Phase 1 study of EUS-guided photodynamic therapy for locally advanced pancreatic cancer.

BACKGROUND AND AIMS: Locally advanced pancreatic cancer (LAPC) has a poor prognosis. There are limited data describing the use of photodynamic therapy (PDT) for pancreatic cancer in humans. We hypothesized that EUS-guided PDT for LAPC is safe, technically feasible, and produces a dose- and time-dependent increasing degree of image-defined tumor necrosis. METHODS: In a single-center, prospective, dose-escalation phase 1 study, patients with treatment-naïve LAPC received intravenous porfimer sodium (Concordia Laboratories Inc, St Michael, Barbados) followed 2 days later by EUS-PDT. EUS-PDT was performed by puncture with a 19-gauge needle and insertion of a 1.0-cm light diffuser (Pioneer Optics, Bloomfield, Conn) and illumination with a 630-nm light (Diomed Inc, Andover, Mass). A CT scan 18 days after PDT was done to assess for change in pancreatic necrosis. Nab-paclitaxel (125 mg/ m2 intravenously) and gemcitabine (1000 mg /m2 intravenously) were initiated 7 days after CT and given weekly for 3 of 4 weeks (1 cycle) until disease progression or unacceptable toxicity. RESULTS: Twelve patients (mean age, 67 ± 6 years; 8 male) with tumors (mean diameter, 45.2 ± 12.9 mm) in the head and/or neck (8) or body and/or tail (4) underwent EUS-PDT. Compared with baseline imaging, increased volume and percentage of tumor necrosis were observed in 6 of 12 patients (50%) after EUS-PDT. The mean overall increases in volume and percentage necrosis were 10 ± 26 cm3 (P = .20) and 18% ± 22% (P = .016), respectively. After a median follow-up of 10.5 months (range, 1.0-37.4 months), median progression-free (PFS) and overall survival (OS) were 2.6 months (95% confidence interval, 0.7, not estimable) and 11.5 months (95% confidence interval, 1.1, 16.9), respectively. Surgical resection was attempted in 2 patients, and pathology showed a complete response (n = 1) and residual 2-mm tumor (n = 1). There were 8 serious adverse events and none related to EUS or EUS-PDT. CONCLUSION: EUS-PDT for LAPC appears to be safe and produces measurable imaged-defined tumor necrosis. Phase 2 studies are warranted. (Clinical trial registration number: NCT01770132.).

Ocular blood flow and oxygen delivery to the retina in primary open-angle glaucoma patients: the addition of dorzolamide to timolol monotherapy.

PURPOSE: To assess the effects of adding dorzolamide to timolol monotherapy on ocular haemodynamics and retinal oxygen saturation in patients with primary open-angle glaucoma (POAG). METHODS: Twenty-four patients (12 healthy, 12 with POAG) were treated with dorzolamide/timolol combination (DT) versus timolol maleate 0.5% twice daily in a randomized, crossover, double-blind study conducted over a period of 18 months. Patients received each treatment for 8 months then crossed over to the other treatment after a 1-month washout and second baseline. Goldmann applanation tonometry, Heidelberg retinal flowmetry (HRF), colour Doppler imaging (CDI) and retinal photographic oximetry were performed at each visit. RESULTS: DT significantly reduced intraocular pressure (IOP) in both glaucomatous [right eye (OD) -13.15%, left eye (OS) -14.43%; p < 0.036] and non-glaucomatous (OD -12.4%, OS -13.88%; p < 0.039) patients compared to timolol after 8 months of treatment. DT significantly reduced the number of zero blood flow pixels in the superior (-39.72%; p < 0.014) and inferior (-51.44%; p < 0.008) retina in the non-glaucomatous group and inferior retina in the glaucomatous group (-55.38%, p < 0.006). The continuation of timolol monotherapy from baseline did not change (p < 0.05) any measured parameter and neither treatment had a significant effect (p < 0.05) on retinal oximetry or CDI parameters. CONCLUSION: The addition of dorzolamide to timolol monotherapy decreases IOP and increases retinal blood flow in the superficial retinal vasculature in both glaucomatous and healthy patients following 8 months of treatment. The combination of increased retinal blood flow with consistent oxygen saturation may potentially increase oxygen delivery to the retina.

Longitudinal assessment of plus disease in retinopathy of prematurity using color Doppler imaging.

Retinal vascular changes and the development of plus disease are the hallmarks of retinopathy of prematurity (ROP). The purpose of this study was to evaluate whether or not serial examinations of retrobulbar blood flow characteristics, as measured by color Doppler imaging (CDI) performed repeatedly over a period of several weeks, would be useful for predicting those infants at risk for developing plus disease and to determine whether this technique may be used as an objective tool for confirming the presence of plus disease. Of the 73 infants followed in this study, 14 (19%) developed plus disease confirmed by a panel of experts. When comparing the group of infants developing plus disease with those infants who did not develop plus disease, we did not find any significant differences in the retrobulbar blood flow characteristics of either the central retinal or ophthalmic arteries. Color Doppler imaging did not appear to be a clinically useful tool in the longitudinal management of ROP, nor did it appear to be useful as an objective determinant of plus disease in these premature infants.

Effects of exercise on intraocular pressure and ocular blood flow: a review.

Glaucoma is a disease characterized by progressive optic neuropathy resulting in retinal ganglion cell death, which affects approximately 68 million people worldwide. Risk factors include intraocular pressure (IOP), genetics, race, age, and vascular factors. Exercise is known to affect IOP and systemic cardiovascular factors and, therefore, may affect glaucoma pathophysiology. This review discusses the results of articles relevant to glaucoma, IOP, ocular blood flow (OBF), and exercise. Isometric and dynamic exercises have been studied with respect to effects on IOP and OBF. Isometric exercise results in an acute decrease in IOP, which correlates with hypocapnia. Dynamic exercise results in a more pronounced but also short duration decrease in IOP. Physical fitness is associated with lower baseline IOP but diminished acute IOP-lowering response to exercise. Upon cessation of exercise, values return to pretrained levels within 1 month. In glaucoma patients, these IOP-lowering effects are greater than in healthy subjects. In healthy subjects, OBF is unchanged during exercise due to vascular autoregulation. This autoregulation fails at ocular perfusion pressures greater than 70% above baseline. In conclusion exercise in glaucoma patients results in acutely lowered IOP and lower baseline IOP. The effects of exercise on the prevention of glaucoma and glaucomatous progression remain unknown. The role of exercise in glaucoma management should be investigated.

Color Doppler imaging and ocular pulse amplitude in glaucomatous and healthy eyes.

PURPOSE: To determine factors influencing color Doppler imaging (CDI) measurements, to compare retrobulbar flow velocities between patients with glaucoma and healthy controls, and to describe the correlation between CDI and ocular pulse amplitude (OPA). METHODS: Patients with normal tension (n=28) or primary open angle glaucoma (n=19) and healthy controls (n=22) underwent CDI and OPA measurements. Intraocular pressure, corneal thickness, blood pressure, and heart rate were also measured. Spearman correlations were used to explore relations among these variables. A regression model for repeated measures was applied to compare between diagnostic groups the flow velocity indices in the retrobulbar vessels. RESULTS: Retrobulbar diastolic blood flow velocities correlated with diastolic blood pressure and perfusion pressure (range of Spearman rho [rho] coefficients=0.25-0.28; p=0.044-0.013 for the different vessels). Corneal thickness showed a positive correlation with systolic and diastolic flow velocities in the central retinal artery (rho=0.29 and 0.31; p=0.017 and 0.011 for peak systolic and end diastolic velocity, respectively). Systolic and diastolic blood flow velocities were reduced in the retrobulbar vessels of patients with normal tension glaucoma (P=0.0004) as well as primary open angle glaucoma (P=0.003) compared to healthy controls. A correlation was found between OPA and the resistive index in the retrobulbar vessels of the healthy controls (range rho=0.42-0.53; p=0.059-0.014). CONCLUSIONS: Retrobulbar blood flow velocities are reduced in patients with primary open angle glaucoma and normal tension glaucoma. Blood pressure and corneal thickness may influence CDI measurements. OPA correlates with the resistive index in CDI.

Interobserver repeatability of heidelberg retinal flowmetry using pixel-by-pixel analysis.

PURPOSE: To determine the interobserver reproducibility of Heidelberg retinal flowmeter (HRF) blood flow measurements using independently selected study areas for pixel-by-pixel analysis. PATIENTS AND METHODS: Blood flow measurements were performed on 257 scans from 15 patients, 14 of whom had glaucoma or ocular hypertension. HRF was used to record capillary perfusion in a 2560x640 mum area of the supratemporal peripapillary region and pixel-by-pixel analysis was performed from an area adjacent to the optic disc with a minimum of 1600 pixels. Each observer independently selected the area for analysis. The percentage of pixels with <1 arbitrary unit of flow (no flow) and 10, 25, 50, 75, and 90th percentiles of flow values was calculated. Interobserver variability was assessed by estimating the intraclass correlation coefficient (ICC) and its 95% confidence interval. Bland-Altman plots of the difference between the 2 physicians versus the average of the 2 physicians for each outcome were created. RESULTS: ICC was 0.79 (range: 0.74 to 0.83) for mean flow values. For 0, 10, 25, 50, 75, and 90th percentiles of flow, the ICC was 0.67 (0.60 to 0.73), 0.74 (0.68 to 0.79), 0.82 (0.78 to 0.86), 0.85 (0.82 to 0.88), 0.85 (0.81 to 0.88), and 0.77 (0.72 to 0.82), respectively. Zero flow pixels had a nonsignificant mean difference between observers (P=0.542), whereas the remainder of the flow values demonstrated significant mean differences. CONCLUSIONS: This study demonstrates that independent observers can review high-quality HRF scans and may produce different absolute values while retaining strong consistency of agreement when independently selecting areas for analysis using the pixel-by-pixel method.

The effect of latanoprost on ocular blood flow.

PURPOSE: To investigate the effect of latanoprost on ocular hemodynamics in healthy subjects. METHODS: In a randomized, double-masked, placebo-controlled crossover study, 12 healthy subjects received either placebo or latanoprost for 4 weeks in one randomly chosen eye. Following a 4-week washout period, each patient received the opposite treatment. Blood pressure, heart rate, logMar visual acuity, contrast sensitivity, iris photography, intraocular pressure (IOP), Heidelberg retinal flowmetry, and color Doppler imaging measurements were taken at baseline and post-treatment. Heidelberg retinal flowmetry images were analyzed using the pixel-by-pixel analysis. Color Doppler imaging measurements included peak systolic velocity and end diastolic velocities (cm/s), and the calculated resistance index. Pre- and post-treatment values were compared by Wilcoxon signed rank tests (P < 0.05 was considered to be statistically significant). RESULTS: There were no significant changes in heart rate, blood pressure, contrast sensitivity, or visual acuity with either treatment. Latanoprost demonstrated a significant reduction in both IOP (P = 0.005) and retinal blood flow at the 10th (P = 0.009) and 25th (P = 0.009) percentiles of Heidelberg retinal flowmetry measurements in the superior temporal region. Latanoprost, however, did not reduce blood flow in the inferior temporal region and did not significantly elevate the percentage of zero-flow pixels of the temporal peripapillary area. CONCLUSION: Latanoprost has mostly neutral effects on ocular circulation. These findings must be investigated in glaucoma patients who may respond differently than healthy subjects due to faulty vascular autoregulation.

The effects of raloxifene hydrochloride on ocular hemodynamics and visual function.

OBJECTIVE: To assess the comprehensive effects of raloxifene hydrochloride on retinal, choroidal and retrobulbar hemodynamics and on visual function in post-menopausal women. DESIGN: Twenty-four post-menopausal women (age 55 +/- 3.8 years) were recruited for this cross-sectional study: 12 received placebo and 12 received raloxifene hydrochloride 60 mg once a day for 3 months. Baseline measurements of both groups included heart rate (HR), blood pressure (BP), visual acuity, contrast sensitivity and intraocular pressure (IOP) for both eyes. A comprehensive ocular blood flow (OBF) assessment was obtained for each patient in a randomly chosen study eye. Retinal blood flow data was obtained using confocal scanning laser Doppler flowmetry [Heidelberg Retinal Flowmeter (HRF)]. Color Doppler imaging (CDI) was used to assess retrobulbar hemodynamics in the ophthalmic, central retinal, short nasal and temporal posterior ciliary arteries. Baseline vision and hemodynamics in post-menopausal subjects were compared using paired Student's t tests, and the percentage change in baseline versus 3-month parameters was analyzed. RESULTS: There were no statistically significant differences between 3 months of raloxifene therapy and placebo in terms of age, HR, arterial or mean BP, visual acuity, contrast sensitivity, IOP or retinal or retrobulbar blood flow. CONCLUSION: Raloxifene therapy at 60 mg/day had no clinically significant impact on BP, IOP or OBF in post-menopausal women.

Pulsatile ocular blood flow: relationship with flow velocities in vessels supplying the retina and choroid.

BACKGROUND: Although ocular tonography measures a pulsatile component of the ocular perfusion, the retinal and/or choroidal components of this pulsatile flow remain undefined. AIM: To compare ocular tonography with the assessment of flow velocities in arteries supplying the retina, choroid and entire orbit. METHODS: 22 normal eyes from 11 subjects were studied. Pulsatile ocular blood flow (POBF) was measured using the ocular blood flow tonograph, and flow velocities in the ophthalmic, central retinal (CRA) and temporal short posterior ciliary arteries (TSPCA) using colour Doppler imaging. The correlation between POBF and retrobulbar flow velocities was determined. RESULTS: POBF correlated significantly with peak systolic velocity (PSV) of the CRA (r = 0.56, p = 0.007) and the TSPCA (r = 0.48, p = 0.02), and with the resistive index of the TSPCA (r = 0.45, p = 0.04). Additionally, pulse amplitude (PSV-end diastolic velocity) in the CRA and the TSPCA correlated significantly with POBF measurements (each p<0.05). However, POBF did not correlate with any flow velocity indices in the ophthalmic artery. CONCLUSION: POBF is associated with systolic and pulsatile components of blood flow velocities in both the CRA and the TSPCA. This result suggests that POBF determinations are influenced by the pulsatile components of both choroidal and retinal perfusion.

Relationship of cerebral blood flow and central visual function in primary open-angle glaucoma.

PURPOSE: To investigate the relations between middle cerebral artery (MCA) blood flow velocities and central visual function measured by foveal cone electroretinograms (ERG) and visual field. METHODS: Fifteen primary open-angle glaucoma patients were recruited. The eye with the more severe visual field defect (full threshold 24-2) and/or optic disc damage was chosen. Measurements included brachial arterial pressure, heart rate, visual acuity (logMAR), contrast sensitivity (CSV-1000), central visual field (Humphrey SITA 10-2), foveal cone ERG, and transcranial Doppler. Pearson correlation coefficients were estimated to assess the strength of the linear relationship between the MCA flow velocity and the other measured parameters. RESULTS: Visual field was successfully completed in 12 eyes. We were unable to obtain ERG responses and MCA velocity readings for 1 patient. A significant correlation was observed between MCA mean flow velocity and focal cone ERG amplitude [r=0.69, n=13, confidence interval (CI) 0.22, 0.90, P=0.009], but correlation between mean foveal cone ERG implicit time and middle cerebral was not statistically significant (r=0.011, n=13, CI 0.47, 0.63). A significant correlation was also observed between MCA mean flow velocity and mean sensitivity (r=0.76, n=12, CI 0.32, 0.93, P=0.005), and mean defect (r=0.73, n=12, CI 0.28, 0.92, P=0.007) of the central visual field, logMAR visual acuity (r=0.57, n=14, CI 0.05, 0.84, P=0.036), and contrast sensitivity (r=0.61, n=13, CI 0.09, 0.87, P=0.027). CONCLUSIONS: Our findings suggest that in certain primary open-angle glaucoma patients diminished central visual function may be one manifestation of widespread cerebrovascular insufficiency.

A comparative analysis of the effects of the fixed combination of timolol and dorzolamide versus latanoprost plus timolol on ocular hemodynamics and visual function in patients with primary open-angle glaucoma.

AIMS: The aim of this study was to assess the effects of fixed combination of timolol and dorzolamide and latanoprost plus timolol on retinal, choroidal, and retrobulbar hemodynamics and visual function in primary open-angle glaucoma (OAG) subjects. METHODS: Sixteen (16) OAG patients (age, 63.5 +/- 10.8 years; 9 male) were evaluated in a randomized, crossover, double-blind study design after 4 weeks of treatment of latanoprost with timolol and fixed combination of timolol and dorzolamide. After randomization, 9 right eyes and 7 left eyes were included in the hemodynamic portion of the study. Measurements included: adverse events check, visual acuity, contrast sensitivity, blood pressure, heart rate, intraocular pressure (IOP), and fundus examination. Ocular blood flow was assessed using confocal scanning laser Doppler flowmetry, color Doppler imaging, and scanning laser ophthalmoscopy. RESULTS: Both therapies were effective at lowering IOP, whereas there was no statistically significant difference between latanoprost plus timolol and the fixed combination of timolol and dorzolamide (13.9% and 12.2% reduction, respectively; P = 0.5533). Fixed combination of timolol and dorzolamide significantly increased central retinal artery end diastolic blood flow velocity (P = 0.0168) and lowered resistance to flow (P = 0.0279). Temporal posterior ciliary artery peak systolic and end diastolic velocities were significantly increased with the fixed combination of timolol and dorzolamide (P = 0.0125 and 0.0238, respectively). Latanoprost plus timolol had no significant effects on ocular blood flow during 4 weeks of treatment. There were no statistically significant differences in adverse events, blood pressure, heart rate, visual acuity, contrast sensitivity scanning laser ophthalmoscopy, or Heidelberg Retinal Flowmeter for any treatment period. CONCLUSIONS: Fixed combination of timolol and dorzolamide therapy might increase blood flow in OAG patients while attaining a similar IOP reduction compared to latanoprost plus timolol. Visual function, however, was not different in this short-term comparison between the two treatments.

The role of optic nerve blood flow in the pathogenesis of glaucoma.

Many theories have surfaced regarding the exact mechanisms behind glaucomatous damage, but the complex nature of the disease and the inaccessibility of the internal structures of the human eye have limited current knowledge. Increased intraocular pressure is the risk factor most often associated with glaucomatous optic neuropathy; ischemic insult to the optic nerve has also been suggested as a possible cause of cellular damage. The aim of this review is to cover the possible role of optic nerve head hemodynamics in the pathogenesis of glaucoma.

Nocturnal blood pressure reduction: effect on retrobulbar hemodynamics in glaucoma.

BACKGROUND: Several studies suggest that nocturnal reductions in systemic blood pressure (BP) may be associated with onset or progression of glaucomatous optic neuropathy. The present study aimed to find out whether reductions in nocturnal BP are linked to retrobulbar blood flow perturbations in glaucoma patients. METHODS: Fifteen patients with non-progressing glaucoma and 15 controls were studied in the evening ("baseline") and then at a point of significantly reduced arterial BP during the night. Flow velocities were measured with color Doppler imaging (CDI) in the ophthalmic, central retinal, and nasal and temporal short posterior ciliary arteries, and with transcranial Doppler (TCD) in the middle cerebral artery. BP, corrected for posture, was monitored throughout the night. RESULTS: Maximal posture-corrected nocturnal BP reductions were similar in patients and controls. The reductions were about 10% for each group ( P<0.01). At baseline, patients had lower peak systolic and end-diastolic velocity ( P<0.05) in the short posterior ciliary arteries than controls. Flow velocities in these arteries remained constant in glaucoma patients, while controls showed significant declines. Patients and controls demonstrated blood flow velocities unchanged from baseline in the central retinal, ophthalmic, and middle cerebral arteries during nocturnal BP reduction. CONCLUSIONS: In patients with non-progressing glaucoma there was no evidence of cerebral or retrobulbar hemodynamic abnormalities during nocturnal BP dips. Posterior ciliary arterial blood flow velocities were similar in glaucoma patients and controls during nocturnal BP dips.