Mucocutaneous toxicities from MEK inhibitors: a scoping review of the literature.

BACKGROUND: MEK inhibitors cause a wide spectrum of mucocutaneous toxicities which can delay or interrupt life-saving therapy. PURPOSE: To summarize the morphology, incidence, and clinical presentation of mucocutaneous toxicities from MEK inhibitors via a scoping review of the literature. METHODS: We conducted a scoping review of the published literature, including clinical trials, retrospective and prospective studies, reviews, and case reports and series. All included literature was analyzed by a panel of pediatric and adult oncodermatologists. RESULTS: Of 1626 initial citations, 227 articles met final inclusion criteria. Our review identified follicular reactions, ocular toxicities, xerosis, eczematous dermatitis, edema, and paronychia as the most common mucocutaneous side effects from MEK inhibitor therapy. Grade 1 and 2 reactions were the most prevalent and were typically managed while continuing treatment; however, grade 3 toxicities requiring dose reductions or treatment interruptions were also reported. CONCLUSION: Mucocutaneous toxicities to MEK inhibitor therapy are common and most often mild in severity. Early recognition and treatment can mitigate disruptions in oncologic therapy.

Use of teledermatology by dermatology hospitalists is effective in the diagnosis and management of inpatient disease.

BACKGROUND: Patient outcomes are improved when dermatologists provide inpatient consultations. Inpatient access to dermatologists is limited, illustrating an opportunity to use teledermatology. Little is known about the ability of dermatologists to accurately diagnose disease and manage inpatients with teledermatology, particularly when using nondermatologist-generated clinical data. METHODS: This prospective study assessed the ability of teledermatology to diagnose disease and manage 41 dermatology consultations from a large urban tertiary care center, using internal medicine referral documentation and photographs. Twenty-seven dermatology hospitalists were surveyed. Interrater agreement was assessed by the κ statistic. RESULTS: There was substantial agreement between in-person and teledermatology assessment of the diagnosis with differential diagnosis (median κ = 0.83), substantial agreement in laboratory evaluation decisions (median κ = 0.67), almost perfect agreement in imaging decisions (median κ = 1.0), and moderate agreement in biopsy decisions (median κ = 0.43). There was almost perfect agreement in treatment (median κ = 1.0), but no agreement in follow-up planning (median κ = 0.0). There was no association between raw photograph quality and the primary plus differential diagnosis or primary diagnosis alone. LIMITATIONS: Selection bias and single-center nature. CONCLUSIONS: Teledermatology may be effective in the inpatient setting, with concordant diagnosis, evaluation, and management decisions.

Prevalence estimates for pyoderma gangrenosum in the United States: An age- and sex-adjusted population analysis.

BACKGROUND: The disease burden of pyoderma gangrenosum (PG) is poorly understood. OBJECTIVE: To determine standardized overall and age-, sex-, and race-specific prevalence estimates for PG among adults in the United States. METHODS: Cross-sectional analysis of 1971 patients with PG identified using electronic health records data from a diverse population-based sample of more than 58 million patients. RESULTS: The age- and sex-standardized prevalence of PG among the study population was 0.0058%, or 5.8 PG cases (95% confidence interval [CI], 5.6-6.1) per 100,000 adults. Adjusted prevalence was nearly twice as high among women (7.1 cases [95% CI, 6.7-7.5] per 100,000) than men (4.4 cases [95% CI, 4.0-4.7] per 100,000). Patients between the ages of 70 and 79 years had the highest standardized prevalence (9.8 cases [95% CI, 8.8-10.9] per 100,000), with patients aged ≥50 years representing nearly 70% of all PG cases. Standardized prevalence was similar among white and African American patients. The female-to-male ratio of PG was >1.8 across all age groups. LIMITATIONS: Analysis of electronic health records data may result in misclassification bias. CONCLUSION: PG is a rare disease that most commonly affects women and those aged ≥50 years.

Real-world risk of new-onset inflammatory bowel disease among patients with psoriasis exposed to interleukin 17 inhibitors.

BACKGROUND: Information on the real-world risk of inflammatory bowel disease (IBD) among patients with psoriasis exposed to interleukin-17 inhibitor (IL-17i) is limited. OBJECTIVE: To compare IBD risk in patients with psoriasis with and without IL-17i exposure. METHODS: Retrospective cohort analysis of patients with psoriasis with and without IL-17i exposure identified by using electronic health records data. Primary outcomes were 6-month and 1-year IBD incidence. RESULTS: Crude 6-month IBD incidence was 0.16% (3/1821) among patients with psoriasis exposed to any IL-17i, 0.24% (3/1246) among those exposed to secukinumab alone, and 0.11% (239/213,060) among those unexposed. Crude 1-year IBD incidence was 0.27% (5/1821) among IL-17i-exposed patients with psoriasis, 0.32% (4/1246) among those exposed to secukinumab alone, and 0.19% (412/213,060) among those unexposed. In adjusted analysis, there was no significant difference in odds of developing IBD at 6 months (odds ratio, 1.42; 95% confidence interval, 0.45-4.43) and 1 year (odds ratio, 1.37; 95% confidence interval, 0.57-3.33) between exposed and unexposed patients with psoriasis. Similarly, there was no significant difference in odds of developing IBD at 6 months and 1 year between secukinumab-exposed and -unexposed patients with psoriasis. LIMITATIONS: Analysis may have been limited by the low number of outcome events. CONCLUSION: The incidence of IBD among patients with psoriasis exposed to IL-17i is low, and the risk appears similar to that for unexposed patients with psoriasis.

Interstitial granulomatous dermatitis and granulomatous arteritis in the setting of PD-1 inhibitor therapy for metastatic melanoma.

Checkpoint inhibition has become an important target in the management of malignant melanoma. As anti-CTLA4 inhibitors and anti-PD1 antibodies are increasingly utilized, reports of immune-related adverse events (IRAEs) are becoming more frequent. Common noted cutaneous IRAEs are morbilliform, lichenoid, bullous, granulomatous, psoriasiform, and eczematous eruptions. We report a case of interstitial granulomatous dermatitis and granulomatous arteritis in the setting of nivolumab (anti-PD1) monotherapy for metastatic melanoma. There are many different causes for granulomatous vasculitis, such as herpes virus infection, lymphoproliferative disorders, systemic vasculitis, and inflammatory bowel disease. This report adds to the growing literature on granulomatous IRAEs due to checkpoint inhibition.

Prevalence estimates for pemphigoid in the United States: A sex-adjusted and age-adjusted population analysis.

BACKGROUND: The burden of the pemphigoid group of autoimmune blistering diseases is poorly understood. OBJECTIVE: To estimate standardized overall and sex-specific, age-specific, and race-specific prevalence estimates for pemphigoid among adults in the United States. METHODS: Cross-sectional analysis of electronic health records data for a demographically heterogeneous population-based sample of >55 million patients across all 4 census regions. RESULTS: Overall pemphigoid prevalence was 0.012%, or 12 pemphigoid patients/100,000 adults. Prevalence of pemphigoid among those aged ≥60 years was 0.038%, or 37.7 cases/100,000 adults. Prevalence increased ∼2-fold within each successive age group and was highest among patients aged ≥90 years (123.6 [95% CI 115.2-132.5] cases/100,000 adults). Adjusted prevalence in women was 12.7 (95% CI 12.3-13.2) cases/100,000 adults, slightly more than that in men (11.0 [95% CI 10.5-11.6] cases/100,000 adults). Adjusted prevalences were similar for blacks (15.4 [95% CI 14.0-17.0] cases/100,000 adults) and whites (13.5 [95% CI 13.0-13.9] cases/100,000 adults). LIMITATIONS: Analysis of electronic health data might result in disease misclassification. CONCLUSION: Pemphigoid is rare in the United States. Patients aged ≥60 years comprise the majority of cases.

Incidence of hidradenitis suppurativa in the United States: A sex- and age-adjusted population analysis.

BACKGROUND: The true incidence of hidradenitis suppurativa (HS) is unknown. OBJECTIVE: To determine standardized incidence estimates for HS in the United States. METHODS: We used a retrospective cohort analysis, including incident HS cases identified using electronic health records data for a demographically heterogeneous population-based sample of >48 million unique patients across all 4 census regions. We calculated standardized 1- and 10-year cumulative incidences for the overall population and for sex-, age-, and race-specific groups. RESULTS: There were 5410 new HS diagnoses over a 1-year period, with an incidence of 11.4 (95% confidence interval [CI], 11.1-11.8) cases per 100,000 population. One-year incidence in women was 16.1 (95% CI, 15.5-16.6) per 100,000, more than twice that of men [6.8 (95% CI, 6.5-7.2) per 100,000; P < .0001]. Age group-specific incidence was highest among patients 18 to 29 years of age [22.0 (95% CI, 21.0-23.2) per 100,000]. Incidence among African Americans [30.6 (95% CI, 29.1-32.2) per 100,000] was >2.5 times that of whites [11.7 (95% CI, 11.3-12.2) per 100,000; P < .0001]. The average annual overall incidence over 10 years was 8.6 (95% CI, 8.6-8.7) per 100,000 population. LIMITATIONS: The use of deidentified claims prevented validation for a larger case subset. CONCLUSION: HS incidence has increased over the past decade and disproportionately involves women, young adults, and African Americans.

Validation of a Case-Finding Algorithm for Hidradenitis Suppurativa Using Administrative Coding from a Clinical Database.

BACKGROUND: Requisite to the application of clinical databases for observational research in hidradenitis suppurativa (HS) is the identification of an accurate case cohort. OBJECTIVE: To assess the validity of utilizing administrative codes to establish the HS cohort from a large clinical database. METHODS: In this retrospective study using chart review as the reference standard, we calculated several estimates of the diagnostic accuracy of at least 1 ICD-9 code for HS. RESULTS: Estimates of the diagnostic accuracy of at least 1 ICD-9 code for HS include sensitivity 100% (95% CI 98-100), specificity 83% (95% CI 77-88), positive predictive value 79% (95% CI 72-85), negative predictive value 100% (95% CI 98-100), accuracy 90% (95% CI 86-93), and kappa statistic 79% (95% CI 73-86). CONCLUSION: The case-finding algorithm employing at least 1 ICD-9 code for HS provides balance in achieving accuracy and adequate power, both necessary in the evaluation of a less common disease and its potential association with uncommon or even rare events.

Outcome Measurement Instruments Used to Evaluate Dermatologic Adverse Events in Cancer Trials: A Systematic Review.

Importance: Assessment of type, severity, and impact of dermatologic adverse events (DAEs) necessitates well-developed and validated clinician-reported outcome measures (ClinROMs) and patient-reported outcome measures (PROMs) that evaluate concepts specific to mucocutaneous toxic effects and that allow appropriate interpretation and comparison of DAEs across trials. Objective: To evaluate heterogeneity and quality of ClinROMs and PROMs used to assess DAEs from systemic cancer therapy. Evidence Review: Two systematic reviews were conducted by searching PubMed and Embase databases from inception through March 7, 2023, and April 12, 2023. The first search included randomized clinical trials and observational studies reporting systemic cancer treatment-induced DAEs assessed by a ClinROM or PROM. The second included studies evaluating measurement properties of frequently used ClinROM and PROM instruments. The Consensus-Based Standards for the Selection of Health Measurement Instruments risk of bias tool was used to evaluate methodologic quality of validation assessments. Findings: A total of 395 studies were included. The Common Terminology Criteria for Adverse Events (CTCAE) was utilized in 331 studies meeting inclusion criteria (83.8%). At least 1 skin-related PROM was infrequently utilized in systemic chemotherapy clinical trials (79 studies [20.0%]). Most frequently utilized PROMs were the Dermatology Life Quality Index (DLQI; 34 studies [8.6%]) and Skindex-16 (20 studies [5.1%]). Among studies capturing DAEs, 115 (29.1%) reported a nondescript term (ie, rash) as the only DAE. Eight studies described 44 property assessments of the CTCAE, DLQI, and Skindex. There were no studies evaluating content validity, intrarater reliability, or measurement error for the CTCAE, DLQI, or Skindex. There were no studies evaluating structural validity, internal consistency, and responsiveness of DLQI or Skindex. Interrater reliability and responsiveness were each assessed for 1 DAE-related component of the CTCAE. Construct validity for CTCAE, DLQI, and Skindex was evaluated in 29 (65.9%), 3 (6.8%), and 9 (20.5%) assessments, respectively. Conclusions and Relevance: In this systematic review, there was a narrow spectrum of ClinROMs and PROMs with limited validity for the measurement of DAEs in the context of systemic chemotherapy interventions in clinical trials. Report of trial DAEs often had low morphologic specificity and meaning. Based on existing gaps in measurement and report of DAEs, a frequent and impactful adverse event to chemotherapy, the framework for evaluating cutaneous toxic effects in oncology trials may need collaborative reevaluation.

Defining D-irAEs: consensus-based disease definitions for the diagnosis of dermatologic adverse events from immune checkpoint inhibitor therapy.

With an increasing number of patients eligible for immune checkpoint inhibitors, the incidence of immune-related adverse events (irAEs) is on the rise. Dermatologic immune-related adverse events (D-irAEs) are the most common and earliest to manifest, often with important downstream consequences for the patient. Current guidelines lack clarity in terms of diagnostic criteria for D-irAEs. The goal of this project is to better define D-irAE for the purposes of identification, diagnosis, and future study of this important group of diseases.The objectives of this project were to develop consensus guidance for an approach to D-irAEs including disease definitions and severity grading. Knowing that consensus among oncologists, dermatologists, and irAE subspecialists would be critical for usability, we formed a Dermatologic irAE Disease Definition Panel. The panel was composed of 34 experts, including oncologists, dermatologists, a rheumatologist, and an allergist/immunologist from 22 institutions across the USA and internationally. A modified Delphi consensus process was used, with two rounds of anonymous ratings by panelists and two virtual meetings to discuss areas of controversy. Panelists rated content for usability, appropriateness, and accuracy on 9-point scales in electronic surveys and provided free text comments. A working group aggregated survey responses and incorporated them into revised definitions. Consensus was based on numeric ratings using the RAND/UCLA Appropriateness Method with prespecified definitions.Following revisions based on panelist feedback, all items received consensus in the second round of ratings. Consensus definitions were achieved for 10 core D-irAE diagnoses: ICI-vitiligo, ICI-lichen planus, ICI-psoriasis, ICI-exanthem, ICI-bullous pemphigoid, ICI-Grover's, ICI-eczematous, ICI-eruptive atypical squamous proliferation, ICI-pruritus without rash, and ICI-erosive mucocutaneous. A standard evaluation for D-irAE was also found to reach consensus, with disease-specific exceptions detailed when necessary. Each disorder's description includes further details on disease subtypes, symptoms, supportive exam findings, and three levels of diagnostic certainty (definite, probable, and possible).These consensus-driven disease definitions standardize D-irAE classification in a useable framework for multiple disciplines and will be the foundation for future work. Given consensus on their accuracy and usability from a representative panel group, we anticipate that they can be used broadly across clinical and research settings.

Genetically determined ABCB5 functionality correlates with pigmentation phenotype and melanoma risk.

ABCB5 is a multidrug resistance (MDR) member of the ATP-binding cassette (ABC) superfamily of active transporters and represents a marker for chemoresistant malignant melanoma-initiating cells. ABCB5 expression is closely linked to tumorigenicity and progression of diverse human malignancies, including melanoma, and is functionally required for tumor growth. Here, we genotyped 585 melanoma cases and 605 age-matched controls for 44 ABCB5 tagging single nucleotide polymorphisms (SNPs) to span a region covering 108.2kb of the gene on the 7p21.1 locus. We identified three SNPs that were associated with decreased melanoma risk in additive models: rs10231520 (OR: 0.83, 95% CI: 0.70-0.98), rs17817117 (OR: 0.82, 95% CI: 0.68-0.98), and rs2301641 (OR: 0.83, 95% CI: 0.69-0.98). Additionally, the rs2301641 SNP was associated with non-red compared to red hair color (OR: 0.38, 95% CI: 0.14-1.03) in controls. Twelve human melanoma cell lines were genotyped for the rs2301641 SNP, which encodes a non-synonymous ABCB5 amino acid change (K115E). Functional studies revealed that the E form associated with lower melanoma risk correlated significantly with decreased ABCB5 transport capacity (P<0.01) and increased melanin production (P<0.05). Our results identify novel associations of the ABCB5 K115E polymorphism with human pigmentation phenotype and melanoma risk and point to potential functional roles of ABCB5 in melanomagenesis. Moreover, they provide a first example that functional variation in a prospective cancer stem cell marker can be associated with disease risk for the corresponding malignancy.

Necrotizing Sweet syndrome: a new variant of neutrophilic dermatosis mimicking necrotizing fasciitis.

BACKGROUND: We report a series of patients initially given the diagnosis of necrotizing fasciitis whose course progressed despite surgical debridement, antibiotic therapy, or both, but who responded rapidly to systemic corticosteroids. OBJECTIVE: We sought to evaluate the clinical data, histopathologic and microbiology information, and treatment course of this unusual entity. METHODS: This was a descriptive study/case series. RESULTS: Three immunocompromised patients who presented with signs and symptoms of necrotizing fasciitis were included. They appeared septic, failed multiple courses of antibiotics, demonstrated pathergy, and two of them underwent extensive surgical debridement. None of the cases yielded a microbial source. Dermatologic consultation and histopathology confirmed deep Sweet syndrome in all cases, with marked necrosis of the soft tissue--including myonecrosis--in the two patients with debridement. All patients responded rapidly to high-dose systemic corticosteroids. LIMITATIONS: To our knowledge, this is the first report of this unusual presentation; there are a limited number of cases. CONCLUSION: We propose that these cases represent a new variant of neutrophilic dermatosis: "necrotizing Sweet syndrome," an acute necrotizing neutrophilic dermatosis. This subtype is also characterized by the rapid onset of progressive erythematous, warm, edematous cutaneous lesions with deep-tissue neutrophilic infiltration and soft-tissue necrosis, in the absence of infectious cause. Awareness of this entity and early dermatologic consultation is critical as debridement results in expansion of the process, resulting in additional and aggressive resection--a vicious cycle with significant possible morbidity.

Clinical Characteristics, Disease Course, and Outcomes of Patients With Acute Generalized Exanthematous Pustulosis in the US.

Importance: Acute generalized exanthematous pustulosis (AGEP) is a rare, severe cutaneous adverse reaction associated with systemic complications. Currently available data are largely limited to small retrospective case series. Objective: To describe the clinical characteristics, disease course, and outcomes of a heterogeneous group of patients with AGEP across the US. Design, Setting, and Participants: A retrospective review of a case series of patients was conducted from January 1, 2000, through July 31, 2020. All 340 included cases throughout 10 academic health systems in the US were scored retrospectively using the EuroSCAR scoring system, and patients with a score corresponding to probable or definite AGEP and aged 18 years or older were included. Main Outcomes and Measures: Patient demographic characteristics, clinical course, suspected causative agent, treatment, and short- and long-term outcomes. Results: Most of the 340 included patients were women (214 [62.9%]), White (206 [60.6%]), and non-Hispanic (239 [70.3%]); mean (SD) age was 57.8 (17.4) years. A total of 154 of 310 patients (49.7%) had a temperature greater than or equal to 38.0 °C that lasted for a median of 2 (IQR, 1-4) days. Of 309 patients, 263 (85.1%) developed absolute neutrophilia and 161 patients (52.1%) developed either absolute or relative eosinophilia. Suspected causes of AGEP were medications (291 [85.6%]), intravenous contrast agents (7 [2.1%]), infection (3 [0.9%]), or unknown (39 [11.5%]). In 151 cases in which a single medication was identified, 63 (41.7%) were ß-lactam antimicrobials, 51 (33.8%) were non-ß-lactam antimicrobials, 9 (6.0%) were anticonvulsants, and 5 (3.3%) were calcium channel blockers. The median time from medication initiation to AGEP start date was 3 (IQR, 1-9) days. Twenty-five of 298 patients (8.4%) had an acute elevation of aspartate aminotransferase and alanine aminotransferase levels, with a peak at 6 (IQR, 3-9) days. Twenty-five of 319 patients (7.8%) experienced acute kidney insufficiency, with the median time to peak creatinine level being 4 (IQR, 2-5) days after the AGEP start date. Treatments included topical corticosteroids (277 [81.5%], either alone or in combination), systemic corticosteroids (109 [32.1%]), cyclosporine (10 [2.9%]), or supportive care only (36 [10.6%]). All-cause mortality within 30 days was 3.5% (n = 12), none of which was suspected to be due to AGEP. Conclusions and Relevance: This retrospective case series evaluation of 340 patients, the largest known study cohort to date, suggests that AGEP onset is acute, is usually triggered by recent exposure to an antimicrobial, may be associated with liver or kidney complications in a minority of patients, and that discontinuation of the triggering treatment may lead to improvement or resolution.

Isolation of tumorigenic circulating melanoma cells.

Circulating tumor cells (CTC) have been identified in several human malignancies, including malignant melanoma. However, whether melanoma CTC are tumorigenic and cause metastatic progression is currently unknown. Here, we isolate for the first time viable tumorigenic melanoma CTC and demonstrate that this cell population is capable of metastasis formation in human-to-mouse xenotransplantation experiments. The presence of CTC among peripheral blood mononuclear cells (PBMC) of murine recipients of subcutaneous (s.c.) human melanoma xenografts could be detected based on mRNA expression for human GAPDH and/or ATP-binding cassette subfamily B member 5 (ABCB5), a marker of malignant melanoma-initiating cells previously shown to be associated with metastatic disease progression in human patients. ABCB5 expression could also be detected in PBMC preparations from human stage IV melanoma patients but not healthy controls. The detection of melanoma CTC in human-to-mouse s.c. tumor xenotransplantation models correlated significantly with pulmonary metastasis formation. Moreover, prospectively isolated CTC from murine recipients of s.c. melanoma xenografts were capable of primary tumor initiation and caused metastasis formation upon xenotransplantation to secondary murine NOD-scid IL2Rγ(null) recipients. Our results provide initial evidence that melanoma CTC are tumorigenic and demonstrate that CTC are capable of causing metastatic tumor progression. These findings suggest a need for CTC eradication to inhibit metastatic progression and provide a rationale for assessment of therapeutic responses of this tumorigenic cell population to promising emerging melanoma treatment modalities.

Cutaneous immune-related adverse events to checkpoint inhibitors.

The development of immunotherapy has led to a paradigm shift in the treatment of both solid and hematologic malignancies. As immunomodulatory therapies are employed with increasing frequency, a greater number of immune-related adverse reactions are being reported, and the majority of these involve the skin. As a result, dermatologists are increasingly becoming involved in the management of these cutaneous adverse reactions-often providing critical recommendations regarding ongoing cancer treatment. Cutaneous immune-related adverse reactions can vary significantly from patient to patient, making early recognition and timely intervention imperative to mitigate associated morbidity and potential treatment interruption. Although there is considerable overlap in the cutaneous adverse events caused by these immune checkpoint inhibitors, specific eruptions are characteristically associated with particular checkpoint inhibitors. In addition, a patient's comorbidities or immune status can play a significant role in the presentation and management of such adverse reactions. This review characterizes and provides management guidelines for the various cutaneous toxicities associated with checkpoint inhibitor therapy, including CTLA-4 inhibitors, PD-1 inhibitors, and PD-L1 inhibitors. © 2020 Elsevier Inc. All rights reserved.

Investing in the future of inpatient dermatology: the evolution and impact of specialized dermatologic consultation in hospitalized patients.

Inpatient dermatology has transitioned from units that admitted and cared for patients with chronic dermatoses to consultative services that provide a wide breadth of care, leading to a paradigm shift in the role and impact of dermatologists in the inpatient setting. Consultative dermatology provides a distinct and essential service in the care of hospitalized patients, leading to improved care quality along with reductions in inappropriate health care spending.

Characterization of the 2016-2017 Dermatology Standardized Letter of Recommendation.

Objective: We aimed to analyze the reformatted standard letter of recommendation (SLOR) for dermatology residents to examine trends in grading and content based on the positions of the letter writers, their backgrounds, and their relationship with the applicant, as well as to evaluate the SLOR's ability to discriminate applicants. Design: This was a retrospective characterization study of dermatology SLORs from the 2016-17 application cycle. Setting: We examined SLORs received by The Ohio State University, the University of Oklahoma, and Hofstra University Northwell Health dermatology residency programs. Participants: We included dermatology residency applicants and their letter writers from the 2016-17 application cycle. Results: A total of 141 SLORs were analyzed from 115 applicants. SLORs demonstrated grade inflation from letter writers of all backgrounds. Ratings for research potential and inquisitive nature were significantly lower than ratings for other categories. Letter writers with limited clinical and research contact graded applicants significantly lower than did writers who had more extensive contact. Word boxes were underutilized. Conclusion: The dermatology SLOR is useful in differentiating applicants, and ratings correlate with the relationships that letter writers have with their applicants. Residency programs should be aware of these findings when evaluating letters of recommendation for applicants.