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Purpose: To report on the Stereotactic Body Radiation Therapy (SBRT) credentialing experience during the Phase III Ontario Clinical Oncology Group (OCOG) LUSTRE trial for stage I non-small cell lung cancer. Methods: Three credentialing requirements were required in this process: (a) An institutional technical survey; (b) IROC (Imaging and Radiation Oncology Core) thoracic phantom end-to-end test; and (c) Contouring and completion of standardized test cases using SBRT for one central and one peripheral lung cancer, compared against the host institution as the standard. The main hypotheses were that unacceptable variation would exist particularly in OAR definition across all centres, and that institutions with limited experience in SBRT would be more likely to violate per-protocol guidelines. Results: Fifteen Canadian centres participated of which 8 were new, and 7 were previously established (≥2 years SBRT experience), and all successfully completed surveys and IROC phantom testing. Of 30 SBRT test plans, 10 required replanning due to major deviations, with no differences in violations between new and established centres (p = 0.61). Mean contouring errors were highest for brachial plexus in the central (C) case (12.55 ± 6.62 mm), and vessels in the peripheral (P) case (13.01 ± 12.55 mm), with the proximal bronchial tree (PBT) (2.82 ± 0.78 C, 3.27 ± 1.06 P) as another variable structure. Mean dice coefficients were lowest for plexus (0.37 ± 0.2 C, 0.37 ± 0.14 P), PBT (0.77 ± 0.06 C, 0.75 ± 0.09 P), vessels (0.69 ± 0.29 C, 0.64 ± 0.31 P), and esophagus (0.74 ± 0.04 C, 0.76 ± 0.04 P). All plans passed per-protocol planning target volume (PTV) coverage and maximum/volumetric organs-at-risk constraints, although variations existed in dose gradients within and outside the target. Conclusions: Clear differences exist in both contouring and planning with lung SBRT, regardless of centre experience. Such an exercise is important for studies that rely on high precision radiotherapy, and to ensure that implications on trial quality and outcomes are as optimal as possible.

PurposeFluoro-2-deoxyglucose positron-emission tomography (FDG-PET/CT) is now considered a standard investigation for the staging of new cases of stage III NSCLC. However, there is not published level 3 evidence demonstrating the impact of FDG-PET/CT on appropriate therapy in this setting. Using retrospective population-based data, we sought to examine the role and timing that FDG-PET/CT scans play in influencing treatment choice, as well as survival in patients diagnosed with stage III NSCLC.Materials and methodsA retrospective cohort of patients diagnosed with stage III NSCLC from 2009-2017 in Ontario were identified from the IC/ES (formerly Institute of Clinical Evaluative Sciences) database. FDG-PET/CT utilization over time, trends in mediastinal biopsy technique and usage, the impact of FDG-PET/CT on overall survival (OS), and its influence on use of concurrent chemoradiotherapy (CRT) were explored. The impact of timing of pre-treatment FDG-PET/CT on OS was also analyzed (≤28 days prior to treatment, 29-56 days prior, and >56 days prior).ResultsBetween 2007 and 2017, a total of 13 796 people were diagnosed with stage III NSCLC in Ontario. FDG-PET/CT utilization increased over time with 0% of cases in 2007 and 74% in 2017 with pre-treatment FDG-PET/CT scans. The number of patients who received a mediastinal biopsy similarly increased in this timeframe increasing from 41% to 53%. More patients with pre-treatment FDG-PET/CT scans received curative-intent therapy than those who did not: 23% vs 13% for CRT (p

Abstract Many populations of long‐distance migrant shorebirds are declining rapidly. Since the 1970s, the lesser yellowlegs (Tringa flavipes) has experienced a pronounced reduction in abundance of ~63%. The potential causes of the species' decline are complex and interrelated. Understanding the timing of migration, seasonal routes, and important stopover and non‐breeding locations used by this species will aid in directing conservation planning to address potential threats. During 2018–2022, we tracked 118 adult lesser yellowlegs using GPS satellite tags deployed on birds from five breeding and two migratory stopover locations spanning the boreal forest of North America from Alaska to Eastern Canada. Our objectives were to identify migratory routes, quantify migratory connectivity, and describe key stopover and non‐breeding locations. We also evaluated predictors of southbound migratory departure date and migration distance. Individuals tagged in Alaska and Central Canada followed similar southbound migratory routes, stopping to refuel in the Prairie Pothole Region of North America, whereas birds tagged in Eastern Canada completed multi‐day transoceanic flights covering distances of >4000 km across the Atlantic between North and South America. Upon reaching their non‐breeding locations, lesser yellowlegs populations overlapped, resulting in weak migratory connectivity. Sex and population origin were significantly associated with the timing of migratory departure from breeding locations, and body mass at the time of GPS‐tag deployment was the best predictor of southbound migratory distance. Our findings suggest that lesser yellowlegs travel long distances and traverse numerous political boundaries each year, and breeding location likely has the greatest influence on migratory routes and therefore the threats birds experience during migration. Further, the species' dependence on wetlands in agricultural landscapes during migration and the non‐breeding period may make them vulnerable to threats related to agricultural practices, such as pesticide exposure.

Abstract Purpose Metastatic epidural spinal cord compression (MESCC) is a devastating complication of advanced malignancy, which can result in neurologic complications and significant deterioration in overall function and quality of life. Most patients are not candidates for optimal surgical decompression and as a result, receive urgent 3D conformal radiotherapy (3DCRT) to prevent or attempt to reverse neurologic progression. Multiple trials indicate that response and ambulatory rates after 3DCRT are inferior to surgery. The advent of stereotactic body radiation therapy (SBRT) has created a method with which a “radiosurgical decompression” boost may facilitate improve outcomes for MESCC patients. Methods We are conducting a pilot study to investigate SBRT boost after urgent 3D CRT for patients with MESCC. The aim of the study is to establish feasibility of this two-phase treatment regimen, and secondarily to characterize post-treatment ambulation status, motor response, pain control, quality of life and survival. Discussion We describe the study protocol and present a case report of one patient. A quality assurance review was conducted after the first seven patients, and resultant dose-constraints were revised to improve safety and feasibility of planning through more conservative organ at risk constraints. There have been no severe adverse events (grade 3–5) to date. We have illustrated clinical and dosimetric data of an example case, where a patient regained full strength and ambulatory capacity. Conclusions Our study aims to determine if SBRT is a feasible option in addition to standard 3DCRT for MESCC patients, with the goal to consider future randomized trials if successful. Having a robust quality assurance process in this study ensures translatability going forward if future trials with multicenter and increased patient representation are to be considered. Trial registration clinicaltrials.gov; registration no. NCT03529708; https://clinicaltrials.gov/ct2/show/NCT03529708 ; First posted May 18, 2018.

Abstract The roots of precision cancer therapy began at the Mayo Clinic in 1914 when surgical pathologist Albert C. Broders began collecting data showing that cancers of the same histologic type behaved differently. In March 1920, based upon 6 years of clinical follow‐up, Broders published his first paper, utilizing data from over 500 cases of squamous cell carcinoma of the lip that he had blindly divided into four histologic grades based upon degree of differentiation, showing that numerical tumor "grading" allowed him to predict patient prognosis. Before this, surgeons had no scientific way to evaluate prognosis. Broders then replicated his work using other types of tumors at other body sites, as did several Mayo Fellows and pathologists at other institutions. Cuthbert Dukes in London, England not only replicated Broders’ findings with rectal adenocarcinomas, he also used the same data to develop the first tumor “staging” methodology by focusing upon depth of local invasion and presence or absence of lymph node metastases. Soon, tumor grading, tumor staging, or the combination of both represented state‐of‐the‐art prognostic techniques for scientific cancer care. This brief historical vignette celebrates the 100th anniversary of Broders’ first paper, which is the starting point for the long road to personalized cancer care.

Abstract Due to a long running research bias toward the breeding season, there are major gaps in knowledge on the basic nonbreeding ecology of many species, preventing a full‐annual cycle focus in ecology and conservation. Exacerbating this problem is the fact that many species are extremely difficult to detect outside of breeding. Here, we demonstrate a partial solution to this problem by using archival GPS tags to examine the overwintering ecology of a migratory nocturnal bird, the eastern whip‐poor‐will (Antrostomus vociferous). We deployed tags on 21 individuals and were able to recover 11 (52%) one year later. Tags collected high precision (approx. 10 m) points throughout the nonbreeding period. With continuous time movement models, we used these data to estimate overwintering home ranges. All individuals exhibited at least one bounded home range during this phase of the annual cycle, three of eleven had two wintering locations, and home range area ranged from 0.50 to 10.85 ha. All overwintering home ranges contained closed‐canopy forest land cover (42%–100%), and no other land cover type represented >40% of any home range. We found some evidence, with caveats, that total edge within the landscape surrounding the home range was negatively related to home range area. The prevalence of contiguous closed‐canopy forest cover in overwintering home ranges contrasts with apparent breeding habitat preferences, which includes clear‐cuts and other, more open, habitats. This study is the first to reveal key aspects of overwintering space use in this species by using archival GPS to overcome both logistical and methodological limitations. Expanded use of such technology is critical to gathering basic ecological and distributional data, necessary for achieving a more complete understanding of full‐annual cycles of animal populations.

Thomas D. Kinney and Duke University started the first formal university-based training program for pathologists’ assistants in 1969. Over the next 2 years, 2 more university-based programs were established. All 3 programs were affiliated with nearby Veterans Administration Hospitals and were funded as a pilot study by the US Veterans Administration to address a looming shortage of pathologists. Early graduates of these programs discovered that the concept of pathologists’ assistants with well-defined skill sets encompassing both surgical and autopsy pathology was not initially accepted by important elements of organized pathology. Indeed, many academic pathologists were opposed to the concept from the outset. In the face of such opposition, a group of practicing pathologists’ assistants created and incorporated their own professional organization, the American Association of Pathologists’ Assistants, to provide support, advocacy, and continuing education for individual practicing pathologists’ assistants. The history of the American Association of Pathologists’ Assistants and its role in the establishment and success of the pathologists’ assistant profession are described utilizing personal communications as well as published historical sources.

Understanding spatial and temporal movement patterns of migratory birds throughout the annual cycle can help identify potential population threats. The behavior and habitat use of birds during migration and stopover periods is particularly understudied in many species. In this study, we used high spatial resolution archival GPS tags to track Rusty Blackbirds (Euphagus carolinus) from one eastern (New Hampshire) and two western (Alaska and Alberta) breeding populations across the annual cycle. We sought to determine: 1) migratory connectivity of the three distinct populations; 2) migratory phenology, behavior, and time spent during each phase of the annual cycle; and 3) habitat use of individuals throughout the nonbreeding period. We retrieved 7 tags from 30 tagged individuals following 1-year deployments. We found that four Alberta individuals overwintered in the Mississippi Alluvial Valley, two Alaska individuals overwintered in either the Great Plains or the Mississippi Alluvial Valley, and the single New Hampshire individual overwintered on the Southeastern Coastal Plain. Length of annual cycle stages varied among individuals, with the combined migratory periods occupying between 12% and 48% of the annual cycle. Stopover behavior was also widely variable, as minimum convex polygons of stopovers ranged from < 1 hectare to 505 km² and stopover durations ranged from 1 to 35 days (n = 40 stopovers). Birds predominantly used woody wetlands and emergent marsh during the nonbreeding period, but habitat use differed between roosting and foraging. Marshes were used more for nocturnal roosting, whereas woody wetlands were used for diurnal foraging. Our results can help efforts to conserve this declining species by targeting regions and habitats at specific times of year for management during the nonbreeding period. In particular, the large amount of time spent during migration periods suggests conservation efforts in stopover regions are just as important as those on the wintering grounds.

Calgary Laboratory Services provides global hospital and community laboratory services for Calgary and surrounding areas (population 1.4 million) and global academic support for the University of Calgary Cumming School of Medicine. It developed rapidly after the Alberta Provincial Government implemented an austerity program to address rising health care costs and to address Alberta’s debt and deficit in 1994. Over roughly the next year, all hospital and community laboratory test funding within the province was put into a single budget, fee codes for fee-for-service test billing were closed, roughly 40% of the provincial laboratory budget was cut, and roughly 40% of the pathologists left the province of Alberta. In Calgary, in the face of these abrupt changes in the laboratory environment, private laboratories, publicly funded hospital laboratories and the medical school department precipitously and reluctantly merged in 1996. The origin of Calgary Laboratory Services was likened to an “unhappy shotgun marriage” by all parties. Although such a structure could save money by eliminating duplicated services and excess capacity and could provide excellent city-wide clinical service by increasing standardization, it was less clear whether it could provide strong academic support for a medical school. Over the past decade, iterations of the Calgary Laboratory Services model have been implemented or are being considered in other Canadian jurisdictions. This case study analyzes the evolution of Calgary Laboratory Services, provides a metric-based review of academic performance over time, and demonstrates that this model, essentially arising as an unplanned experiment, has merit within a Canadian health care context.

Coencapsulation with Sertoli-enriched testicular cell fractions prolongs islet graft survival time compared with islet encapsulation alone in a highly discordant tilapia (fish)-to-mouse xenotransplantation model. Here we investigate whether Fas ligand (Fas-L) expression by testicular Sertoli cells is responsible for this additional protective effect. Sertoli-enriched testicular cell fractions (7 × 10 6 cells) harvested from either Fas-L-defective (group I) or Fas-L-positive (group II) mice were coencapsulated in alginate gel spheres with fish islets and then transplanted into streptozotocin-diabetic Balb/c recipients. Group III mice received encapsulated islets without coencapsulated Sertoli cells. After transplantation, blood glucose levels were monitored three times per week. Mean graft survival times for the three groups were: group I = 35.6 ± 10.2 days (n = 9), group II = 31.3 ± 9.4 days (n = 7), and group III = 23.3 ± 2.2 days (n = 6) (ANOVA, p = 0.043). Coencapsulation, regardless of the Fas-L status of the Sertoli cell donors, modestly prolonged graft survival. There was no significant difference between Fas-L-deficient and Fas-L-positive donors. Our results suggest that Fas/Fas-L interaction is not responsible for the additional protection afforded to encapsulated discordant islet xenografts by coencapsulation with Sertoli cells.

The islet tissue, called Brockmann bodies, in certain teleost fish is anatomically distinct from the pancreatic exocrine tissue and can be easily identified macroscopically. Expensive islet isolation procedures, such as required when procuring islet tissue from mammalian pancreases, are unnecessary. Tilapia islets transplanted into diabetic athymic nude mice will produce long-term normoglycemia and mammalian-like glucose tolerance profiles. Encapsulated tilapia islets function well after transplantation into euthymic recipients. Additionally, tilapia are potentially ideal xenogeneic donors because of markedly lower donor production costs, minimal islet procurement costs, and possibly decreased xenozoonotic potential relative to mammalian donors. Tilapia islets appear to be appropriately glucose responsive with high insulin output, can be cryopreserved, and are much more resistant to hypoxia than mammalian islets. Because tilapia and human insulin differ by 17 amino acids, we have cloned, sequenced, and modified the tilapia insulin gene by site-directed mutagenesis resulting in a tilapia insulin gene that codes for “humanized” insulin while still maintaining all of the tilapia regulatory (noncoding) sequences. We have now produced small numbers of founder transgenic tilapia with incorporation of our humanized tilapia insulin gene construct, and we have shown transmission and expression of the transgene in the beta cells and serum of their F1 offspring. Our ultimate goal is to achieve homologous recombination and to breed for homozygosity for the hybrid insulin gene. Subsequent generations of transgenic tilapia will undergo a program of genomic optimization selecting for growth, survival, and fecundity as well as stability of the transgene. Islets from the resulting transgenic fish, after extensive characterization, could be harvested, encapsulated, and then transplanted into diabetic patients.

In certain species of fish, the insulin-producing tissue is uniquely located in separate structures called Brockmann bodies (BBs). Tilapia BBs have been shown to be a simple and inexpensive source of islet cells for xenotransplantation research. Each donor tilapia contains roughly 12-15 BBs, measuring from 0.3 to 5.0 mm in maximum dimension, in a triangular region of adipose tissue bounded by the liver, stomach, and spleen/gallbladder. At present, the larger BBs (usually 2-4) are harvested by microdissecting these “BB regions” using jeweler's forceps and microvascular scissors while being visualized with the aid of a dissecting microscope. It is a simple but time-consuming task that would not be applicable for harvesting massive amounts of BB tissue for large animal studies. Therefore, we have developed an easier and more efficient method of harvesting BBs based on a standard enzymatic method for isolating human adipocytes. BB regions are harvested from donor fish and pooled into a 50 mL plastic tube containing collagenase Type II (3 mg/mL) in Hank's balanced salt solution (HBSS); the tube is then placed in a 37°C waterbath/shaker for roughly 15 min. The exact length of the digestion interval is determined by visual inspection of the tube to determine whether the BBs have been liberated. The digestion is then stopped by adding excess cold HBSS. The adipocytes float while the BBs and residual connective tissue (i.e., a few blood vessels, nerves, and bile ducts) form a pellet. The pellet is washed several times in HBSS and then placed in a culture dish. The BBs are easily handpicked with a siliconized pipette. Based on functional data and DNA content, this new method roughly doubles or triples our yield of BB tissue per donor fish. To determine whether BBs harvested in this manner functioned in a manner similar to those harvested by microdissection, we performed a series of transplants using mass-harvested BBs. Long-term normoglycemia was achieved in streptozotocin-diabetic nude mice and mean graft survival time was not altered in streptozotocin-diabetic euthymic balb/c mice. However, the total weight of donor fish required per recipient was decreased by 50% in both strains.

Islets of Langerhans isolated from the pancreas and encapsulated in alginate-polylysine-alginate microspheres can potentially serve as a self-regulating supply of insulin in response to glucose loads. A longitudinal ultrastructural and immunohistochemical study of encapsulated rat islets cultured in CMRL-1969 media at a constant glucose concentration of 5.5 mmol/L (100 mg%) allowed several observations. First, acinar cells, which remain attached to isolated islets, disappeared within 1 wk in tissue culture. Damaged endocrine cells also disappeared at this time. Phagocytic cells having ultrastructural features suggesting that they are macrophages emerged from the islets within about a week and ingested portions of the inner layer of capsule polymer. These macrophage-like cells retained these polymers until their death which occurred at around 1-2 mo after isolation; at no time did we observe phagocytic cells actually breaching the microsphere capsules. Beta cells remained well-granulated over 90 days of culture but accumulated lipofuscin-like residual bodies. Under these conditions, these bodies began to accumulate appreciably after about one week in culture.

A method is described to facilitate extensive abdominal surgery in diabetic rats using temporary renal subcapsular islet isografts. The procedure is performed in three stages —each separated by 2 wk. After each rat is made diabetic (Step 1), an isogenic islet transplant is performed beneath the left renal capsule (Step 2). Step 3 is the operative procedure, followed by a left nephrectomy. Finally, it is shown how the islet isograft can be excised from the nephrectomy specimen and “recycled” into another diabetic rat (Step 2). Using this three step process, it is possible to decrease the mortality rate following orthotropic liver transplantation in diabetic rats from 100% to about 30%. This procedure can also be used to facilitate other extensive surgical procedures in diabetic rats.