University Health Network

Introduction Patients with pancreatic ductal adenocarcinoma (PDAC) face challenging treatment decisions following their diagnosis. We developed and validated a survival prognostication model using routinely available clinical information, patient-reported symptoms, performance status, and initial cancer-directed treatment. Methods This retrospective cohort study included PDAC patients from 2007 to 2020 using linked administrative databases in Ontario, Canada. Patients were randomly selected for model development (75%) and validation (25%). Using the development cohort, a multivariable Cox proportional hazards regression with backward stepwise variable selection was used to predict the probability of survival. Model performance was assessed on the validation cohort using the concordance index and calibration plots. Results There were 17,450 patients (49% female) with a median age of 72 (IQR 63-81) and a mean survival time of nine months. In the derivation cohort, 1,469 (11%) patients had early stage, 4,202 (32%) had advanced stage disease, and 7,417 (57%) had unknown stage. The following factors were associated with an increased risk of death by more than 10%: tumour in the tail of the pancreas, advanced stage, hospitalization three months prior to diagnosis, congestive heart failure or dementia, low, moderate, or high pain score, moderate or high appetite score, high dyspnea and tiredness score, and a performance status score of 60-70 or lower. The calibration plot indicated good agreement with a C index of 0.76. Discussion This model accurately predicted one-year survival for PDAC using clinical factors, symptoms, and performance status. This model may foster shared decision making for patients and their providers.

Background Hospitalized older adults have unique physical, emotional, and psychosocial needs. We sought to understand older patients’ and care partners’ experiences with multicomponent interventions that support age-friendly care and identify areas for improvement. Methods We conducted a mixed methods study using surveys and interviews to explore older adult patients’ (65 years or older) and their care partners’ experiences with hospital-delivered multicomponent initiatives. We recruited participants from the Geriatric Rehabilitation (GRU) and Musculoskeletal (MSK) Rehabilitation units in a Canadian academic hospital from October 2021 to April 2022 until we reached data saturation and no new themes emerged. Results We recruited 18 participants, 10 patients (mean age 78 years, 80.0% female) and 8 care partners (mean age 61, 87.5% female). Surveys revealed overall positive experiences with multicomponent interventions. Interviews revealed five themes: 1) various forms of companionship for patients, 2) recreation and entertainment, 3) physical activity, 4) communication, and 5) pleasant physical environment. Having forms of companionship and proper communication with the care team were highlighted as areas of importance. Physical activity was highly valued, but participants expressed hesitation around safety of mobilizing without physiotherapists. Recreational activities helped distract from social isolation during a hospital stay and participants had diverse preferences for activities. Participants had strong memories of the physical environment, including the lack of natural light, institutionallike décor, and smells. Conclusion Companionship, recreation and entertainment, physical activity, communication, and the physical environment were important to hospitalized patients and their care partners. Hospital administrators and policy makers should consider these when targeting areas to improve care for the aging population.

Pathobiology of the intact human retina has been challenging to study due to its relative inaccessibility and limited sample availability. Thus, there is a great need for new translational models that can maintain human retinal integrity and cytoarchitecture. The role of physiologic intraocular pressure (IOP) and fluid flow on retinal tissue has not been well studied. Here, we present an ex vivo organotypic model to assess the impact of physiological intraocular perfusion on retinal cytoarchitecture and cell survival. We demonstrate that retinal cytoarchitecture is remarkably well preserved following re-establishment of physiological IOP and aqueous humor dynamics for up to 24 h in ex vivo whole globe porcine and human eyes, comparable to freshly preserved control eyes. Accordingly, cell death was minimized in the perfused retinas, which also displayed normal markers of cellular metabolism and astrogliosis. These results are in marked contrast to contralateral control eyes without active perfusion, which displayed excessive cell death and disrupted cytoarchitecture at the same time point. These experiments demonstrate the critical impact that physiological pressure and fluid flow have on retinal tissue, and introduce a new pre-clinical model to study human and porcine retinal health and degeneration in a relevant biomechanical setting.

Antibodies are essential to immune homeostasis due to their roles in neutralizing pathogenic agents. However, failures in central and peripheral checkpoints that eliminate autoreactive B cells can undermine self-tolerance and generate autoantibodies that mistakenly target self-antigens, leading to inflammation and autoimmune diseases. While autoantibodies are well-studied in autoimmune and in some communicable diseases, their roles in chronic conditions, such as obesity and aging, are less understood. Obesity and aging share similar aspects of immune dysfunction, such as diminished humoral responses and heightened chronic inflammation, which can disrupt immune tolerance and foster autoantigen production, thus giving rise to autoreactive B cells and autoantibodies. In return, these events may also contribute to the pathophysiology of obesity and aging, to the associated autoimmune disorders linked to these conditions, and to the development of immunosenescence, an age-related decline in immune function that heightens vulnerability to infections, chronic diseases, and loss of self-tolerance. Furthermore, the cumulative exposure to antigens and cellular debris during obesity and aging perpetuates pro-inflammatory pathways, linking immunosenescence with other aging hallmarks, such as proteostasis loss and mitochondrial dysfunction. This review examines the mechanisms driving autoantibody generation during obesity and aging and discusses key putative antigenic targets across these conditions. We also explore the therapeutic potential of emerging approaches, such as CAR-T/CAAR-T therapies, vaccines, and BiTEs, to tackle autoimmune-related conditions in aging and obesity.

Purpose of review Despite technical and therapeutic advances, only 20–40% of patients with colorectal liver metastases (CRLM) have resectable disease. Historically, the remaining patients with unresectable, liver-only CRLM would receive palliative chemotherapy, with a median survival of 8 months. Recent findings Liver transplantation has emerged as a viable option for selected patients with CRLM. This advancement stems from improved understanding of tumour genomics and biology and better patient selection criteria. The results of recent prospective clinical trials have further ignited enthusiasm for liver transplantation as a viable therapeutic option. Living donor liver transplantation (LDLT) offers several advantages over deceased donor liver transplantation (DDLT) for this disease, including reduced wait-time and optimized timing and coordination of oncologic therapy. On-going LDLT clinical trials have demonstrated favourable outcomes as compared with other liver transplantation indications. However, there is no established consensus or standardization in the implementation of LDLT for CRLM, beyond trials and centre-specific protocols. Summary LDLT is an excellent therapeutic option in highly selected patients with CRLM. Refining prognostic factors and selection criteria will help to further optimize the utility and broaden the acceptance and implementation of LDLT for patients with CRLM.

Objective To evaluate the efficacy of neoadjuvant chemotherapy combination with liposomal irinotecan, 5-fluorouracil, leucovorin, and oxaliplatin in patients with locally advanced rectal cancer. Methods This was a phase 2, nonrandomized, multicenter study in adults with stage II or III rectal cancer and an Eastern Cooperative Oncology Group performance status of 0 to 1. Total neoadjuvant therapy (TNT) consisted of neoadjuvant chemotherapy combination with liposomal irinotecan (60 mg/m ² ), oxaliplatin (60 mg/m ² ), leucovorin (400 mg/m ² ), and fluorouracil (2400 mg/m²), followed by chemoradiotherapy [ie, capecitabine (825 mg/m ² ) and radiotherapy according to the standard of care]. The primary efficacy endpoint was the proportion of patients who achieved clinical complete response (cCR), defined as the normalization of pelvic magnetic resonance imaging, rectoscopy, computed tomography scan, and tumor markers. Results The median follow-up was 32.3 months. Of the 30 patients who underwent TNT and were evaluated, 6 (20.0%; 95% CI: 5.2%-34.8%) patients achieved a cCR. There were no deaths. The median disease-free survival (DFS) for patients with cCR was not reached after a follow-up of 32 months; the 1-year DFS rate was 90.0% (95% CI: 71.0%-100%), and the 2-year and 3-year DFS rates were 80.0% (95% CI: 55.0%-100%). No grade ≥4 adverse events (AEs) were observed. Grade 3 AEs occurred in 18 patients (60%), most frequent was diarrhea (n = 9, 30%). Eleven (36.7%) patients experienced serious AEs, with diarrhea being the most frequent (n = 6, 20.0%). Conclusion TNT with 5-fluorouracil, leucovorin, and oxaliplatin and chemoradiation is a safe and effective therapeutic alternative for the management of locally advanced rectal cancer.

Timely diagnostic tools are needed to improve antibiotic treatment. Pairing metagenomic sequencing with genomic neighbor typing algorithms may support rapid clinically actionable results. We created resistance-associated sequence elements (RASE) databases for Escherichia coli and Klebsiella spp . and used them to predict antibiotic susceptibility in directly sequenced (Oxford Nanopore) urine specimens from critically ill patients. RASE analysis was performed on pathogen-specific reads from metagenomic sequencing. We evaluated the ability to predict (i) multi-locus sequence type (MLST) and (ii) susceptibility profiles. We used neighbor typing to predict MLST and susceptibility phenotype of E. coli (64/80) and Klebsiella spp . (16/80) from urine samples. When optimized by lineage score, MLST predictions were concordant for 73% of samples. Similarly, a RASE-susceptible prediction for a given isolate was associated with a specificity and a positive likelihood ratio (LR+) for susceptibility of 0.65 (95% CI, 0.54–0.76) and 2.26 (95% CI, 1.75–2.92), respectively, with an increase in the probability of susceptibility of 10%. A RASE-non-susceptible prediction was associated with a sensitivity and a negative likelihood ratio (LR-) for susceptibility of 0.79 (95% CI, 0.74–0.84) and 0.32 (95% CI, 0.24–0.43) respectively, with a decrease in the probability of susceptibility of 20%. Numerous antibiotic classes could reasonably be reconsidered empiric therapy by shifting empiric probabilities of susceptibility across relevant treatment thresholds. Moreover, these predictions can be available within 6 h. Metagenomic sequencing of urine specimens with neighbor typing provides rapid and informative predictions of lineage and antibiotic susceptibility with the potential to impact clinical decision-making. IMPORTANCE Urinary tract infections (UTIs) are a common diagnosis in hospitals and are often treated empirically with broad-spectrum antibiotics. These broad-spectrum agents can select for resistance in these bacteria and co-colonizing organisms. The use of narrow-spectrum agents is desirable as an antibiotic stewardship measure; however, it is counterbalanced by the need for adequate therapy. Identification of causative organisms and their antibiotic susceptibility can help direct treatment; however, conventional testing requires days to produce actionable results. Methods to quickly and accurately predict susceptibility phenotypes for pathogens causing UTI could thus improve both patient outcomes and antibiotic stewardship. Here, expanding on previous work showing accurate prediction for certain Gram-positive pathogens, we demonstrate how the use of RASE from metagenomic sequencing can provide informative and rapid phenotype prediction results for common Gram-negative pathogens in UTI, highlighting the future potential of this method to be used in clinical settings to guide empiric antibiotic selection.

Despite rapid advances in the field of rheumatology, many patients with rheumatoid arthritis suffer from chronic and debilitating systemic disease, with a high symptom burden and limited life expectancy. In this paper, we demonstrate an approach to managing a patient with rheumatoid arthritis with life-limiting illness for the palliative care physician. In particular, we focus on the systemic nature of rheumatoid arthritis and nuances around medication management towards the end of life. It is our hope that this paper can serve as a guide for the palliative care clinician to decrease end-of-life morbidity from rheumatic disease and rheumatic medications.

Objective To determine if serum interferon (IFN)-α levels at the time of a lupus nephritis (LN) flare are associated with renal outcomes. Methods Patients with an LN flare who had a preflare estimated glomerular filtration rate (eGFR) ≥60 mL/min were included in the study. The following outcomes were ascertained: (1) Time to first and second LN flares during follow-up, (2) Time to a sustained decline in eGFR by 30% and 50%, and progression to end-stage renal disease (ESRD, <15 mL/min), and (3) Time to an adverse renal event (≥2 renal flares and/or at least a 30% sustained decline in eGFR during follow-up). Serum IFN-α was measured by Simoa. Results 92 patients with active LN were included in the study. Elevated serum baseline levels of IFN-α predicted poor renal outcomes. Patients with higher baseline IFN-α had a greater risk of having two or more subsequent LN flares (HR: 1.31 (1.08–1.59), p=0.006), sustained 30% decline in eGFR (HR: 1.27 (1.14–1.40), p<0.001), 50% decline in eGFR (HR: 1.27 (1.12–1.33), p<0.001) and progressing to ESRD (HR: 1.29 (1.14–1.47), p<0.001). Receiver operating characteristic analysis identified an IFN-α cut-off, 0.6 pg/ml, for predicting an adverse renal event. Conclusions Elevated serum IFN-α levels measured at the time of an LN flare are associated with poor renal outcomes, including the development of ≥2 LN flares, and a clinically meaningful decline in kidney function.

Objectives To describe lumbar spine (LS) trabecular bone score (TBS) values after SCI, and to explore the differences in fractures risk assessment between FRAX® and TBS-adjusted FRAX® in individuals living with chronic SCI. Methods Baseline dual-energy x-ray absorptiometry (DXA) scans from an established cohort were acquired using a Hologic Discovery QDR 4500. TBS measurements were performed using the TBS iNsightTM software version 2.1.2.0. A Welch's t-test was performed to explore differences in TBS, FRAX®, and TBS-adjusted FRAX® between men and women, between participants ≤49 years and ≥50 years, and between subgroups with and without history of fracture and with complete and incomplete injury. Results We analyzed 37 scans; the mean TBS was 1.336 ± 0.107. The mean 10-year fracture risk was 8.8% ± 11.4% for major osteoporotic fracture and 4.0% ± 10.8% for hip fracture according to FRAX®, and 6.6% ± 2.8% for major osteoporotic fracture and 2.8% ± 6.7% for hip fractures according to TBS-adjusted FRAX®. The 10-year fracture risk for major osteoporotic fractures was higher in individuals with a prior fragility fracture compared to those without, according to FRAX® (p = .033) and TBS-adjusted FRAX® (p = .001). Conclusion Over a half of our sample presented a partially degraded bone microarchitecture based on TBS. TBS was not different between people with motor complete and motor incomplete injury or with and without prior fragility fracture. Future studies are needed to define the clinical relevance of TBS and TBS-adjusted FRAX® in people with chronic SCI.

The sinoatrial node regulates the heart rate throughout life. Failure of this primary pacemaker results in life-threatening, slow heart rhythm. Despite its critical function, the cellular and molecular composition of the human sinoatrial node is not resolved. Particularly, no cell surface marker to identify and isolate sinoatrial node pacemaker cells has been reported. Here we use single-nuclei/cell RNA sequencing of fetal and human pluripotent stem cell-derived sinoatrial node cells to reveal that they consist of three subtypes of pacemaker cells: Core Pacemaker, Sinus Venosus, and Transitional Cells. Our study identifies a host of sinoatrial node pacemaker markers including MYH11, BMP4, and the cell surface antigen CD34. We demonstrate that sorting for CD34⁺ cells from stem cell differentiation cultures enriches for sinoatrial node cells exhibiting a functional pacemaker phenotype. This sinoatrial node pacemaker cell surface marker is highly valuable for stem cell-based disease modeling, drug discovery, cell replacement therapies, and the targeted delivery of therapeutics to sinoatrial node cells in vivo using antibody-drug conjugates.

Background Musculoskeletal complications are one of the most common reasons for a patient with a spinal cord injury (SCI) to be rehospitalized. Bone loss due to immobilization and changes in metabolic processes because of the SCI lead to an increased risk of fractures. Objective To evaluate the prevalence and demographic characteristics of people living with an SCI who had a secondary fracture. Methods We used population health administrative data from Ontario, Canada, in individuals with either traumatic (TSCI) or nontraumatic SCI (NTSCI). Records of duplicate cases, missing unique patient identifier numbers, individuals not eligible for provincial health insurance, and age <18 years were excluded. Only records of fractures treated in the emergency department or acute care hospital were included. Descriptive statistics were used to summarize data, using counts and percentages that described the numbers and proportions of fractures by type disaggregated by sex, age groups, and type of SCI. Results A total of 14,168 unique records were identified with 4486 as TSCI and 9682 as NTSCI between April 1, 2004 and March 31, 2020 and were followed up to March 31, 2021. Overall, 11% of the cohort had a subsequent fracture with no difference between TSCI and NTSCI. Hip fractures accounted for 21% of the fractures, wrists accounted for 12%, spine 11%, and tibia 11%. The average time to the first subsequent fracture after the SCI was 3.97 (SD 3.4) years. Conclusion Monitoring and management of fracture risk needs attention in the first 2 years, with a focus on NTSCI.

Objective To evaluate modified versions of the Belimumab International Study in Lupus Nephritis (BLISS-LN) belimumab study primary efficacy renal response (mPERR) and complete renal response (mCRR) criteria (excluding mandatory corticosteroid tapering) as predictors of real-world, long-term renal outcomes among patients with lupus nephritis (LN). Methods This retrospective, observational study (GSK Study 212866) used deidentified data between 1970 and 2015 from the University of Toronto Lupus Cohort from adults diagnosed with systemic lupus erythematosus and biopsy-proven Class III±V, IV±V or V LN. At 24 months postbiopsy, patients were retrospectively indexed as responders/non-responders based on mPERR (estimated glomerular filtration rate (eGFR) ≤20% below biopsy value/≥60 mL/min/1.73 m ² and urine protein:creatinine ratio (uPCR) ≤0.7 g/day) or mCRR (eGFR ≤10% below biopsy value/≥90 mL/min/1.73 m ² and uPCR ≤0.5 g/day) criteria. The association between index mPERR (primary outcome) or mCRR (secondary outcome) status and long-term (up to 25 years, until censoring or death) renal survival (no progression to end-stage kidney disease (eGFR <30 mL/min/1.73 m ² , dialysis or transplant) or death) was assessed. Results Overall, 179 patients were included in the analysis (mPERR responders, n=128; non-mPERR responders, n=51). Most patients were female (87.2%); the mean (SD) age was 34.1 (11.3) years. Long-term renal survival was attained for 78.9% of mPERR responders and 60.8% of non-mPERR responders; achieving mPERR was associated with an increased likelihood of long-term renal survival versus not achieving mPERR (log-rank p=0.0119). Overall, 102 patients were mCRR responders, and 77 were non-mCRR responders. Long-term renal survival was attained for 80.4% of mCRR responders and 64.9% of non-mCRR responders; achieving mCRR was associated with an increased likelihood of long-term renal survival than not achieving mCRR (log-rank p=0.0259). Conclusions Achieving mPERR or mCRR was associated with improved long-term renal survival, highlighting that these statuses are suitable predictors of long-term renal outcomes in patients with LN.

Background The objective of this research was the development and evaluation of ²⁰³Pb-labelled panitumumab (²⁰³Pb-PSC-panitumumab) as an immuno-SPECT radioligand for the detection of EGFR + head and neck squamous cell carcinoma (HNSCC) in a patient-derived xenograft (PDX) mouse model. The 51.9 h physical half-life and favourable γ-emission (279 keV; 81%) of ²⁰³Pb offer an excellent opportunity for developing immuno-SPECT radioligands. Moreover, ²⁰³Pb has a complementary therapeutic radionuclide (²¹²Pb), making ²⁰³Pb and ²¹²Pb an ideal matched radiotheranostic pair. Results Radiolabeling of panitumumab was performed at a pH of 5.0 and room temperature for 5–10 min with [²⁰³Pb]Pb(OAc)2, and the incorporation efficiency was determined using radio-TLC. ²⁰³Pb-PSC-panitumumab (~ 10 MBq, 140 μl of saline) was injected into the tail vein of NRG mice bearing subcutaneous (s.c.) HNSCC patient-derived xenografts (PDX). SPECT/CT images were acquired at 48 and 120 h post-injection. For biodistribution studies, mice were euthanized five days after ²⁰³Pb-panitumumab injection. The tumour and normal tissues were collected and weighed, and uptake of ²⁰³Pb was measured in a γ-counter. The uptake was calculated as the percent injected dose per gram of each tissue (ID%/g). Blocking experiments were performed by pretreating a group of mice (n = 5) with 1 mg of panitumumab 1 h before administering ²⁰³Pb-PSC-panitumumab. 4–5 chelators of a new lead-specific chelator (PSC) were attached per antibody; radiolabeling efficiency was 99.2 ± 0.7%. The isolated radiochemical yield of ²⁰³Pb-PSC-panitumumab was 41.4 ± 8% (n = 5), and the molar activity was 1.2 ± 0.35 GB/mg. SPECT imaging and biodistribution confirmed high accumulation and retention of ²⁰³Pb-PSC-panitumumab in the tumour (26% ID/g) at 120 h post-injection (p.i.), which could be reduced to 6.2%ID/g at 120 h p.i. by predosing with panitumumab (1 mg) confirming EGFR specificity of ²⁰³Pb-PSC-panitumumab uptake. Conclusions Panitumumab was successfully and reproducibly labelled with ²⁰³Pb in high radiochemical purity using the chelator PSC-NCS. ²⁰³Pb-PSC-panitumumab was specifically accumulated and retained in EGFR + tumours in NRG mice with s.c. HNSCC PDX. ²⁰³Pb-PSC-panitumumab is a suitable immuno-SPECT radioligand for imaging EGFR + tumours and has great potential for combining with ²¹²Pb-PSC-panitumumab in a radiotheranostic strategy for imaging and treating HNSCC.