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Previous studies have implicated intravitreal vascular endothelial growth factor A (VEGF-A) as a target for countering neovascularization and, therefore, age-related macular degeneration. This double-blind, controlled trial comparing ranibizumab, which neutralizes all isoforms of VEGF-A, with photodynamic therapy with verteporfin showed that ranibizumab was better able to retard the progression of predominantly classic neovascular age-related macular degeneration. This trial comparing ranibizumab with photodynamic therapy with verteporfin showed that ranibizumab was better able to retard the progression of predominantly classic neovascular age-related macular degeneration. Age-related macular degeneration is a leading cause of severe and irreversible vision loss in the developed world among people 50 years of age or older. 1 – 4 The neovascular form of the disease is characterized by the growth of abnormal, choroidal blood vessels beneath the macula, which causes severe loss of vision. 5 Two main patterns of choroidal neovascularization that are associated with age-related macular degeneration, as seen on fluorescein angiography, are classic (in which intensely bright fluorescence is seen in early phases of the angiogram and leaks in late phases) and occult (in which leakage is less intense and appears in . . .

Background Vaginal bleeding (VB) is common in women with gynecologic (GYN) malignancies. Radiation therapy (RT) is used for the definitive treatment of GYN cancers and palliation of bleeding. The historical dogma is that high dose-per-fraction radiation leads to more rapid bleeding cessation, yet there is scant data supporting this claim. We sought to examine the effect of RT fraction size on VB via retrospective analysis of patients receiving hypofractionated radiation (HFRT) compared to conventionally fractionated radiation (CFRT) for control of bleeding secondary to GYN malignancies. Methods We identified patients receiving external beam RT for continuous VB from GYN malignancy treated in our department from 2012 to 2020. RT was classified as HFRT (> 2.0 Gy/fx) or CFRT (1.8–2.0 Gy/fx). Demographic information, disease characteristics, and treatment details were collected. The primary endpoint was days from RT initiation until bleeding resolution. Characteristics between groups were compared via Fisher’s exact test. Time to bleeding cessation was assessed via Kaplan–Meier and log-rank test. Univariable and multivariable Cox-proportional hazards were used to identify factors associated with bleeding cessation. Results We identified 43 patients meeting inclusion criteria with 26 and 17 patients receiving CFRT and HFRT, respectively. Comparison of baseline characteristics revealed patients receiving HFRT were older ( p  = 0.001), more likely to be post-menopausal ( p  = 0.002), and less likely to receive concurrent chemotherapy ( p  = 0.004). Time to bleeding cessation was significantly shorter for patients receiving HFRT (log-rank p  < 0.001) with median time to bleeding cessation of 5 days (HFRT) versus 16 days (CFRT). Stratification by dose-per-fraction revealed a dose–response effect with more rapid bleeding cessation with increased dose-per-fraction. While HFRT, age, recurrent disease, prior pelvic RT, and prior systemic therapy were associated with time to bleeding cessation on univariable analysis, HFRT was the only factor significantly associated with time to bleeding cessation in the final multivariable model (HR 3.26, p  = 0.008). Conclusions Patients with continuous VB from GYN tumors receiving HFRT experienced more rapid bleeding cessation than those receiving CFRT. For patients with severe VB, initiation of HFRT to control malignancy related bleeding quickly may be warranted.

Previous studies have suggested that targeting intravitreal vascular endothelial growth factor A (VEGF-A) counters choroidal neovascularization and hence age-related macular degeneration. A double-blind, placebo-controlled trial of ranibizumab, which neutralizes all isoforms of VEGF-A, for treatment of minimally classic and occult age-related macular degeneration retarded the progression of the disease and improved visual acuity in some patients. For the treatment of minimally classic and occult age-related macular degeneration, ranibizumab retarded the progression of the disease and improved visual acuity in some patients. Age-related macular degeneration is a leading cause of irreversible blindness among people who are 50 years of age or older in the developed world. 1 – 3 The neovascular form of the disease usually causes severe vision loss and is characterized by the abnormal growth of new blood vessels under or within the macula, the central portion of the retina responsible for high-resolution vision. Neovascularization in this disease is classified by fluorescein angiography into major angiographic patterns termed classic and occult, which may be associated with various degrees of aggressiveness of disease, vision loss, and response to various treatment options. 4 Pharmacologic therapies . . .

Background Shifts in intracellular arginine (Arg) and sulfur amino acid (SAA) redox metabolism modulate macrophage activation, polarization and phenotype. Despite their importance in inflammation and redox regulatory pathways, comprehensive analysis of these metabolic networks was not previously possible with existing analytical methods. Methods The Arg/thiol redox LC-MS/MS metabolomics assay permits simultaneous assessment of amino acids and derivative products generated from Arg and SAA metabolism. Using this assay, LPS-induced changes in macrophage amino acid metabolism were monitored to identify pathway shifts during activation and their linkage to cellular redox regulation. Results Metabolite concentrations most significantly changed after treatment of a macrophage-like cell line (RAW) with LPS for 24 hrs were citrulline (Cit) (48-fold increase), ornithine (Orn) (8.5-fold increase), arginine (Arg) (66% decrease), and aspartic acid (Asp) (73% decrease). The ratio Cit + Orn/Arg + Asp (CO/AA) was more sensitive to LPS stimulation than other amino acid ratios commonly used to measure LPS-dependent inflammation (e.g., SAM/SAH, GSH/GSSG) and total media NOx. The CO/AA ratio was also the first ratio to change significantly after LPS treatment (4 hrs). Changes in the overall metabolomic profile over time indicated that metabolic pathways shifted from Arg catabolism to thiol oxidation. Conclusions Simultaneous quantification of Arg and SAA metabolic pathway shifts following LPS challenge of macrophage indicate that, in this system, the Arg-Citrulline/NO cycle and arginase pathways are the amino acid metabolic pathways most sensitive to LPS-challenge. The cellular (Cit + Orn)/(Arg + Asp) ratio, which summarizes this pathway, was more responsive to lower concentrations of LPS and responded earlier than other metabolic biomarkers of macrophage activation including GSH redox. It is suggested that the CO/AA ratio is a redox- independent early biomarker of macrophage activation. The ability to measure both the CO/AA and GSH-redox ratios simultaneously permits quantification of the relative effects of LPS challenge on macrophage inflammation and oxidative stress pathways. The use of this assay in humans is discussed, as are clinical implications.

Aims To evaluate pazopanib eye drops in patients with subfoveal choroidal neovascularisation secondary to age-related macular degeneration. Methods 70 patients with minimally classic or occult subfoveal choroidal neovascularisation were randomly assigned to 5 mg/mL TID, 2 mg/mL TID, and 5 mg/mL QD pazopanib eye drops for 28 days in a multicentre, double-masked trial with an optional safety extension for up to 5 additional months. The primary outcomes were central retinal thickness (CRT) and best-corrected visual acuity (BCVA) at Day 29. Results No significant decrease from baseline in CRT was observed overall; however, an exploratory analysis showed improvement in CRT (mean decrease of 89 μm) in patients with the CFH TT genotype who received 5 mg/mL TID (p=0.01, n=5). Mean increases in BCVA were observed in the 5 mg/mL TID overall (4.32 letters (p=0.002, n=26)) and in those that with CFH Y402H TT (6.96 letters (p=0.02, n=5)) and CT (4.09 letters (p=0.05, n=9)) genotypes. No safety signals that precluded continued investigation were detected. Conclusions 5 mg/mL pazopanib eye drops resulted in mean improvement in BCVA at Day 29 and improvements in vision. However, improvement in macular oedema for age-related macular degeneration was found only in the subset of subjects with the CFH Y402H TT genotype, warranting further investigation.

OBJECTIVEThe objective of this study was to evaluate the University of Alabama at Birmingham experience with routine intraoperative ultrasound (IUS)–guided tandem placement for cervical cancer. METHODSBetween 1999 and 2008, 243 cervical cancer patients underwent IUS-guided tandem placement. One hundred thirty-nine patients received low-dose-rate brachytherapy, and 104 received high-dose-rate brachytherapy. Three hundred fifty-six IUS-guided procedures were performed. Clinical and imaging data were retrospectively analyzed to evaluate complications requiring reinsertion of tandem placement in the context of IUS. RESULTSAll 243 cervical cancer patients completed intracavitary brachytherapy. Five (1.4%) of 356 IUS-guided applicator placements resulted in uterine perforation. All of these patients underwent successful tandem insertion on the second attempt, and no significant clinical sequelae occurred. Intraoperative ultrasound enabled direct uterine visualization and facilitated real-time feedback for selection of a suitable tandem length and curvature; no suboptimal placements requiring return to the operating room occurred (excluding perforation). CONCLUSIONSIn this large series, IUS guidance substantially increased the rate of successful applicator placement and diminished the rate of uterine perforation relative to historical controls. We strongly recommend the use of IUS guidance during operative intrauterine tandem placement for cervical cancer.

ObjectiveTo evaluate the incidence and risk factors for mesorectal node metastasis (MRNM) in locally advanced cervical cancer.Methods/MaterialsWe performed an observational retrospective cohort study of 122 patients with cervical cancer who received definitive chemo-radiation treatment between December 2013 and June 2017 to evaluate the incidence of MRNM. Three diagnostic radiologists assessed all available pre-treatment images. In this study, the pelvic node metastasis was defined as ≥ 1.0 cm and MRNM as ≥ 0.5 cm for CT and MRI scans and as a maximum standardized uptake value of > 2.5 for PET/CT. The relationship of MRNM with FIGO stage, pelvic node metastasis, and mesorectal fascia involvement was evaluated.ResultsThe incidence of MRNM in all 122 patients was 8 (6.6%). However, in advanced stage (III– IV) patients, MRNM occurred in 4 of 39 (10.3%) compared with 4 of 83 (4.8%) in early stage (IB1–IIB) patients (p = 0.27). In patients with a positive pelvic node, MRNM occurred in 7 of 55 (12.7%) and 1 of 67 (1.5%) in those with negative pelvic node (p = 0.02). In addition, the incidence of MRNM was 3 of 9 (33.3%) in the presence of mesorectal fascia involvement and 5 of 113 (4.4%) among those without mesorectal fascia involvement (p = 0.013).ConclusionThis study indicates that pelvic node metastasis and mesorectal fascia involvement are high-risk factors for MRNM. Therefore, vigilance of reviewing images in the mesorectum for MRNM is necessary for high-risk patients.

Purpose To investigate added morbidity associated with the addition of pelvic elective nodal irradiation (ENI) to hypofractionated radiotherapy to the prostate. Methods and materials Two-hundred twelve patients, treated with hypofractionated radiotherapy to the prostate between 2004 and 2011, met the inclusion criteria for the analysis. All patients received 70 Gy to the prostate delivered over 28 fractions and 103 (49%) received ENI consisting of 50.4 Gy to the pelvic lymphatics delivered simultaneously in 1.8 Gy fractions. The mean dose-volume histograms were compared between the two subgroups defined by use of ENI, and various dose-volume parameters were analyzed for effect on late lower gastrointestinal (GI) and genitourinary (GU) toxicity. Results Acute grade 2 lower GI toxicity occurred in 38 (37%) patients receiving ENI versus 19 (17%) in those who did not (p = 0.001). The Kaplan-Meier estimate of grade ≥ 2 lower GI toxicity at 3 years was 15.3% for patients receiving ENI versus 5.3% for those who did not (p = 0.026). Each rectal isodose volume was increased for patients receiving ENI up to 50 Gy (p ≤ 0.021 for each 5 Gy increment). Across all patients, the absolute V 70 of the rectum was the only predictor of late GI toxicity. When subgroups, defined by the use of ENI, were analyzed separately, rectal V 70 was only predictive of late GI toxicity for patients who received ENI. For patients receiving ENI, V 70  > 3 cc was associated with an increased risk of late GI events. Conclusions Elective nodal irradiation increases the rates of acute and late GI toxicity when delivered simultaneously with hypofractioanted prostate radiotherapy. The use of ENI appears to sensitize the rectum to hot spots, therefore we recommend added caution to minimize the volume of rectum receiving 100% of the prescription dose in these patients.

Purpose. High-risk prostate cancer patients often receive radiotherapy (RT) to pelvic lymphatics (PLs). The aim of this study was to determine the safety margin around clinical target volume for PL (PL-CTV) to construct planning target volume for PL (PL-PTV) and for planning elective PL irradiation. Methods and Materials. Six patients who received RT to PL as part of prostate cancer treatment were identified. To determine average daily shifts of PL, the right and left IVs were contoured at 3 predetermined slices on the daily MV scans and their daily shifts were measured at these 3 levels using a measuring tool. Results. A total of 1,932 observations were made. Daily shifts of IV were random in distribution, and the largest observed shift was 13.6 mm in lateral and 15.4 mm in AP directions. The mean lateral and AP shifts of IV were 2.1 mm (±2.2) and 3.5 mm (±2.7), respectively. The data suggest that AP and lateral margins of 8.9 mm and 6.5 mm are necessary. Conclusions. With daily alignment to the prostate, we recommend an additional PL-CTV to PL-PTV conversion margin of 9 mm (AP) and 7 mm (lateral) to account for daily displacement of PL relative to the prostate.

The objective of this study was to evaluate the University of Alabama at Birmingham experience with routine intraoperative ultrasound (IUS)-guided tandem placement for cervical cancer. Between 1999 and 2008, 243 cervical cancer patients underwent IUS-guided tandem placement. One hundred thirty-nine patients received low-dose-rate brachytherapy, and 104 received high-dose-rate brachytherapy. Three hundred fifty-six IUS-guided procedures were performed. Clinical and imaging data were retrospectively analyzed to evaluate complications requiring reinsertion of tandem placement in the context of IUS. All 243 cervical cancer patients completed intracavitary brachytherapy. Five (1.4%) of 356 IUS-guided applicator placements resulted in uterine perforation. All of these patients underwent successful tandem insertion on the second attempt, and no significant clinical sequelae occurred. Intraoperative ultrasound enabled direct uterine visualization and facilitated real-time feedback for selection of a suitable tandem length and curvature; no suboptimal placements requiring return to the operating room occurred (excluding perforation). In this large series, IUS guidance substantially increased the rate of successful applicator placement and diminished the rate of uterine perforation relative to historical controls. We strongly recommend the use of IUS guidance during operative intrauterine tandem placement for cervical cancer.