Topping-Off a Long Thoracic Stabilization With Semi-Rigid Constructs May Have Favorable Biomechanical Effects to Prevent Proximal Junctional Kyphosis: A Biomechanical Comparison.

STUDY DESIGN: In-vitro cadaveric biomechanical study. OBJECTIVES: Long posterior spinal fusion is a standard treatment for adult spinal deformity. However, these rigid constructs are known to alter motion and stress to the adjacent non-instrumented vertebrae, increasing the risk of proximal junctional kyphosis (PJK). This study aimed to biomechanically compare a standard rigid construct vs constructs "topped off" with a semi-rigid construct. By understanding semi-rigid constructs' effect on motion and overall construct stiffness, surgeons and researchers could better optimize fusion constructs to potentially decrease the risk of PJK and the need for revision surgery. METHODS: Nine human cadaveric spines (T1-T12) underwent non-destructive biomechanical range of motion tests in pure bending or torsion and were instrumented with an all-pedicle-screw (APS) construct from T6-T9. The specimens were sequentially instrumented with semi-rigid constructs at T5: (i) APS plus sublaminar bands; (ii) APS plus supralaminar hooks; (iii) APS plus transverse process hooks; and (iv) APS plus short pedicle screws. RESULTS: APS plus transverse process hooks had a range of motion (ie, relative angle) for T4-T5 and T5-T6, as well as an overall mechanical stiffness for T1-T12, that was more favourable, as it reduced motion at adjacent levels without a stark increase in stiffness. Moreover, APS plus transverse process hooks had the most linear change for range of motion across the entire T3-T7 range. CONCLUSIONS: Present findings suggest that APS plus transverse process hooks has a favourable biomechanical effect that may reduce PJK for long spinal fusions compared to the other constructs examined.

Implementation frameworks for polypharmacy management within healthcare organisations: a scoping review.

BACKGROUND: Several guidelines support polypharmacy management in individual patients. More organisational-level focus is needed on the use of implementation frameworks. AIM: To characterise the peer reviewed literature on implementation frameworks, focussing on barriers and facilitators to implementation at organisational level in the context of polypharmacy management. METHOD: A scoping review protocol was devised, supporting retrieval of studies published in English, reporting from any sector of practice. Medline, International Pharmaceutical Abstracts, Cumulative Index of Nursing and Allied Health Literature and Business Source Complete were searched to January 2022 using Medical Subject Headings including: 'polypharmacy', 'deprescriptions', 'strategic planning' and 'organizational innovation'. A narrative approach to data synthesis was applied. Searching, data extraction and synthesis were undertaken independently by two reviewers. RESULTS: After screening 797 records eight papers remained. Two were descriptive outlining details of specific initiatives, six used qualitative methods to explore determinants for implementation including barriers and enablers. Organisation level barriers included: poor organisational culture with a lack of sense of urgency and national plans, resource availability and communication issues including patient information and at transitions of care. Organisational facilitators included availability of government funding and regulatory environment promoting patient safety, a national emphasis on quality of care for older adults, co-ordinated national efforts and local evidence. CONCLUSION: Limited literature focusses on the use of implementation frameworks at organisational levels. This review highlights the need for further work on implementation frameworks in this context to help achieve effective organisational change.

Negative Association of Smoking History With Clinically Manifest Cardiac Sarcoidosis: A Case-Control Study.

Background: The etiology of sarcoidosis is still unknown and is likely related to a genetic susceptibility to unidentified environmental trigger(s). Our group and others have extensively described a specific phenotype of primarily Caucasian patients who have clinically manifest cardiac sarcoidosis (CS). In this study, we sought to explore whether smoking is associated with this specific phenotype of sarcoidosis. Methods: We performed a case-control study. Cases with clinically manifest CS were prospectively enrolled in the Cardiac Sarcoidosis Multi-Center Prospective Cohort Study (CHASM-CS registry; NCT01477359) and answered a standardized smoking history questionnaire. Cases were matched 10:1 with controls from the Ontario Health Study. Pretreatment positron emission tomography scans with 18F-fluorodeoxyglucose were compared for smokers vs nonsmokers. Results: Eighty-seven cases met the inclusion criteria. A total of 82 of 87 (94.3%) answered the questionnaire and were matched with 820 controls. A clear negative association of sarcoidosis and smoking was found, with 23 of 82 CS cases (28.0%) being current or ex-smokers, vs 392 of 820 controls (47.8%; P = 0.0006). CS patients with a smoking history had significantly less lifetime consumption (8.31 ± 9.20 pack-years) than the controls (15.34 ± 10.84 pack-years; P < 0.003). On 18F-fluorodeoxyglucose-positron emission tomography scan, the mean standardized uptake value of the left ventricle was 4.2 ± 8.98 in lifetime nonsmokers vs 2.89 ± 2.07 in patients with a smoking history (P < 0.0001). Conclusions: We describe a strong negative association between smoking history and clinically manifest CS. Nonsmokers had more severe myocardial inflammation (greater mean standardized uptake value of the left ventricle) than did patients with a smoking history. Further research is needed to understand these associations and whether they have therapeutic potential.

Introduction: L'étiologie de la sarcoïdose est encore inconnue et est possiblement liée à une susceptibilité génétique à un ou des déclencheurs environnementaux inconnus. Notre groupe et d'autres groupes ont exposé sous tous ses aspects un phénotype particulier chez des patients principalement blancs qui ont une sarcoïdose cardiaque (SC) manifeste sur le plan clinique. Dans la présente étude, nous avons cherché à explorer si le tabagisme est associé à ce phénotype particulier de la sarcoïdose. Méthodes: Nous avons réalisé une étude cas témoins. Les cas qui avaient une SC manifeste sur le plan clinique ont été inscrits de façon prospective à l'étude CHASM-CS (Cardiac Sarcoidosis Multi-Center Prospective Cohort Study, registre CHASM-CS; NCT01477359) et ont répondu à un questionnaire standardisé sur les antécédents de tabagisme. Les cas ont été appariés 10:1 aux témoins de l'Étude sur la santé Ontario. Nous avons comparé avant le traitement la tomographie par émission de positons au 18F-fluorodéoxyglucose des fumeurs vs des non-fumeurs. Résultats: Quatre-vingt-sept cas répondaient aux critères d'inclusion. Un total de 82 sur 87 (94,3 %) cas ont rempli le questionnaire et ont été appariés à 820 témoins. Nous avons observé une association négative claire entre la sarcoïdose et le tabagisme, soit 23 sur 82 cas de SC (28,0 %) qui fumaient actuellement ou étaient des ex-fumeurs vs 392 sur 820 témoins (47,8 % ; P = 0,0006). Les patients atteints de SC qui avaient des antécédents de tabagisme avaient une consommation significativement moindre durant leur vie (8,31 ± 9,20 paquets-années) que les témoins (15,34 ± 10,84 paquets-années ; P < 0,003). À la tomographie par émission de positons au 18F-fluorodéoxyglucose, la valeur moyenne de fixation normalisée du ventricule gauche était de 4,2 ± 8,98 chez les non-fumeurs de toujours vs 2,89 ± 2,07 chez les patients qui avaient des antécédents de tabagisme (P < 0,0001). Conclusions: Nous démontrons une forte association négative entre les antécédents de tabagisme et la SC manifeste sur le plan clinique. Les non-fumeurs avaient plus d'inflammation myocardique grave (une plus grande valeur moyenne de fixation normalisée du ventricule gauche) que les patients qui avaient des antécédents de tabagisme. D'autres recherches sont nécessaires pour comprendre ces associations et savoir s'ils ont un potentiel thérapeutique.

Biomechanical Comparison of a 3-Loop Pulley and a 4-Loop Pulley Suture for Tenorrhaphy in the Canine Gastrocnemius Tendon.

OBJECTIVE: The aim of this study was to compare a 3-loop pulley (3LP) suture pattern with a 4-loop pulley (4LP) suture pattern for the tenorrhaphy of the canine gastrocnemius tendon STUDY DESIGN: Randomized, cadaveric, biomechanical study of 30 canine gastrocnemius tendons. Tendons were transected and repaired with either 3LP or 4LP suture pattern with 2-0 polypropylene. A tensile load was applied at 25 mm/min until construct failure. The load required to form a 1 mm gap, 3 mm gap and maximum load at failure was recorded and compared between groups. RESULTS: The estimated mean load to form a 1 mm gap for the 3LP and 4LP was 28.4 N (95% confidence interval [CI]: 24.0-32.6N) and 45.5 N (95% CI: 40.7-50.1N) respectively. The 4LP mean load to form a 1 mm gap was 17.1 N (95% CI: 11.7-22.5N) greater than the 3LP. The estimated mean load to form a 3mm gap for the 3LP and 4LP was 39.7 N (95% CI: 34.1-45.4N) and 55.0 N (95% CI: 49.3-60.9N) respectively. The mean load to form a 3mm gap was 15.3 N (95% CI: 8.5-21.9N) greater in the 4LP than the 3LP. The estimated mean load for failure in the 3LP and 4LP was 41.2 N (95% CI: 35.6-46.9 N) and 54.3 N (95% CI: 48.7-60.3 N) respectively. CONCLUSION: A 4LP pattern was biomechanically superior to a 3LP pattern, as demonstrated by a greater load required to form both a 1 and 3 mm gap and a greater load for failure CLINICAL SIGNIFICANCE: A 4LP suture pattern better resists gap formation and requires greater load prior to construct failure compared with a 3LP, in this canine gastrocnemius model.

Examination of Genetic Susceptibility in Radiation-Associated Meningioma.

Previous epidemiological studies have demonstrated elevated susceptibility to ionizing radiation in some families, thus suggesting the presence of genetic components that conferred increased rate of radiation-associated meningioma (RAM). In this study, we exome-sequenced and investigated the segregation pattern of rare deleterious variants in 11 RAM pedigrees. In addition, we performed a rare-variant association analysis in 92 unrelated familial cases of RAM that were ancestry-matched with 88 meningioma-free controls. In the pedigree analysis, we found that each family carried mostly a unique set of rare deleterious variants. A follow-up pathway analysis of the union of the genes that segregated within each of the 11 pedigrees identified a single statistically significant (q value = 7.90E-04) "ECM receptor interaction" set. In the case-control association analysis, we observed no statistically significant variants or genes after multiple testing correction; however, examination of ontological categories of the genes that associated with RAM at nominal P values <0.01 identified biologically relevant pathways such as DNA repair, cell cycle and apoptosis. These results suggest that it is unlikely that a small number of highly penetrant genes are involved in the pathogenesis of RAM. Substantially larger studies are needed to identify genetic risk variants and genes in RAM.

Age, Not Sex, Modifies the Effect of Frailty on Long-term Outcomes After Cardiac Surgery.

OBJECTIVE: To examine the prevalence of frailty in surgical patients and determine whether age and sex modify the relationship between frailty and long-term mortality. BACKGROUND: Frailty is a complex and prevalent clinical syndrome. The cardiac surgery literature consists mostly of small, single-center studies, and the epidemiology of frailty remains to be fully elucidated in a real-world surgical population. METHODS: This retrospective cohort study included patients who underwent coronary artery bypass grafting, and/or aortic, mitral or tricuspid valve surgery in Ontario, Canada, between 2008 and 2016. The primary outcome was all-cause mortality. Survival probabilities were calculated using the Kaplan-Meier method, and the association of covariates with the hazard of death was assessed using multivariable Cox proportional hazard models. Frailty was assessed using the Johns Hopkins Adjusted Clinical Groups frailty-defining diagnoses indicator. RESULTS: Of 72,824 patients, 11,685 (16%) were frail. At median 5 ±â€Š2 years of follow-up, 2921 (25.0%) frail patients and 8637 (14.1%) non-frail patients had died [adjusted hazard ratio 1.60; 95% confidence interval (CI), 1.53-1.68]. The adjusted hazard ratio was highest in patients who underwent isolated mitral (2.18; 95% CI, 1.71-2.77) and mitral + aortic valve surgery (1.85; 95% CI, 1.33-2.58) and lowest after coronary artery bypass grafting + mitral valve surgery (1.38; 95% CI, 1.11-1.70). Age, but not sex, modified the effect of frailty on mortality; such that the rate of death decreased linearly with increasing patient age. CONCLUSIONS: We observed a high prevalence of frailty in patients undergoing cardiac surgery, and a statistically significant association between frailty and long-term mortality after cardiac procedures. Importantly, the rate of death was inversely proportional to age, such that frailty had a stronger adverse impact on younger patients. Our findings highlight the need to incorporate frailty into the preoperative risk stratification and investigate strategies to support younger patients who are frail.

Prevalence of growth hormone deficiency in patients with unexplained chronic fatigue after undergoing bone marrow transplantation in adulthood.

PURPOSE: Many patients who undergo bone marrow transplantation (BMT) in adulthood experience unexplained chronic fatigue which can have a major impact on their health-related quality of life (QoL). Pre-BMT treatment regimens increase the risk of developing acquired growth hormone deficiency (GHD), which results in a clinical syndrome with decreased energy and has additionally been linked to metabolic syndrome. METHODS: Using the gold-standard insulin hypoglycemic test (IHT), we evaluated the prevalence of GHD in 18 post-BMT adult patients with unexplained chronic fatigue, as well as the correlation between peak serum GH response and QoL scores, the metabolic syndrome, and insulin resistance. Peak serum GH cut-point less than 3.0 ug/L was used for the diagnosis of severe GHD. The Fatigue Severity Scale and Quality of Life in Adult GHD Assessment questionnaires were used to quantify fatigue symptoms. RESULTS: The prevalence of severe GHD within this sample of 18 patients was 50%. A trend between lower peak serum GH response and higher fatigue and QoL-AGHDA scores was observed. CONCLUSIONS: GHD may represent a remediable contributor to post-BMT chronic fatigue in adults, further studies are needed to evaluate the potential role of screening and GH replacement therapy in this vulnerable patient population. IMPLICATIONS FOR CANCER SURVIVORS: GHD may be a treatable explanation for disabling post-BMT fatigue pending results of intervention studies.

Outcome and prognosis for canine appendicular osteosarcoma treated with stereotactic body radiation therapy in 123 dogs.

Canine appendicular osteosarcoma is commonly treated with limb amputation; however, limb-sparing options are frequently desired or necessary for a subset of patients. We evaluated 123 patients and 130 sites treated with stereotactic body radiation therapy (SBRT). Eighty-two out of 98 dogs (84%) had maximum lameness improvement at a median of 3 weeks for a median of 6 months duration. Histopathologic evaluation of available samples from amputation or necropsy revealed >80% tumor necrosis in 50% of limbs consistent with local disease control. Of evaluable patients, 41% fractured and 21% pursued an amputation after treatment. Fine needle aspirate (n = 52) and needle core biopsy (n = 28) did not result in increased fracture risk compared to those without tumor sampling (n = 50). Median survival time (MST) was 233 days and time to first event was 143 days. Gross tumor volume and planned target volume were significantly inversely associated with survival and tumor location was significantly associated with survival. Dogs with salvage amputation had a significantly longer MST compared to those without (346 vs 202 days; P = .04). The presence of metastatic disease at the time of treatment in 15 dogs did not significantly impact survival time (200 vs 237 days without metastasis; P = .58). Skin side effects correlated significantly with dose with 33% of patients with acute grade 3 effects developing consequential late grade 3 effects. While SBRT improves lameness in most patients, further investigation is needed to identify candidates with minimal early fracture risk prior to initiating therapy.

Exploring Occupational, Recreational, and Environmental Associations in Patients With Clinically Manifest Cardiac Sarcoidosis.

BACKGROUND: Sarcoidosis is a condition of unknown etiology. A number of occupational, recreational, and environmental exposures have been associated with the development of extra-cardiac sarcoidosis. Patients with clinically manifest cardiac sarcoidosis (CS) have a distinct clinical phenotype. We sought to explore the exposures associated with clinically manifest CS. METHODS: Two groups of patients were recruited in a prospective registry: cases (patients with clinically manifest CS) and controls (patients without sarcoidosis and who had similar cardiac presentations to cases). A validated survey, previously used in other sarcoidosis phenotypes, was sent to all patients. RESULTS: A total of 113 patients met the inclusion criteria and were sent the survey, of whom 79 of 113 (69.9%) completed the survey. We found 3 environmental associations. First, we found a negative association of CS with smoking, with 8 of 43 (18.6%) CS patients being current or ex-smokers compared to 17 of 36 (47.2%) of the controls. Second, we found a positive association with mold exposure, with 21 of 43 (48.8%) CS patients having a prior history of mold exposure compared to 9 of 36 (25.0%) of the controls. After multivariable analysis, there remained significant associations between CS and smoking (odds ratio 0.14 [95% confidence interval 0.04-0.51], P = 0.002) and mold exposure (odds ratio 5.69 [95% confidence interval 1.68-19.25], P = 0.005). Finally, patients with CS and self-reported acne had a significantly longer duration of active acne (7.82 ± 3.97 years) than did control patients 2.67 ± 1.03 years (P = 0.006). CONCLUSIONS: We found a negative association between smoking history and the diagnosis of CS. We also found a significant 5-fold increase in mold exposure and a positive association with duration of acne in patients with CS compared to controls.

CONTEXTE: Les causes de la sarcoïdose demeurent inconnues. Un certain nombre de facteurs de risque professionnels, récréatifs et environnementaux ont toutefois été associés à la survenue de la sarcoïdose extracardiaque. Les patients qui sont atteints d'une sarcoïdose cardiaque cliniquement manifeste ont un phénotype clinique particulier. Nous nous sommes penchés sur les facteurs de risque associés à cette maladie. MÉTHODOLOGIE: Nous avons recruté deux groupes de patients à partir d'un registre de données prospectives : des cas de sarcoïdose cardiaque (présentant les manifestations cliniques de la sarcoïdose cardiaque) et des cas témoins (patients sans sarcoïdose, mais qui présentaient des signes et des symptômes cardiaques similaires à ceux des patients atteints de sarcoïdose cardiaque). Nous avons envoyé à l'ensemble des participants un questionnaire validé et déjà utilisé auprès de patients présentant d'autres phénotypes de sarcoïdose. RÉSULTATS: Au total, 113 patients répondaient aux critères d'inclusion. Nous avons envoyé le questionnaire à ces 113 patients, et 79 d'entre eux (69,9 %) y ont répondu. Nous avons détecté trois facteurs environnementaux. Nous avons d'abord noté une association négative entre la sarcoïdose cardiaque et le tabagisme : 8 patients atteints de sarcoïdose cardiaque sur 43 (18,6 %) fumaient ou avaient déjà fumé, comparativement à 17 témoins sur 36 (47,2 %). Nous avons ensuite observé une association positive avec l'exposition aux moisissures : 21 patients atteints de sarcoïdose cardiaque sur 43 (48,8 %) avaient des antécédents d'une telle exposition, comparativement à 9 des 36 témoins (25,0 %). Les associations entre la sarcoïdose cardiaque et le tabagisme et l'exposition aux moisissures sont demeurées significatives après une analyse multivariée (risque relatif approché [RRA] pour le tabagisme : 0,14 [intervalle de confiance {IC} à 95 % : 0,04-0,51], p = 0,002; RRA pour l'exposition aux moisissures : 5,69 [IC à 95 % : 1,68-19,25], p = 0,005). Finalement, chez les patients atteints de sarcoïdose cardiaque et d'acné autodéclarée, la durée de l'acné était significativement plus longue (7,82 ± 3,97) que celle relevée chez les témoins (2,67 ± 1,03; p = 0,006). CONCLUSIONS: Nous avons détecté une association négative entre les antécédents de tabagisme et le diagnostic de sarcoïdose cardiaque. Nous avons également observé que l'exposition aux moisissures était 5 fois plus élevée et que l'acné est présente plus longtemps chez les patients atteints de sarcoïdose cardiaque que chez les témoins.

Comparison of the use of a vessel-sealing device versus ligatures for occlusion of uterine tissues during ovariohysterectomy or ovariectomy in rabbits (Oryctolagus cuniculus).

OBJECTIVE: To compare the bursting strength of the uterine horns (UHs) and cervical-vestibule junction (CVJs) of rabbits following sealing with a vessel-sealing device (VSD) or encircling ligatures. SAMPLE: UHs and CVJs collected from 30 rabbit (Oryctolagus cuniculus) cadavers. PROCEDURES: UHs and CVJs were randomly assigned to sealing with encircling Miller knot ligatures (LIG; n = 10 CVJs and 20 UHs) or a VSD (12 CVJs and 24 UHs). Lumens were infused with saline (0.9% NaCl) solution under pressure until seals burst or to a maximum pressure of 300 mm Hg. RESULTS: For CVJs, median (range) bursting pressure of the LIG and VSD groups was > 300 mm Hg (224 to > 300 mm Hg) and 35 mm Hg (0 to 60 mm Hg), respectively. Five of 12 CVJs in the VSD group failed at pressures < 33 mm Hg. For UHs, median (range) bursting pressure of the LIG and VSD groups was 255 mm Hg (120 to > 300 mm Hg) and 154 mm Hg (range, 44 to 202 mm Hg), respectively. CONCLUSIONS AND CLINICAL RELEVANCE: The evaluated VSD was effective in sealing UHs at bursting pressures well in excess of expected physiologic pressures, indicating that the VSD may be useful for ovariectomy procedures in rabbits. However, CVJ seals created with the VSD were ineffective and could potentially burst at low pressures, which could predispose to urine entering the abdomen. Given these results, we do not recommend sealing of the CVJ with a VSD for ovariohysterectomy in rabbits.

Crystal structures of human ENPP1 in apo and bound forms.

Cancer is one of the leading causes of mortality in humans, and recent work has focused on the area of immuno-oncology, in which the immune system is used to specifically target cancerous cells. Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is an emerging therapeutic target in human cancers owing to its role in degrading cyclic GMP-AMP (cGAMP), an agonist of the stimulator of interferon genes (STING). The available structures of ENPP1 are of the mouse enzyme, and no structures are available with anything other than native nucleotides. Here, the first X-ray crystal structures of the human ENPP1 enzyme in an apo form, with bound nucleotides and with two known inhibitors are presented. The availability of these structures and a robust crystallization system will allow the development of structure-based drug-design campaigns against this attractive cancer therapeutic target.

Update on the subcutaneous administration of rituximab in Canadian cancer centres.

Results of studies comparing subcutaneous (sc) with intravenous (iv) rituximab indicate that the two formulations are comparable in efficacy, but most patients and health care professionals prefer the sc route, commonly because of shorter chair time and reduced risk of infusion-related reactions. Recent Canadian data, including those from the scuba study reported here, support the results of earlier international studies showing a reduction in preparation and administration time with the sc formulation, lower cost of administration, and reduced drug wastage because of the fixed sc dosing. Given the significant time and cost savings of the sc formulation, that formulation is generally preferred over the iv formulation for the treatment of follicular lymphoma, diffuse large B cell lymphoma, and chronic lymphocytic leukemia.

The Proteasome Inhibitor Ixazomib Inhibits the Formation and Growth of Pulmonary and Abdominal Osteosarcoma Metastases in Mice.

Osteosarcoma is the most common form of primary bone cancer. Over 20% of osteosarcoma patients present with pulmonary metastases at diagnosis, and nearly 70% of these patients fail to respond to treatment. Previous work revealed that human and canine osteosarcoma cell lines are extremely sensitive to the therapeutic proteasome inhibitor bortezomib in vitro. However, bortezomib has proven disappointingly ineffective against solid tumors including sarcomas in animal experiments and clinical trials. Poor tumor penetration has been speculated to account for the inconsistency between in vitro and in vivo responses of solid tumors to bortezomib. Here we show that the second-generation proteasome inhibitor ixazomib, which reportedly has enhanced solid tumor penetration compared to bortezomib, is toxic to human and canine osteosarcoma cells in vitro. We used experimental osteosarcoma metastasis models to compare the efficacies of ixazomib and bortezomib against primary tumors and metastases derived from luciferase-expressing KRIB or 143B human osteosarcoma cell lines in athymic mice. Neither proteasome inhibitor reduced the growth of primary intramuscular KRIB tumors, however both drugs inhibited the growth of established pulmonary metastases created via intravenous inoculation with KRIB cells, which were significantly better vascularized than the primary tumors. Only ixazomib slowed metastases from KRIB primary tumors and inhibited the growth of 143B pulmonary and abdominal metastases, significantly enhancing the survival of mice intravenously injected with 143B cells. Taken together, these results suggest ixazomib exerts better single agent activity against osteosarcoma metastases than bortezomib. These data provide hope that incorporation of ixazomib, or other proteasome inhibitors that penetrate efficiently into solid tumors, into current regimens may improve outcomes for patients diagnosed with metastatic osteosarcoma.

Parathyroid hormone receptor 1 (PTHR1) is a prognostic indicator in canine osteosarcoma.

Osteosarcoma (OS) is the most common malignant primary bone tumour in humans and dogs. Several studies have established the vital role of parathyroid hormone-related protein (PTHrP) and its receptor (PTHR1) in bone formation and remodeling. In addition, these molecules play a role in the progression and metastasis of many human tumour types. This study investigated the expression of PTHR1 and PTHrP in canine OS tissues and assessed their prognostic value. Formalin-fixed, paraffin-embedded tissue samples from 50 dogs diagnosed with primary OS were immunolabeled with antibodies specific for PTHR1 and PTHrP. The immunostaining intensity of tumours from patients with OS was correlated with survival time. Both PTHR1 and PTHrP were detected in all OS samples (n = 50). Dogs with OS tumours showing high immunostaining intensity for PTHR1 (n = 36) had significantly shorter survival times (p = 0.028, Log Rank; p = 0.04, Cox regression) when compared with OS that had low immunostaining intensity for PTHR1 (n = 14).PTHrP immunostaining intensity did not correlate with survival time (p > 0.05). The results of this study indicate that increased expression of PTHR1 antigen in canine OS is associated with poor prognosis. This suggests that PTHR1 may be useful as a prognostic indicator in canine OS.

Fragment screening for a protein-protein interaction inhibitor to WDR5.

The WD40-repeat protein WDR5 scaffolds various epigenetic writers and is a critical component of the mammalian SET/MLL histone methyltransferase complex. Dysregulation of the MLL1 catalytic function is associated with mixed-lineage leukemia, and antagonism of the WDR5-MLL1 interaction by small molecules has been proposed as a therapeutic strategy for MLL-rearranged cancers. Small molecule binders of the "WIN" site of WDR5 that cause displacement from chromatin have been additionally implicated to be of broader use in cancer treatment. In this study, a fragment screen with Surface Plasmon Resonance (SPR) was used to identify a highly ligand-efficient imidazole-containing compound that is bound in the WIN site. The subsequent medicinal chemistry campaign-guided by a suite of high-resolution cocrystal structures with WDR5-progressed the initial hit to a low micromolar binder. One outcome from this study is a moiety that substitutes well for the side chain of arginine; a tripeptide containing one such substitution was resolved in a high resolution structure (1.5 Å) with a binding mode analogous to the native tripeptide. SPR furthermore indicates a similar residence time (k d = ∼0.06 s-1) for these two analogs. This novel scaffold therefore represents a possible means to overcome the potential permeability issues of WDR5 ligands that possess highly basic groups like guanidine. The series reported here furthers the understanding of the WDR5 WIN site and functions as a starting point for the development of more potent WDR5 inhibitors that may serve as cancer therapeutics.

A network approach to developing immuno-oncology combinations in Canada.

Immune checkpoint inhibitors have revolutionized care for many cancer indications, with considerable effort now being focused on increasing the rate, depth, and duration of patient response. One strategy is to combine immune strategies (for example, ctla-4 and PD-1/L1-directed agents) to harness additive or synergistic efficacy while minimizing toxicity. Despite encouraging results with such combinations in multiple tumour types, numerous clinical challenges remain, including a lack of biomarkers that reliably predict outcome, the emergence of therapeutic resistance, and optimal management of immune-related toxicities. Furthermore, the selection of ideal combinations from the myriad of immune, systemic, and locoregional therapies has yet to be determined. A longitudinal network-based approach could offer advantages in addressing those critical questions, including long-term follow-up of patients beyond individual trials. The molecular cancer registry Personalize My Treatment, managed by the Networks of Centres of Excellence nonprofit organization Exactis Innovation, is uniquely positioned to accelerate Canadian immuno-oncology (io) research efforts throughout its national network of cancer sites. To gain deeper insight into how a pan-Canadian network could advance research in io combinations, Exactis invited preeminent clinical and scientific advisors from across Canada to a roundtable event in November 2017. The present white paper captures the expert advice provided: leverage longitudinal patient data collection; facilitate network collaboration and assay harmonization; synergize with existing initiatives, networks, and biobanks; and develop an io combination trial based on Canadian discoveries.

Canadian consensus: oligoprogressive, pseudoprogressive, and oligometastatic non-small-cell lung cancer.

Background: Little evidence has been generated for how best to manage patients with non-small-cell lung cancer (nsclc) presenting with rarer clinical scenarios, including oligometastases, oligoprogression, and pseudoprogression. In each of those scenarios, oncologists have to consider how best to balance efficacy with quality of life, while maximizing the duration of each line of therapy and ensuring that patients are still eligible for later options, including clinical trial enrolment. Methods: An expert panel was convened to define the clinical questions. Using case-based presentations, consensus practice recommendations for each clinical scenario were generated through focused, evidence-based discussions. Results: Treatment strategies and best-practice or consensus recommendations are presented, with areas of consensus and areas of uncertainty identified. Conclusions: In each situation, treatment has to be tailored to suit the individual patient, but with the intent of extending and maximizing the use of each line of treatment, while keeping treatment options in reserve for later lines of therapy. Patient participation in clinical trials examining these issues should be encouraged.

Patient eligibility for hematopoietic stem cell transplantation: a review of patient-associated variables.

Assessing patient eligibility for hematopoietic stem cell transplantation (HSCT) remains a complex, multifaceted challenge. Among these challenges, the paucity of comprehensive clinical data to guide decision making remains problematic coupled with unclear trade-offs between patient, disease and local HSCT center factors. Moreover, it is unclear that the modification of poor patient characteristics will improve post-HSCT outcomes. However, the use of Comorbidity Indices and Comprehensive Geriatric Assessments helps meet this challenge, but may be limited by overlapping patient characteristics. The increasing consideration for pre-HSCT psychosocial assessments and interventions remains to be studied. Ultimately, the decision to proceed with a HSCT remains interdisciplinary while considering the available evidence discussed in this review.