Immunohistochemistry-Based Taxonomical Classification of Bladder Cancer Predicts Response to Neoadjuvant Chemotherapy.

BACKGROUND: Platinum-based neoadjuvant chemotherapy (NAC) increases the survival of patients with organ-confined urothelial bladder cancer (UBC). In retrospective studies, patients with basal/squamous (BASQ)-like tumors present with more advanced disease and have worse prognosis. Transcriptomics-defined tumor subtypes are associated with response to NAC. AIM: To investigate whether immunohistochemical (IHC) subtyping predicts NAC response. METHODS: Patients with muscle-invasive UBC having received platinum-based NAC were identified. Tissue microarrays were used to type tumors for KRT5/6, KRT14, GATA3, and FOXA1. OUTCOMES: progression-free survival and disease-specific survival; univariable and multivariate Cox regression models were applied. RESULTS: We found a very high concordance between mRNA and protein expression. Using IHC-based hierarchical clustering, we classified 126 tumors in three subgroups: BASQ-like (FOXA1/GATA3 low; KRT5/6/14 high), Luminal-like (FOXA1/GATA3 high; KRT5/6/14 low), and mixed-cluster (FOXA1/GATA3 high; KRT5/6 high; KRT14 low). Applying multivariable analyses, patients with BASQ-like tumors were more likely to achieve a pathological response to NAC (OR 3.96; p = 0.017). The clinical benefit appeared reflected in the lack of significant survival differences between patients with BASQ-like and luminal tumors. CONCLUSIONS: Patients with BASQ-like tumors-identified through simple and robust IHC-have a higher likelihood of undergoing a pathological complete response to NAC. Prospective validation is required.

Performance characteristics of multicolor versus blue light and infrared imaging in the identification of reticular pseudodrusen.

PURPOSE: To describe the appearance of reticular pseudodrusen on multicolor imaging and to evaluate its diagnostic accuracy as compared with the two modalities that may be considered the current reference standard, blue light and infrared imaging. METHODS: Retrospective study in which all multicolor images (constructed from images acquired at 486 nm-blue, 518 nm-green and 815 nm-infrared) of 45 consecutive patients visited in a single center was reviewed. Inclusion criteria involved the presence of >1 reticular pseudodrusen on a 30° × 30° image centered on the fovea as seen with the blue light channel derived from the multicolor imaging. Three experienced observers, masked to each other's results with other imaging modalities, independently classified the number of reticular pseudodrusen with each modality. RESULTS: The median interobserver agreement (kappa) was 0.58 using blue light; 0.65 using infrared; and 0.64 using multicolor images. Multicolor and infrared modalities identified a higher number of reticular pseudodrusen than blue light modality in all fields for all observers (p < 0.0001). Results were not different when multicolor and infrared were compared (p ≥ 0.27). CONCLUSIONS: These results suggest that multicolor and infrared are more sensitive and reproducible than blue light in the identification of RPD. Multicolor did not appear to add a significant value to infrared in the evaluation of RDP. Clinicians using infrared do not need to incorporate multicolor for the identification and quantification of RPD.

Evaluation of two strategies for the interpretation of tumour markers in pleural effusions.

BACKGROUND: Pleural effusions present a diagnostic challenge. Approximately 20% are associated with cancer and some 50% require invasive procedures to perform diagnosis. Determination of tumour markers may help to identify patients with malignant effusions. Two strategies are used to obtain high specificity in the differential diagnosis of malignant pleural effusions: a) high cut-off, and b) fluid/serum (F/S) ratio and low cut-off. The aim of this study is to compare these two strategies and to establish whether the identification of possible false positives using benign biomarkers - ADA, CRP and % of polymorphonuclear cells - improves diagnostic accuracy. METHODS: We studied 402 pleural effusions, 122 of them malignant. Benign biomarkers were determined in pleural fluid, and CEA, CA72-4, CA19-9 and CA15-3 in pleural fluid and serum. RESULTS: Establishing a cut-off value for each TM for a specificity of 100%, a joint sensitivity of 66.5% was obtained. With the F/S strategy and low cut-off points, sensitivity was 77% and specificity 98.2%, Subclassifying cases with negative benign biomarkers, both strategies achieved a specificity of 100%; sensitivity was 69.9% for single determination and 80.6% for F/S ratio. CONCLUSIONS: The best interpretation of TM in the differential diagnosis of malignant pleural effusions is obtained using the F/S ratio in the group with negative benign biomarkers.

ANATOMICAL AND FUNCTIONAL OUTCOMES OF SYMPTOMATIC IDIOPATHIC VITREOMACULAR TRACTION: A Natural History Study From the Pan American Collaborative Retina Study Group.

PURPOSE: To describe the natural history of eyes with symptomatic idiopathic vitreomacular traction (VMT). METHODS: Retrospective multicenter study of 168 eyes with spectral-domain optical coherence tomography (SD-OCT) findings consistent with idiopathic VMT. All eyes were graded according to SD-OCT findings. Grade 1 was defined as incomplete cortical vitreous separation with foveal attachment. Grade 2 was defined as Grade 1 plus intraretinal cysts or clefts. Grade 3 was defined as Grade 2 plus a foveal detachment. All patients were followed for at least 6 months. RESULTS: There were 168 patients (51 men) with a mean age of 68.8 ± 10.7 years. Patients were followed for a mean of 22.7 ± 20.1 months. The mean duration of symptoms before the initial presentation was 3.65 ± 5.42 months. At baseline, 72 eyes had Grade 1, 74 eyes had Grade 2, and 22 eyes had Grade 3 SD-OCT findings. Over the follow-up period, 36 eyes (21.4%) had spontaneous resolution of the VMT with normalization of the foveal anatomy. The mean time to resolution was 12.3 ± 12.6 months. An unfavorable anatomical outcome occurred in 7.7% (13 of 168) of the eyes, with 6 eyes developing a lamellar macular hole and 7 eyes developing a full-thickness macular hole. This occurred at a mean of 10.3 ± 10.7 months after the presentation. Subgroup analysis based on baseline SD-OCT grade showed that 4.1% (3 of 73) of Grade 1 eyes compared with 6.8% (5 of 74) of Grade 2 eyes, and 23.8% (5 of 21) of Grade 3 eyes developed a full-thickness macular hole or lamellar macular hole (P = 0.0109, chi-square test). In the remaining 119 eyes, at the last follow-up, 65 eyes had Grade 1, 42 eyes had Grade 2, and 12 eyes had Grade 3 VMT. On average, the best-corrected visual acuity improved from 0.40 ± 0.35 logarithm of the minimum angle of resolution (Snellen, 20/50) at baseline to 0.35 ± 0.36 logarithm of the minimum angle of resolution (Snellen, 20/45; P = 0.0372), and the mean central macular thickness improved from 350 ± 132 µm to 323 ± 121 µm. CONCLUSION: Spontaneous resolution of VMT occurred in 21.4% (36 of 168) of eyes after a mean follow-up of 11.4 ± 12.6 months. An unfavorable anatomical outcome occurred in 7.7% (13 of 168) of eyes. The baseline SD-OCT grade may predict the progression to full-thickness macular hole.

FEEDER VESSEL LASER PHOTOCOAGULATION FOR IDIOPATHIC, SUBFOVEAL POLYPOIDAL CHOROIDAL VASCULOPATHY NOT RESPONDING TO EITHER ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY OR PHOTODYNAMIC THERAPY.

PURPOSE: To describe the management of a subfoveal polypoidal choroidal vasculopathy case refractory to antiangiogenic treatment and to photodynamic therapy. METHODS: Case report. A 65-year-old male patient presented with a diagnosis of exudative age-related macular degeneration of his left eye and unsuccessful response to eight antiangiogenic injections. Visual acuity was 20/33. Fluorescein angiography, spectral domain optical coherence tomography, and indocyanine green angiography confirmed the diagnosis of polypoidal choroidal vasculopathy. Two photodynamic therapy sessions along with two ranibizumab injections were performed, but no response was obtained. Identification and photocoagulation of the polyp feeder vessels was performed. RESULTS: Polypoidal structures regressed, intraretinal and subretinal exudation resolved, and visual acuity was preserved with no adverse events. CONCLUSION: Indocyanine green angiography-guided feeder vessel diode laser photocoagulation in selected cases of polypoidal choroidal vasculopathy may be considered an effective alternative therapy, especially in those refractory to both photodynamic therapy and antiangiogenic therapy.

Increased Fundus Autofluorescence and Progression of Geographic Atrophy Secondary to Age-Related Macular Degeneration: The GAIN Study.

PURPOSE: To define the role of increased fundus autofluorescence (FAF), a surrogate for lipofuscin content, as a risk factor for progression of geographic atrophy (GA). DESIGN: Prospective natural history cohort study, the GAIN (Characterization of geographic atrophy progression in patients with age-related macular degeneration). METHODS: setting: Single-center study conducted in Barcelona, Spain. PATIENTS: After screening of 211 patients, 109 eyes of 82 patients with GA secondary to age-related macular degeneration and a minimum follow-up of 6 months were included. OBSERVATION PROCEDURES: Lipofuscin content was classified independently by 2 masked observers according to FAF patterns described previously. Bivariate, stratified, and multivariable analyses were used to explore the associations between GA growth and independent variables. Mediation analysis was used to evaluate the contribution of FAF patterns to GA progression. MAIN OUTCOME: Progression of GA in mm(2)/year as measured with FAF. RESULTS: Median follow-up was 18 months (range, 6-42). Median GA growth was 1.61 mm(2)/year. FAF, baseline area of atrophy, and time of follow-up were independently associated with GA progression (P < .004). FAF patterns and baseline area of atrophy were strongly associated (P < .0001), suggesting potential confounding. Mediation analysis suggested that most of the effect of FAF patterns on GA growth was actually caused by baseline area of atrophy. CONCLUSIONS: FAF patterns, baseline area of atrophy, and time of follow-up were associated with GA progression. However, FAF patterns seem to be a consequence (not a cause) of enlarging atrophy and their effect on GA progression seems mostly driven by baseline area of atrophy.

Paraproteinemic maculopathy.

PURPOSE: Paraproteinemia relates to monoclonal gammopathy-producing pathologic antibodies with serous macular detachment being an uncommon ocular manifestation. We ascertained the clinical course of maculopathy in paraproteinemia and investigated the effect of various therapeutic methods on the resolution of subretinal deposits. DESIGN: Multicenter, retrospective, observational case series. PARTICIPANTS: The records of patients with paraproteinemia with optical coherence tomography (OCT) documentation of serous macular detachment were reviewed. METHODS: Data collection included coexisting morbidity, rheology data (immunoglobulin level, hematocrit, and blood viscosity), clinical examination results, and OCT findings. MAIN OUTCOME MEASURES: Best-corrected visual acuity (BCVA), height and basal area of the serous macular detachment, and systemic versus local therapies. RESULTS: A total of 33 cases were collected: 10 new and 23 previously reported in the literature. Diabetes was present in 7 patients, systemic hypertension in 9 patients, and anemia in 18. Mean initial immunoglobulin level was 6497 mg/dl, and mean serum viscosity was 5.5 centipoise (cP). Mean logarithm of the minimum angle of resolution initial vs. final BCVA was 0.55 (Snellen equivalent, 20/71) vs. 0.45 (20/56) in the right eye and 0.38 (20/48) vs. 0.50 (20/63) in the left eye. After mean follow-up of 7 months (range, 0-51 months). Systemic therapies included plasmapheresis (18), chemotherapy (30), blood transfusions (2), transplantation of progenitor hematopoietic cells (2), and oral rituximab (10). Immunoglobulin levels normalized in 8 patients and were unchanged in 1 after plasmapheresis, chemotherapy, or both. Ocular therapy in 8 patients included vitrectomy (1), laser photocoagulation (4), intravitreal bevacizumab (5), intravitreal triamcinolone (2), intravitreal dexamethasone implant (1), intravitreal rituximab (1), and sub-Tenon corticosteroid (1). The maculopathy resolved partially or completely in 17 patients and worsened or remained unchanged in 14 patients over median follow-up of 7 months. Maculopathy was unilateral in 9 cases and occurred at a lower initial immunoglobulin level in diabetics. There was a positive correlation between area of the detachment and serum viscosity. CONCLUSIONS: Paraproteinemic maculopathy can be unilateral. Decreasing the blood immunoglobulin level is the primary goal of therapy for paraproteinemic maculopathy, and this can be achieved by a systemic route. Coexisting diabetes facilitates leakage of immunoglobulins at lower levels than in nondiabetics.

Intravitreal bevacizumab at 4-month intervals for prevention of macular edema after plaque radiotherapy of uveal melanoma.

PURPOSE: To evaluate the efficacy of intravitreal bevacizumab for prevention of macular edema after plaque radiotherapy of uveal melanoma. DESIGN: Retrospective, single-center, nonrandomized, interventional comparative study. PARTICIPANTS: Patients with uveal melanoma treated with plaque radiotherapy were divided into 2 groups: a bevacizumab group and a control group. INTERVENTION: The bevacizumab group received intravitreal bevacizumab injection at the time of plaque removal and every 4 months thereafter for 2 years (total, 7 injections). The control group had no intravitreal bevacizumab injection. Both groups had periodic follow-up with ophthalmoscopy and optical coherence tomography (OCT). MAIN OUTCOME MEASURES: Development of OCT-evident macular edema. RESULTS: There were 292 patients in the bevacizumab group and 126 in the control group. The median foveolar radiation dose was 4292 cGy (bevacizumab) and 4038 cGy (control; P = 0.327). The cumulative incidence of OCT-evident macular edema over 2 years (bevacizumab group vs. control group) was 26% versus 40% (P = 0.004), respectively; that for clinically evident radiation maculopathy was 16% versus 31% (P = 0.001), respectively; that for moderate vision loss was 33% versus 57% (P < 0.001), respectively; and that for poor visual acuity was 15% versus 28% (P = 0.004), respectively. There was no statistically significant difference in clinically evident radiation papillopathy (P = 0.422). Kaplan-Meier estimates at 2 years showed statistically significantly reduced rates of OCT-evident macular edema (P = 0.045) and clinically evident radiation maculopathy (P = 0.040) in the bevacizumab group compared with controls. CONCLUSIONS: Patients receiving intravitreal bevacizumab injection every 4 months after plaque radiotherapy for uveal melanoma demonstrated OCT-evident macular edema, clinically evident radiation maculopathy, moderate vision loss, and poor visual acuity less frequently over a period of 2 years than patients not receiving the injections.

Bimonthly half-dose ranibizumab in large pigment epithelial detachment and retinal angiomatous proliferation with high risk of retinal pigment epithelium tear: a case report.

INTRODUCTION: The management of large pigment epithelial detachments (PEDs) associated with retinal angiomatous proliferation (RAP) remains a challenge due to the high risk of retinal pigment epithelial (RPE) tear. We describe the successful progressive anatomical result and the maintenance of visual acuity to bimonthly, half-dose ranibizumab in a patient with this condition. PURPOSE: To describe the management of a large PED secondary to RAP with bimonthly, half-dose ranibizumab. METHOD: Case report. PATIENT: A 71-year-old woman presented with visual symptoms due to an enlarged PED, compared with previous visits, secondary to a RAP lesion, with a visual acuity of 20/32. To reduce the risk of an RPE tear and a significant decrease in vision, we discussed with the patient the possibility of treating the lesion in a progressive manner, with more frequent but smaller doses of ranibizumab. The patient was treated biweekly with 0.25 mg of ranibizumab until fattening of the PED. RESULTS: The large PED fattened progressively, and visual acuity was preserved with no adverse events. DISCUSSION: The use of half-dose antiangiogenic therapy may be useful in managing large vascularized PED associated with RAP, in an attempt to reduce the risk of RPE tear.

Retinal venous occlusions: diagnosis and choice of treatments.

Retinal vascular occlusive disorders constitute one of the major causes of blindness and impaired vision. There is marked controversy on their pathogeneses, clinical features and particularly their management. Recently, advances in clinical research added antivascular endothelial growth factor, corticosteroids and sustained-release implants to our armamentarium in the management of retinal vein occlusions. The purpose of our paper is to provide an update and a brief review on the current treatment options of retinal vein occlusions.

Scleral necrosis after plaque radiotherapy of uveal melanoma: a case-control study.

PURPOSE: To identify risk factors and outcome of scleral necrosis after plaque radiotherapy of uveal melanoma. DESIGN: Case-control study. PARTICIPANTS: A total of 73 cases with scleral necrosis and 73 controls without necrosis after plaque radiotherapy. Controls were matched for anteroposterior tumor epicenter and follow-up duration. INTERVENTION: Plaque radiotherapy with iodine-125, cobalt-60, iridium-192, or ruthenium-106. MAIN OUTCOME MEASURES: Scleral necrosis. RESULTS: Of 5057 patients treated with plaque radiotherapy for uveal melanoma, 73 (1%) developed radiotherapy-induced scleral necrosis. Scleral necrosis occurred in <1% of patients (3/1140) when plaque radiotherapy was used for tumors <3 mm in thickness, 1% of patients (33/3155) with 3- to 8-mm tumor thickness, and 5% of patients (37/762) with >8-mm-thick tumors. On the basis of tumor location, scleral necrosis was detected after plaque radiotherapy of iris melanoma in 0% of patients (0/91), ciliary body melanoma in 29% of patients (67/235), and choroid melanoma in <1% of patients (6/4731). The mean time interval between plaque radiotherapy and scleral necrosis was 32 months (median, 23 months; range, 4-126 months). The mean basal dimension of scleral necrosis was 4 mm (median, 3 mm; range, 1-15 mm), equivalent to 29% of mean tumor base (median, 24%; range, 6%-100%) and 22% of mean plaque size (median, 19%; range, 5%-75%). Multivariate analysis of factors that predicted clinically evident scleral necrosis included ciliary body (P = 0.0001) and pars plana to ora serrata (P < 0.0001) locations of anterior tumor margin, tumor thickness ≥ 6 mm (P = 0.0001), and radiation dose ≥ 400 Gy to the outer sclera (P = 0.0455). Scleral necrosis remained stable in 48% of patients (35/73), increased in size/severity in 48% of patients (35/73), or progressed to scleral perforation in 4% of patients (3/73) over a mean follow-up of 79 months (median, 54 months; range, 5-351 months). Treatment of scleral necrosis included observation in 81% of patients (59/73), scleral patch graft in 14% of patients (10/73), and enucleation in 5% of patients (4/73). CONCLUSIONS: Scleral necrosis after plaque radiotherapy of uveal melanoma was detected in 1% of cases. Factors predictive of scleral necrosis included increasing tumor thickness, ciliary body and peripheral choroidal location, and higher radiation dose to sclera. Most patients (81%) did not require treatment, and 4% evolved to full-thickness perforation. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

A prognostic score based on clinical factors and biomarkers for advanced non-small cell lung cancer.

AIMS: The objective of the present study is to determine the prognostic value of clinical variables and biomarkers in patients with advanced stages of NSCLC and establish a prognostic classification of these patients. METHODS: For 135 patients with advanced NSCLC we determined their clinical variables and their levels of CEA, CA 125, CYFRA 21-1, albumin, LDH, erythrosedimentation and leukocytes. RESULTS: Multivariate analysis identified PS (ECOG) >1, metastases, no anti-neoplastic treatment, CA 125 >35 U/mL, CYFRA 21-1 >3.3 ng/mL and leukocytes >10'000/µL, as independent prognostic factors for survival. Patients were classified into 3 groups according to the number of adverse prognostic factors (APF). One point was assigned for each APF, except for chemotherapy treatment. Patients with 0-1 APF represented our reference group: patients with 2-3 APF had HR=2.7 (95% CI: 1.5-4.6), while patients with 4-5 APF had HR=8.8 (95% CI: 4.6-16.8). This "score" maintained the differences between risk groups both in patients who received antineoplastic treatment and in those who did not. CONCLUSION: The application of a score that includes clinical data and biomarkers may improve the prognostic classification of NSCLC patients.

Diagnostic accuracy of tumour markers in serous effusions: a validation study.

The utility of tumour markers (TM) in the differential diagnosis of cancer in serous effusion (fluid effusion (FE)) has been the subject of controversy. The aim of this study was to prospectively validate our previous study and to assess whether the addition of adenosine deaminase (ADA), C-reactive protein (CRP) or percentage of polymorphonuclear cells (%PN) allows the identification of false positives. In this study, carcinoembryonic antigen, cancer antigen 15-3, cancer antigen 19-9, ADA, CRP and %PN in FE were determined in 347 patients with 391 effusions. Effusions were considered as malignant effusion when at least one TM in serum exceeded the cutoff and the ratio FE/S was higher than 1.2. Also, cases with values of ADA, CRP and %PN above the established cutoffs in serous effusion were considered as potential false positives. The combined sensitivity and specificity of the three TM was 76.2 % (95 % confidence intervals (CI) 67.8-83.3 %) and 97.0 % (95 % CI 94.1-98.7), respectively. Subanalysis of the 318 cases with previous criteria and negative ADA, CRP and %PN obtained sensitivities of 78.4 % (95 % CI 69.4-85.6) and a specificity of 100 % (95 % CI 98.2-100). The results obtained validate our previous study and are improved with the addition of ADA, CRP and %PN. TM in serous effusions and serum could be useful for the diagnostic assessment of patients with serous effusions.

Posterior scleritis resembling acute retinal necrosis syndrome.

PURPOSE: To report a challenging diagnosis of posterior scleritis in a patient with features of retinal necrosis. METHODS: Single observational case report. RESULTS: A 74-year-old man presented with atypical anterior scleritis in the left eye. Funduscopy showed subretinal inflammatory infiltration resembling acute retinal necrosis. The patient was treated with indomethacin, with resolution of the process. CONCLUSION: Typical signs of posterior scleritis include serous retinal detachment and choroidal folds in the posterior pole. Nonetheless, an atypical presentation can also occur, with peripheral whitish or subretinal inflammatory infiltrate, serous retinal detachment, and hemorrhages, resembling an acute retinal necrosis syndrome.

Total regression of extensive conjunctival intraepithelial neoplasia with superficial corneal invasion treated with topical mitomycin C 0.02%.

OBJECTIVE: To report complete resolution of extensive conjunctival intraepithelial neoplasia in a patient treated with topical mitomycin C. METHODS: Based on clinical examination, impression cytology was performed on the corneal-conjunctival lesion. Management consisted of topical mitomycin 0.02%, administered four times a day for four 1-week cycles, with 1 week off between cycles. RESULTS: Complete resolution of the neoplasm was observed by slit lamp examination at 5 weeks of treatment, and histological resolution by 7 weeks of treatment. There were no complications due to the use of mitomycin. CONCLUSIONS: Topical mitomycin C 2 mg/ml (0.02%) may be a safe and effective treatment for conjunctival intraepithelial neoplasm prior to surgical removal.