Optogenetic approaches to vision restoration.

Inherited retinal disease (IRD) affects about 1 in 3000 to 1 in 5000 individuals and is now believed to be the most common cause of blindness registration in developed countries. Until recently, the management of such conditions had been exclusively supportive. However, advances in molecular biology and medical engineering have now seen the rise of a variety of approaches to restore vision in patients with IRDs. Optogenetic approaches are primarily aimed at rendering secondary and tertiary neurons of the retina light-sensitive in order to replace degenerate or dysfunctional photoreceptors. Such approaches are attractive because they provide a "causative gene-independent" strategy, which may prove suitable for a variety of patients with IRD. We discuss theoretical and practical considerations in the selection of optogenetic molecules, vectors, surgical approaches and review previous trials of optogenetics for vision restoration. Optogenetic approaches to vision restoration have yielded promising results in pre-clinical trials and a phase I/II clinical trial is currently underway (ClinicalTrials.gov NCT02556736). Despite the significant inroads made in recent years, the ideal optogenetic molecule, vector and surgical approach have yet to be established.

Novel non-contiguous exon duplication in choroideremia.

The importance of establishing a genetic diagnosis in patients with a choroideremia phenotype has been underscored by the advent of gene replacement therapy for this condition. Here, we describe a complex imbalance at the CHM locus in a male patient with classical disease. At the DNA level, this imbalance consists of 2 non-contiguous duplications (exons 1-2 and 9-12). Further characterization suggests the generation of 2 independent CHM transcriptional units, one of which may produce a deleted form of the Rab escort protein 1 protein. Expression of such a type of aberrant protein in photoreceptors may have important implications when considering gene therapy for this disorder.

Collaborative case conferences in rectal cancer: case series in a tertiary care centre.

BACKGROUND: In many hospitals, resource barriers preclude the use of preoperative multidisciplinary cancer conferences (mccs) for consecutive patients with cancer. Collaborative cancer conferences (cccs) are modified mccs that might overcome such barriers. METHODS: We established a ccc at an academic tertiary care centre to review preoperative plans for patients with rectal cancer. Attendees included only surgeons who perform colorectal cancer procedures and a radiologist with expertise in cross-sectional imaging. Individual reviews began with the primary surgeon presenting the case information and initial treatment recommendations. Cross-sectional images were then reviewed, the case was discussed, and consensus on ccc-treatment recommendations was achieved. Outcomes for the present study were changes in treatment recommendations defined as "major" (that is, redirection of patient to preoperative radiation from straight-to-surgery or uncertain plan, or redirection of the patient to straight-to-surgery from preoperative radiation or plan uncertain) or as "minor" (that is, referral to a multidisciplinary cancer clinic, request additional tests, change type of neoadjuvant therapy, change type of surgery). Chart reviews provided relevant patient, tumour, and treatment information. RESULTS: Between September 2011 and September 2012, 101 rectal cancer patients were discussed at a ccc. Of the 35 management plans (34.7%) that were changed as a result, 8 had major changes, and 27 had minor changes. Available patient and tumour factors did not predict for a change in treatment recommendation. CONCLUSIONS: Preoperative cccs at a tertiary-care centre changed treatment recommendations for one third of patients with rectal cancer. Given that no specific factor predicted for a treatment plan change, it is likely prudent that all rectal cancer patients undergo some form of collaborative review.

Eastern Canadian Colorectal Cancer Consensus Conference 2013: emerging therapies in the treatment of pancreatic, rectal, and colorectal cancers.

The annual Eastern Canadian Colorectal Cancer Consensus Conference held in Montreal, Quebec, 17-19 October 2013, marked the 10-year anniversary of this meeting that is attended by leaders in medical, radiation, and surgical oncology. The goal of the attendees is to improve the care of patients affected by gastrointestinal malignancies. Topics discussed during the conference included pancreatic cancer, rectal cancer, and metastatic colorectal cancer.

Outcomes following a limited approach to radiotherapy in rectal cancer.

BACKGROUND: Variation in the use of neoadjuvant and adjuvant radiotherapy for rectal cancer suggests an opportunity to avoid it in all but patients at highest risk of local recurrence. METHODS: Between 1 July 1999 and 1 February 2006, patients with primary rectal cancer were treated by a single surgeon operating at McMaster University, Hamilton, Ontario, Canada. Digital rectal examination and pelvic computed tomography were used to determine whether the mesorectal margin was threatened by tumour and thus whether preoperative radiotherapy would be needed. The study outcome was local tumour recurrence. RESULTS: Forty-six (48 per cent) of 96 patients received preoperative radiation therapy. The median follow-up was 4·2 years. Tumours were fixed or tethered in 31 (67 per cent) of the 46 irradiated patients. In contrast, no tumour was fixed in unirradiated patients and only ten (20 per cent) of the 50 tumours were tethered. The proportion of patients with stage I or II tumours based on final pathology was similar: 61 per cent (28 of 46) and 56 per cent (28 of 50) in irradiated and unirradiated groups respectively (P = 0·287). There were four (9 per cent) and two (4 per cent) local recurrences among irradiated and unirradiated patients respectively (P = 0·422). CONCLUSION: Limiting preoperative radiotherapy in rectal cancer to patients with a threatened circumferential margin does not compromise patient outcome.

Rectal cancer surgery and regional lymph nodes.

In patients with rectal cancer, the status of regional or mesorectal lymph nodes is central to both tumor staging and predicting local and distant recurrence. The importance of mesorectal lymph nodes in rectal cancer should inform treatment decisions around pre-operative diagnostic imaging, surgical techniques, pathologic assessment, and the use of radiation therapy.

Urea and carbamate derivatives of primaquine: synthesis, cytostatic and antioxidant activities.

The novel urea primaquine derivatives 3 were prepared by aminolysis of primaquine benzotriazolide 2 with several hydroxyamines and ethylendiamine, while carbamates 4 were synthesized from the same precursor 2 and alcohols. All compounds are fully chemically characterized and evaluated for their cytostatic and antioxidant activities. The most prominent antiproliferative activity was obtained by compounds 3c, 3d, 3g, and 5b (IC(50)=9-40 microM). 1-(5-Hydroxypentyl)-3-[4-(6-methoxy-quinolin-8-ylamino)-pentyl]urea (3c) showed extreme selectivity toward SW 620 colon cancer cells (IC(50)=0.2 microM) and a bit less toward lung cancer cells H 460. Hydroxyurea 3h showed the highest interaction with DPPH. Primaquine twin drug 3g showed very significant inhibition on LOX soybean (IC(50)=62 microM). Almost all the tested derivatives highly inhibited lipid peroxidation, significantly stronger than primaquine phosphate.

Patterns of care in the initial management of women with ovarian cancer in Ontario.

BACKGROUND: To facilitate the planning of future resources for cancer services in Ontario, Cancer Care Ontario commissioned an evaluation of operative services delivered for ovarian cancers. The affected population was characterized in terms of age, location of residence, and SES. Operative care delivery was described in terms of inpatient verses outpatient access, LHIN of treatment, surgical specialist providing treatment, and specific operative procedures. The investigations and consults around the time of diagnosis are described. METHODS: Women with an incident diagnosis of an ovarian malignancy were identified from 1 April 2003 to 31 March 2004 using the Ontario Cancer Registry. Record linkages were created to other provincial health databases such as the Ontario Health Insurance Plan. RESULTS: We report on 963 women with ovarian cancer. The incidence of disease was related to increasing age. Access to surgery correlated with the highest income quintile, urban residence and LHIN. Twenty-seven percent of women did not have surgery for their ovarian cancer. Women of younger age were more like to receive surgery for ovarian cancer. Use of a laparotomy for biopsy was most common in community hospital (40%). Lymphadenectomy rates were low overall; rates for gynecologic oncologists were 13.2%. All women were assessed by CXR. CT scan of abdomen and pelvis occurred in 77% of women. MRIs were done infrequently. Medical oncology were involved in 26.6% of the patients. CONCLUSIONS: These pilot data would be enhanced with further information such as comorbidity, treatment intent (palliative/curative), histology, grade and stage. However, there are clear referral patterns to academic centres which means a need for manpower and hospital resources to deal with this population.

Patterns of surgical care for uterine cancers in Ontario.

OBJECTIVES: To facilitate the planning of future resources for cancer services in Ontario, Cancer Care Ontario commissioned an evaluation of operative services delivered for uterine cancer. METHODS: Women with an incident diagnosis of a uterine malignancy were identified from 1 April 2003 to 31 March 2004 using the Ontario Cancer Registry. Record linkages were created to other provincial health databases such as the Ontario Health Insurance Plan. RESULTS: Uterine cancer affected 1,436 women. Disease specific rates of cancer were higher in rural areas and those from the highest income quintiles. Surgery occurred in 94.7% of women. Use of surgery did not appear to vary by SEC, urban/rural residence or LHIN. Gynecologists conducted 76.1% of the operations. Lymphadenectomy took place in 18.7% of women. Lymphadenectomy rates were highest in gynecologic oncologists (43.3%). All women were assessed by CXR. Radiation therapy consults were preformed in half of the women with uterine cancer but treatment was only delivered in half of those seen. Medical oncologists saw about 6.3% of women with uterine cancers. CONCLUSIONS: There appear to be variations in incidence rates of uterine cancer with disease being more frequent in those of the highest SES. In two-thirds of the population, surgery is delivered in the region where the patient lives. Subspecialty care from gynecologic oncologists was provided to one-third of women. Rates of lymphadenectomy as part of a surgical attempt to assess disease spread appear low. These pilot data would be enhanced with further information such as comorbidity, treatment intent (palliative/curative), histology, grade and stage.

Patterns of care for the initial management of cervical cancer in Ontario.

OBJECTIVE: To facilitate the planning of resources for cancer services in Ontario, Cancer Care Ontario commissioned an evaluation of operative services delivered for cervical cancer. METHODS: Women with an incident diagnosis of cervical cancer were identified from 1 April, 2003 to 31 March, 2004 using the Ontario Cancer Registry. Record linkages were created to other provincial health databases such as the Ontario Health Insurance Plan. RESULTS: There were 513 incident cases. Disease-specific rates of cancer were higher in rural areas and those from lower income quintiles. Forty-three percent of women had no surgery. Use of surgery did not appear to vary by SEC, urban/rural residence or LHIN. Women of younger age were more like to receive surgery for cervical cancer. Gynecologists conducted 63% of the operations. Gynecologics were most likely to complete a lymphadenectomy (70.3%). All women were assessed by CXR. Only 22% of women had a CT scan of the abdomen and pelvis. Radiation consults were performed in half of the women with cervix cancer but treatment was only delivered to half of those seen. Medical oncologists saw about 10% of women with cervical cancers. CONCLUSIONS: There appear to be variations in incidence rates of cervical cancer, with cancers being more frequent in rural areas. In two-thirds of the population, surgery is performed in the region where the patient lives. Subspecialty care from gynecologic oncologists was provided to one-third of women. These preliminary data would be enhanced with further information such as comorbidity, treatment intent (palliative/curative), histology, grade and stage.

Patterns of care in the initial management of women with vulvar cancers in Ontario.

BACKGROUND: To facilitate the planning of future resources for cancer services in Ontario, Cancer Care Ontario commissioned an evaluation of operative services delivered for vulvar cancer. METHODS: Women with an incident diagnosis of vulvar malignancy were identified from 1, April 2003 to 31 March, 2004 using the Ontario Cancer Registry. Record linkages were created to other provincial health databases such as the Ontario Health Insurance Plan. RESULTS: Vulvar cancers affected 148 women. Disease specific rates of cancer were higher in rural areas and in women in the lower income quintiles. No surgery occurred in 17.6% of women. Use of surgery did not appear to vary by urban/rural residence or LHIN. Ontario's 17 gynecologic oncologists performed 75% of the surgeries. Groin lymphadenectomy rate was 52.8%. Surgery was performed in the LHIN of residence for 41% of women. All women were assessed by CXR. CT scan of the abdomen and pelvis occurred in 77%. MRIs were done infrequently. Radiation consults were preformed in half of the women with vulvar cancer but treatment was only delivered in half of those seen. Medical oncologists saw about 10% of women with gynecologic cancers. CONCLUSIONS: There appear to be variations in incidence rates of vulvar cancer with disease being more frequent in rural areas. Subspecialty care from gynecologic oncologists was provided to 75% of women. Rates of lymphadenectomy as part of a surgical attempt occurred in 52.8% of women. These data would be enhanced with further information such as comorbidity, treatment intent (palliative/curative), histology, grade and stage.

First-in-human study of the safety and viability of intraocular robotic surgery.

Microsurgery of the retina would be dramatically improved by instruments that offer supra-human precision. Here, we report the results of a first-in-human study of remotely controlled robot-assisted retinal surgery performed through a telemanipulation device. Specifically, 12 patients requiring dissection of the epiretinal or inner limiting membrane over the macula were randomly assigned to either undergo robot-assisted-surgery or manual surgery, under general anaesthesia. We evaluated surgical success, duration of surgery and amount of retinal microtrauma as a proxy for safety. Surgical outcomes were equally successful in the robotic-surgery and manual-surgery groups. Differences in the amount of retinal microtrauma between the two groups were statistically insignificant, yet dissection took longer with robotic surgery (median time, 4 min 5 s) than with manual surgery (1 min 20 s). We also show the feasibility of using the robot to inject recombinant tissue plasminogen activator under the retina to displace sight-threatening haemorrhage in three patients under local anaesthesia. A safe and viable robotic system for intraocular surgery would enable precise and minimally traumatic delivery of gene therapy or cell therapy to the retina.

Is color vision deficiency an advantage under scotopic conditions?

PURPOSE: To examine experimentally whether color vision deficiency confers a selective advantage under scotopic conditions. METHODS: Red-green color-deficient subjects, monochromats, and age-matched color-normal control subjects were examined. In each subject the time course of dark adaptation, scotopic visual field sensitivity, and performance on a scotopic perceptual task were measured. RESULTS: No significant differences were found between red-green color-deficient subjects and control subjects on any of the three tests. Our small sample of monochromats had higher absolute thresholds than the corresponding control subjects, but their performance at the scotopic visual field test and perceptual task did not differ significantly from that of color-normal subjects. CONCLUSIONS: No evidence was found that red-green color deficiency or monochromatism confers a selective advantage under scotopic conditions.

Hospital volume, calendar age, and short term outcomes in patients undergoing repair of abdominal aortic aneurysms: the Ontario experience, 1988-92.

OBJECTIVE: To determine, for abdominal aortic aneurysm surgery, whether a previously reported relationship between hospital case volume and mortality rate was observed in Ontario hospitals and to assess the potential impact of age on the mortality rate for elective surgery. DESIGN: Population based observational study using administrative data. SETTING: All Ontario hospitals where repair of abdominal aortic aneurysm as a primary procedure was performed during 1988-92. PATIENTS: These comprised 5492 patients with unruptured abdominal aortic aneurysms and 1203 patients with ruptured abdominal aortic aneurysms admitted to hospital between 1988-92 for repair of abdominal aortic aneurysm as a primary procedure. MAIN OUTCOMES: In-hospital death and length of in-hospital stay. RESULTS: The case fatality rate was 3.8% for unruptured abdominal aortic aneurysms and 40.0% for ruptured abdominal aortic aneurysms. For unruptured cases, after adjustment for patient and hospital covariates, each 10 case per year increase in hospital volume was related to a 6% reduction in relative odds of death (odds ratio (OR) 0.94, 95% confidence intervals 0.88, 0.99) and 0.29 days reduction (95% CI -0.22, -0.35) in postoperative in-hospital stay. Female sex (OR 1.53, 95% CI 1.08, 2.18) and transfer from another acute care hospital (OR 4.37, 95% CI 2.62, 7.29) were associated with increased case fatality rates among patients in the unruptured category. For ruptured cases, neither the case fatality rate nor postoperative in-hospital stay were significantly related to hospital volume. The case fatality rates increased linearly and substantially with advancing age both for unruptured and ruptured aneurysms, and the excess risk of postoperative death in ruptured as compared to unruptured aneurysms was substantially higher in older patients. CONCLUSION: The relationship between hospital volume and mortality or morbidity was very modest and observed only for elective surgery. Case fatality rates in patients with ruptured abdominal aortic aneurysms remained 10 times higher than for patients with unruptured abdominal aortic aneurysms, despite improvements in overall mortality in comparison to previously published data. More effective detection of aneurysms, including elective repair for those once considered "high risk" older patients, might further reduce the toll from ruptured aortic aneurysms.

Hospital procedure volume and teaching status do not influence treatment and outcome measures of rectal cancer surgery in a large general population.

A clear benefit of increased hospital procedure volume or teaching hospital status on outcomes of rectal cancer surgery has yet to be shown. Few have examined treatment differences that may lead to varying outcomes. This study assessed the impact of hospital procedure volume and teaching status on both treatment and outcome measures of rectal cancer surgery in a large general population. Data were obtained for 1072 incident cases of rectal adenocarcinoma diagnosed in 1990 from Ontario, Canada, and treated with a major resection. Hospitals were classified by teaching status and procedure volume. Pathology reports were examined for 418 procedures. Abdominoperineal resections accounted for 31.0% of all procedures. There were no clinically significant differences in treatment measures, operative mortality, and long-term survival among the hospital groups according to both univariate and multivariate analyses. In conclusion, the absence of a hospital volume or teaching status effect on treatment and outcome measures suggests that for rectal cancer surgery in Ontario, centralization of procedures into high-volume or teaching centers is unlikely to improve surgical quality.

Colour discrimination ellipses in patients with dominant optic atrophy.

Many colour tests require a visual acuity of at least 0.1, making them unsuitable for low vision patients. To assess colour vision in patients with sub-normal acuity, we re-designed a previously described test so that its spatial details would be coarse enough to be resolvable by subjects with severe visual impairment. The test measures chromatic discrimination along 20 axes evenly spaced in CIE 1976 L*u*v* colour space. We detail the results for this test in a group of patients with dominant optic atrophy. Despite the lack of evidence for genetic heterogeneity in dominant optic atrophy, we observed phenotypic variation both between and within families.

Cone dystrophy phenotype associated with a frameshift mutation (M280fsX291) in the alpha-subunit of cone specific transducin (GNAT2).

AIM: To describe the phenotype of a three generation consanguineous Pakistani family containing six individuals with autosomal recessive cone dystrophy caused by mutation in GNAT2. METHODS: Five of the six affected individuals underwent an ophthalmological examination, electrodiagnostic testing, fundus photography, autofluorescence imaging, and detailed psychophysical testing. RESULTS: All five examined patients had a history of nystagmus from infancy, photophobia, defective colour vision, and poor visual acuity. The nystagmus in three of the individuals had lessened with time. Fundus examination revealed an abnormal foveal appearance, without frank atrophy or pigmentation. Electroretinography (ERG) revealed absent ISCEV cone flicker ERGs with some preservation of responses to short wavelength stimulation. Rod ERGs showed no definite abnormality, but maximal (mixed rod-cone) response a-wave amplitudes were mildly subnormal. Rudimentary residual colour vision was detected in three individuals. There is clinical evidence of progressive visual acuity reduction in two older individuals. CONCLUSION: Mutation in the alpha-subunit of cone specific transducin (GNAT2) is characterised by an infantile onset cone dystrophy. Some affected individuals may show deterioration of visual acuity with time.

Trends and variations in the use of vascular surgery in Ontario.

OBJECTIVE: To measure changes over time in overall surgical rates and geographic rate variations for three major vascular procedures (abdominal aortic aneurysm repairs, peripheral vascular disease procedures and carotid endarterectomies). BACKGROUND: There is little research literature on population-based usage profiles of vascular procedures. The three procedures profiled were all subject to marked shifts in evidence or surgical opinions, raising the issue of the interplay between temporal trends and geographic variations in their use. METHODS: Based on Ontario's hospital discharge abstracts and census data, population-based usage rates were calculated by site of patient residence from 1981 to 1991. Extent of rate variation was summarized with the coefficient of variation, systematic component of variation and the adjusted-likelihood ratio chi2. Spearman rank correlations were also calculated to assess stability of county rankings for each procedure. RESULTS: The overall rates of peripheral vascular procedures and repair for abdominal aortic aneurysms fell 24% and increased 42% respectively. The overall rate of carotid endarterectomies dropped from 46/100,000 in 1981 to 20/100,000 in 1989, but by 1991 had increased to 37/100,000. Through the decade measures of variation fell minimally for all three procedures. CONCLUSION: Overall use of vascular procedures shifted in apparent response to new research evidence and technologies. Despite marked changes in surgical rates, the extent of geographic variation was stable, suggesting that differing factors influence overall surgical rates and geographic rate variations. Audit at the local level using primary clinical data is needed to understand why disparities in use persist.

Post radial keratotomy RGP fitting--a case study.

The procedure of radial keratotomy produces an abnormal corneal topography, with the central cornea being flatter than the periphery. As a result, fitting the post-radial keratotomy (RK) patient with rigid gas permeable (RGP) lenses can be an enormously difficult task. Unlike standard lens designs, the Ortho-K series of lenses, originally designed for use in orthokeratology, possess a back peripheral radius (BPR) which is steeper than the back optic zone radius (BOZR). It is proposed that these lenses may provide a more acceptable fit than conventional RGPs for the post-RK patient.