifying high-risk plaque features and for quantifying plaque progression or regression after treatment.

Hybrid glycophorin and red blood cell antigen genotyping in Asian American type O blood donors with Mia phenotype.

BACKGROUND: The GP.Mur glycophorin with Mia phenotype is relatively common and clinically significant in the Southeast Asian populations. The aim of this study is to genotype Mia -positive Asian American type O blood donors. Red blood cell (RBC) minor antigens were also determined in the same cohort. STUDY DESIGN AND METHODS: Asian American blood donors of the Gulf Coast Regional Blood Center (Houston, TX) were screened using a typing reagent (NOVACLONE Anti-Mia Monoclonal IgG Typing Reagent, Dominion Biologicals Ltd) from March 2016 to July 2018. Aliquots of Mia -positive blood from type O donors were subjected to serologic confirmation using Mia - and/or Mur-specific GAMA210 and 64D6 monoclonal antibodies, and two human antisera. Extracted genomic DNA was amplified by polymerase chain reaction (PCR) using GYP hybrid gene/allele-specific primers followed by bidirectional Sanger sequencing. Zygosity for GYP*Mur and GYP*Bun was determined using TaqMan real-time PCR assay. Phenotypes of 35 RBC antigens and three phenotypic variants were determined with use of an in vitro diagnostic test, PreciseType HEA Molecular BeadChip Test (Immucor). RESULTS: By screening 4600 blood donations in the Houston metropolitan area, 209 samples from 103 unique donors were identified to be Mia -positive. By PCR and sequencing analysis, 97 of the 103 Mia -positive donors carried hybrid genes GYP*Mur (89.7% including two homozygotes), GYP*Bun (6.2%), GYP*Vw (3.1%) and GYP*Hut (1.0%). Concordance between serology and DNA analysis was 98%, 99%, and 100% for the GAMA210, 64D6, and human antisera, respectively. Genotyping of RBC antigens showed that the Mia -positive donors were predominantly associated M+ N- S- s+ (48.5%) and M+ N+ S- s+ (38.1%) phenotypes. CONCLUSIONS: The GP.Mur glycophorin is most prevalent in the Mia -positive Asian American type O blood donors.