Diagnostic discordance among histopathological reviewers of melanocytic lesions.

BACKGROUND: Histopathological examination is adequate for the diagnosis of most cutaneous melanocytic neoplasms. However, there is a subset that is either difficult to definitively diagnose or would have diagnostic disagreement upon review by multiple dermatopathologists if a more exhaustive review was performed. METHODS: Melanocytic lesions underwent an independent, blinded diagnostic histopathological review of hematoxylin and eosin-stained sections. Each lesion was reviewed by three to six dermatopathologists and categorized as benign, malignant, or unknown malignant potential (UMP). Diagnoses were grouped as concordant (all the same designation); opposing (received benign and malignant designations); majority (single designation with the highest number of diagnoses, no benign/malignant opposing designations); and non-definitive (equal number of non-opposing designations [i.e., benign/UMP or malignant/UMP]). Lesions with equivocal designations (concordant or majority UMP, opposing, majority, and non-definitive) were utilized in a patient treatment model of projected surgical treatment discrepancies. RESULTS: In total, 3317 cases were reviewed, and 23.8% of lesions received equivocal diagnoses. Of these, 7.3% were majority benign, 4.8% were majority malignant, 2.7% were majority UMP, 0.5% were concordant UMP, 6.9% were opposing, and 1.6% were non-definitive. Patient treatment models of those with equivocal lesions (n = 788) revealed a potential of overall surgical treatment variations ranging from 18% to 72%, with the highest variation amongst lesions with opposing, non-definitive, or majority UMP (40%-72%) diagnoses. CONCLUSION: Histopathologic review in this large cohort demonstrated substantial diagnostic variation, with 23.8% of cases receiving equivocal diagnoses. We identified diagnostic ambiguity even in lesions where a definitive diagnosis was previously rendered by a single real-world dermatopathologist. The combined clinical impact of diagnostic discordance or a final diagnosis of UMP is highlighted by high diagnosis-dependent treatment variation in the patient treatment model, which could be underreported in a real-world setting, where review by more than one to two dermatopathologists is relatively rare.

Standardization of key performance indicators and metrics for investigational drug services (IDS): Consensus recommendations among IDS specialists.

DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. PURPOSE: There are currently no consensus guidelines on establishing metrics for investigational drug services (IDS). Because of the complexity of research protocols, it remains difficult for sites to track pharmacy productivity and create a baseline for IDS growth within the institution, as well as to perform benchmarking with peer institutions. The goal of this study was to help establish practical guidance for IDS metrics and site utility as applicable. METHODS: This was a survey-based project conducted by the metrics subgroup of the Hematology/Oncology Pharmacy Association (HOPA) IDS special interest group (SIG), which was formed specifically for this analysis. Three surveys developed by the metrics subgroup were sent to members of the IDS HOPA SIG to gather metrics. The first survey included questions about what metrics IDS sites currently collect. The identified metrics were then condensed into categories. Through a consensus-based approach, standardized definitions were established and applied to future surveys. The 2 subsequent surveys sent to HOPA SIG members helped create a list of top recommended metrics that are recommended for every IDS site to track. RESULTS: A total of 3 surveys were sent to 75 recipients, with the response rate ranging from 24% to 38%. From these surveys and consensus with the metrics subgroup, 5 top recommended metrics were identified: (1) active protocols; (2) dispenses; (3) new clinical trials initiated; (4) patients treated; and (5) clinical interventions. CONCLUSION: These recommended metrics should serve as guidance and allow for standardization to help ensure adequate resources are available for IDS pharmacy staff. These recommendations should serve as a basis for standardization and benchmarking with peer institutions.

Neuroleptic strategies for terminal agitation in patients with cancer and delirium at an acute palliative care unit: a single-centre, double-blind, parallel-group, randomised trial.

BACKGROUND: The role of neuroleptics for terminal agitated delirium is controversial. We assessed the effect of three neuroleptic strategies on refractory agitation in patients with cancer with terminal delirium. METHODS: In this single-centre, double-blind, parallel-group, randomised trial, patients with advanced cancer, aged at least 18 years, admitted to the palliative and supportive care unit at the University of Texas MD Anderson Cancer Center (Houston, TX, USA), with refractory agitation, despite low-dose haloperidol, were randomly assigned to receive intravenous haloperidol dose escalation at 2 mg every 4 h, neuroleptic rotation with chlorpromazine at 25 mg every 4 h, or combined haloperidol at 1 mg and chlorpromazine at 12·5 mg every 4 h, until death or discharge. Rescue doses identical to the scheduled doses were administered at inception, and then hourly as needed. Permuted block randomisation (block size six; 1:1:1) was done, stratified by baseline Richmond Agitation Sedation Scale (RASS) scores. Research staff, clinicians, patients, and caregivers were masked to group assignment. The primary outcome was change in RASS score from time 0 to 24 h. Comparisons among group were done by modified intention-to-treat analysis. This completed study is registered with ClinicalTrials.gov, NCT03021486. FINDINGS: Between July 5, 2017, and July 1, 2019, 998 patients were screened for eligibility, with 68 being enrolled and randomly assigned to treatment; 45 received the masked study interventions (escalation n=15, rotation n=16, combination n=14). RASS score decreased significantly within 30 min and remained low at 24 h in the escalation group (n=10, mean RASS score change between 0 h and 24 h -3·6 [95% CI -5·0 to -2·2]), rotation group (n=11, -3·3 [-4·4 to -2·2]), and combination group (n=10, -3·0 [-4·6 to -1·4]), with no difference among groups (p=0·71). The most common serious toxicity was hypotension (escalation n=6 [40%], rotation n=5 [31%], combination n=3 [21%]); there were no treatment-related deaths. INTERPRETATION: Our data provide preliminary evidence that the three strategies of neuroleptics might reduce agitation in patients with terminal agitation. These findings are in the context of the single-centre design, small sample size, and lack of a placebo-only group. FUNDING: National Institute of Nursing Research.

Fetal Adrenal Gland Volume a Novel Predictor of Onset of Labor.

INTRODUCTION: There is a definite need to find a highly sensitive and specific, noninvasive, and cost-effective marker for prediction of preterm labor. We hypothesize that a measurement of adrenal gland volume can predict a preterm as well as a term labor. MATERIALS AND METHODS: Two hundred and sixty-eight pregnant women were enrolled in the study at 28-34 weeks' antenatal visit. Final analysis was done in 204. All of them were subjected to 2D ultrasonographic measurement of the corrected fetal adrenal gland volume (cFAGV) and fetal adrenal zone parameters including the width ratio and depth ratio. The cohort was followed up to term, and a reassessment of cFAGV and fetal adrenal zone parameters was repeated between 37 and 39 weeks. Women who presented with features of preterm labor had a scan at the time of presentation to record cFAGV and fetal adrenal zone parameters. RESULTS: Women, who developed features of preterm labor eventually, had a significantly high cFAGV (404.70 mm3/kg body weight) during the first scan compared to those who reached term asymptomatically (241.35 mm3/kg body weight). A cutoff value of 271.16 mm3/kg body weight showed 90% sensitivity and 81.9% specificity. Fetal adrenal gland width ratio had the best efficacy (sensitivity 96.67%, specificity 86.2%) followed by cFAGV (sensitivity 96.67%, specificity 83%) for predicting preterm delivery. CONCLUSION: 2D ultrasound measurement of fetal adrenal gland parameters can be used as a marker for prediction of preterm delivery. cFAGV at term can also be used to predict the possibility of spontaneous onset of labor.

Multiple melanocytic nevi restricted to mycosis fungoides patches in pediatric and young-adult patients. The potential role of local immunosuppression.

We described the development of multiple melanocytic nevi within long-standing MF patches in four young patients. Mycosis fungoides (MF) patches are characterized by a regulatory-like cytokine profile leading to local immune suppression. The proliferation of nevomelanocytes is regulated by cellular senescence mechanisms mediated by immune system. The immunosuppressive effect of MF infiltrate in conjunction with the systemic effect of treatments may play a specific role in the nevomelanogenesis of the patients herein described.

Mycophenolate Mofetil Treatment of Systemic Sclerosis Reduces Myeloid Cell Numbers and Attenuates the Inflammatory Gene Signature in Skin.

Fewer than half of patients with systemic sclerosis demonstrate modified Rodnan skin score improvement during mycophenolate mofetil (MMF) treatment. To understand the molecular basis for this observation, we extended our prior studies and characterized molecular and cellular changes in skin biopsies from subjects with systemic sclerosis treated with MMF. Eleven subjects completed ≥24 months of MMF therapy. Two distinct skin gene expression trajectories were observed across six of these subjects. Three of the six subjects showed attenuation of the inflammatory signature by 24 months, paralleling reductions in CCL2 mRNA expression in skin and reduced numbers of macrophages and myeloid dendritic cells in skin biopsies. MMF cessation at 24 months resulted in an increased inflammatory score, increased CCL2 mRNA and protein levels, modified Rodnan skin score rebound, and increased numbers of skin myeloid cells in these subjects. In contrast, three other subjects remained on MMF >24 months and showed a persistent decrease in inflammatory score, decreasing or stable modified Rodnan skin score, CCL2 mRNA reductions, sera CCL2 protein levels trending downward, reduction in monocyte migration, and no increase in skin myeloid cell numbers. These data summarize molecular changes during MMF therapy that suggest reduction of innate immune cell numbers, possibly by attenuating expression of chemokines, including CCL2.

Risk Assessment at 11-14-Week Antenatal Visit: A Tertiary Referral Center Experience from South India.

Background: Present study carried out in a tertiary referral hospital in South India attempts to determine the predictive value of integrated screening at 11-14-week antenatal visit. Objectives: To determine the detection rate of fetal abnormalities at 11-14 weeks and also to predict the placental dysfunction disorders based on early integrated evaluation. Method: Integrated screening performed on 440 women between 11 and 14 weeks, including detailed maternal history [medical history, bad obstetric history (BOH)], body mass index (BMI), mean arterial pressure (MAP), detailed ultrasound and maternal serum biochemistry as part of combined first-trimester screening for aneuploidy. Results: There were two proven Down's syndrome foetuses; both detected with combined screening test. There were 12 fetuses with major anomalies, out of whom 7 (58.3%) detected in 11-14-week scan. Among 440, 114 pregnancies (25.9%) developed complications in pregnancy, including 33 (7.5%) gestational hypertension, 8 (1.8%) pre-eclampsia, 41 (9.38%) SGA, 13 (2.9%) abortions, 22 (5%) indicated and 9 (2.04%) spontaneous preterm deliveries, 38 (8.63%) GDM and 3 (0.6%) stillbirth/IUD. Among the risk factors, age >35 years, BMI >23 kg/m2, BOH, MAP >105 mmHg and PAPP-A <0.5 MoM correlated well with adverse outcome. Using early integrated screening, 78.9% of obstetric complications could be predicted although 306 (69.5%) were labeled high risk, among whom 90 (29.4%) developed adverse pregnancy outcomes. Conclusions: Majority of fetal abnormalities can be detected, and majority adverse pregnancy outcomes can be predicted at 11-14-week antenatal visit, although this study shows high screen positivity and low specificity in a tertiary referral unit.

Effect of Lorazepam With Haloperidol vs Haloperidol Alone on Agitated Delirium in Patients With Advanced Cancer Receiving Palliative Care: A Randomized Clinical Trial.

Importance: The use of benzodiazepines to control agitation in delirium in the last days of life is controversial. Objective: To compare the effect of lorazepam vs placebo as an adjuvant to haloperidol for persistent agitation in patients with delirium in the setting of advanced cancer. Design, Setting, and Participants: Single-center, double-blind, parallel-group, randomized clinical trial conducted at an acute palliative care unit at MD Anderson Cancer Center, Texas, enrolling 93 patients with advanced cancer and agitated delirium despite scheduled haloperidol from February 11, 2014, to June 30, 2016, with data collection completed in October 2016. Interventions: Lorazepam (3 mg) intravenously (n = 47) or placebo (n = 43) in addition to haloperidol (2 mg) intravenously upon the onset of an agitation episode. Main Outcomes and Measures: The primary outcome was change in Richmond Agitation-Sedation Scale (RASS) score (range, -5 [unarousable] to 4 [very agitated or combative]) from baseline to 8 hours after treatment administration. Secondary end points were rescue neuroleptic use, delirium recall, comfort (perceived by caregivers and nurses), communication capacity, delirium severity, adverse effects, discharge outcomes, and overall survival. Results: Among 90 randomized patients (mean age, 62 years; women, 42 [47%]), 58 (64%) received the study medication and 52 (90%) completed the trial. Lorazepam + haloperidol resulted in a significantly greater reduction of RASS score at 8 hours (-4.1 points) than placebo + haloperidol (-2.3 points) (mean difference, -1.9 points [95% CI, -2.8 to -0.9]; P < .001). The lorazepam + haloperidol group required less median rescue neuroleptics (2.0 mg) than the placebo + haloperidol group (4.0 mg) (median difference, -1.0 mg [95% CI, -2.0 to 0]; P = .009) and was perceived to be more comfortable by both blinded caregivers and nurses (caregivers: 84% for the lorazepam + haloperidol group vs 37% for the placebo + haloperidol group; mean difference, 47% [95% CI, 14% to 73%], P = .007; nurses: 77% for the lorazepam + haloperidol group vs 30% for the placebo + haloperidol group; mean difference, 47% [95% CI, 17% to 71%], P = .005). No significant between-group differences were found in delirium-related distress and survival. The most common adverse effect was hypokinesia (3 patients in the lorazepam + haloperidol group [19%] and 4 patients in the placebo + haloperidol group [27%]). Conclusions and Relevance: In this preliminary trial of hospitalized patients with agitated delirium in the setting of advanced cancer, the addition of lorazepam to haloperidol compared with haloperidol alone resulted in a significantly greater reduction in agitation at 8 hours. Further research is needed to assess generalizability and adverse effects. Trial Registration: clinicaltrials.gov Identifier: NCT01949662.

A Novel Nonantibiotic Nitroglycerin-Based Catheter Lock Solution for Prevention of Intraluminal Central Venous Catheter Infections in Cancer Patients.

For long-term central lines (CL), the lumen is the major source of central line-associated bloodstream infections (CLABSI). The current standard of care for maintaining catheter patency includes flushing the CL with saline or heparin. Neither agent has any antimicrobial activity. Furthermore, heparin may enhance staphylococcal biofilm formation. We evaluated the safety and efficacy of a novel nonantibiotic catheter lock solution for the prevention of CLABSI. Between November 2015 and February 2016, we enrolled 60 patients with hematologic malignancies who had peripherally inserted central catheters (PICC) to receive the study lock solution. The study lock consisted of 15 or 30 µg/ml of nitroglycerin in combination with 4% sodium citrate and 22% ethanol. Each lumen was locked for at least 2 h once daily prior to being flushed. After enrollment of 10 patients at the lower nitroglycerin dose without evidence of toxicity, the dose was escalated to the higher dose (30 µg/ml). There were no serious related adverse events or episodes of hypotension with lock administration. Two patients experienced mild transient adverse events (one headache and one rash) possibly related to the lock and that resolved without residual effect. The CLABSI rate was 0 on lock days versus 1.6/1,000 catheter days (CD) off lock prophylaxis, compared with a rate of 1.9/1,000 CD at the institution in the same patient population. In conclusion, the nitroglycerin-based lock prophylaxis is safe and well tolerated. It may prevent CLABSI when given daily to cancer patients. Large, prospective, randomized clinical trials are needed to validate these findings. (This study has been registered at ClinicalTrials.gov under identifier NCT02577718.).

Eccrine Syringofibroadenoma in Association With Acquired Epidermodysplasia Verruciformis.

A 75-year-old man with human immunodeficiency virus infection and numerous biopsy-proven warts for 10 years, refractory to cryosurgery, cimetidine, and topical imiquimod, presented with numerous pink to hypopigmented verrucous papules and plaques involving the face, trunk, buttocks, and groin. Laboratory evaluation revealed a CD4 T-cell count of 62 cells per microliter and human immunodeficiency virus viral load of <117 copies per milliliter. Biopsy of a plaque groin lesion was performed. Histopathology revealed vertically oriented anastomosing strands of basaloid epithelium arising from multiple points along the epidermis in a background fibrovascular stroma. Ductal differentiation was identified. Areas of epidermis showed compact orthokeratosis, coarse hypergranulosis, and keratinocytes with abundant steel-blue-gray cytoplasm, indicative of viral cytopathic changes. Cytologic atypia was not identified. Human papillomavirus (HPV) genotyping of this lesion was positive for types 5 and 14. Overall, the findings were consistent with epidermodysplasia verruciformis in association with eccrine syringofibroadenoma (ESFA). The patient was subsequently treated with acitretin and showed clinical improvement. ESFA is an uncommon benign adnexal tumor with unknown pathogenesis. Although its association with HPV has rarely been reported, ESFA in the setting of acquired epidermodysplasia verruciformis has not been described. The development of ESFA in this case may be the result of HPV-induced cellular transformation.

Varied Presentations of Pediatric Lipoblastoma: Case Series and Review of the Literature.

Lipoblastoma is a rare neoplasm of embryonal adipose tissue most often encountered on the trunk and extremities of children. It commonly presents as a painless subcutaneous soft tissue mass, but there are other unique clinical presentations that are important to recognize. The differential is broad and includes sarcoma, vascular tumor, myofibroma, and other fibromatoses. We present three varied, distinct cases of pediatric lipoblastoma and review the literature on this condition.

Atypical Spitzoid Neoplasms in Childhood: A Molecular and Outcome Study.

The natural history of atypical Spitz neoplasms remains poorly understood, resulting in significant patient and clinician anxiety. We sought to better characterize outcomes that correlated with molecular features by performing a prospective cohort study of pediatric atypical spitzoid neoplasms in which fluorescence in situ hybridization studies were obtained for diagnosis. Cases with sufficient tissue underwent additional retrospective assessment for translocations in ALK, NTRK1, BRAF, RET, and ROS1. Among 246 total patients assessed, 13% had a positive fluorescence in situ hybridization result. Follow-up data was available in 85 patients. Two patients had a recurrence of whom 1 had distant metastasis. Both patients had homozygous deletions in 9p21. Homozygous deletions in 9p21 significantly correlated with recurrence of disease (P = 0.027). Fifteen (36%) of 42 cases were found to have a kinase fusion protein. However, the presence of kinase fusions was nonprognostic of recurrence (P > 0.99). This study was limited by the availability and length of follow-up data and the number of adverse outcomes. The majority of atypical spitzoid neoplasms in childhood have indolent behavior. Although the subgroup of patients with homozygous deletions in 9p21 is at higher risk for aggressive clinical behavior, their prognosis seems considerably better than similarly staged conventional melanoma.

A Comparison of Morphologic and Molecular Features of BRAF, ALK, and NTRK1 Fusion Spitzoid Neoplasms.

Recent studies have identified translocations involving the kinase domains of ALK, NTRK1, BRAF, RET, and ROS in spitzoid neoplasms. Subsequent studies have also characterized morphologic features corresponding to ALK and NTRK1 translocations. In this study, we sought to further compare morphologic features across a range of 49 genetically defined spitzoid neoplasms with ALK, NTRK1, BRAF, or RET fusions to determine discriminating features. We also compared them with a group of 22 spitzoid neoplasms, which were confirmed to be negative for fusions in ALK, NTRK1, BRAF, and RET. Features with the highest discriminatory value included diameter of the lesion, dermal architecture, and certain cytomorphologic features. Specifically, cases with a large diameter (≥9 mm) and wedge-shaped, plexiform dermal architecture of nests of large, spindle-shaped cells were most likely to have an ALK fusion. NTRK1-fused cases were most likely of the fusions to have Kamino bodies and were typically arranged in smaller nests with smaller predominantly spindle-shaped cells, occasionally forming rosettes. BRAF fusion cases were the only fusion subtype to have a predominance of epithelioid cells, were less organized in nests, and commonly had a sheet-like growth pattern or dysplastic Spitz architecture. BRAF fusion cases were most likely to have high-grade nuclear atypia, to be diagnosed as spitzoid melanoma, to have a positive result by melanoma fluorescence in situ hybridization assay, and to develop copy number gains in the kinase domain of the fusion protein. On the basis of experience from this cohort, BRAF-fused cases appear most likely to progress to melanoma.

Primary Cutaneous Mammary Analog Secretory Carcinoma With ETV6-NTRK3 Translocation.

Mammary analog secretory carcinoma (MASC) is a recently described tumor of the salivary glands named for its morphological and molecular similarity to secretory carcinoma of the breast. Many primary carcinomas arising from the adnexal glands also share similar morphology to those arising from the breast. Brandt et al first described primary cutaneous MASC in 2009 and since then only 2 other cases have been reported. Herein, we describe a long-standing mass on the arm of an otherwise healthy 40-year-old female. Histologic examination revealed a circumscribed but unencapsulated, nodular tumor composed of bland epithelial cells arranged in solid and microcystic growth patterns. The cells showed vacuolated cytoplasm and round to oval nuclei with vesicular chromatin. Intraluminal homogenous eosinophilic secretions were present. Mitotic figures were not identified. The tumor cells stained positive for CK8/18, CK7, and S100 but were negative for other markers performed, including estrogen receptor, progesterone receptor, HER2/neu, paired box 8 (PAX8), and thyroid transcription factor 1 (TTF1). As the patient clinically had no other masses or known carcinomas, a diagnosis of primary cutaneous MASC was rendered. The ETV6-NTRK3 fusion transcript was subsequently detected by reverse transcriptase polymerase chain reaction amplification, further supporting the diagnosis. We present this case to review the histologic features of MASC and highlight the importance of recognizing this lesion not only as a possible cutaneous metastasis but also as a primary cutaneous tumor.