An unusual paraesophageal and diaphragmatic SDHA-deficient gastrointestinal stromal tumor (GIST) metastases case report.

Background: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract and have diverse tumor biology. Succinate dehydrogenase (SDH)-deficient GIST, comprise less than 10% of all GIST, with mutational loss of the catalytic SDHA subunit being the most common subtype. Contrary to typical GISTs harboring inactivating mutations in KIT/PDGFRA, SDH-deficient GIST has varying biology and behavior, occurring at a younger age, often metastatic on presentation and frequently refractory to conventional tyrosine kinase inhibitors (TKI). Liver and peritoneum are their most common sites of metastases, and extra-abdominal spread to the diaphragm or mediastinum has not been previously described. Case Description: Herein, we present a case of a 44-year-old female patient with a history of SDHA-deficient GISTs with multiple previous metastasectomies who presented with recurrence to the paraesophageal region and diaphragm which was identified upon routine positron emission tomography (PET) surveillance. Patient subsequently underwent a robotic assisted metastasectomy using a thoracic approach. Follow up was obtained 2 months following procedure and there was no evidence of recurrence. Conclusions: SDHA-deficient GISTs have unique tumor biology and management of metastatic lesions remains an area of debate and discovery. Overall, this report highlights the need for comprehensive knowledge of the disease, a skilled surgical team, and multi-disciplinary involvement in order to optimize care and ensure favorable outcomes in this patient population.

Current State of Pleural-Directed Adjuncts Against Malignant Pleural Mesothelioma.

Multimodality therapy including surgical resection is the current paradigm in treating malignant pleural mesothelioma (MPM), a thoracic surface cancer without cure. The main limitation of all surgical approaches is the lack of long-term durability because macroscopic complete resection (R1 resection) commonly predisposes to locoregional relapse. Over the years, there have been many studies that describe various intrapleural strategies that aim to extend the effect of surgical resection. The majority of these approaches are intraoperative adjuvants. Broadly, there are three therapeutic classes that employ diverse agents. The most common, widely used group of adjuvants are comprised of direct therapeutics such as intracavitary chemotherapy (± hyperthermia). By comparison, the least commonly employed intrathoracic adjuvant is the class comprised of drug-device combinations like photodynamic therapy (PDT). But the most rapidly evolving (new) class with much potential for improved efficacy are therapeutics delivered by specialized drug vehicles such as a fibrin gel containing cisplatin. This review provides an updated perspective on pleural-directed adjuncts in the management of MPM as well as highlighting the most promising near-term technology breakthroughs.

Promising therapeutic potential of tumor suppressor microRNAs for malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is an aggressive and recalcitrant surface neoplasm that defies current multimodality treatments. MicroRNAs (miRNAs) are small noncoding RNAs that epigenetically regulate multiple gene networks and cellular processes. In cancer, miRNA dysregulation is associated with tumorigenesis, with tumor suppressor miRNAs underexpressed or lost, while oncogenic miRNAs are overexpressed. Consequently, miRNAs have emerged as potential therapeutic candidates. Because loss of tumor suppressors predominates the pathophysiology of MPM, re-expressing tumor suppressor miRNAs could be an effective therapeutic strategy. This review highlights the most promising MPM-specific tumor suppressor miRNAs that could be developed into novel therapeutics, the supporting data, and what is known about their molecular mechanism(s).

Adoptive Cellular Therapy with Autologous Tumor-Infiltrating Lymphocytes and T-cell Receptor-Engineered T Cells Targeting Common p53 Neoantigens in Human Solid Tumors.

Adoptive cellular therapy (ACT) targeting neoantigens can achieve durable clinical responses in patients with cancer. Most neoantigens arise from patient-specific mutations, requiring highly individualized treatments. To broaden the applicability of ACT targeting neoantigens, we focused on TP53 mutations commonly shared across different cancer types. We performed whole-exome sequencing on 163 patients with metastatic solid cancers, identified 78 who had TP53 missense mutations, and through immunologic screening, identified 21 unique T-cell reactivities. Here, we report a library of 39 T-cell receptors (TCR) targeting TP53 mutations shared among 7.3% of patients with solid tumors. These TCRs recognized tumor cells in a TP53 mutation- and human leucocyte antigen (HLA)-specific manner in vitro and in vivo. Twelve patients with chemorefractory epithelial cancers were treated with ex vivo-expanded autologous tumor-infiltrating lymphocytes (TIL) that were naturally reactive against TP53 mutations. However, limited clinical responses (2 partial responses among 12 patients) were seen. These infusions contained low frequencies of mutant p53-reactive TILs that had exhausted phenotypes and showed poor persistence. We also treated one patient who had chemorefractory breast cancer with ACT comprising autologous peripheral blood lymphocytes transduced with an allogeneic HLA-A*02-restricted TCR specific for p53R175H. The infused cells exhibited an improved immunophenotype and prolonged persistence compared with TIL ACT and the patient experienced an objective tumor regression (-55%) that lasted 6 months. Collectively, these proof-of-concept data suggest that the library of TCRs targeting shared p53 neoantigens should be further evaluated for the treatment of patients with advanced human cancers. See related Spotlight by Klebanoff, p. 919.

Contrast sensitivity isocontours of the central visual field.

Standard automated perimetry (SAP), the most common form of perimetry used in clinical practice, is associated with high test variability, impacting clinical decision making and efficiency. Contrast sensitivity isocontours (CSIs) may reduce test variability in SAP by identifying regions of the visual field with statistically similar patterns of change that can be analysed collectively and allow a point (disease)-to-CSI (normal) comparison in disease assessment as opposed to a point (disease)-to-point (normal) comparison. CSIs in the central visual field however have limited applicability as they have only been described using visual field test patterns with low, 6° spatial sampling. In this study, CSIs were determined within the central 20° visual field using the 10-2 test grid paradigm of the Humphrey Field Analyzer which has a high 2° sampling frequency. The number of CSIs detected in the central 20° visual field was greater than previously reported with low spatial sampling and stimulus size dependent: 6 CSIs for GI, 4 CSIs for GII and GIII, and 3 CSIs for GIV and GV. CSI number and distribution were preserved with age. Use of CSIs to assess visual function in age-related macular degeneration (AMD) found CSI guided analysis detected a significantly greater deviation in sensitivity of AMD eyes from normal compared to a standard clinical pointwise comparison (-1.40 ± 0.15 dB vs -0.96 ± 0.15 dB; p < 0.05). This work suggests detection of CSIs within the central 20° is dependent on sampling strategy and stimulus size and normative distribution limits of CSIs can indicate significant functional deficits in diseases affecting the central visual field such as AMD.

Development of a Spatial Model of Age-Related Change in the Macular Ganglion Cell Layer to Predict Function From Structural Changes.

PURPOSE: To develop location-specific models of normal, age-related changes in the macular ganglion cell layer (GCL) from optical coherence tomography (OCT). Using these OCT-derived models, we predicted visual field (VF) sensitivities and compared these results to actual VF sensitivities. DESIGN: Retrospective cohort study. METHODS: Single eyes of 254 normal participants were retrospectively enrolled from the Centre for Eye Health (Sydney, Australia). Macular GCL measurements were obtained using Spectralis OCT. Cluster algorithms were performed to identify spatial patterns demonstrating similar age-related change. Quadratic and linear regression models were subsequently used to characterize age-related GCL decline. Forty participants underwent additional testing with Humphrey VFs, and 95% prediction intervals were calculated to measure the predictive ability of structure-function models incorporating cluster-based pooling, age correction, and consideration of spatial summation. RESULTS: Quadratic GCL regression models provided a superior fit (P value <.0001-.0066), establishing that GCL decline commences in the late 30s across the macula. The equivalent linear rates of GCL decline showed eccentricity-dependent variation (0.13 µm/yr centrally vs 0.06 µm/yr peripherally); however, average, normalized GCL loss per year was consistent across the 64 macular measurement locations at 0.26%. The 95% prediction intervals describing predicted VF sensitivities were significantly narrower across all cluster-based structure-function models (3.79-4.99 dB) compared with models without clustering applied (5.66-6.73 dB, P < .0001). CONCLUSIONS: Combining spatial clustering with age-correction based on regression models allowed the development of robust models describing GCL changes with age. The resultant superior predictive ability of VF sensitivity from ganglion cell measurements may be applied to future models of disease development to improve detection of early macular GCL pathology.

Consistency of Structure-Function Correlation Between Spatially Scaled Visual Field Stimuli and In Vivo OCT Ganglion Cell Counts.

Purpose: To investigate the effect of stimulus size and disease status on the structure-function relationship within the central retina, we correlated the differential light sensitivity (DLS) with Goldmann stimulus size I to V (GI-V) and optical coherence tomography (OCT) derived in vivo ganglion cell count per stimulus area (GCc) within the macular area in normal subjects and patients with early glaucoma. Methods: Humphrey Field Analyzer 10-2 visual field data with GI through V and Spectralis OCT macular ganglion cell layer (GCL) thickness measurements were collected from normal and early glaucoma cohorts including 25 subjects each. GCc was calculated from GCL thickness data and correlated with DLSs for different stimulus sizes. Results: Correlation coefficients attained with smaller stimulus size were higher compared to larger stimulus sizes in both normal (GI-GII: R2 = 0.41-0.43, GIII-GV: R2 = 0.16-0.41) and diseased cohorts (GI-GII: R2 = 0.33-0.41, GIII-GV: R2 = 0.19-0.36). Quadratic regression curves for combined GI to V data demonstrated high correlation (R2= 0.82-0.90) and differed less than 1 dB of visual sensitivity within the GCc range between cohorts. The established structure-function relationship was compatible with a histologically derived model correlation spanning the range predicted by stimulus sizes GI to GIII. Conclusions: Stimulus sizes within critical spatial summation area (GI-II) improved structure-function correlations in the central visual field. The structure-function relationship was identical in both normal and diseased cohort when GI to GV data were combined. Congruency of GI and GII structure-function correlation with those previously derived with GIII from more peripheral locations further suggests that the structure-function relationship is governed by the number of ganglion cell per stimulus area.

Cell membrane-anchored MUC4 promotes tumorigenicity in epithelial carcinomas.

The cell surface membrane-bound mucin protein MUC4 promotes tumorigenicity, aggressive behavior, and poor outcomes in various types of epithelial carcinomas, including pancreatic, breast, colon, ovarian, and prostate cancer. This review summarizes the theories and findings regarding MUC4 function, and its role in epithelial carcinogenesis. Based on these insights, we developed an outline of the processes and mechanisms by which MUC4 critically supports the propagation and survival of cancer cells in various epithelial organs. MUC4 may therefore be a useful prognostic and diagnostic tool that improves our ability to eradicate various forms of cancer.

Reconciling visual field defects and retinal nerve fibre layer asymmetric patterns in retrograde degeneration: an extended case series.

BACKGROUND: Accurate diagnosis in patients presenting with lesions at various locations within the visual pathway is challenging. This study investigated functional and structural changes secondary to such lesions to identify patterns useful to guide early and effective management. METHODS: Over 10,000 records from patients referred for optic nerve head assessment were reviewed and 31 patients with a final diagnosis of likely neuropathic lesions posterior to the eye were included in the current study. Fundus photographs, optic coherence tomography images and visual field tests were evaluated for changes with respect to retinal nerve fibre layer topography and prediction of structure-function paradigms. Emerging clinical patterns were examined for their consistency with the likely anatomical origin of the underlying insult in the presence of varying diagnoses. RESULTS: Data from patients with lesions along the visual system allowed identification of retinal nerve fibre layer asymmetry correlated with visual field defects and ganglion cell analysis. Bilateral discordance in retinal nerve fibre loss easily discernible from an altered pattern of the temporal-superior-nasal-inferior-temporal curve was characteristic for post-chiasmal lesions. These sometimes-subtle changes supported diagnosis in cases with multiple aetiologies or with ambiguous visual field analysis and/or ganglion cell loss. CONCLUSION: Intricate knowledge of the retinal architecture and projections allows coherent predictions of functional and structural deficits following various lesions affecting the visual pathway. The integration of adjunct imaging and retinal nerve fibre layer thinning will assist clinicians to guide clinical investigations toward a likely diagnosis in the light of significant individual variations. The case series presented in this study aids in differential diagnosis of retrograde optic neuropathies by using retinal nerve fibre layer asymmetric patterns as an important clinical marker.

Pattern Recognition Analysis Reveals Unique Contrast Sensitivity Isocontours Using Static Perimetry Thresholds Across the Visual Field.

Purpose: To determine the locus of test locations that exhibit statistically similar age-related decline in sensitivity to light increments and age-corrected contrast sensitivity isocontours (CSIs) across the central visual field (VF). We compared these CSIs with test point clusters used by the Glaucoma Hemifield Test (GHT). Methods: Sixty healthy observers underwent testing on the Humphrey Field Analyzer 30-2 test grid using Goldmann (G) stimulus sizes I-V. Age-correction factors for GI-V were determined using linear regression analysis. Pattern recognition analysis was used to cluster test locations across the VF exhibiting equal age-related sensitivity decline (age-related CSIs), and points of equal age-corrected sensitivity (age-corrected CSIs) for GI-V. Results: There was a small but significant test size-dependent sensitivity decline with age, with smaller stimuli declining more rapidly. Age-related decline in sensitivity was more rapid in the periphery. A greater number of unique age-related CSIs was revealed when using smaller stimuli, particularly in the mid-periphery. Cluster analysis of age-corrected sensitivity thresholds revealed unique CSIs for GI-V, with smaller stimuli having a greater number of unique clusters. Zones examined by the GHT consisted of test locations that did not necessarily belong to the same CSI, particularly in the periphery. Conclusions: Cluster analysis reveals statistically significant groups of test locations within the 30-2 test grid exhibiting the same age-related decline. CSIs facilitate pooling of sensitivities to reduce the variability of individual test locations. These CSIs could guide future structure-function and alternate hemifield asymmetry analyses by comparing matched areas of similar sensitivity signatures.

Determining Spatial Summation and Its Effect on Contrast Sensitivity across the Central 20 Degrees of Visual Field.

PURPOSE: Recent studies propose that the use of target stimuli within or close to complete spatial summation reveal larger threshold elevation in ocular disease. The Humphrey Visual Field Analyzer (HFA) is used to assess visual function yet the spatial summation characteristics are unexplored for the central macular region. We therefore wanted to establish the relationship between contrast sensitivity and stimulus size (spatial summation) within the central 20° visual field using the high sampling density of the 10-2 test grid. METHODS: Thresholds were measured for one eye from 37 normal subjects using the HFA 10-2 test grid with all five Goldmann (G) targets (GI to GV). Subject data were converted to 50-year-old equivalent using published and calculated location-specific decade correction factors. Spatial summation curves were fitted for all data at all locations. The size of Ricco's critical area (Ac) within which complete spatial summation operates (k = 1), and the slope of partial summation (k < 1: to characterize partial summation), was established. RESULTS: The 50-year-old age normative data were determined for all Goldmann stimulus sizes for the 10-2 HFA test grid and showed a marked change in contrast sensitivity for small test stimuli (e.g. GI) and little change in larger test stimuli (e.g. GV). Both the Ac and k values did not vary with age allowing for the application of the age correction factors. Ac and k values increased with eccentricity with GI remaining within complete spatial summation and GII was close or within complete spatial summation. GIII or larger test sizes were always outside complete spatial summation operating within various levels of partial summation. CONCLUSIONS: The developed normative data now allows comparisons of data sets with high sampling density using the 10-2 grid irrespective of subject age. Test size is important when assessing ocular disease yet only GI or GII stimuli operate close to or within complete spatial summation in the macula. Current visual field testing protocols employ GIII which is always outside complete spatial summation and operates under various values of partial summation: GIII may not be the most suitable test size to assess ocular disease affecting the macula.