A Phase II study assessing Long-Term Response to Ibrutinib Monotherapy in recurrent or refractory CNS Lymphoma.

BACKGROUND: Ibrutinib is a first-in-class inhibitor of Bruton tyrosine kinase (BTK). We previously reported the safety and short-term antitumor activity of ibrutinib in 20 patients with relapsed or refractory (r/r) primary (PCNSL) or secondary CNS lymphoma (SCNSL). PATIENTS AND METHODS: We enrolled 26 additional patients with r/r PCNSL/SCNSL into the dose-expansion cohort of the trial into a combined cohort of 46 patients (31 PCNSLs, 15 SCNSLs). Patients received ibrutinib at 560mg or 840mg daily in the dose-escalation and 840mg daily in the expansion cohort. Median follow up was 49.9 and 62.1 months for patients with PCNSL and SCNSL, respectively. We sequenced DNA from available tumor biopsies and cerebrospinal fluid (CSF) collected before and during ibrutinib therapy. RESULTS: Tumor responses were observed in 23/31 (74%) PCNSLs and 9/15 (60%) SCNSLs, including 12 complete responses in PCNSL and 7 in SCNSL. Median progression-free survival (PFS) for PCNSL was 4.5 months (95%CI: 2.8-9.2) with 1y-PFS at 23.7% (95%CI: 12.4%-45.1%). Median duration of response (DOR) in the 23 PCNSL responders was 5.5 months. Median PFS in SCNSL was 5.3 months (95%CI: 1.3-14.5) with a median DOR 8.7 months for the 9 responders. Exploratory biomarker analysis suggests that mutations in TBL1XR1 may be associated with a long-term response to ibrutinib in PCNSL (p=0.0075). Clearance of circulating tumor DNA from CSF was associated with complete and long-term ibrutinib response. CONCLUSIONS: Our study confirms single-agent activity of ibrutinib in r/r CNS lymphoma and identifies molecular determinants of response based on long-term follow up. CLINICAL TRIAL INFORMATION: NCT02315326.

Ocular side effects of anticancer agents used in the treatment of gynecologic cancers.

The treatment landscape of gynecologic cancers has expanded in recent years to include targeted and immune-based therapies. These therapies often have ocular side effects not seen with conventional chemotherapies, some of which can cause significant visual impairment if not recognized in a timely fashion. Clinicians must know how to appropriately identify, mitigate, and treat these ocular adverse events. Management often involves working with an interdisciplinary team of eye specialists, and it is important to know when to refer patients for specialized care. Proactive identification of eye specialists, especially in rural and community settings where access to care can be limited, may be necessary. Here, we discuss the management of common ocular toxicities seen with novel anticancer agents used to treat gynecologic cancers.

MEK Inhibitor-Associated Ocular Hypertension.

Introduction: Mitogen-activated protein kinase kinase (MEK) inhibitors are targeted anticancer agents that are prescribed to treat a broad range of cancers. Despite their strong efficacy profile, MEK inhibitors have been associated with ocular toxicities, most notably, self-limited serous detachments of the neurosensory retina. In this report, we outline 3 cases of a rarely documented toxicity, MEK inhibitor-associated ocular hypertension. Case Presentations: In the first case, a 69-year-old female with metastatic cholangiocarcinoma presented with an intraocular pressure (IOP) of 25 mm Hg right eye (OD) and 27 mm Hg left eye (OS) 2 months after starting trametinib therapy. Similarly, in the second case, a 26-year-old female with Langerhans cell histiocytosis presented with an elevated IOP of 24 mm Hg bilaterally (OU) 13 months after beginning treatment with an investigational MEK inhibitor. In the third case, a 46-year-old male with Langerhans cell histiocytosis presented with a new onset of elevated IOP of 24 mm Hg 21 days after initiating treatment with cobimetinib. All 3 patients' IOP returned to normal following dorzolamide/timolol administration and continued their cancer therapy. Discussion/Conclusion: This report presents 3 cases of elevated IOP in patients taking three distinct MEK inhibitors which would suggest that IOP-elevating effects exist across the class of MEK inhibitors. All 3 patients had a satisfactory response to topical pressure-lowering drops while continuing their life-preserving MEK inhibitor drug dose, indicating that discontinuation of therapy may not be necessary. Due to the increasing use of MEK inhibitors, it is important that ophthalmologists familiarize themselves with the broad range of potential adverse ocular effects of MEK inhibitors.

Ocular findings in patients with histiocytosis and association with clinical and molecular features.

BACKGROUND/AIMS: Ocular manifestations of histiocytosis and their genetic underpinnings are poorly characterised. This study characterises ocular sites of histiocytosis, notate genetic alterations and correlates to histiocytosis clinical features including subtype and sites of disease. METHODS: Prospective registry-based study of predominantly adult histiocytosis patients at a single-institution tertiary referral centre. 180 eyes of 90 patients (46 males, 44 females) with histiocytosis (Erdheim-Chester disease 34, Rosai-Dorfman 20, xanthogranuloma 7, mixed histiocytosis 13, Langerhans cell histiocytosis (LCH) 15, ALK-positive histiocytosis 1). Ocular findings were categorised by the structure involved. Histiocytosis subtype, sites of disease and genetic status were correlated to ocular findings. RESULTS: Ocular disease was present in more than half the histiocytosis patient cohort and occurred with other disease sites. Ocular findings were statistically significantly different across histiocytic subtypes with LCH subtypes having the lowest proportion of ocular findings (7%) and all other subtypes having rates of ocular findings which were five times that of patients with LCH (p=0.0009). Of patients with ocular findings, 41% of patients reported ocular symptoms and were significantly more in the group with ocular disease present versus those patients without ocular involvement. The presence of ocular findings was not statistically different by BRAFV600E, MAP2K1 or RAS isoform mutational status. CONCLUSIONS: Ocular disease is a common feature of histiocytosis with significant visual symptomatology and occurrence in tandem with multisystem sites. Ocular findings vary by histiocytic subtype. The mutational profile of the cohort reflects known mutations in this clinical population, with no specific driver mutation associated with ocular disease.

Nanocapsules Comprised of Purified Protein: Construction and Applications in Vaccine Research.

Nanoparticles show great promise as a platform for developing vaccines for the prevention of infectious disease. We have been investigating a method whereby nanocapsules can be formulated from protein, such that the final capsules contain only the cross-linked protein itself. Such nanocapsules are made using a silica templating system and can be customised in terms of size and porosity. Here we compare the construction and characteristics of nanocapsules from four different proteins: one a model protein (ovalbumin) and three from infectious disease pathogens, namely the influenza virus, Helicobacter pylori and HIV. Two of the nanocapsules were assessed further. We confirm that nanocapsules constructed from the urease A subunit of H. pylori can reduce subsequent infection in a vaccinated mouse model. Further, we show that capsules constructed from the HIV gp120 protein can be taken up by dendritic cells in tissue culture and can be recognised by antibodies raised against the virus. These results point to the utility of this method in constructing protein-only nanocapsules from proteins of varying sizes and isoelectric points.

Mixed histiocytic neoplasms: A multicentre series revealing diverse somatic mutations and responses to targeted therapy.

Histiocytic neoplasms are diverse clonal haematopoietic disorders, and clinical disease is mediated by tumorous infiltration as well as uncontrolled systemic inflammation. Individual subtypes include Langerhans cell histiocytosis (LCH), Rosai-Dorfman-Destombes disease (RDD) and Erdheim-Chester disease (ECD), and these have been characterized with respect to clinical phenotypes, driver mutations and treatment paradigms. Less is known about patients with mixed histiocytic neoplasms (MXH), that is two or more coexisting disorders. This international collaboration examined patients with biopsy-proven MXH with respect to component disease subtypes, oncogenic driver mutations and responses to conventional (chemotherapeutic or immunosuppressive) versus targeted (BRAF or MEK inhibitor) therapies. Twenty-seven patients were studied with ECD/LCH (19/27), ECD/RDD (6/27), RDD/LCH (1/27) and ECD/RDD/LCH (1/27). Mutations previously undescribed in MXH were identified, including KRAS, MAP2K2, MAPK3, non-V600-BRAF, RAF1 and a BICD2-BRAF fusion. A repeated-measure generalized estimating equation demonstrated that targeted treatment was statistically significantly (1) more likely to result in a complete response (CR), partial response (PR) or stable disease (SD) (odds ratio [OR]: 17.34, 95% CI: 2.19-137.00, p = 0.007), and (2) less likely to result in progression (OR: 0.08, 95% CI: 0.03-0.23, p < 0.0001). Histiocytic neoplasms represent an entity with underappreciated clinical and molecular diversity, poor responsiveness to conventional therapy and exquisite sensitivity to targeted therapy.

Clearance of plasma cell free DNA in metastatic uveal melanoma with radiographic response to immune checkpoint inhibitors.

Purpose: To report a case of metastatic uveal melanoma treated with immune checkpoint inhibition in which serial circulating tumor DNA (ctDNA) was assessed throughout treatment. Observations: A 33-year-old man was diagnosed with metastatic uveal melanoma and initially had progression of disease following hepatic embolization and nivolumab/ipilimumab. At the time, plasma ctDNA GNA11 and SF3B1 were measurable and repeat ctDNA showed increased variant allele frequency following further progression of disease on vorinostat. Following additional nivolumab/ipilimumab, radiographic response was noted and repeat ctDNA became undetectable and remained so at 27 months follow up. Conclusions and importance: Clearance of cell free DNA in metastatic uveal melanoma may be associated with radiographic response to immune checkpoint inhibitors.

Circulating Tumor DNA Posttreatment Measurements and Clinical Correlates in Retinoblastoma.

Importance: Plasma measurements of RB1 circulating tumor DNA (ctDNA) after completion of treatment may be associated with the development of metastases in patients with retinoblastoma. Objective: To determine if the absence of previously detectable plasma ctDNA is associated with metastasis-free survival in patients with a minimum of 1 year follow-up after treatment of retinoblastoma. Design, Setting, and Participants: This cohort study was conducted from June 2019 to September 2023. Patients with retinoblastoma who had measurable ctDNA levels at diagnosis and had repeated ctDNA measurements after ocular treatment (enucleation or intra-arterial chemotherapy) with a minimum of 1 year of follow-up (mean [SD], 28.2 [10.3] months) were included in the study. Patients were recruited from a single-center, tertiary cancer hospital. Exposure: Memorial Sloan Kettering's New York State-approved gene test, which interrogates 129 known cancer genes (called ACCESS), was performed on plasma samples before and after ocular treatments. All exons of the RB1 gene are included in the test and listed as ctDNA in this article. Main Outcomes and Measures: Plasma ctDNA level before treatment, after completion of ocular treatment, and development or absence of metastases. Results: A total of 24 patients (mean [SD] age, 20.7 [17.1] months; 15 female [62.5%]) were included in the study. None of the 23 patients who had a measurable ctDNA level and then no detectable ctDNA level after completion of ocular treatment developed metastases with a minimum of 1 year of follow-up. One patient had persistent measurable ctDNA after initial treatment and developed metastases. Conclusion and Relevance: Patients with retinoblastoma who had a measurable ctDNA level at diagnosis did not develop metastases if the plasma ctDNA level became unrecordable after ocular treatment; 1 patient who had persistent measurable ctDNA after treatment did develop metastasis.

Solid Lipid Nanoparticles Delivering a DNA Vaccine Encoding Helicobacter pylori Urease A Subunit: Immune Analyses before and after a Mouse Model of Infection.

In this study, novel solid lipid particles containing the adjuvant lipid monophosphoryl lipid A (termed 'SLN-A') were synthesised. The SLN-A particles were able to efficiently bind and form complexes with a DNA vaccine encoding the urease alpha subunit of Helicobacter pylori. The resultant nanoparticles were termed lipoplex-A. In a mouse model of H. pylori infection, the lipoplex-A nanoparticles were used to immunise mice, and the resultant immune responses were analysed. It was found that the lipoplex-A vaccine was able to induce high levels of antigen-specific antibodies and an influx of gastric CD4+ T cells in vaccinated mice. In particular, a prime with lipoplex-A and a boost with soluble UreA protein induced significantly high levels of the IgG1 antibody, whereas two doses of lipoplex-A induced high levels of the IgG2c antibody. In this study, lipoplex-A vaccination did not lead to a significant reduction in H. pylori colonisation in a challenge model; however, these results point to the utility of the system for delivering DNA vaccine-encoded antigens to induce immune responses and suggest the ability to tailor those responses.

Advancements in super-selective catheterization and drug selection for intra-arterial chemotherapy for retinoblastoma: a 15-year evolution.

BACKGROUND: Retinoblastoma (Rb) is the most common primary ocular malignancy of childhood. Left untreated, it is 100% fatal and carries a substantial risk of impaired vision and removal of one or both eyes. Intra-arterial chemotherapy (IAC) has become a pillar in the treatment paradigm for Rb that allows for better eye salvage and vision preservation without compromising survival. We describe the evolution of our technique over 15 years. METHODS: A retrospective chart review was conducted of 571 patients (697 eyes) and 2391 successful IAC sessions over 15 years. This cohort was separated into three 5-year periods (P1, P2, P3) to assess trends in IAC catheterization technique, complications, and drug delivery. RESULTS: From a total of 2402 attempted IAC sessions, there were 2391 successful IAC deliveries, consistent with a 99.5% success rate. The rate of successful super-selective catheterizations over the three periods ranged from 80% in P1 to 84.9% in P2 and 89.2% in P3. Catheterization-related complication rates were 0.7% in P1, 1.1% in P2, and 0.6% in P3. Chemotherapeutics used included combinations of melphalan, topotecan and carboplatin. The rate of patients receiving triple therapy among all groups was 128 (21%) in P1, 487 (41.9%) in P2, and 413 (66.7%) in P3. CONCLUSIONS: The overall rate of successful catheterization and IAC started high and has improved over 15 years, and catheterization-related complications are rare. There has been a significant trend towards triple chemotherapy over time.

Ocular toxicities of fibroblast growth factor receptor inhibitors: A review.

Fibroblast growth factor receptor (FGFR) inhibitors are an emerging class of small molecule targeted cancer drugs with promising therapeutic possibilities for a wide variety of malignancies. While ocular adverse events from FGFR inhibitors are reported in clinical trials, subsequent case studies continue to reveal new toxicities. Disease pathology affecting multiple parts of the eye has been reported, but the ocular surface and the retina are the most commonly encountered areas affected by FGFR inhibitors, manifesting as dry eye and FGFR inhibitor-associated retinopathy, respectively. Corneal thinning and melt is a rare but serious and potentially vision-threatening complication of FGFR inhibitor toxicity. Similarities between toxicities observed from other targeted cancer therapy drugs and FGFR inhibitors may help us understand underlying pathophysiological changes. The management of these adverse events requires close ophthalmologic follow-up and may require discontinuation of the offending agents in some cases.

Plasma Circulating Tumor DNA to Assist in the Diagnose of Unknown Primary Malignancy Underlying Choroidal Metastases.

PURPOSE: Management of suspected choroidal metastases requires diagnostic imaging and an invasive, sometimes intraocular, biopsy to determine the primary malignancy. This multistep process takes time which may impact morbidity and mortality. METHODS: Retrospective review of one case. RESULTS: A 56-year-old woman presented with bilateral amelanotic choroidal masses suspicious for metastases of unknown origin. Plasma circulating tumor DNA revealed EGFR, PTEN, SMAD4, a profile consistent with non-small cell lung cancer. Subsequent radiographic imaging and scapular biopsy revealed lung adenocarcinoma and genetic profile concordant with the liquid biopsy. Patient was started on EGFR-inhibitor, Osimertinib1, with measurable systemic and ocular response. CONCLUSION: Plasma circulating tumor DNA revealed the genetic profile of the primary malignancy underlying choroidal metastases of unknown origin; aiding in the prompt diagnosis and detecting the driver mutation which guided management with targeted therapy.

An Evaluation of Urease A Subunit Nanocapsules as a Vaccine in a Mouse Model of Helicobacter pylori Infection.

Using removable silica templates, protein nanocapsules comprising the A subunit of Helicobacter pylori urease (UreA) were synthesised. The templates were of two sizes, with solid core mesoporous shell (SC/MS) silica templates giving rise to nanocapsules of average diameter 510 nm and mesoporous (MS) silica templates giving rise to nanocapsules of average diameter 47 nm. Both were shown to be highly monodispersed and relatively homogenous in structure. Various combinations of the nanocapsules in formulation were assessed as vaccines in a mouse model of H. pylori infection. Immune responses were evaluated and protective efficacy assessed. It was demonstrated that vaccination of mice with the larger nanocapsules combined with an adjuvant was able to significantly reduce colonisation.

Pharmacokinetics of Orbital Topotecan After Ophthalmic Artery Chemosurgery and Intravenous Infusion in the Swine Model.

Purpose: Surgery, multiagent systemic chemotherapy, and radiation are used for patients with orbital retinoblastoma but are associated with unacceptable short- and long-term toxicity (including death). We studied orbital and systemic exposure of topotecan in the swine model after ophthalmic artery chemosurgery (OAC) and intravenous (IV) delivery. Methods: Landrace pigs (n = 3) underwent 30-minute OAC of topotecan (4 mg), and samples were serially obtained from the femoral artery and from a microdialysis probe inserted into the lateral rectus muscle sheath of the infused eye as a surrogate of the orbital irrigation. Animals were recovered, and, after a wash-out period, plasma and microdialysate samples from the contralateral eye were collected after a 30-minute IV infusion of topotecan (4 mg). Samples were quantified by high-performance liquid chromatography, and population pharmacokinetic analysis was conducted using MonolixSuite. Results: After OAC, median topotecan exposure in the orbit was 5624 ng × h/mL (range 3922-12531) compared to 23 ng × h/mL (range 18-75) after IV infusion. Thus, topotecan exposure in the orbit was 218-fold (range 75-540) higher after OAC than after IV infusion despite comparable systemic exposure (AUCpl) between routes (AUCpl, OAC: 141 ng × h/mL [127-191] versus AUCpl, IV: 139 ng × h/mL [126-186]). OAC was more selective to target the orbit because the median (range) orbital-to-plasma exposure ratio was 44 (28-65) after OAC compared to 0.18 (0.13-0.40) after IV infusion. Conclusions: OAC of topotecan resulted in higher orbital exposure than after IV infusion and was a more selective route for local drug delivery. Patients with orbital retinoblastoma may benefit from a multimodal treatment strategy including OAC therapy.

Retinopathy, Optic Neuropathy, and Cataract in Childhood Cancer Survivors Treated With Radiation Therapy: A PENTEC Comprehensive Review.

PURPOSE: Few reports describe the risks of late ocular toxicities after radiation therapy (RT) for childhood cancers despite their effect on quality of life. The Pediatric Normal Tissue Effects in the Clinic (PENTEC) ocular task force aims to quantify the radiation dose dependence of select late ocular adverse effects. Here, we report results concerning retinopathy, optic neuropathy, and cataract in childhood cancer survivors who received cranial RT. METHODS AND MATERIALS: A systematic literature search was performed using the PubMed, MEDLINE, and Cochrane Library databases for peer-reviewed studies published from 1980 to 2021 related to childhood cancer, RT, and ocular endpoints including dry eye, keratitis/corneal injury, conjunctival injury, cataract, retinopathy, and optic neuropathy. This initial search yielded abstracts for 2947 references, 269 of which were selected as potentially having useful outcomes and RT data. Data permitting, treatment and outcome data were used to generate normal tissue complication probability models. RESULTS: We identified sufficient RT data to generate normal tissue complication probability models for 3 endpoints: retinopathy, optic neuropathy, and cataract formation. Based on limited data, the model for development of retinopathy suggests 5% and 50% risk of toxicity at 42 and 62 Gy, respectively. The model for development of optic neuropathy suggests 5% and 50% risk of toxicity at 57 and 64 Gy, respectively. More extensive data were available to evaluate the risk of cataract, separated into self-reported versus ophthalmologist-diagnosed cataract. The models suggest 5% and 50% risk of self-reported cataract at 12 and >40 Gy, respectively, and 50% risk of ophthalmologist-diagnosed cataract at 9 Gy (>5% long-term risk at 0 Gy in patients treated with chemotherapy only). CONCLUSIONS: Radiation dose effects in the eye are inadequately studied in the pediatric population. Based on limited published data, this PENTEC comprehensive review establishes relationships between RT dose and subsequent risks of retinopathy, optic neuropathy, and cataract formation.

Outcomes after interruption of targeted therapy in patients with histiocytic neoplasms.

Little is known about outcomes following interruption of targeted therapy in adult patients with histiocytic neoplasms. This is an IRB-approved study of patients with histiocytic neoplasms whose BRAF and MEK inhibitors were interrupted after achieving complete or partial response by 18-fluorodeoxyglucose positron emission tomography (FDG-PET). 17/22 (77%) of patients experienced disease relapse following treatment interruption. Achieving a complete response prior to interruption, having a mutation other than BRAFV600E, and receiving MEK inhibition only were each associated with a statistically significant improvement in relapse-free survival. Relapse is common following treatment interruption however some patients may be suitable for limited-duration treatment.