Distinguishing wet from dry age-related macular degeneration using three-dimensional computer-automated threshold Amsler grid testing

Background/aims: With the increased efficacy of current therapy for wet age-related macular degeneration (AMD), better ways to detect wet AMD are needed. This study was designed to test the ability of three-dimensional contrast threshold Amsler grid (3D-CTAG) testing to distinguish wet AMD from dry AMD. Methods: Conventional paper Amsler grid and 3D-CTAG tests were performed in 90 eyes: 63 with AMD (34 dry, 29 wet) and 27 controls. Qualitative comparisons were based upon the three-dimensional shapes of central visual field (VF) defects. Quantitative analyses considered the number and volume of the three-dimensional defects. Results: 25/34 (74%) dry AMD and 6/29 (21%) wet AMD eyes had no distortions on paper Amsler grid. Of these, 5/25 (20%) dry and 6/6 (100%) wet (p=0.03) AMD eyes exhibited central VF defects with 3D-CTAG. Wet AMD displayed stepped defects in 16/28 (57%) eyes, compared with only 2/34 (6%) of dry AMD eyes (p=0.002). All three volumetric indices of VF defects were two- to four-fold greater in wet than dry AMD (p<0.006). 3D-CTAG had 83.9% positive and 90.6% negative predictive values for wet AMD. Conclusions: 3D-CTAG has a higher likelihood of detecting central VF defects than conventional Amsler grid, especially in wet AMD. Wet AMD can be distinguished from dry AMD by qualitative and quantitative 3D-CTAG criteria. Thus, 3D-CTAG may be useful in screening for wet AMD, quantitating disease severity, and providing a quantitative outcome measure of therapy

Paleohydrological Reconstruction from Late Holocene Records in Interdune Lakes (N'Guigmi, Northern Bank of the Lake Chad, Niger)

An old erg covers the northern part of the Lake Chad basin. This dune landform allowed the formation of many inter- dune ponds of various sizes. Still present in certain zones where the groundwater level is high (e.g. Kanem, southern Manga), these ponds formed in the past a vast network of lacustrine microsystems, as shown by the nature and the dis- tribution of their deposits. In the Manga, these interdune deposits represent the main sedimentary records of the Holo- cene environmental succession. Their paleobiological (pollens, diatoms, ostracods) and geochemical (δ18O, δ13C, Sr/ Ca) contents are often the basis for paleoenvironmental reconstruction. On the other hand, their sedimentological char- acters are rarely exploited. This study of palustro-lacustrine deposits of the Holocene N'Guigmi lake (northern bank of the Lake Chad; Niger) is based on the relationships between the sedimentological features and the climato-hydrological fluctuations. The mineralogical parameters (e.g. calcium carbonate content, clay mineralogy) and the nature of autoch- thonous mineralization (i.e. amorphous silica, clays, calcium carbonates) can be interpreted using a straightforward hy- dro-sedimentary model. Established to explain the geochemical dynamics of Lake Chad, this model is based on a bio- geochemical cycle of the main elements (i.e. silicium, calcium) directly controlled by the local hydrological balance (i.e. rainfall/evaporation ratio). All these results show that a detailed study of sedimentological features can provide impor- tant paleohydrological informations about the regional aridification since ca 6500 14C BP

Oxo-aglaiastatin-mediated inhibition of translation initiation

We thank Dr. Elias George (McGill University) for the kind gift of Pgp-1-expressing HeLa cells. RIM was supported by a doctoral fellowship from the Cole Foundation. This research was supported by a grant from the Canadian Institutes of Health Research (FDN-148366) to JP. J.A.P., Jr. is supported by NIH Grant R35 GM118173. Work at the Boston University Center for Molecular Discovery is supported by Grant R24 GM111625. (Cole Foundation; FDN-148366 - Canadian Institutes of Health Research; R35 GM118173 - NIH; R24 GM111625)Published versionSupporting documentatio

A Systematic Review of the Clinical Implementation of Pelvic Magnetic Resonance Imaging (MR)-Only Planning for External Beam Radiation Therapy

The use of magnetic resonance imaging (MRI) scans alone for radiotherapy treatment planning (MR-only planning) has been highlighted as one method of improving patient outcomes. Recent technological advances have meant that introducing MR-only planning to the clinic is now becoming a reality, with several specialist radiotherapy clinics treating patients with this technique. As such, substantial efforts are being made to introduce this technique into wide-spread clinical implementation. A systematic review of publications investigating the clinical implementation of pelvic MR-only radiotherapy treatment planning was undertaken following the PRISMA guidelines. The Medline, Embase, Scopus, Science Direct, CINAHL and Web of Science databases were searched (timespan: all years to 2nd January 2019). Twenty six articles met the inclusion criteria. The studies were grouped into the following categories: 1. MR acquisition and synthetic-CT generation verification, 2. MR distortion quantification and phantom development, 3. Clinical validation of patient treatment positioning in an MR-only workflow and 4. MR-only commissioning processes. Key conclusions from this review are: i) MR-only planning has been clinically implemented for prostate cancer treatments; ii) A substantial amount of work remains to translate MR-only planning into wide spread clinical implementation for all pelvic sites; iii) MR scanner distortions are no longer a barrier to MR-only planning; however they must be managed appropriately; iv) MR-only based patient positioning verification shows promise, however limited evidence is reported in the literature and further investigation is required; and v) a number of MR-only commissioning processes have been reported which can aid centres as they undertake local commissioning, however this needs to be formalised in guidance from national bodies

Preoperative radiotherapy combined with 5 days per week capecitabine chemotherapy in locally advanced rectal cancer

There is increasing evidence supporting the use of preoperative chemoradiotherapy in patients with locally advanced rectal cancer in an attempt to facilitate complete surgical resection with clear margins. We describe our experience of using a 5-day per week regime of preoperative capecitabine chemoradiotherapy. Between November 2004 and September 2006, 70 patients with MRI-defined locally advanced rectal cancer were selected for treatment. Capecitabine was given at a dose of 900 mg m−2 for 5 days per week combined with 45 Gy of radiotherapy in 25 doses. This regime was well tolerated with 89% of our patients receiving the full dose of chemotherapy and 96% receiving the full dose of radiotherapy. Ninety-three per cent proceeded to macroscopically complete surgical resection. The pathological complete response rate was 9.2% with a node-negative rate of 66%. A negative circumferential margin was achieved by 79% of the patients who underwent resection. Compared to studies using a 7-day per week capecitabine schedule, our results show increased compliance and less dose reductions with comparable pathological outcome

SPARC, a phase-I trial of pre‐operative, margin intensified, stereotactic body radiation therapy for pancreatic cancer

Background and purpose: Following resection of pancreatic cancer, risk of positive margins and local recurrence remain high, especially for borderline-resectable pancreatic cancer (BRPC). We aimed to establish the maximum tolerated dose of a margin-intensified five-fraction stereotactic body radiotherapy (SBRT) regimen designed to treat the region at risk. / Materials and methods: We conducted a prospective multicentre phase-1 rolling-six dose-escalation study. BRPC patients received pre-operative SBRT, with one dose to the primary tumour and an integrated boost to the region where tumour was in contact with vasculature. Four dose-levels were proposed, with starting dose 30 Gy to primary PTV and 45 Gy to boost volume (PTV_R), in five daily fractions. Primary endpoint was maximum tolerated dose (MTD), defined as highest dose where zero of three or one of six patients experienced dose-limiting toxicity (DLT). / Results: Twelve patients were registered, eleven received SBRT. Radiotherapy was well tolerated with all treatment completed as scheduled. Dose was escalated one level up from starting dose without encountering any DLT (prescribed 32.5 Gy PTV, 47.5 Gy PTV_R). Nine serious adverse reactions or events occurred (seven CTCAE Grade 3, two Grade 4). Two patients went on to have surgical resection. Median overall survival for SBRT patients was 8.1 months. The study closed early when it was unable to recruit to schedule. / Conclusion: Toxicity of SBRT was low for the two dose-levels that were tested, but MTD was not established. Few patients subsequently underwent resection of pancreatic tumour after SBRT, and it is difficult to draw conclusions regarding the safety or toxicity of these therapies in combination

A phase I/II study of irinotecan when added to 5-fluorouracil and leucovorin and pelvic radiation in locally advanced rectal cancer: a Colorectal Clinical Oncology Group Study

The objective of this study was to evaluate the maximum tolerated dose (MTD) and recommended dose of irinotecan administered as a 5-day schedule synchronously with 5-fluorouracil (5FU), leucovorin (LV) and preoperative pelvic radiation (45 Gy) for primary borderline/unresectable, locally advanced rectal cancer. The study used escalating doses of intravenous irinotecan (6, 8, 10, 12, 14, 16, 18, and 20 mg m−2) administered on days 1–5 and 29–33 followed by low dose LV (20 mg m−2) and 5FU (350 mg m−2 over 1 h) in sequential cohorts. Preoperative pelvic radiotherapy using a three- or four-field technique and megavoltage photons comprised 45 Gy given in 25 fractions, 1.8 Gy per fraction. Surgery in the form of mesorectal excision was performed 6–10 weeks later. Histopathological examination of the resected specimen was performed according to techniques of Quirke, and compared with clinical staging. A distance of 1 mm or less between the peripheral extent of the tumour and the radial resection margin defined an involved circumferential resection margin (CRM). The MTD was determined as the dose causing more than a third of patients to have a dose-limiting toxicity (DLT) defined as specific grade 3 or 4 toxicities. Once the MTD was reached, a further 14 patients were treated at the dose level below the MTD. In total, 57 patients received irinotecan at the eight dose levels. The final cohort reached DLT after only four patients had been enrolled. The median age was 62 years (range 26–75), 37 male and 20 female subjects. The MTD of irinotecan in this schedule was 20 mg m−2 when three out of four patients experienced DLT. Dose limiting grade 3 or 4 diarrhoea was reported in seven out of 57 patients, three at the 20 mg m−2 dose level. Serious haematological toxicity (grade 3) was minimal and reported in only three patients; one grade 3 neutropaenia, one grade 4 neutropaenia and one grade 3 febrile neutropaenia and anaemia. Compliance was good with 93 and 89% of patients completing radiotherapy and chemotherapy, respectively. The remaining patients had only minor deviations from protocol therapy. Eight patients did not proceed to surgery, in six cases because they remained unresectable or had developed metastatic disease, one patient was unfit for surgery and one died as a result of complications from radiotherapy. Forty-nine patients underwent a potentially curative surgical resection. Histopathological examination of the resected specimen demonstrated pCR 12 out of 49 (24%) and 12 out of 57 (21%) overall. A histologically confirmed clear circumferential resection margin (CRM) was achieved in 39 out of 49 (80%) of those resected, and 39 out of 57 (68%) overall. In conclusion, MTD with this scheduled regimen of irinotecan is 20 mg m−2 (days 1–5 and 29–33). The acceptable toxicity and compliance at 18 mg m−2 recommend testing this dose in future phase III studies. The tumour downstaging and complete resection rates (negative CRM) are encouragingly high for this very locally advanced group

SPARC, a phase-I trial of pre‐operative, margin intensified, stereotactic body radiation therapy for pancreatic cancer

Background and purpose: Following resection of pancreatic cancer, risk of positive margins and local recurrence remain high, especially for borderline-resectable pancreatic cancer (BRPC). We aimed to establish the maximum tolerated dose of a margin-intensified five-fraction stereotactic body radiotherapy (SBRT) regimen designed to treat the region at risk. / Materials and methods: We conducted a prospective multicentre phase-1 rolling-six dose-escalation study. BRPC patients received pre-operative SBRT, with one dose to the primary tumour and an integrated boost to the region where tumour was in contact with vasculature. Four dose-levels were proposed, with starting dose 30 Gy to primary PTV and 45 Gy to boost volume (PTV_R), in five daily fractions. Primary endpoint was maximum tolerated dose (MTD), defined as highest dose where zero of three or one of six patients experienced dose-limiting toxicity (DLT). / Results: Twelve patients were registered, eleven received SBRT. Radiotherapy was well tolerated with all treatment completed as scheduled. Dose was escalated one level up from starting dose without encountering any DLT (prescribed 32.5 Gy PTV, 47.5 Gy PTV_R). Nine serious adverse reactions or events occurred (seven CTCAE Grade 3, two Grade 4). Two patients went on to have surgical resection. Median overall survival for SBRT patients was 8.1 months. The study closed early when it was unable to recruit to schedule. / Conclusion: Toxicity of SBRT was low for the two dose-levels that were tested, but MTD was not established. Few patients subsequently underwent resection of pancreatic tumour after SBRT, and it is difficult to draw conclusions regarding the safety or toxicity of these therapies in combination

Motivic Serre invariants, ramification, and the analytic Milnor fiber

We show how formal and rigid geometry can be used in the theory of complex singularities, and in particular in the study of the Milnor fibration and the motivic zeta function. We introduce the so-called analytic Milnor fiber associated to the germ of a morphism f from a smooth complex algebraic variety X to the affine line. This analytic Milnor fiber is a smooth rigid variety over the field of Laurent series C((t)). Its etale cohomology coincides with the singular cohomology of the classical topological Milnor fiber of f; the monodromy transformation is given by the Galois action. Moreover, the points on the analytic Milnor fiber are closely related to the motivic zeta function of f, and the arc space of X. We show how the motivic zeta function can be recovered as some kind of Weil zeta function of the formal completion of X along the special fiber of f, and we establish a corresponding Grothendieck trace formula, which relates, in particular, the rational points on the analytic Milnor fiber over finite extensions of C((t)), to the Galois action on its etale cohomology. The general observation is that the arithmetic properties of the analytic Milnor fiber reflect the structure of the singularity of the germ f.Comment: Some minor errors corrected. The original publication is available at http://www.springerlink.co