Molecular Imaging of p53 in Mouse Models of Cancer Using a Radiolabeled Antibody TAT Conjugate with SPECT.

Mutations of p53 protein occur in over half of all cancers, with profound effects on tumor biology. We present the first-to our knowledge-method for noninvasive visualization of p53 in tumor tissue in vivo, using SPECT, in 3 different models of cancer. Methods: Anti-p53 monoclonal antibodies were conjugated to the cell-penetrating transactivator of transcription (TAT) peptide and a metal ion chelator and then radiolabeled with 111In to allow SPECT imaging. 111In-anti-p53-TAT conjugates were retained longer in cells overexpressing p53-specific than non-p53-specific 111In-mIgG (mouse IgG from murine plasma)-TAT controls, but not in null p53 cells. Results: In vivo SPECT imaging showed enhanced uptake of 111In-anti-p53-TAT, versus 111In-mIgG-TAT, in high-expression p53R175H and medium-expression wild-type p53 but not in null p53 tumor xenografts. The results were confirmed in mice bearing genetically engineered KPC mouse-derived pancreatic ductal adenocarcinoma tumors. Imaging with 111In-anti-p53-TAT was possible in KPC mice bearing spontaneous p53R172H pancreatic ductal adenocarcinoma tumors. Conclusion: We demonstrate the feasibility of noninvasive in vivo molecular imaging of p53 in tumor tissue using a radiolabeled TAT-modified monoclonal antibody.

Navigated Focal Laser of Macular Telangiectasia Type I (Adult-Onset Coats' Disease).

We aimed to evaluate the anatomical and functional outcome of selective photocoagulation of idiopathic macular telangiectasia type 1 by navigated focal laser (Navilas, OD-OS GmBH). Consecutive patients with idiopathic macular telangiectasia type 1 were included in the analysis. All patients were treated with navigated focal laser, planned on multimodal imaging. Seven eyes of seven patients were retrospectively analyzed. Navigated laser photocoagulation of idiopathic macular telangiectasia type 1 successfully occluded the microaneurysms, inducing regression of macular edema and exudation, significative improvement in best-corrected visual acuity at 3 (P = 0.035) and 6 months (P = 0.034) and a decrease in central macular thickness at 3 (P = 0.01) and 6 months (P = 0.01). Patients with idiopathic macular telangiectasia type 1 are ideal candidates for navigated laser treatment. Navigated focal treatment has been shown to be effective and safe in occluding aneurysmal dilations without any side effects. [Ophthalmic Surg Lasers Imaging Retina 2024;55:545-551.].

TRAMADOL-ASSOCIATED BILATERAL CYSTOID MACULAR EDEMA.

PURPOSE: To describe a case of bilateral cystoid macular edema in a patient with long-standing tramadol hydrochloride use. METHODS: Observational case report. RESULTS: A 73-year-old female patient was referred for progressive, bilateral decreased visual acuity. The patient was phakic with a best-corrected visual acuity at presentation was 20/50 on the right eye and 20/64 on the left eye. The patient had a history of low back pain and had been on tramadol hydrochloride 200 mg/day for 16 years. Bilateral cystoid macular edema was confirmed by means of multimodal imaging, including optical coherence tomography angiography. Tramadol intake was progressively reduced over one month and then completely interrupted. At 3 months follow-up, the cystoid macular edema had completely resolved and the best-corrected visual acuity improved in both eyes. CONCLUSION: Cystoid macular edema may be associated with longstanding treatment with tramadol hydrochloride. Tramadol hydrochloride-associated cystoid macular edema is described and its resolution on tramadol cessation.

Predicting the early visual outcomes in sellar-suprasellar lesions compressing the chiasm: the role of SD-OCT series of 20 patients operated via endoscopic endonasal approach.

BACKGROUND: Tumors involving the sellar area often cause visual disorders due to optic nerves/chiasm compression, so that surgery is required. However, the likelihood of visual improvement/restoration is variable. Optical coherence tomography (OCT) is a valid diagnostic tool for defining pathological conditions of the optic apparatus. We herein investigated the role of the SD-OCT and the best corrected visual acuity in predicting postoperative visual recovery, in patients complaining of chiasm compression due to sellar-suprasellar lesions. METHODS: We retrospectively analyzed 20 patients (7 females and 13 males; mean age 50.8±17.87 years, range 11-83), with optic chiasm/nerve compression that underwent endoscopic endonasal approach at the Division of Neurosurgery of the University of Naples Federico II, Naples, Italy, between June 2014 and February 2015. Preoperative ophthalmological assessment focused on BCVA Snellen charts, standard automated perimetry test and SD-OCT. Test were repeated at two weeks, one and three months after surgery. RESULTS: A significant thickness reduction in all the patients, as compared to the control group was noted: GCC thickness reduction remained mostly unchanged postoperatively: 42.9% of the patients had altered visual acuity (VA), while the Perimetry revealed 90% of altered preoperative MD values (MD>-2.00): perimetry improvement was noted in 93% of cases and visual acuity in 91.3% of cases. A direct correlation between preoperative retinal status and functional recovery was identified considering the values of pRNFL and GCC. CONCLUSIONS: OCT provides valuable information regarding the entity of compression also in patients without any visual field defects. Although several factors should be taken into consideration, we retain that preoperative RNFL and GCC thickness values can be claimed as a reliable predictor of visual recovery in those patients presenting chiasm compression.

OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY IMAGING OF CHOROIDAL NEOVASCULARIZATION SECONDARY TO CHOROIDAL RUPTURE TREATED BY INTRAVITREAL RANIBIZUMAB.

PURPOSE: To describe optical coherence tomography angiography findings at baseline and during the follow-up of choroidal neovascularization secondary to choroidal rupture (CR) in a patient with kidney transplant treated by a single intravitreal injection of ranibizumab. METHODS: The clinical course, conventional multimodal imaging findings including ultra-widefield fundus color photography and fundus autofluorescence (Optos California, Marlborough, MA), spectral-domain optical coherence tomography (SD-OCT Spectralis; Heidelberg Engineering, Heidelberg, Germany), fluorescein angiography (FA; Heidelberg Engineering, Heidelberg, Germany), indocyanine green angiography ,and optical coherence tomography angiography (Plex-Elite, Carl Zeiss Meditec, Inc, Dublin, CA) findings at baseline and during the follow-up of a patient with choroidal neovascularization secondary to CR. RESULTS: A 19-year-old young man with a history of blunt trauma presented with acute visual decline of the right eye. He had a systemic history of kidney transplant. His best-corrected visual acuity was 20/200 in the right eye and 20/20 in the left eye at baseline. Funduscopic examination and ultra-widefield fundus autofluorescence imaging revealed a double vertical macular lesion corresponding to a CR in the right eye. Spectral-domain optical coherence tomography, fluorescein angiography, and indocyanine green angiography revealed active Type 2 choroidal neovascularization secondary to the CR. Optical coherence tomography angiography showed a high-flow neovascular network consistent with conventional multimodal imaging. One month after intravitreal injection of ranibizumab, bestcorrected visual acuity was 20/100, optical coherence tomography angiography showed a contraction and remodeling of the neovascular flow, and exudative signs disappeared on multimodal imaging. No side effect was detected. CONCLUSION: Optical coherence tomography angiography is able to detect choroidal neovascularization secondary to CR at baseline and during the follow-up after a single intravitreal injection of ranibizumab. Ranibizumab was effective in the treatment of this sight-threatening lesion in a patient with a history of kidney transplant.

SUBRETINAL TRANSIENT HYPOREFLECTIVITY IN AGE-RELATED MACULAR DEGENERATION: A Spectral Domain Optical Coherence Tomography Study.

PURPOSE: To describe and assess the prognostic significance of subretinal transient hyporeflectivity (STHR) on a novel spectral domain optical coherence tomography (SD-OCT) in age-related macular degeneration. METHODS: Consecutive patients with age-related macular degeneration (AMD) presenting STHR, defined as a small, well-defined, round subretinal, hyporeflective lesion, on SD-OCT and without exudative signs were included. Clinical examination and SD-OCT (SPECTRALIS, Heidelberg Engineering, Heidelberg, Germany) were analyzed at inclusion, 1 month before inclusion, and until the onset of exudative signs during the 12-month follow-up. RESULTS: Thirty-five STHR in 21 eyes of 20 patients were included. Among the 21 eyes, 2 eyes had early AMD, 1 eye had nonexudative asymptomatic macular neovascularization, and 18 eyes presented late AMD: 17 eyes neovascular AMD and 1 eye geographic atrophy. During the 2-month follow-up, 97.1% (34/35) of STHR disappeared. During the 12-month follow-up, 57.1% of eyes (12/21) developed exudative signs on 1 eye with early AMD and 11 eyes with neovascular AMD. CONCLUSION: Subretinal transient hyporeflectivity is a novel SD-OCT sign in patients with AMD. The eyes with isolated STHR should be closely monitored on a monthly basis to detect further exudation.

Irregular vascular network identified with OCT-A in angioid streaks: A probable predictor of active choroidal neovascularization (case series).

PURPOSE: To evaluate the risk of active choroidal neovascularization (CNV) in presence of deep irregular vascular network (IVN) in eyes with angioid streaks (AS). METHODS: Observational case series including three treatment-naive eyes with angioid streaks and IVN, without CNV. Patients were followed-up during 18 months with multimodal imaging including structural optical coherence tomography (OCT) and OCT Angiography (OCT-A) to detect possible neovascular complication. RESULTS: On OCT-A, IVN was detected as a peripapillary and/or macular high-flow lesion, filling the spaces between the angioid streaks in the outer retina slab. Repeated OCT-A could detect an active CNV emerging from the IVN, as a high-flow rich anastomotic vascular network with a perilesional dark halo. Patient was treated with intravitreal injections of Bevacizumab on a Pro Re Nata regimen, with a decreased CNV area and lower vascular density on control OCT-A. CONCLUSION: OCT-A shown to be helpful in detecting the presence of IVN in asymptomatic eyes with AS during a routine examination. In our series, the IVN seems to be predictor of active CNV, needing a close surveillance and frequent follow-up to allow early treatment upon CNV activation.

TWO-YEAR FOLLOW-UP OF A RETINAL ASTROCYTIC HAMARTOMA IMAGED BY OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY.

PURPOSE: To report a case of retinal astrocytic hamartoma imaged by optical coherence tomography angiography (OCTA), followed for 2 years. METHODS: Observational case report. RESULTS: A 25-year-old woman was referred for an incidental retinal lesion in the left eye (LE). At baseline, the best-corrected visual acuity in the LE was 20/32, and fundus examination showed the presence of a round, pigmented lesion in juxtafoveal region, corresponding, on spectral domain OCT, to a hyperreflective lesion within nerve fiber layer. Optical coherence tomography angiography revealed the presence of a high-flow lesion in the superficial capillary plexus segmentation. The patient was followed up for 2 years: best-corrected visual acuity remained stable and multimodal imaging, including OCTA, confirmed the benign and stable nature of the lesion. At baseline, the total lesion area on OCTA (superficial capillary plexus) was 0.181 mm2, whereas vascular density was 52.080%; the total area was 0.204 mm2, and vascular density was 53.740% at 2-year follow-up. CONCLUSION: Optical coherence tomography angiography is helpful not only for the diagnosis and follow-up of such rare tumors, but also it gives insights as to how these tumors develop and how they affect surrounding structures.

Selective Photocoagulation of Capillary Macroaneurysms by Navigated Focal Laser.

BACKGROUND AND OBJECTIVE: To evaluate the anatomical and functional outcome of selective photocoagulation of capillary macroaneurysms (CMAs) by navigated focal laser. PATIENTS AND METHODS: Consecutive patients with solitary or secondary CMAs greater than 150 mm in diameter were included in this analysis. All patients were treated with navigated focal laser and received multimodal imaging. RESULTS: Seventeen eyes of 17 patients were retrospectively analyzed. Navigated laser photocoagulation of the CMAs successfully occluded 100% of the CMAs, inducing significative improvement in best-corrected visual acuity at 3 (P = .002) and 6 months (P = .001) and a decrease in central macular thickness (CMT) at 3 (P = .0004) and 6 months (P = .0004). CONCLUSIONS: Solitary or secondary CMAs arising from retinal capillaries are candidates for navigated laser treatment. Navigated focal treatment was able to close all CMAs in this series with an improvement in vision and CMT. [Ophthalmic Surg Lasers Imaging Retina. 2021;52:366-373.].

Swept-Source OCTA Imaging of a Presumed Solitary Circumscribed Retinal Astrocytic Proliferation.

Presumed solitary circumscribed retinal astrocytic proliferation (pSCRAP) is a rare, benign retinal tumor, typically presenting as a yellow-white, well-defined lesion. It was first qualified as astrocytic, but thanks to the development of optical coherence tomography (OCT), the lesion was identified as a deep glial lesion, as the nerve fiber layer appeared to be spared. Herein, the authors report the case of a 90-year-old man with inferopapillary pSCRAP who benefited from swept-source OCT angiography images. [Ophthalmic Surg Lasers Imaging Retina. 2021;52:232-235.].

Modulating the unfolded protein response with ONC201 to impact on radiation response in prostate cancer cells.

Prostate cancer (PCa) is the most common non-cutaneous cancer in men and a notable cause of cancer mortality when it metastasises. The unfolded protein response (UPR) can be cytoprotective but when acutely activated can lead to cell death. In this study, we sought to enhance the acute activation of the UPR using radiation and ONC201, an UPR activator. Treating PCa cells with ONC201 quickly increased the expression of all the key regulators of the UPR and reduced the oxidative phosphorylation, with cell death occurring 72 h later. We exploited this time lag to sensitize prostate cancer cells to radiation through short-term treatment with ONC201. To understand how priming occurred, we performed RNA-Seq analysis and found that ONC201 suppressed the expression of cell cycle and DNA repair factors. In conclusion, we have shown that ONC201 can prime enhanced radiation response.

OCTA-guided navigated laser therapy for advanced macula neovascularization secondary to age related macular degeneration.

INTRODUCTION: To evaluate the effects of the Navilas system guided by optical coherence tomography angiography for advanced macular neovascularization (MNV) secondary to age-related macular degeneration (AMD). METHODS: Prospective case-series including nine eyes presenting with advanced MNV with persistence of exudative signs, no longer responding to anti-VEGF therapy, best-corrected visual acuity at least of 1.3 logMar. All patients were treated with Navilas guided by overlaid optical coherence tomography angiography (OCTA) images at the site of branching large neovascular trunks. RESULTS: Occlusion of large neovascular trunks successfully occurred in all nine included patients. OCTA analysis revealed, at 1 month follow up, MNV total area decreasing from 6.2 ± 3.1 to 2.6 ± 3.4 mm2. At 6 months follow up, mean MNV area was 3.3 ± 3.4 mm2 (p = 0.008). CONCLUSION: This preliminary study showed that Navilas treatment guided by OCTA may represent an attractive therapeutic option in advanced neovascular lesions secondary to AMD.

Optical coherence tomography angiography in myopic choroidal neovascularization after intravitreal ranibizumab.

PURPOSE:: To describe the optical coherence tomography angiography characteristics of myopic patients with choroidal neovascularization secondary to pathologic myopia during ranibizumab therapy. METHODS:: Nineteen patients were enrolled in this prospective study (13 females, 6 males, mean age 55.25 ± 9.63 years) for a total of 20 eyes examined (14 right eyes, 6 left eyes). Images were analyzed independently by two examiners. RESULTS:: Mean follow-up was 5.75 ± 1.88 months, with a mean intravitreal injections of 1.90 ± 0.44. Mean best-corrected visual acuity at baseline was 0.39 ± 0.18 logMAR versus 0.26 ± 0.16 logMAR 6 months after treatment. The neovascular area (Z = -2.091, p = 0.037) was significantly reduced after treatment, whereas vessel density was not (Z = -1.848, p = 0.065). Moreover, the best-corrected visual acuity was increased (Z = -3.055, p = 0.002). Neovascular area was significantly correlated with best-corrected visual acuity, at both baseline and follow-up (p < 0.05). CONCLUSION:: Our data suggest that optical coherence tomography angiography is a reproducible non-invasive examination with which to monitor changes in the neovascular area in patients with pathologic myopia treated with ranibizumab.

Centrifugal Extension of Retinal Atrophy in Retinal Pigment Epithelium Tears Secondary to Age-Related Macular Degeneration.

BACKGROUND AND OBJECTIVE: To investigate the progression of retinal atrophy in patients with retinal pigment epithelium (RPE) tears secondary to neovascular age-related macular degeneration. PATIENTS AND METHODS: In this retrospective case series, patients were analyzed at two high-volume referral centers. The extension of the areas without RPE was analyzed yearly from baseline to last examination through fundus autofluorescence (FAF) imaging using Region Finder (Heidelberg Engineering, Heidelberg, Germany). RESULTS: Sixteen eyes of 14 patients were included in the study. Mean follow-up was 70.11 months ± 15.5 months. The average area of atrophy was 6.89 mm2 ± 5.4 mm2 at baseline and 9.21 mm2 ± 7.7 mm2 at the last visit (P < .0001). This accounts for a progression of 0.36 mm2 ± 0.46 mm2/year. In all cases, FAF revealed centrifugal extension of retinal atrophy. CONCLUSIONS: In this series, the area of retinal atrophy enlarged over time. Atrophy enlargement is characterized by centrifugal extension from the base of the tear. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:705-710.].

OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY CHANGES IN EARLY TYPE 3 NEOVASCULARIZATION AFTER ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR TREATMENT.

PURPOSE: To investigate the morphologic changes on optical coherence tomography angiography (OCTA) of treatment-naive Type 3 neovascularization secondary to exudative age-related macular degeneration after 1 year of anti-vascular endothelial growth factor therapy. METHODS: Consecutive patients diagnosed with treatment-naive early-stage Type 3 neovascularization were enrolled in this retrospective study. All patients underwent color fundus photographs/MultiColor (Heidelberg Engineering) imaging, fluorescein angiography, indocyanine green angiography, structural spectral domain OCT, and OCTA Optovue RTVue XR Avanti (Optovue) at baseline, and repeated OCTA and structural spectral domain OCT at Month 12. Qualitative analysis of the 3 × 3 OCTA examinations at baseline and Month 12 was then compared, to assess changes after anti-vascular endothelial growth factor therapy. RESULTS: A total of 15 treatment-naive eyes of 15 consecutive patients were included in the analysis. At 12-month follow-up after pro-re-data anti-vascular endothelial growth factor therapy (5.75 ± 1.48 injections of ranibizumab, and injections of 6.33 ± 1.21 of aflibercept), OCTA demonstrated persistence of the deep capillary plexus abnormalities in 13/15 eyes. In the outer retina and choriocapillaris, the initial lesion became undetectable in 7/15 cases, accompanied by choriocapillaris atrophy. The abnormal vascular complex persisted in the form of a tuft-shaped lesion in the outer retinal segmentation in 9/15 eyes, which in the choriocapillaris segmentation was associated with sub-retinal pigment epithelium neovascularization in 8 cases. CONCLUSION: Optical coherence tomography angiography showed that the tuft-shaped abnormal outer retinal lesion, frequently associated with a small clew-like flow signal in the choriocapillaris, after 1 year of anti-vascular endothelial growth factor therapy, either becomes undetectable or develops sub-retinal pigment epithelium neovascularization.

Intraretinal changes in the presence of epiretinal traction.

BACKGROUND: To determine the correlation between the area of morphological changes on the macular surface, the depth of intraretinal changes and the best-corrected visual acuity (BCVA) in patients with idiopathic epiretinal membrane. METHODS: In this prospective cross-sectional study, 38 patients underwent BCVA testing with a Snellen eye chart. The depth of traction, photoreceptor outer segment layer (PROS) thickness, central macular thickness (CMT) and presence of intraretinal cysts were measured using the Avanti RTVue XR and 3D Widefield Enface OCT instruments. Enface sections were performed at the inner limiting membrane (ILM) line level (ILM offset). Patients were categorized into two groups: in group 1 (n = 21), the depth of traction was within 90 µm from the ILM, and in group 2 (n = 17) it was beyond 90 µm from the ILM. The main outcome measure was the correlation between area of epiretinal traction and BCVA according to the depth of traction. RESULTS: In group 1, the depth of traction was 55.15 ± 14.28 µm, the area of traction was 38.95 ± 13.63 mm2, PROS thickness was 51.20 ± 7.23 µm, and CMT was 362.65 ± 41.08 µm. In group 2, the depth of traction was 112.24 ± 10.89 µm, the area of traction was 25.18 ± 4.07 mm2, PROS thickness was 50.24 ± 9.01 µm, and mean CMT was 534.29 ± 126.81 µm. Statistically significant differences in depth of traction, area of traction and CMT were found between the two groups (P < 0.001). The relationship between structure and function between the area of traction and BCVA was better explained in group 2 (r = 0.814, P < 0.001). CONCLUSIONS: We found that intraretinal changes were induced by the ERM, and varied according to the depth of traction measured with en face analysis. In the case of traction deeper than 90 µm, we found a significant correlation between the inner area of the epiretinal traction and BCVA. We believe that retinal stress induced by epiretinal traction is better characterized by combining information provided by sagittal and transverse OCT scans, thus defining its prognostic significance in ERM.

P2X7 targeting inhibits growth of human mesothelioma.

Malignant pleural mesothelioma (MPM) is an aggressive tumor refractory to anti-blastic therapy. MPM cells show several genetic and biochemical defects, e.g. overexpression of oncogenes, downregulation of onco-suppressor genes, dysregulation of microRNA, or alteration of intracellular Ca2+ homeostasis and of apoptosis. No information is as yet available on purinergic signalling in this tumor. Signalling via the P2X7 (P2RX7 or P2X7R) purinergic receptor is attracting increasing attention as a pathway involved in cancer cell death or proliferation. In this report we show that the P2X7R is expressed by three MPM cell lines established from MPM patients but not by mesothelial cells from healthy subjects (healthy mesothelial cells, HMCs). MPM cell proliferation was inhibited by in vitro incubation in the presence of selective P2X7R antagonists, as well as by stimulation with the P2X7R agonist BzATP. Systemic administration of the selective P2X7R blocker AZ10606120 inhibited in vivo growth of MPM tumors whether implanted subcutaneously (s.c.) or intraperitoneally (i.p.). Our findings suggest that the P2X7R might be a novel target for the therapy of mesothelioma.

The endoscopic endonasal approach for the management of craniopharyngiomas.

Craniopharyngiomas are disembryogenetic, benign, tumors that origin from squamous epithelial remnants of Rathke's pouch, developing from any segment of its course, virtually from rhino-pharynx to the hypothalamus. Historically, different microscopic transcranial routes, have been advocated as possible surgical options for the treatment of craniopharyngiomas. The endonasal technique offers a direct approach that permits access to the suprasellar, retrosellar and retroclival space, obviating brain retraction; it provides the advantage of appraoching cranioopharyngiomas without optic nerve manipulation and/or retraction. We herein present the surgical nuances of the endoscopic endonasal approach for the treatment of craniopharyngiomas, highlighting hints, advantages and drawbacks, also in regards of the anatomy dealt with. The endoscopic endonasal technique has been emerging as a viable approach/alternative for the treatment of this disease as the endoscope itself increased its safety and effectiveness. It allows the removal of both infra and supradiaphragmatic lesions - eventually involving the third ventricle chamber but not extending laterally off the ICA out of the visibility and maneuverability of the instruments - avoiding brain and optic nerve manipulation and retraction, with good visualization of the pituitary gland and stalk and the main neurovascular structures.