Endothelial activation is associated with intestinal epithelial injury, systemic inflammation and treatment regimen in children living with vertically acquired HIV-1 infection.

BACKGROUND: Premature development of cardiovascular disease in children living with HIV-1 (CLWH) may be associated with compromised gut barrier function, microbial translocation, immune activation, systemic inflammation and endothelial activation. Biomarkers of these pathways may provide insights into pathogenesis of atherosclerotic disease in CLWH. METHODS: This was a cross-sectional study of CLWH enrolled in the multicentre Early Pediatric Initiation-Canadian Child Cure Cohort (EPIC4 ) who were on antiretroviral therapy (ART) with undetectable viral load. Plasma biomarkers of intestinal epithelial injury [intestinal fatty acid binding protein-1 (IFABP)], systemic inflammation [tumour necrosis factor (TNF) and interleukin-6 (IL-6)] and endothelial activation [angiopoietin-2 (Ang2), soluble vascular endothelial growth factor-1 (sVEGFR1) and soluble endoglin (sEng)] were quantified by enzyme-linked immunosorbent assay. Correlation and factor analysis of biomarkers were used to examine associations between innate immune pathways. RESULTS: Among 90 CLWH, 16% of Ang2, 15% of sVEGFR1 and 23% of sEng levels were elevated relative to healthy historic controls. Pairwise rank correlations between the three markers of endothelial activation were statistically significant (ρ = 0.69, ρ = 0.61 and ρ = 0.65, P < 0.001 for all correlations). An endothelial activation index, derived by factor analysis of the three endothelial biomarkers, was correlated with TNF (ρ = 0.47, P < 0.001), IL-6 (ρ = 0.60, P < 0.001) and intestinal fatty acid binding protein-1 (ρ = 0.67, P < 0.001). Current or past treatment with ritonavir-boosted lopinavir (LPV/r) was associated with endothelial activation (odds ratio = 5.0, 95% CI: 1.7-17, P = 0.0020). CONCLUSIONS: Endothelial activation is prevalent in CLWH despite viral suppression with combination ART and is associated with intestinal epithelial injury, systemic inflammation and treatment with LPV/r.

Adjuvant bevacizumab for melanoma patients at high risk of recurrence: survival analysis of the AVAST-M trial.

Background: Bevacizumab is a recombinant humanised monoclonal antibody to vascular endothelial growth factor shown to improve survival in advanced solid cancers. We evaluated the role of adjuvant bevacizumab in melanoma patients at high risk of recurrence. Patients and methods: Patients with resected AJCC stage IIB, IIC and III cutaneous melanoma were randomised to receive either adjuvant bevacizumab (7.5 mg/kg i.v. 3 weekly for 1 year) or standard observation. The primary end point was detection of an 8% difference in 5-year overall survival (OS) rate; secondary end points included disease-free interval (DFI) and distant metastasis-free interval (DMFI). Tumour and blood were analysed for prognostic and predictive markers. Results: Patients (n=1343) recruited between 2007 and 2012 were predominantly stage III (73%), with median age 56 years (range 18-88 years). With 6.4-year median follow-up, 515 (38%) patients had died [254 (38%) bevacizumab; 261 (39%) observation]; 707 (53%) patients had disease recurrence [336 (50%) bevacizumab, 371 (55%) observation]. OS at 5 years was 64% for both groups [hazard ratio (HR) 0.98; 95% confidence interval (CI) 0.82-1.16, P = 0.78). At 5 years, 51% were disease free on bevacizumab versus 45% on observation (HR 0.85; 95% CI 0.74-0.99, P = 0.03), 58% were distant metastasis free on bevacizumab versus 54% on observation (HR 0.91; 95% CI 0.78-1.07, P = 0.25). Forty four percent of 682 melanomas assessed had a BRAFV600 mutation. In the observation arm, BRAF mutant patients had a trend towards poorer OS compared with BRAF wild-type patients (P = 0.06). BRAF mutation positivity trended towards better OS with bevacizumab (P = 0.21). Conclusions: Adjuvant bevacizumab after resection of high-risk melanoma improves DFI, but not OS. BRAF mutation status may predict for poorer OS untreated and potential benefit from bevacizumab. Clinical Trial Information: ISRCTN 81261306; EudraCT Number: 2006-005505-64.

Transcriptional signatures mediated by acetylation overlap with early-stage Alzheimer's disease.

The mechanisms by which environmental influences lead to the development of complex neurodegenerative diseases are largely unknown. It is known, however, that epigenetic mechanisms can mediate alterations in transcription due to environmental influences. In order to identify genes susceptible to regulation in the adult cortex by one type of epigenetic mechanism, histone, and protein acetylation, we treated mice with the histone deacetylase inhibitor Trichostatin A (TSA). After 1 week of treatment with TSA, RNA was extracted from the brain cortices of mice and gene expression differences were analyzed by microarray profiling. The altered genes were then compared with genes differentially expressed in microarray studies of disease by database and literature searches. Genes regulated by TSA were found to significantly overlap with differentially expressed genes in the Alzheimer's disease (AD) brain. Several TSA-regulated genes involved in chromatin remodeling and epigenetic reprogramming including histone cluster 1, H4 h (Hist1H4 h), methionine adenosyltransferase II, alpha (Mat2a), and 5-methyltetrahydrofolate homocysteine reductase (Mtrr) overlapped with genes altered in early-stage AD in gray matter. We also show that the expression of hemoglobin, which has been shown to be altered in neurons in the AD brain, is regulated by TSA treatment. This analysis suggests involvement of epigenetic mechanisms in neurons in early stages of AD.

Safety of zoledronic acid and incidence of osteonecrosis of the jaw (ONJ) during adjuvant therapy in a randomised phase III trial (AZURE: BIG 01-04) for women with stage II/III breast cancer.

The AZURE trial is an ongoing phase III, academic, multi-centre, randomised trial designed to evaluate the role of zoledronic acid (ZOL) in the adjuvant therapy of women with stage II/III breast cancer. Here, we report the safety and tolerability profile of ZOL in this setting. Eligible patients received (neo)adjuvant chemotherapy and/or endocrine therapy and were randomised to receive neither additional treatment nor intravenous ZOL 4 mg. ZOL was administered after each chemotherapy cycle to exploit potential sequence-dependent synergy. ZOL was continued for 60 months post-randomisation (six doses in the first 6 months, eight doses in the following 24 months and five doses in the final 30 months). Serious (SAE) and non-serious adverse event (AE) data generated during the first 36 months on study were analysed for the safety population. 3,360 patients were recruited to the AZURE trial. The safety population comprised 3,340 patients (ZOL 1,665; control 1,675). The addition of ZOL to standard treatment did not significantly impact on chemotherapy delivery. SAE were similar in both treatment arms. No significant safety differences were seen apart from the occurrence of osteonecrosis of the jaw (ONJ) in the ZOL group (11 confirmed cases; 0.7%; 95% confidence interval 0.3-1.1%). ZOL in the adjuvant setting is well tolerated, and can be safely administered in addition to adjuvant therapy including chemotherapy. The adverse events were consistent with the known safety profile of ZOL, with a low incidence of ONJ.

Three-dimensional telesurgery and remote proctoring over a 5G network.

PURPOSE: To present 2 cases of vitreoretinal surgery performed on a three-dimensional (3D) heads-up display surgical platform with real-time transfer of 3D video over a fifth-generation (5G) cellular network. METHODS: An epiretinal membrane peel and tractional retinal detachment repair performed at Massachusetts Eye and Ear in April 2019 were broadcast live to the Verizon 5G Lab in Cambridge, MA. RESULTS: Both surgeries were successful. The heads-up digital surgery platform, combined with a 5G network, allowed telesurgical transfer of high-quality 3D vitreoretinal surgery with minimal degradation. Average end-to-end latency was 250 ms, and average round-trip latency was 16 ms. Fine surgical details were observed remotely by a proctoring surgeon and trainee, with real-time communication via mobile phone. CONCLUSIONS: This pilot study represents the first successful demonstration of vitreoretinal surgery transmitted over a 5G network. Telesurgery has the potential to enhance surgical education, provide intraoperative consultation and guidance from expert proctors, and improve patient outcomes, especially in remote and low-resource areas.

Pulmonary zygomycosis in solid organ transplant recipients in the current era.

Fifty-eight solid organ transplant recipients with zygomycosis were studied to assess the presentation, radiographic characteristics, risks for extra-pulmonary dissemination and mortality of pulmonary zygomycosis. Pulmonary zygomycosis was documented in 31 patients (53%) and developed a median of 5.5 months (interquartile range, 2-11 months) posttransplantation. In all, 74.2% (23/31) of the patients had zygomycosis limited to the lungs and 25.8% (8/31) had lung disease as part of disseminated zygomycosis; cutaneous/soft tissue (50%, 4/8) was the most common site of dissemination. Pulmonary disease presented most frequently as consolidation/mass lesions (29.0%), nodules (25.8%) and cavities (22.6%). Patients with disseminated disease were more likely to have Mycocladus corymbifer as the causative pathogen. The mortality rate at 90 days after the treatment was 45.2%. In summary, pulmonary zygomycosis is the most common manifestation in solid organ transplant recipients with zygomycosis, and disseminated disease often involves the cutaneous/soft tissue sites but not the brain.

CD200R deletion promotes a neutrophil niche for Francisella tularensis and increases infectious burden and mortality.

Pulmonary immune control is crucial for protection against pathogens. Here we identify a pathway that promotes host responses during pulmonary bacterial infection; the expression of CD200 receptor (CD200R), which is known to dampen pulmonary immune responses, promotes effective clearance of the lethal intracellular bacterium Francisella tularensis. We show that depletion of CD200R in mice increases in vitro and in vivo infectious burden. In vivo, CD200R deficiency leads to enhanced bacterial burden in neutrophils, suggesting CD200R normally limits the neutrophil niche for infection. Indeed, depletion of this neutrophil niche in CD200R-/- mice restores F. tularensis infection to levels seen in wild-type mice. Mechanistically, CD200R-deficient neutrophils display significantly reduced reactive oxygen species production (ROS), suggesting that CD200R-mediated ROS production in neutrophils is necessary for limiting F. tularensis colonisation and proliferation. Overall, our data show that CD200R promotes the antimicrobial properties of neutrophils and may represent a novel antibacterial therapeutic target.

The response to prism deviations in human infants.

Previous research has suggested that infants are unable to make a corrective eye movement in response to a small base-out prism placed in front of one eye before 14-16 weeks [1]. Three hypotheses have been proposed to explain this early inability, and each of these makes different predictions for the time of onset of a response to a larger prism. The first proposes that infants have a 'degraded sensory capacity' and so require a larger retinal disparity (difference in the position of the image on the retina of each eye) to stimulate disparity detectors [2]. This predicts that infants might respond at an earlier age than previously reported [1] when tested using a larger prism. The second hypothesis proposes that infants learn to respond to larger retinal disparities through practice with small disparities [3]. According to this theory, using a larger prism will not result in developmentally earlier responses, and may even delay the response. The third hypothesis proposes that the ability to respond to prismatic deviation depends on maturational factors indicated by the onset of stereopsis (the ability to detect depth in an image on the basis of retinal disparity cues only) [4] [5], predicting that the size of the prism is irrelevant. To differentiate between these hypotheses, we tested 192 infants ranging from 2 to 52 weeks of age using a larger prism. Results showed that 63% of infants of 5-8 weeks of age produced a corrective eye movement in response to placement of a prism in front of the eye when in the dark. Both the percentage of infants who produced a response, and the speed of the response, increased with age. These results suggest that infants can make corrective eye movements in response to large prismatic deviations before 14-16 weeks of age. This, in combination with other recent results [6], discounts previous hypotheses.

TEXAS (Taxotere EXperience with Anthracyclines Study) trial: mature results of activity/toxicity of docetaxel given with anthracyclines in a community setting, as first line therapy for MBC.

PURPOSE: The TEXAS (Taxotere EXperience with Anthracyclines Study) study examined docetaxel in combination with an anthracycline, as first line treatment of metastatic breast cancer (MBC), in everyday practice, and compared the findings with a randomised controlled trial. METHODS: Four hundred and seventy patients were registered on the TEXAS trial. Patients were assigned, according to treating clinician's discretion, to either doxorubicin 50 mg/m2 or epirubicin 75 mg/m2 both given day1 15 min intravenous bolus every 3 weeks, followed by docetaxel 75 mg/m2, day 1, 1 h intravenous infusion every 3 weeks. RESULTS: The overall response rate (ORR) was approximately 61%. The main toxicity reported was neutropenia, with 75 patients (55%) in the AT group and 203 (61%) in the ET arm. Febrile neutropenia or neutropenic sepsis was reported for 32 (24%) of the AT arm and 78 (23%) of the ET arm. CONCLUSIONS: This open access study demonstrates that AT or ET are highly active treatments for MBC, with similar response rates to those observed in a phase III clinical trial. This may be important for patients with rapidly progressive visceral disease. Side effects can be managed effectively with growth factors and/or prophylactic antibiotic.

The lymph nodes draining the small intestine and colon are anatomically separate and immunologically distinct.

Dendritic cells (DCs) in the small intestine (SI) and colon are fundamental to direct intestinal immune responses; they migrate to the mesenteric lymph nodes (MLNs) and prime T cells. We demonstrate anatomical segregation of lymphatic drainage from the intestine, specifically that DCs from the SI and colon migrate to different nodes within the MLN, here called the sMLN and cMLN. As a consequence, different frequencies of DC subsets observed in the SI and colon are reflected among the DCs in the sMLN and cMLN. Consistent with the SI's function in absorbing food, fed antigen is presented in the sMLN, but not in the cMLN. Furthermore, the levels of expression of CCR9 and α4ß7 are increased on T cells in the sMLN compared with the cMLN. DCs from the cMLN and colon are unable to metabolize vitamin A to retinoic acid (RA); thus, DCs may contribute to the differential expression of tissue homing markers observed in the sMLN and cMLN. In summary, the sMLN and cMLN, and the DCs that migrate to these LNs are anatomically and immunologically separate. This segregation allows immune responses in the SI and colon to be controlled independently.

Detection of bone metastases in breast cancer by 18FDG PET: differing metabolic activity in osteoblastic and osteolytic lesions.

PURPOSE: 99mTechnetium methylene diphosphonate (99mTc MDP) bone scintigraphy is currently the method of choice for the detection of bone metastases, but 18F-fluoro-deoxy-D-glucose positron emission tomography (18FDG PET) offers superior spatial resolution and improved sensitivity. We have compared 18FDG PET with 99mTc MDP bone scintigraphy in patients with skeletal metastases from breast cancer and have analyzed the data in subgroups based on radiographic characteristics of lesions. PATIENTS AND METHODS: Twenty-three women with breast cancer and confirmed bone metastases were studied with both 99mTC MDP bone scintigraphy and 18FDG PET, and the number of lesions detected and the quantitation of uptake (standardized uptake values [SUVs]) of 18FDG in osteolytic and osteoblastic metastases were compared. Survival was compared for both lytic and blastic bone metastases and for patients with high and low accumulation of 18FDG. RESULTS: 18FDG PET detected more lesions than 99mTc MDP scintigraphy (mean, 14.1 and 7.8 lesions, respectively; P < .01). However, 18FDG detected fewer bone metastases compared with 99mTc MDP scintigraphy in a subgroup of patients with osteoblastic disease (P < .05). Higher SUVs were observed for osteolytic than osteoblastic disease (mean, 6.77 and 0.95, respectively; P < .01). Survival was lower in patients with osteolytic disease compared with the remainder (P=.01). A difference in survival was not found for those patients with high SUVs (> 3.6; P=.4). CONCLUSION: 18FDG PET is superior to bone scintigraphy in the detection of osteolytic breast cancer metastases, which led to a poorer prognosis. In contrast, osteoblastic metastases show lower metabolic activity and are frequently undetectable by PET. The biologic explanation for this observation remains to be elucidated.

Randomized, double-blind, placebo-controlled, multicenter trial of 6% miltefosine solution, a topical chemotherapy in cutaneous metastases from breast cancer.

PURPOSE: To compare 6% miltefosine solution (Miltex; Asta Medica, Frankfurt, Germany), a new topical cytostatic drug, with placebo as palliative treatment for cutaneous metastases from breast cancer. PATIENTS AND METHODS: In a double-blind, placebo-controlled, multicenter phase III study, a total of 52 patients with inoperable progressive skin lesions from histologically or cytologically confirmed breast cancer, not manageable by radiotherapy or systemic treatment, with superficial or flat skin lesions (estimated depth of invasion < or = 1 cm) were randomized to receive either 6% miltefosine solution or placebo. The solution was applied at the dose of 2 drops/10 cm(2), once daily during the first week and twice daily thereafter until treatment failure. RESULTS: Treatment groups were well balanced for patient characteristics at study entry except for a small difference in age. Time to treatment failure (TTF), the primary parameter of this study, showed miltefosine solution to be significantly superior to placebo (P = .007); the median TTF in the miltefosine solution group was nearly three times longer than that in the placebo group (56 days v 21 days). The rate of response based on intention to treat patients was 33.3% for miltefosine solution compared with 3.7% for placebo (P = .006). Cutaneous reactions were seen mainly in the miltefosine group, with the type and frequency similar to those observed in previous studies. CONCLUSION: 6% Miltefosine solution is confirmed as an effective palliative treatment option for cutaneous metastases from breast cancer. Skin reactions, when present, are well tolerated and only occasionally require cessation of treatment.

Paclitaxel versus doxorubicin as first-line single-agent chemotherapy for metastatic breast cancer: a European Organization for Research and Treatment of Cancer Randomized Study with cross-over.

PURPOSE: To compare the efficacy of paclitaxel versus doxorubicin given as single agents in first-line therapy of advanced breast cancer (primary end point, progression-free survival ¿PFS) and to explore the degree of cross-resistance between the two agents. PATIENTS AND METHODS: Three hundred thirty-one patients were randomized to receive either paclitaxel 200 mg/m(2), 3-hour infusion every 3 weeks, or doxorubicin 75 mg/m(2), intravenous bolus every 3 weeks. Seven courses were planned unless progression or unacceptable toxicity occurred before the seven courses were finished. Patients who progressed within the seven courses underwent early cross-over to the alternative drug, while a delayed cross-over was optional for the remainder of patients at the time of disease progression. RESULTS: Objective response in first-line therapy was significantly better (P =.003) for doxorubicin (response rate ¿RR, 41%) than for paclitaxel (RR, 25%), with doxorubicin achieving a longer median PFS (7.5 months for doxorubicin v 3.9 months for paclitaxel, P <.001). In second-line therapy, cross-over to doxorubicin (91 patients) and to paclitaxel (77 patients) gave response rates of 30% and 16%, respectively. The median survival durations of 18.3 months for doxorubicin and 15.6 months for paclitaxel were not significantly different (P =.38). The doxorubicin arm had greater toxicity, but this was counterbalanced by better symptom control. CONCLUSION: At the dosages and schedules used in the present study, doxorubicin achieves better disease and symptom control than paclitaxel in first-line treatment. Doxorubicin and paclitaxel are not totally cross-resistant, which supports further investigation of these drugs in combination or in sequence, both in advanced disease and in the adjuvant setting.

Palliation of pain associated with metastatic bone cancer using samarium-153 lexidronam: a double-blind placebo-controlled clinical trial.

PURPOSE: To evaluate the effectiveness and safety of samarium-153 (153Sm) lexidronam (EDTMP) in a double-blind, placebo-controlled study. PATIENTS AND METHODS: Patients with painful bone metastases secondary to a variety of primary malignancies were randomized to receive 153Sm-EDTMP 0.5 or 1.0 mCi/kg, or placebo. Treatment was unblinded for patients who did not respond by week 4, with those who had received placebo eligible to receive 1.0 mCi/kg of active drug in an open-label manner. Patient and physician evaluations were used to assess pain relief, as was concurrent change in opioid analgesia. RESULTS: One hundred eighteen patients were enrolled onto the study. Patients who received 1.0 mCi/kg of active drug had significant reductions in pain during each of the first 4 weeks in both patient-rated and physician-rated evaluations. Pain relief was observed in 62% to 72% of those who received the 1.O-mCi/kg dose during the first 4 weeks, with marked or complete relief noted in 31% by week 4. Persistence of pain relief was seen through week 16 in 43% of patients who received 1.0 mCi/kg, of active drug. A significant correlation (P = .01) was observed between reductions in opioid analgesic use and pain scores only for those patients who received 1.0 mCi/kg 153Sm-EDTMP. Bone marrow suppression was mild, reversible, and not associated with grade 4 toxicity. CONCLUSION: A single dose of 1.0 mCi/kg of 153Sm-EDTMP provided relief from pain associated with bone metastases. Pain relief was observed within 1 week of administration and persisted until at least week 16 in the majority of patients who responded.

DOTS implementation in a middle-income country: development and evaluation of a novel approach.

BACKGROUND: DOTS is widely accepted as the most cost-effective strategy for tuberculosis (TB) control. However, there is little published information regarding methods for implementation in middle-income countries. METHODS: Over 3 years, the Canadian Lung Association assisted the Ecuadorian TB programme to implement DOTS for over half the nation's total population. A multilevel strategy developed by a team of Ecuadorian health professionals provided initial, in-service, replica and reinforcement training at the local level, and training at national level for specialist physicians, specialist societies and medical schools. Evaluation was based on international guidelines for case finding, treatment and laboratory quality control, and costs of all implementation activities. RESULTS: By January 2004, DOTS training had been provided to 1954 health professionals and 199 smear microscopy technicians, and DOTS was implemented in all 496 health facilities. Case detection activities at the local level increased substantially. Cure and treatment completion improved to 83% of new cases. Overall concordance of laboratory quality control readings was 98.7%. The total cost of DOTS implementation was US dollar 3 049 585. CONCLUSIONS: To achieve international targets for TB control, DOTS implementation in a middle-income country required intensive training at the local level and at multiple other levels.

Impact of tamoxifen on the pharmacokinetics and endocrine effects of the aromatase inhibitor letrozole in postmenopausal women with breast cancer.

This study examined whether the addition of tamoxifen to the treatment regimen of patients with advanced breast cancer being treated with the aromatase inhibitor letrozole led to any pharmacokinetic or pharmacodynamic interaction. Twelve of 17 patients completed the core period of the trial in which 2.5 mg/day letrozole was administered alone for 6 weeks and in combination with 20 mg/day tamoxifen for the subsequent 6 weeks. Patients responding to treatment continued on the combination until progression of disease or any other reason for discontinuation. Plasma levels of letrozole were measured at the end of the 6-week periods of treatment with letrozole alone and the combination and once more between 4 and 8 months on combination therapy. No further measurements were done thereafter. Hormone levels were measured at 2-week intervals throughout the core period. Marked suppression of estradiol, estrone, and estrone sulfate occurred with letrozole treatment, and this was not significantly affected by the addition of tamoxifen. However, plasma levels of letrozole were reduced by a mean 37.6% during combination therapy (P<0.0001), and this reduction persisted after 4-8 months of combination therapy. Letrozole is the first drug to be described in which this pharmacokinetic interaction occurs with tamoxifen. The mechanism is likely to be a consequence of an induction of letrozole-metabolizing enzymes by tamoxifen but was not further addressed in this study. It is possible that the antitumor efficacy of letrozole may be affected. Thus, sequential therapy may be preferable with these two drugs. It is not known whether tamoxifen interacts with other members of this class of drugs or with other drugs in combination.

Breaking the silence: an HIV-related educational intervention for medical students in Zimbabwe.

PROBLEM: A culture of silence surrounding HIV is a major contributor to continued HIV transmission and poor care for people living with HIV/AIDS. AIM: To encourage medical leadership in addressing stigma and fear related to HIV at individual and community levels OBJECTIVE: To pilot a mini-course for final year medical students in Zimbabwe that demonstrates stigma-reduction knowledge and skills needed to communicate information about HIV to patients, to address ethical implications of testing versus not testing for HIV, to increase awareness of the medical and preventive benefits of knowing one's HIV status and showing people how to cope with the emotional burden of dealing with HIV everyday. DESIGN: Methods of proven effectiveness for training medical students in ethics and communication skills were used such as presentations by well respected role models and opinion leaders, role-playing, small group discussions, accompanied by materials indicating local resources, in three afternoon teaching sessions. SETTING: University of Zimbabwe College of Medicine. PARTICIPANTS: 60 medical students, six lecturers, two facilitators and a group of actors. MAIN OUTCOME MEASURES: Evaluation of the course by students showed appreciation of the course as measured on a scale of one to five for content and usefulness with requests for further inputs into the curriculum; model of mini-course that can be used by other medical schools in the southern Africa region and other areas of emerging HIV epidemics. CONCLUSIONS: A brief educational intervention can help medical students to cope with the extraordinary challenge of providing care in high HIV prevalence countries and may contribute towards better leadership in addressing HIV epidemics.

Bisphosphonates' use in metastatic bone disease.

Bisphosphonates already have an established role in the management of the skeletal complications of metastatic bone disease. The development of new, highly potent compounds has led to investigation into their use as preventive agents in the adjuvant setting. The aim of the paper is to evaluate the evidence for their use in prevention and treatment.

Treatment outcomes after 3 years in neovascular age-related macular degeneration using a treat-and-extend regimen.

PURPOSE: To determine 3-year treatment outcomes after 1 to 3 years of ranibizumab or bevacizumab therapy using a treat-and-extend regimen in patients with neovascular age-related macular degeneration (AMD). DESIGN: Retrospective, interventional, consecutive case series. METHODS: We treated 212 eyes from 196 patients diagnosed with treatment-naive neovascular AMD between January 2009 and March 2013; they were treated with either ranibizumab or bevacizumab for a minimum of 1 year, using a treat-and-extend regimen. The main outcome measures were change from baseline best-corrected Snellen visual acuity (BCVA), proportion of eyes losing <3 BCVA lines, proportion of eyes gaining ≥ 3 BCVA lines, change from baseline central retinal thickness, and mean number of injections at 1, 2 and 3 years of follow-up. RESULTS: The mean follow-up period was 1.88 years (median, 2 years). At baseline, mean BCVA was 20/139; it improved to 20/79 (P < 0.001) after 1 year of treatment and was maintained at 20/69 and 20/64 at 2 and 3 years follow-up (P < 0.001), respectively. At baseline, mean central retinal thickness was 351 µm and significantly decreased to 285 µm, 275 µm and 276 µm at 1, 2 and 3 years of follow-up (P < 0.001), respectively. Patients received, on average, 7.6, 5.7 and 5.8 injections over years 1, 2 and 3 of treatment, respectively. At final follow-up, 94% of eyes had lost <3 lines BCVA, and 34.4% of eyes had gained ≥ 3 lines BCVA. CONCLUSIONS: The treat-and-extend regimen is effective in achieving and maintaining visual and anatomic improvements in patients with neovascular AMD for up to 3 years of treatment.