Assessment of urine colour using a wallet card: a randomised study of a novel patient self-care tool during chemoradiation for oesophageal cancer.

BACKGROUND: Patients undergoing neoadjuvant chemoradiation for oesophageal cancer often experience dehydration from decreased fluid intake and increased losses. Despite frequent clinical visits during treatment, patients can still present with dehydration, suggesting the need for increased patient awareness and engagement around adverse event management at home. Evidence for benefits of self-monitoring may help motivate patients to engage proactively in their own care to improve their treatment experience. METHODS: We performed a randomised single-centre study of a urine colour self-monitoring card (UCC) during chemoradiation therapy for oesophageal cancer, compared with standard dietitian counselling. Primary outcome was self-efficacy as determined by the Self-Management Resource Centre Self-Efficacy for Managing Chronic Disease Scale (SMCD). Secondary outcomes included Burge thirst scores, Edmonton Symptom Assessment System scores (ESAS), patient-initiated hydrations, creatinine rise and satisfaction with the UCC. RESULTS: Thirty-five patients were randomised. UCC use was not associated with improved SMCD or ESAS scores compared with standard counselling. The card was highly rated by patients as a welcome tool for self-monitoring. CONCLUSIONS: No beneficial effect on self-efficacy or dehydration markers with UCC use was demonstrated. The study nonetheless drew attention to several factors potentially hindering its use for effective self-care: the unexpected severity of other symptoms consuming patients' attention, reduced sensitivity of urine colour due to chemotherapy, absence of active inquiry by the healthcare team and the inconvenient location of the UCC in wallet/purse. Urine colour monitoring in patients with oesophageal cancer to improve the patient experience during treatment warrants further study but supported by active healthcare provider inquiry, more accessible format of the card, and possibly home vital checks to increase its sensitivity in the clinical context.

Comparison of intraocular pressure measured by iCare tonometers and Goldmann applanation tonometer.

OBJECTIVE: To evaluate the relationship between the Goldmann applanation tonometer (GAT) and the iCare PRO and iCare IC200 tonometers in measuring intraocular pressure (IOP) in adult eyes with a diagnosis of glaucoma or glaucoma suspect. PARTICIPANTS AND METHODS: One hundred and one eyes from 101 participants diagnosed with glaucoma or glaucoma suspect were evaluated in this study. IOP was measured by iCare PRO and iCare IC200 tonometers in a randomized sequence followed by IOP measurements by the GAT tonometer and then central corneal thickness measurements. After the IOP measurements, participants scored their comfort level using a visual analog scale with each tonometer. Intraclass correlation coefficient (ICC) and Bland-Altman analysis were used to investigate the agreement among tonometers. SPSS and Microsoft Excel programs were used for statistical analysis. RESULTS: Overall, there was good agreement among the 3 tonometers used in this study. The ICC for the iCare PRO and the iCare IC200 was 0.95 (p < 0.001), and the ICC for the iCare PRO and the GAT and the iCare IC200 and the GAT was >0.80 (p < 0.001). However, both iCare tonometers underestimated IOP by approximately 2 mm Hg compared with the GAT. Furthermore, 84% of iCare readings fall within ±5 mm Hg of GAT measurements. Neither body mass index nor central corneal thickness affected the IOP agreement among the tonometers. Participant response on visual analog scale rated IOP measurements by iCare tonometers to be more comfortable than the GAT. CONCLUSION: Our results demonstrated a good agreement between iCare tonometers and GAT; but iCare tonometers underestimated IOP compared to the GAT.

A Randomized, Controlled Comparison of 180 Versus 360 Degrees Selective Laser Trabeculoplasty in Open Angle Glaucoma and Glaucoma Suspects.

PRCIS: Three hundred sixty degrees selective laser trabeculoplasty (SLT) produces greater intraocular pressure (IOP) lowering effects with no changes in safety profile compared with 180 degrees SLT. PURPOSE: To determine whether there is any difference in the IOP lowering effects and safety profiles of 180 versus 360 degrees SLT, using a paired-eye design to limit confounders. METHODS: This single-center randomized control trial included patients presenting with treatment naïve open angle glaucoma or glaucoma suspects. Once enrolled, 1 eye was randomized to 180 degrees SLT, and the other was treated with 360 degrees SLT. Patients were followed for 1 year and assessed for change in visual acuity, Goldmann IOP, Humphrey visual fields, retinal nerve fiber layer thickness, optical coherence tomography derived cup to disc ratio, and any adverse events or requirements for additional medical interventions. RESULTS: A total of 40 patients (80 eyes) were included in the study. IOP in the 180 degrees group was reduced from 25.3±2.3 mm Hg to 21.5±2.7 mm Hg, and in the 360 degrees group, from 25.5±2.1 mm Hg to 19.9±2.6 mm Hg ( P <0.01), both at 1 year. There was no significant difference in the number of adverse events or serious adverse events in the 2 groups. There were no statistically significant differences in visual acuity, Humphrey visual field mean deviation, retinal nerve fiber layer thickness, or C:D ratio at 1-year follow-up. CONCLUSION: At 1 year, 360 degrees SLT was more efficacious at lowering IOP compared with 180 degrees SLT with a similar safety profile in patients with open angle glaucoma and glaucoma suspects. Further studies are needed to determine the long-term effects.

Validation of a surface-based deformable MRI-3D ultrasound image registration algorithm toward clinical implementation for interstitial prostate brachytherapy.

PURPOSE: The purpose of this study was to evaluate and clinically implement a deformable surface-based magnetic resonance imaging (MRI) to three-dimensional ultrasound (US) image registration algorithm for prostate brachytherapy (BT) with the aim to reduce operator dependence and facilitate dose escalation to an MRI-defined target. METHODS AND MATERIALS: Our surface-based deformable image registration (DIR) algorithm first translates and scales to align the US- and MR-defined prostate surfaces, followed by deformation of the MR-defined prostate surface to match the US-defined prostate surface. The algorithm performance was assessed in a phantom using three deformation levels, followed by validation in three retrospective high-dose-rate BT clinical cases. For comparison, manual rigid registration and cognitive fusion by physician were also employed. Registration accuracy was assessed using the Dice similarity coefficient (DSC) and target registration error (TRE) for embedded spherical landmarks. The algorithm was then implemented intraoperatively in a prospective clinical case. RESULTS: In the phantom, our DIR algorithm demonstrated a mean DSC and TRE of 0.74 ± 0.08 and 0.94 ± 0.49 mm, respectively, significantly improving the performance compared to manual rigid registration with 0.64 ± 0.16 and 1.88 ± 1.24 mm, respectively. Clinical results demonstrated reduced variability compared to the current standard of cognitive fusion by physicians. CONCLUSIONS: We successfully validated a DIR algorithm allowing for translation of MR-defined target and organ-at-risk contours into the intraoperative environment. Prospective clinical implementation demonstrated the intraoperative feasibility of our algorithm, facilitating targeted biopsies and dose escalation to the MR-defined lesion. This method provides the potential to standardize the registration procedure between physicians, reducing operator dependence.

Real-World Analysis of Durvalumab after Chemoradiation in Stage III Non-Small-Cell Lung Cancer.

The 2017 PACIFIC trial heralded the incorporation of routine adjuvant durvalumab following curative-intent chemoradiation for stage III non-small-cell lung cancer (NSCLC). However, carefully selected clinical trial populations can differ significantly from real-world populations, which can have implications on treatment toxicities and outcomes, making it difficult to accurately counsel patients. Consequently, we performed a real-world, retrospective analysis of outcomes and toxicities in 118 patients with stage III NSCLC treated with durvalumab after platinum-based chemoradiotherapy. The data were collected from patients who underwent treatment at a single, tertiary-level Canadian cancer centre from May 2018 to October 2020. The variables collected included patient demographics, treatment specifics, progression-free survival, overall survival, and immune-related adverse events (IRAE) from durvalumab. Descriptive statistics were used for toxicity analysis, and progression-free survival and overall survival estimates were calculated using the Kaplan-Meier method. The statistical analyses indicated a 64.4% (n = 76) toxicity rate, with a 21% (n = 25) toxicity rate of grade 3+ IRAEs. The most common documented IRAEs were pneumonitis (n = 44; 40%), followed by rash (n = 20; 18%) and thyroid dysfunction (n = 17; 15%). FEV1 and DLCO were not found to be associated predictors of pneumonitis toxicity. The median PFS and OS were estimated to be >1.7 years and >2.7 years, respectively.

EGFR mutation prevalence, real-world treatment patterns, and outcomes among patients with resected, early-stage, non-small cell lung cancer in Canada.

OBJECTIVES: The ADAURA trial demonstrated the benefit of adjuvant osimertinib among patients with resected, early-stage, epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC). To understand the potential population impact, it is critical to deduce the prevalence, management, and outcomes of this patient population in the real-world setting before use of adjuvant osimertinib. MATERIALS AND METHODS: Using PALEOS (Pan-cAnadian Lung cancEr Observational Study) data (2012-2019), a retrospective, multi-center, observational cohort study was conducted among patients with early-stage (IB-IIIA) resected NSCLC who had not received neoadjuvant therapy. Study outcomes included EGFRm prevalence, treatment patterns, recurrence outcomes, and overall and disease-free survival (OS/DFS). RESULTS: Among patients undergoing reflexive EGFRm testing by a pathologist at time of diagnosis irrespective of disease stage (N = 535), 23 % were EGFRm-positive; 15.9 % had common mutations and 5.6 % had uncommon mutations. Within the EGFRm-positive cohort (N = 156), mean age at diagnosis was 68 years, 65 % of patients were female, and 35 % were of Asian descent. At diagnosis, 48 %, 31 %, and 21 % had stage IB, II, or IIIA disease, respectively; 46 % received adjuvant therapy after resection. Half of patients experienced disease recurrence, typically involving distant sites; central nervous system metastasis varied from 12 % to 15.0 % across disease stages. EGFR tyrosine kinase inhibitors were the most commonly received therapy after first metastatic recurrence. Median OS (DFS) was not reached, 71.2 (22.8) months, and 50.1 (18.0) months among stage IB, II, and IIIA patients. Patients with uncommon EGFRm had a lower probability of survival than those with common EGFRm (2 years: 87 % vs 91 %-94 %; 4 years: 56 % vs 73 %-82 %). CONCLUSION: Approximately-one-quarter of patients with resected, early-stage NSCLC were EGFRm-positive in this study. These patients had high recurrence rates and suboptimal long-term survival after treatment with current therapies. New adjuvant treatments are warranted.

Treatment patterns and outcomes in early-stage ALK-rearranged non-small cell lung cancer.

INTRODUCTION: We evaluated the baseline demographics, treatment patterns, and outcomes of patients with ALK-rearranged early stage (Stage I-III) non-small cell lung cancer (NSCLC). We also evaluated the efficacy and toxicity of durvalumab consolidation treatment in patients with ALK-rearranged unresectable stage III disease. METHODS: Retrospective chart-review analysis of all patients with histologically confirmed stage I-III reflexively tested ALK-rearranged NSCLC managed with curative intent at two Canadian Centers. RESULTS: Of 48 patients, 19 (40%) were stage I, 5 (10%) were stage II and 24 (50%) were stage-III. Median progression-free survival (PFS) was 27.6 months overall (95%CI: 20.5-51.4) and 144.4 months in stage-I, 27.6 months in stage-II and 14.9 months in stage III patients. Of 20 patients with unresectable stage-III disease treated with chemoradiation (9 also received durvalumab consolidation), 18/90% have relapsed. Median PFS was 10.9 months (95%CI:5.9-22.5). A non-significant trend toward improved PFS was seen in patients receiving additional durvalumab compared to patients treated with chemoradiation alone (median PFS, 12.5 vs 5.9 months, p = 0.16). Toxicity-related treatment modifications on subsequent first ALK-TKI at time of metastatic disease were needed in three (33%) patients who had received chemoradiation alone and two (29%) patients with consolidation durvalumab; no relevant pulmonary or hepato-toxicity was observed overall. CONCLUSION: Treatment strategies and PFS of patients with Stage I-III ALK-rearranged NSCLC are similar to patients without molecular driver alterations. Durvalumab consolidation treatment appears generally safe in patients with unresectable stage III ALK-rearranged disease; however, the degree of benefit of such an approach remains unclear.

Methylglyoxal evokes acute Ca2+ transients in distinct cell types and increases agonist-evoked Ca2+ entry in endothelial cells via CRAC channels.

Methylglyoxal (MG) is a by-product of glucose metabolism and its accumulation has been linked to the development of diabetic complications such as retinopathy and nephropathy by affecting multiple signalling pathways. However, its influence on the intracellular Ca2+ homeostasis and particularly Ca2+ entry, which has been reported to be mediated via TRPA1 channels in DRG neurons, has not been studied in much detail in other cell types. In this study, we report the consequences of acute and long-term MG application on intracellular Ca2+ levels in endothelial cells. We showed that acute MG application doesn't evoke any instantaneous changes in the intracellular Ca2+ concentration in immortalized mouse cardiac endothelial cells (MCECs) and murine microvascular endothelial cells (muMECs). In contrast, an MG-induced rise in intracellular Ca2+ level was observed in primary mouse mesangial cells within 30 s, indicating that the modulation of Ca2+ homeostasis by MG is strictly cell type specific. The formation of the MG-derived advanced glycation end product (AGE) MG-H1 was found to be time and concentration-dependent in MCECs. Likewise, MG pre-incubation for 6 h increased the angiotensin II-evoked Ca2+ entry in MCECs and muMECs which was abrogated by inhibition of Calcium release activated calcium (CRAC) channels with GSK-7975A, but unaffected by an inhibitor specific to TRPA1 channels. Quantitative PCR analysis revealed that MG pre-treatment did not affect expression of the genes encoding the angiotensin receptors AT1R (Agtr 1a & Agtr 1b), Trpa1 nor Orai1, Orai2, Orai3, Stim1, Stim2 and Saraf which operate as constituents or regulators of CRAC channels and store-operated Ca2+ entry (SOCE) in other cell types. Together, our results show that long-term MG stimulation leads to the formation of glycation end products, which facilitates the agonist-evoked Ca2+ entry in endothelial cells, and this could be a new pathway that might lead to MG-evoked vasoregression observed in diabetic vasculopathies.

TRPC proteins contribute to development of diabetic retinopathy and regulate glyoxalase 1 activity and methylglyoxal accumulation.

OBJECTIVE: Diabetic retinopathy (DR) is induced by an accumulation of reactive metabolites such as ROS, RNS, and RCS species, which were reported to modulate the activity of cation channels of the TRPC family. In this study, we use Trpc1/4/5/6-/- compound knockout mice to analyze the contribution of these TRPC proteins to diabetic retinopathy. METHODS: We used Nanostring- and qPCR-based analysis to determine mRNA levels of TRPC channels in control and diabetic retinae and retinal cell types. Chronic hyperglycemia was induced by Streptozotocin (STZ) treatment. To assess the development of diabetic retinopathy, vasoregression, pericyte loss, and thickness of individual retinal layers were analyzed. Plasma and cellular methylglyoxal (MG) levels, as well as Glyoxalase 1 (GLO1) enzyme activity and protein expression, were measured in WT and Trpc1/4/5/6-/- cells or tissues. MG-evoked toxicity in cells of both genotypes was compared by MTT assay. RESULTS: We find that Trpc1/4/5/6-/- mice are protected from hyperglycemia-evoked vasoregression determined by the formation of acellular capillaries and pericyte drop-out. In addition, Trpc1/4/5/6-/- mice are resistant to the STZ-induced reduction in retinal layer thickness. The RCS metabolite methylglyoxal, which represents a key mediator for the development of diabetic retinopathy, was significantly reduced in plasma and red blood cells (RBCs) of STZ-treated Trpc1/4/5/6-/- mice compared to controls. GLO1 is the major MG detoxifying enzyme, and its activity and protein expression were significantly elevated in Trpc1/4/5/6-deficient cells, which led to significantly increased resistance to MG toxicity. GLO1 activity was also increased in retinal extracts from Trpc1/4/5/6-/- mice. The TRPCs investigated here are expressed at different levels in endothelial and glial cells of the retina. CONCLUSION: The protective phenotype in diabetic retinopathy observed in Trpc1/4/5/6-/- mice is suggestive of a predominant action of TRPCs in Müller cells and microglia because of their central position in the retention of a proper homoeostasis of the neurovascular unit.