Ophthalmologic Findings in Pediatric Erdheim-Chester Disease: A Literature Review With a Novel Case Report.

PURPOSE: The authors aim to describe the ophthalmologic manifestations of pediatric Erdheim-Chester disease (ECD). METHODS: The authors describe a novel case of ECD presenting as isolated bilateral proptosis in a child and provide a comprehensive review of the documented pediatric cases to observe overall trends and ophthalmic manifestations of disease. Twenty pediatric cases were identified in the literature. RESULTS: The mean age at presentation was 9.6 years (1.8-17 years) with a mean time of symptom presentation to diagnosis of 1.6 years (0-6 years). Nine patients (45%) had ophthalmic involvement at diagnosis, 4 who presented with ophthalmic complaints: 3 with observable proptosis and 1 with diplopia. Other ophthalmic abnormalities included eyelid findings of a maculopapular rash with central atrophy on the eyelids and bilateral xanthelasmas, neuro-ophthalmologic findings of a right hemifacial palsy accompanied by bilateral optic atrophy and diplopia, and imaging findings of orbital bone and enhancing chiasmal lesions. No intraocular involvement was described, and visual acuity was not reported in most cases. CONCLUSIONS: Ophthalmic involvement occurs in almost half of documented pediatric cases. Typically presenting with other symptoms, the case highlights that isolated exophthalmos may be the only clinical sign, and ECD should be included in the differential diagnosis of bilateral exophthalmos in children. Ophthalmologists may be the first to evaluate these patients, and a high index of suspicion and an understanding of the varied clinical, radiographic, pathologic, and molecular findings are critical for prompt diagnosis and treatment of this unusual disease.

Ultrasound Verification of Plaque Brachytherapy Placement in Patients Treated for Primary Uveal Melanoma: A Single-Center Experience.

Introduction: Proper plaque positioning is essential for effective episcleral plaque brachytherapy and can be verified using ultrasound. In this study, we show our center's protocol for intraoperative ultrasound verification of plaque placement and present our single-center local recurrence data in patients with primary UM involving the choroid and/or ciliary body. We also indicate our center's distance metastasis rate for patients presenting with primary UM. Methods: All patients who presented to our institution with UM of the choroid and/or ciliary body between May 2017 and March 2022 and treated with plaque brachytherapy were enrolled. Endpoints include the 24-month local recurrence-free rate (primary) and 24-month metastasis rate (secondary), both estimated using the Kaplan-Meier method (KM). Results: Local Recurrence: 176 patients met the study criteria with median follow-up of 23.2 months. The 24-month recurrence-free probability for this cohort was estimated at 99.1% (95% confidence interval: 0.974-1.00). Metastatic Recurrence: 136 of these patients underwent at least one follow-up surveillance scan. The 24-month metastasis-free survival probability in our cohort was estimated at 87% (95% confidence interval: 81-94%). Conclusions: We show improved local control utilizing ultrasound verification compared to historical controls who received TTT and brachytherapy without intraoperative ultrasound confirmation.

Two cases of von Hippel-Lindau syndrome-associated retinal hemangioblastoma treated with belzutifan.

PURPOSE: To describe two cases of retinal hemangioblastoma (RH) regression following treatment with belzutifan in patients with von Hippel-Lindau (VHL) syndrome. METHODS: Clinical information was extracted from the charts and tumor imaging of two patients with VHL-associated RH. RESULTS: In case 1, a 40-year-old man was treated with belzutifan for spine hemangioblastomas after diagnosis of a 2.0x2.0x1.3 mm left eye RH temporal to the macula associated with intraretinal edema, subretinal fluid, and mild retinal traction. In case 2, a 66-year-old woman presented with a right eye 2.0x1.5x1.3 mm juxtapapillary lesion with subretinal fluid, intraretinal fluid, and nasal traction, and a 4.0x3.5x1.1 mm inferior mid-periphery lesion with subretinal fluid, intraretinal fluid, and active exudation. She was treated for 2.5 years with belzutifan for renal cell carcinoma on the National Institutes of Health trial. The patient in case 1 demonstrated a 10% reduction in largest tumor diameter and 8% reduction in thickness, along with improving subretinal fluid, intraretinal edema, and retinal traction, after 4 weeks of treatment. After 2.5 years of treatment, the patient in case 2 demonstrated similar margins of her now fibrotic-appearing juxtapapillary lesion with a 45% reduction in thickness, along with resolved subretinal fluid and greatly improved intraretinal fluid and traction. The inferior lesion demonstrated 12.5% reduction in largest diameter, 36% reduction in thickness, and was without active subretinal fluid or exudation. Neither patient demonstrated new lesions while on-treatment. CONCLUSION: Belzutifan is a promising treatment for RH with the potential for both rapid and sustained tumor regression.

Etiologies of Melanoma Development and Prevention Measures: A Review of the Current Evidence.

(1) Melanoma is the most aggressive dermatologic malignancy, with an estimated 106,110 new cases to be diagnosed in 2021. The annual incidence rates continue to climb, which underscores the critical importance of improving the methods to prevent this disease. The interventions to assist with melanoma prevention vary and typically include measures such as UV avoidance and the use of protective clothing, sunscreen, and other chemopreventive agents. However, the evidence is mixed surrounding the use of these and other interventions. This review discusses the heritable etiologies underlying melanoma development before delving into the data surrounding the preventive methods highlighted above. (2) A comprehensive literature review was performed to identify the clinical trials, observational studies, and meta-analyses pertinent to melanoma prevention and incidence. Online resources were queried to identify epidemiologic and clinical trial information. (3) Evidence exists to support population-wide screening programs, the proper use of sunscreen, and community-targeted measures in the prevention of melanoma. Clinical evidence for the majority of the proposed preventive chemotherapeutics is presently minimal but continues to evolve. (4) Further study of these chemotherapeutics, as well as improvement of techniques in artificial intelligence and imaging techniques for melanoma screening, is warranted for continued improvement of melanoma prevention.

Cellular therapy for the treatment of solid tumors.

Adoptive cellular therapy (ACT) is a form of cancer immunotherapy in which lymphocytes are removed from patient blood or tumor samples, expanded and/or genetically modified to improve tumor-fighting capabilities, and infused back into the patient. The main forms of ACT include tumor infiltrating lymphocytes (TILs), engineered T cell receptor (TCR) T cells, and chimeric antigen receptor (CAR) T cells. While ACT has had success in hematological malignancies, particularly in B cell lymphomas targeted with CAR T cells, these favorable outcomes have yet to be replicated in solid tumors. Appropriate solid tumor target antigens are difficult to identify for ACT. Trafficking to tumor sites and infiltrating solid tumor burdens remains a problem for ACT cells. Persistence of ACT cells, which is important in creating a durable response, is also a major challenge, partly attributed to the formidable microtumor environment conditions. The costly and time-intensive manufacturing process for ACT is also an obstacle to widespread adoption. In this review, we discuss the challenges of ACT therapy in the treatment of solid tumors and explore the ongoing efforts to improve this immunotherapy approach in non-hematological malignancies.

Clinical impact of COVID-19 on patients with cancer treated with immune checkpoint inhibition.

BACKGROUND: Patients with cancer who are infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are more likely to develop severe illness and die compared with those without cancer. The impact of immune checkpoint inhibition (ICI) on the severity of COVID-19 illness is unknown. The aim of this study was to investigate whether ICI confers an additional risk for severe COVID-19 in patients with cancer. METHODS: We analyzed data from 110 patients with laboratory-confirmed SARS-CoV-2 while on treatment with ICI without chemotherapy in 19 hospitals in North America, Europe and Australia. The primary objective was to describe the clinical course and to identify factors associated with hospital and intensive care (ICU) admission and mortality. FINDINGS: Thirty-five (32%) patients were admitted to hospital and 18 (16%) died. All patients who died had advanced cancer, and only four were admitted to ICU. COVID-19 was the primary cause of death in 8 (7%) patients. Factors independently associated with an increased risk for hospital admission were ECOG ≥2 (OR 39.25, 95% CI 4.17 to 369.2, p=0.0013), treatment with combination ICI (OR 5.68, 95% CI 1.58 to 20.36, p=0.0273) and presence of COVID-19 symptoms (OR 5.30, 95% CI 1.57 to 17.89, p=0.0073). Seventy-six (73%) patients interrupted ICI due to SARS-CoV-2 infection, 43 (57%) of whom had resumed at data cut-off. INTERPRETATION: COVID-19-related mortality in the ICI-treated population does not appear to be higher than previously published mortality rates for patients with cancer. Inpatient mortality of patients with cancer treated with ICI was high in comparison with previously reported rates for hospitalized patients with cancer and was due to COVID-19 in almost half of the cases. We identified factors associated with adverse outcomes in ICI-treated patients with COVID-19.

Immune Checkpoint Inhibition in Non-Melanoma Skin Cancer: A Review of Current Evidence.

Immuno-oncology is a rapidly evolving field with growing relevance in the treatment of numerous malignancies. The prior study of immunotherapy in dermatologic oncology has largely focused on cutaneous melanoma. However, recent focus has shifted to the use of immunotherapy to treat non-melanoma skin cancers (NMSCs), such as basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC), and Merkel cell carcinoma (MCC). NMSCs represent the most ubiquitous cancers globally and, while they have a lower propensity to develop into advanced disease than cutaneous melanoma, their absolute mortality burden has recently surpassed that of melanoma. Patients with advanced NMSC are now benefiting from the successes of immunotherapy, including checkpoint inhibition with anti-CTLA-4 and anti-PD-1 monoclonal antibodies. In this review, we discuss the existing clinical evidence for immunotherapy in the treatment of NMSCs, with an emphasis on checkpoint inhibitor therapies. We highlight key studies in the field and provide up-to-date clinical evidence regarding ongoing clinical trials, as well as future study directions. Our review demonstrates that checkpoint inhibitors are positioned to provide unparalleled results in the previously challenging landscape of advanced NMSC treatment.

Arginine depletion as a therapeutic approach for patients with COVID-19.

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a source of significant morbidity and death worldwide, and effective treatments are urgently needed. Clinical trials have focused largely on direct antiviral therapies or on immunomodulation in patients with severe manifestations of COVID-19. One therapeutic approach that remains to be clinically investigated is disruption of the host-virus relationship through amino acid restriction, a strategy used successfully in the setting of cancer treatment. Arginine is an amino acid that has been shown in nonclinical studies to be essential in the life cycle of many viruses. Therefore, arginine depletion may be an effective therapeutic approach against SARS-CoV-2. Several arginine-metabolizing enzymes in clinical development may be a viable approach to induce a low arginine environment to treat COVID-19 and other viral diseases. Herein, we explore the rationale for arginine depletion as a therapeutic approach for COVID-19.

p38 MAPK inhibition: A promising therapeutic approach for COVID-19.

COVID-19, caused by the SARS-CoV-2 virus, is a major source of morbidity and mortality due to its inflammatory effects in the lungs and heart. The p38 MAPK pathway plays a crucial role in the release of pro-inflammatory cytokines such as IL-6 and has been implicated in acute lung injury and myocardial dysfunction. The overwhelming inflammatory response in COVID-19 infection may be caused by disproportionately upregulated p38 activity, explained by two mechanisms. First, angiotensin-converting enzyme 2 (ACE2) activity is lost during SARS-CoV-2 viral entry. ACE2 is highly expressed in the lungs and heart and converts Angiotensin II into Angiotensin 1-7. Angiotensin II signals proinflammatory, pro-vasoconstrictive, pro-thrombotic activity through p38 MAPK activation, which is countered by Angiotensin 1-7 downregulation of p38 activity. Loss of ACE2 upon viral entry may tip the balance towards destructive p38 signaling through Angiotensin II. Second, SARS-CoV was previously shown to directly upregulate p38 activity via a viral protein, similar to other RNA respiratory viruses that may hijack p38 activity to promote replication. Given the homology between SARS-CoV and SARS-CoV-2, the latter may employ a similar mechanism. Thus, SARS-CoV-2 may induce overwhelming inflammation by directly activating p38 and downregulating a key inhibitory pathway, while simultaneously taking advantage of p38 activity to replicate. Therapeutic inhibition of p38 could therefore attenuate COVID-19 infection. Interestingly, a prior preclinical study showed protective effects of p38 inhibition in a SARS-CoV mouse model. A number of p38 inhibitors are in the clinical stage and should be considered for clinical trials in serious COVID-19 infection.

Conjunctival Melanoma: Current Treatments and Future Options.

Conjunctival melanoma is a rare tumor of the conjunctival epithelium with a heterogenous clinical presentation and a propensity for regional and distant metastatic spread. Guidelines for the treatment of local conjunctival melanoma are well-established, but there are no standard efficacious therapies for metastatic disease. Given that conjunctival melanoma is genetically similar to cutaneous melanoma and mucosal melanomas, targeted therapies effective in the treatment of these diseases, such as BRAF inhibitors and KIT inhibitors, may be effective in the treatment of patients with metastatic conjunctival melanoma. Other targeted small-molecule drugs in the drug development pipeline for the treatment of more prevalent melanomas could also be applicable to conjunctival melanoma. Furthermore, systemic immunotherapy treatments that are now a mainstay in the treatment of cutaneous melanoma, such as programmed cell death-1 and cytotoxic T lymphocyte-associated antigen-4 inhibitors, could also stand to benefit patients with metastatic conjunctival melanoma. Limited case reports provide clues about the effectiveness of both targeted small-molecule inhibitors and immunotherapy in patients with advanced local and metastatic conjunctival melanoma and give credence to the argument that conjunctival melanoma patients should be included in major trials studying new therapies in both cutaneous and mucosal melanomas where applicable.

Novel risk genes and mechanisms implicated by exome sequencing of 2572 individuals with pulmonary arterial hypertension.

BACKGROUND: Group 1 pulmonary arterial hypertension (PAH) is a rare disease with high mortality despite recent therapeutic advances. Pathogenic remodeling of pulmonary arterioles leads to increased pulmonary pressures, right ventricular hypertrophy, and heart failure. Mutations in bone morphogenetic protein receptor type 2 and other risk genes predispose to disease, but the vast majority of non-familial cases remain genetically undefined. METHODS: To identify new risk genes, we performed exome sequencing in a large cohort from the National Biological Sample and Data Repository for PAH (PAH Biobank, n = 2572). We then carried out rare deleterious variant identification followed by case-control gene-based association analyses. To control for population structure, only unrelated European cases (n = 1832) and controls (n = 12,771) were used in association tests. Empirical p values were determined by permutation analyses, and the threshold for significance defined by Bonferroni's correction for multiple testing. RESULTS: Tissue kallikrein 1 (KLK1) and gamma glutamyl carboxylase (GGCX) were identified as new candidate risk genes for idiopathic PAH (IPAH) with genome-wide significance. We note that variant carriers had later mean age of onset and relatively moderate disease phenotypes compared to bone morphogenetic receptor type 2 variant carriers. We also confirmed the genome-wide association of recently reported growth differentiation factor (GDF2) with IPAH and further implicate T-box 4 (TBX4) with child-onset PAH. CONCLUSIONS: We report robust association of novel genes KLK1 and GGCX with IPAH, accounting for ~ 0.4% and 0.9% of PAH Biobank cases, respectively. Both genes play important roles in vascular hemodynamics and inflammation but have not been implicated in PAH previously. These data suggest new genes, pathogenic mechanisms, and therapeutic targets for this lethal vasculopathy.