A plain language summary from pembrolizumab plus ipilimumab following PD-1 antibody failure in melanoma.

WHAT IS THIS SUMMARY ABOUT?: In this article, we discuss the results of our clinical study that looked at the use of two immunotherapy drugs for the treatment of advanced melanoma. Melanoma is considered advanced when it is no longer curable with surgery. WHAT HAPPENED IN THE STUDY?: The two-drug combination, pembrolizumab and ipilimumab, was given to people with melanoma who's cancer had progressed. This study looked at how effective these two drugs were in terms of controlling the melanoma, as well their safety. These results from the study were then compared to the results from previous studies looking at melanoma treatment with ipilimumab on its own, which previously had been the most commonly used drug. WHAT WERE THE RESULTS?: The study, originally published in the Journal of Clinical Oncology, showed that combination treatment with pembrolizumab and ipilimumab was more likely to be effective than ipilimumab on its own. Not all of the study participants benefited, but many of those who did benefit experienced long-term remission from their melanoma without needing more treatment. Around 1/3 of the participants in the study had their tumors shrink compared to previous studies, which showed that ipilimumab was expected to shrink 1 in 8 tumors. The rates of side effects were similar with the pembrolizumab and ipilimumab combination compared to ipilimumab alone.

Ophthalmic manifestations of coronavirus disease 2019 and ocular side effects of investigational pharmacologic agents.

PURPOSE OF REVIEW: To compile and report the ocular manifestations of coronavirus disease 2019 (COVID-19) infection and summarize the ocular side effects of investigational treatments of this disease. RECENT FINDINGS: Conjunctivitis is by far the most common ocular manifestation of COVID-19 with viral particles being isolated from tears/secretions of infected individuals. Multiple therapeutic options are being explored across a variety of medication classes with diverse ocular side effects. SUMMARY: Eye care professionals must exercise caution, as conjunctivitis may be the presenting or sole finding of an active COVID-19 infection. While no currently studied therapeutic agents have been found to reliably treat COVID-19, early vaccination trials are progressing and show promise. A video abstract is available for a more detailed summary. VIDEO ABSTRACT: http://links.lww.com/COOP/A36.

Screening for Diabetic Retinopathy: Strategies for Improving Patient Follow-up.

Diabetic retinopathy is a leading cause of preventable blindness. Timely screening and treatment prevent morbidity, though low follow-up rates remain problematic. Feasible and efficacious methods for increasing screening follow-up rates include patient education, a streamlined referral and scheduling process, and collaboration with local ophthalmologists and primary care providers.

Correction: Reschke, R.; Olson, D.J. Leveraging STING, Batf3 Dendritic Cells, CXCR3 Ligands, and Other Components Related to Innate Immunity to Induce a "Hot" Tumor Microenvironment That Is Responsive to Immunotherapy. Cancers 2022, 14, 2458.

The authors would like to make the following corrections to their published paper [...].

Myeloid Maturity: ATRA to Enhance Anti-PD-1?

Myeloid-derived suppressor cells (MDSC) are associated with resistance to anti-PD-1 therapies. All-trans retinoic acid (ATRA) may induce maturation of MDSCs and alter their immunosuppressive effects. Adding ATRA to pembrolizumab may target this resistance mechanism to enhance the overall impact of anti-PD-1-based immunotherapy. See related article by Tobin et al., p. 1209.

Adoptive Cell Therapy for Nonhematologic Solid Tumors.

The long-term benefits demonstrated by immunotherapy in select tumors have failed to generalize to most nonhematologic solid tumors. Adoptive cell therapy (ACT)-a treatment on the basis of the isolation and engineering of living T cells and other immune cells-has shown early clinical advances. ACT, through tumor-infiltrating lymphocyte therapy, has shown activity in traditionally immunogenic tumors such as melanoma and cervical cancers, and has the potential to improve immune reactivity in these tumor types where traditional therapies have failed. Engineered T-cell receptor and chimeric antigen receptor T-cell therapies have also shown activity in select nonhematologic solid tumors. Through receptor engineering, and improved understanding of tumor antigens, these therapies have the potential to target poorly immunogenic tumors to deliver long-lasting responses. Additionally, non-T-cell therapies such as natural killer-cell therapy may allow for allogeneic forms of ACT. Each form of ACT has trade-offs that will likely limit their application to specific clinical settings. Key challenges with ACT include the logistical challenges of manufacturing, accurate antigen identification, and the risk of on-target, off-tumor toxicity. The successes of ACT are built on decades of advances in cancer immunology, antigen identification, and cell engineering. With continued refinements in these processes, ACT may extend the benefits of immunotherapy to more patients with advanced nonhematologic solid tumors. Herein, we review the major forms of ACT, their successes, and strategies to overcome the trade-offs of current ACTs.

Leveraging STING, Batf3 Dendritic Cells, CXCR3 Ligands, and Other Components Related to Innate Immunity to Induce A "Hot" Tumor Microenvironment That Is Responsive to Immunotherapy.

In a T-cell-inflamed phenotype, tumor eradication works best and is potentiated by immunotherapy such as checkpoint blockade. However, a majority of patients die despite receiving immunotherapy. One reason is insufficient T cell priming and infiltration in the tumor. Nature provides us with innate immune mechanisms in T-cell-inflamed tumors that we can adopt for more personalized immunotherapy strategies. Tumor sensing through innate signaling pathways and efficient antigen-presenting possess a significant role in bridging innate and adaptive immunity and generating a T-cell-inflamed tumor. One approach to strengthen these innate immune mechanisms is to deliver innate immune factors such as STING or activated DCs into the tumor microenvironment, in particular in patients resistant to checkpoint blockade. The low number of DCs in the tumor bed could potentially be increased with the growth factor FMS-like tyrosine kinase 3 ligand (Flt3L). CD103+ DCs are integral for three phases of anti-tumor immunity: priming, recruiting, and re-invigoration of effector T cells. Re-activation of dysfunctional T cells is achieved via co-stimulatory molecules such as the 4-1BB ligand. The presence of myeloid-cell-derived CXCL9 and CXCL10 in the tumor microenvironment can predict response to immunotherapy. We outline recent preclinical and clinical approaches to deliver these crucial components bridging innate and adaptive immunity into the tumor microenvironment.

The effect of allophonic variability on L2 contrast perception: Evidence from perception of English vowels.

Current frameworks of L2 phonetic acquisition remain largely underspecified with respect to the role of L1 allophonic variability in acquisition. Examining the role of L1 allophonic variability, the current study compared the perceptual discrimination of English /i-ɪ/ and /ɛ-æ/ by L1 Korean and L1 Mandarin speakers. Korean and Mandarin vowel inventories differ in that Mandarin employs significantly greater allophonic variation of the mid-region /E/ vowel. Results demonstrated worse perceptual accuracy by L1 Mandarin speakers for the /ɛ-æ/ contrast than L1 Korean speakers. These results suggest that both L1 phonemic inventories and allophonic variation play a role in L2 phonetic acquisition.

Checkpoint Blockade-Induced Dermatitis and Colitis Are Dominated by Tissue-Resident Memory T Cells and Th1/Tc1 Cytokines.

Immune checkpoint blockade is therapeutically successful for many patients across multiple cancer types. However, immune-related adverse events (irAE) frequently occur and can sometimes be life threatening. It is critical to understand the immunologic mechanisms of irAEs with the goal of finding novel treatment targets. Herein, we report our analysis of tissues from patients with irAE dermatitis using multiparameter immunofluorescence (IF), spatial transcriptomics, and RNA in situ hybridization (RISH). Skin psoriasis cases were studied as a comparison, as a known Th17-driven disease, and colitis was investigated as a comparison. IF analysis revealed that CD4+ and CD8+ tissue-resident memory T (TRM) cells were preferentially expanded in the inflamed portion of skin in cutaneous irAEs compared with healthy skin controls. Spatial transcriptomics allowed us to focus on areas containing TRM cells to discern functional phenotype and revealed expression of Th1-associated genes in irAEs, compared with Th17-asociated genes in psoriasis. Expression of PD-1, CTLA-4, LAG-3, and other inhibitory receptors was observed in irAE cases. RISH technology combined with IF confirmed expression of IFNγ, CXCL9, CXCL10, and TNFα in irAE dermatitis, as well as IFNγ within TRM cells specifically. The Th1-skewed phenotype was confirmed in irAE colitis cases compared with healthy colon.

Hyperviscosity Retinopathy Due to Waldenström Macroglobulinemia: A Case Report and Literature Review.

Purpose: This case report describes a case of hyperviscosity retinopathy secondary to the rare systemic hematologic malignant neoplasm Waldenström macroglobulinemia. Methods: Fundus photography, fluorescein angiography, optical coherence tomography (OCT), and OCT angiography were used as imaging modalities to characterize this pathology. Results: A 51-year-old man presented with hyperviscosity retinopathy and uniquely angiographically silent serous macular detachment. Over a 6-month period, he was treated with systemic and local therapies with little improvement in the hyperviscosity retinopathy, serous macular detachments, or visual acuity. Conclusions: Hyperviscosity retinopathy secondary to Waldenström macroglobulinemia presents a challenge to treating ophthalmologists given its rarity and the range of treatment responses described in the literature. Our patient's lack of response to antivascular endothelial growth factor and normal findings in OCT angiography and fluorescein angiography suggested the mechanism of subretinal fluid accumulation was not vascular endothelial growth factor mediated. Visual prognosis was guarded.

Novel response to neoadjuvant anti-PD1 therapy for a patient with retrocaval melanotic schwannoma.

Melanotic schwannoma is a rare nerve sheath tumor composed of melanin-producing Schwann cells with the potential for metastasis. These tumors can be associated with familial tumor syndromes and can cause significant symptoms related to nerve compression and mass effect. Due to the rarity of these lesions, they can be initially misidentified as melanocytomas, pigmented dermatofibrosarcoma protuberans, neurofibromas or malignant melanomas. Surgical excision is the mainstay of treatment with limited benefit from adjuvant systemic chemotherapy or radiation. Modern treatments with immune checkpoint blockade have demonstrated significant improvements in progression-free and overall survival for a variety of cancer histologies; however, anti-PD1 therapy has yet to be evaluated in patients with melanotic schwannoma. This report demonstrates a significant improvement in symptomatology and tumor stability with neoadjuvant anti-PD1 therapy for a retrocaval melanotic schwannoma initially masquerading as malignant melanoma. This report demonstrates the potential benefit of a novel therapeutic option for patients with melanotic schwannoma.

Transcriptional analysis of metastatic uveal melanoma survival nominates NRP1 as a therapeutic target.

Uveal melanoma is a rare form of melanoma with particularly poor outcomes in the metastatic setting. In contrast with cutaneous melanoma, uveal melanoma lacks BRAF mutations and demonstrates very low response rates to immune-checkpoint blockade. Our objectives were to study the transcriptomics of metastatic uveal melanoma with the intent of assessing gene pathways and potential molecular characteristics that might be nominated for further exploration as therapeutic targets. We initially analyzed transcriptional data from The Cancer Genome Atlas suggesting PI3K/mTOR and glycolysis as well as IL6 associating with poor survival. From tumor samples collected in a prospective phase II trial (A091201), we performed a transcriptional analysis of human metastatic uveal melanoma observing a novel role for epithelial-mesenchymal transition associating with survival. Specifically, we nominate and describe initial functional validation of neuropillin-1 from uveal melanoma cells as associated with poor survival and as a mediator of proliferation and migration for uveal melanoma in vitro. These results immediately nominate potential next steps in clinical research for patients with metastatic uveal melanoma.

Pembrolizumab Plus Ipilimumab Following Anti-PD-1/L1 Failure in Melanoma.

PURPOSE: Combination of antiprogrammed cell death protein-1 (PD-1) plus anti-cytotoxic T-cell lymphocyte-4 (anti-CTLA-4) immunotherapy shows greater response rates (RRs) than anti-PD-1 antibody alone in melanoma, but RR after initial anti-PD-1 and programmed death ligand-1 (PD-L1) antibody progression awaits robust investigation. Anti-CTLA-4 antibody alone after anti-PD-1/L1 antibody progression has a historical RR of 13%. We report the results of the first prospective clinical trial evaluating ipilimumab 1 mg/kg plus pembrolizumab following progression on anti-PD-1 immunotherapy. METHODS: Patients with advanced melanoma who had progressed on anti-PD-1/L1 antibody as immediate prior therapy (including non-anti-CTLA-4 antibody combinations) were eligible. Patients received pembrolizumab 200 mg plus ipilimumab 1 mg/kg once every 3 weeks for four doses, followed by pembrolizumab monotherapy. The primary end point was RR by irRECIST. After 35 patients, the trial met the primary end point and was expanded to enroll a total of 70 patients to better estimate the RR. RESULTS: Prior treatments included 60 on anti-PD-1 antibody alone and 10 on anti-PD-1/L1 antibody-based combinations. Thirteen patients had progressed in the adjuvant setting. The median length of prior treatment with anti-PD-1/L1 antibody was 4.8 months. Response assessments included five complete and 15 partial responses, making the irRECIST RR 29% among the entire trial population. The median progression-free survival was 5.0 months, and the median overall survival was 24.7 months. The median duration of response was 16.6 months. There was no difference in median time on prior anti-PD1/L1 or time to PD1 + CTLA4 initiation between responders and nonresponders. Grade 3-4 drug-related adverse events occurred in 27% of patients. Responses occurred in PD-L1-negative, non-T-cell-inflamed, and intermediate tumor phenotypes. CONCLUSION: To our knowledge, this is the first prospective study in melanoma of pembrolizumab plus low-dose ipilimumab after anti-PD-1/L1 immunotherapy failure, demonstrating significant antitumor activity and tolerability.

A case of dual-mechanism immune-related anaemia in a patient with metastatic melanoma treated with nivolumab and ipilimumab.

BACKGROUND: The combination of the immune checkpoint inhibitors (ICIs) ipilimumab and nivolumab is a mainstay of treatment for selected patients with metastatic melanoma. This combination also results in more frequent immune-related adverse events (irAEs) than either ICI alone. These irAEs can be severe and their pathogenesis is poorly understood. CASE PRESENTATION: We report a case of a woman with metastatic melanoma, treated with combined ipilimumab and nivolumab, who developed severe anaemia. While initial workup revealed autoimmune haemolytic anaemia, the anaemia persisted despite corticosteroids and paradoxical reticulocytopenia was observed. Bone marrow biopsy demonstrated a CD8+ T cell-mediated destruction of the red cell precursors implying concurrent pure red cell aplasia. Both processes resolved after the addition of cyclosporine A. CONCLUSIONS: This report describes a rare case of two concurrent mechanisms of haematological irAE in a patient treated with combined ICI therapy. Successful treatment resulted only after the second underlying mechanism of toxicity was uncovered. Prompt recognition of these unusual presentations of rare irAEs is now key to effective irAE management.

Rapid and sustained improvement in treatment-refractory depression through use of acute intravenous ketamine and concurrent transdermal selegiline: A case series.

BACKGROUND: Treatment resistant depression is a significant source of morbidity and mortality. For patients having failed or unable to undergo the electroconvulsive therapy procedure few effective alternative treatments exist. METHODS: A case series is presented where six patients with treatment resistant depression failing both electroconvulsive therapy and oral antidepressants are concomitantly treated with short course intravenous ketamine and longer term selegiline transdermal system. RESULTS: All six patients experienced clinical improvement with intravenous ketamine, with resolution of suicidality, increased food intake, and commitment to treatment adherence. Five patients showed sustained improvement with the selegiline transdermal system. One patient discontinued selegiline after developing peripheral edema and palpitations. LIMITATIONS: This case series included only patients experiencing moderate to severe treatment resistant depression. Availability of long-term follow-up data not available in some cases. CONCLUSION: Intravenous ketamine with simultaneous administration of the selegiline transdermal system is one strategy for treating treatment resistant depression in patients having failed or unable to undergo the electroconvulsive therapy procedure.

Randomized Phase II Trial and Tumor Mutational Spectrum Analysis from Cabozantinib versus Chemotherapy in Metastatic Uveal Melanoma (Alliance A091201).

PURPOSE: The surface receptor MET is highly expressed on primary uveal melanoma; MET inhibitors demonstrated early clinical signals of efficacy in slowing uveal melanoma growth. The primary objective of our study was to compare the progression-free survival rate at 4 months (PFS4) of patients with uveal melanoma treated with cabozantinib or chemotherapy. PATIENTS AND METHODS: Patients with metastatic uveal melanoma and RECIST measurable disease were randomized 2:1 to receive either cabozantinib (arm 1) versus temozolomide or dacarbazine (arm 2) with restaging imaging every two cycles. Cross-over from arm 2 to cabozantinib after progression was allowed (arm 2X). Available tumor specimens were analyzed by whole-exome sequencing (WES) and results were correlated with outcome. RESULTS: Forty-six eligible patients were accrued with 31, 15, and 9 in arms 1, 2, and 2X, respectively. Median lines of prior therapy, including hepatic embolization, were two. Rates of PFS4 in arm 1 and arm 2 were 32.3% and 26.7% (P = 0.35), respectively, with median PFS time of 60 and 59 days (P = 0.964; HR = 0.99). Median overall survival (OS) was 6.4 months and 7.3 months (P = 0.580; HR = 1.21), respectively. Grade 3-4 Common Terminology Criteria for Adverse Events were present in 61.3%, 46.7%, and 37.5% in arms 1, 2, and 2X, respectively. WES demonstrated a mean tumor mutational burden of 1.53 mutations/Mb and did not separate OS ≤ or >1 year (P = 0.14). Known mutations were identified by WES and novel mutations were nominated. CONCLUSIONS: MET/VEGFR blockade with cabozantinib demonstrated no improvement in PFS but an increase in toxicity relative to temozolomide/dacarbazine in metastatic uveal melanoma.

Explaining Cross-Language Asymmetries in Prosodic Processing: The Cue-Driven Window Length Hypothesis.

Cross-language studies have shown that English speakers use suprasegmental cues to lexical stress less consistently than speakers of Spanish and other Germanic languages ; accordingly, these studies have attributed this asymmetry to a possible trade-off between the use of vowel reduction and suprasegmental cues in lexical access. We put forward the hypothesis that this "cue trade-off" modulates intonation processing as well, so that English speakers make less use of suprasegmental cues in comparison to Spanish speakers when processing intonation in utterances causing processing asymmetries between these two languages. In three cross-language experiments comparing English and Spanish speakers' prediction of hypo-articulated utterances in focal sentences and reporting speech, we have provided evidence for our hypothesis and proposed a mechanism, the Cue-Driven Window Length model, which accounts for the observed cross-language processing asymmetries between English and Spanish at both lexical and utterance levels. Altogether, results from these experiments illustrated in detail how different types of low-level acoustic information (e.g., vowel reduction versus duration) interacted with higher-level expectations based on the speakers' knowledge of intonation providing support for our hypothesis. These interactions were coherent with an active model of speech perception that entailed real-time adjusting to feedback and to information from the context, challenging more traditional models that consider speech perception as a passive, bottom-up pattern-matching process.