Presentation and outcomes of KRASG12C mutant non-small cell lung cancer patients with stage IV disease at diagnosis (de novo) versus at recurrence.

Close monitoring after diagnosis of patients with stage I-III non-small cell lung cancer (NSCLC) may result in fitter patients with lower disease burden at the time of metastatic recurrence or progression compared to patients diagnosed initially as stage IV (de novo). We compared the presentation, treatments, and outcomes of patients with KRASG12C-mutated NSCLC with de novo versus recurrent stage IV disease. Of 109 patients, 94% had a smoking history. When compared to patients with KRASG12C-mutated NSCLC who developed stage IV disease at recurrence (n = 38), de novo stage IV patients (n = 71) had worse ECOG performance status (p = 0.007), greater numbers of extra-thoracic metastatic sites (p = 0.001), and were less likely to receive 2nd/3rd line systemic therapy (p = 0.05, p = 0.002) or targeted therapy (p = 0.001). De novo metastatic patients had shorter overall survival than metastatic patients at recurrence (9.1 versus 24.2 months; adjusted-hazard-ratio=1.94 (95% CI: 1.14-3.28; p = 0.01)). There is a critical need for well-tolerated targeted therapies in the first-line setting for metastatic patients with de novo, high-burden, stage IV KRASG12C-mutated NSCLCs.

Immune-Checkpoint Induced Skin Toxicity Masked as Squamous Cell Carcinoma: Case Report on Mimickers of Dermatological Toxicity with PD-1 Inhibition.

BACKGROUND: Immune checkpoint inhibitors (ICI) are increasingly the mainstay of oncology treatment. Immune-related adverse events (irAEs) from ICI therapy differ from cytotoxic adverse events. Cutaneous irAEs are one of the most common irAEs and require careful attention to optimize the quality of life for oncology patients. PATIENT AND METHODS: These are two cases of patients with advanced solid-tumour malignancies treated with PD-1 inhibitor therapy. RESULTS: Both patients developed multiple pruritic hyperkeratotic lesions, which were initially diagnosed as squamous cell carcinoma from skin biopsies. The presentation as squamous cell carcinoma was atypical and, upon further pathology review, the lesions were more in keeping with a lichenoid immune reaction stemming from the immune checkpoint blockade. With the use of oral or topical steroids and immunomodulators, the lesions resolved. CONCLUSIONS: These cases emphasize that patients on PD-1 inhibitor therapy who develop lesions resembling squamous cell carcinoma on initial pathology may require an additional pathology review to assess for immune-mediated reactions, allowing appropriate immunosuppressive therapy to be initiated.

Development and evaluation of a community of practice to improve stem cell donor recruitment in Canada.

Background and Objectives Communities of practice (CoPs) represent effective models to achieve quality outcomes in health care. We report the development and evaluation of a CoP to improve stem cell donor recruitment in Canada. Materials and Methods In September 2017, we invited national stakeholders in stem cell donor recruitment to participate in a Facebook group and regular e-meetings. E-meetings involved speakers and roundtable discussion on topics related to donor recruitment. The Facebook group facilitated sharing of resources. We evaluated stakeholder perspective of the CoP and the impact on recruitment outcomes. Results As of December 2020, the CoP included 382 members who published 243 posts to the Facebook group about patient/donor stories (40%), resources (27%), updates/questions (21%) and recruitment outcomes (12%). In January 2020, we surveyed 44 CoP participants; the majority felt that the Facebook group (86%) and e-meetings (59%) supported the community, and that the CoP fostered collaboration (82%), improved their donor recruitment knowledge (75%) and practice (77%) and improved their ability to recruit needed donors (64%). The launch of the CoP correlated with improved donor recruitment outcomes. In 2016-2017, CoP participants recruited 2918 registrants (46% male; 55.9% non-Caucasian) compared to 4531 registrants in 2018-2019 (52.9% male; 62.7% non-Caucasian). Members of the CoP developed innovative resources to support recruitment efforts and led national campaigns securing coverage in major media outlets. Conclusion We describe the first CoP in stem cell donor recruitment to be formally evaluated. The CoP model may be adopted by donor recruitment organisations, registries and blood banks worldwide to improve recruitment outcomes. HIGHLIGHTS: • A community of practice (CoP) in stem cell donor recruitment was valued by participants and supported efforts to improve recruitment outcomes. • The CoP model may be adopted by donor recruitment organizations, donor registries, and blood banks worldwide to improve recruitment outcomes.

Systemic Inflammatory Markers of Survival in Epidermal Growth Factor-Mutated Non-Small-Cell Lung Cancer: Single-Institution Analysis, Systematic Review, and Meta-analysis.

BACKGROUND: Systemic inflammatory response (SIR) may influence prognosis in epidermal growth factor receptor (EGFR)-mutated (m) non-small-cell lung cancer (NSCLC). Pretreatment SIR markers (neutrophil-to-lymphocyte ratio [NLR], platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio [LMR], lactate dehydrogenase [LDH], and lung immune prognostic index [LIPI]) were assessed as prognostic factors in NSCLC survival. PATIENTS AND METHODS: Retrospective survival analysis (overall survival [OS] and progression-free survival [PFS]) of EGFR-mutated NSCLC patients at Princess Margaret Cancer Centre were performed separately for early (I-IIIa) and late (IIIb-IV) stage disease for individual SIR variables, dichotomized by optimal cutoff points by Kaplan-Meier survival analysis and multivariable Cox proportional hazard modeling. A systematic review and meta-analysis of known SIR studies in patients with late-stage EGFR-mutated were also performed. RESULTS: From 2012 to 2019, in 530 patients, significant adjusted hazard ratios (aHR) for OS comparing high versus low NLR were 2.12 for early stage and 1.79 for late stage disease. Additionally, late stage cohorts had significant associations, as follows: high versus low derived NLR, aHR = 1.53; LMR, aHR = 0.62; LDH, aHR = 2.04; and LIPI, aHR = 2.04. Similar patterns were found for PFS in early stage NLR (aHR = 1.96) and late stage NLR (aHR = 1.46), while for PFS, only late stage derived NLR (aHR = 1.34), LDH (aHR = 1.75), and LIPI (aHR = 1.66) were significant. A meta-analysis confirmed that NLR, LMR, LDH, and LIPI were all significantly associated with OS and PFS in the late stage. CONCLUSION: This primary study and meta-analysis demonstrated that LMR and LDH were significantly associated with late stage EGFR-mutated NSCLC outcomes, and the LIPI scoring system was prognostic. NLR remained an independent prognostic factor across all stages and could represent an early marker of immuno-oncology interactions.

Development and evaluation of stem cell collection procedure diagrams to support the education and recruitment of committed stem cell donors.

BACKGROUND: Diagrams which allow potential unrelated stem cell donors to visualize the stem cell collection process were hypothesized to support the recruitment and education of committed stem cell donors. STUDY DESIGN AND METHODS: A series of bone marrow and peripheral blood stem cell collection procedure diagrams were developed, featuring young adult male donors of varied ethnic backgrounds. Post-implementation, surveys were conducted to evaluate stakeholder perspective on the diagrams' utility. A quality improvement project was conducted at five stem cell drives from 2017 to 2018 at which recruiters did or did not show the diagrams to potential donors. Following the drives, registrants were invited to complete a survey exploring their experience, knowledge and attitude towards donation. RESULTS: The diagrams were implemented in Canada in 07/2016. Of 293 participating registrants (24·7% non-Caucasian males) recruited at five drives between 2017 and 2018, 76% (n = 197) were shown the diagrams. Participants who were shown the diagrams were significantly more likely to report that the recruiters appeared very knowledgeable (89% vs. 76%, P = 0·019) and to report improved self-reported knowledge of stem cell donation (P = 0·010) compared to participants not shown the diagram. Data are also shown demonstrating that stakeholders in donor recruitment used and valued the diagrams and that use of the diagrams was associated with improved donor recruitment outcomes in Canada. CONCLUSION: This report is the first evaluation of stem cell collection diagrams in the literature. The diagrams are relevant to donor registries, recruitment organizations and transplant centres worldwide, and their use may support efforts to educate and recruit committed, ethnically diverse donors.

Real-world health utility scores and toxicities to tyrosine kinase inhibitors in epidermal growth factor receptor mutated advanced non-small cell lung cancer.

BACKGROUND: As the treatment landscape in patients with non-small cell lung cancer (NSCLC) harboring mutations in the epidermal growth factor receptor (EGFRm) continues to evolve, real-world health utility scores (HUS) become increasingly important for economic analyses. METHODS: In an observational cohort study, questionnaires were completed in EGFRm NSCLC outpatients, to include demographics, EQ-5D-based HUS and patient-reported toxicity and symptoms. Clinical and radiologic characteristics together with outcomes were extracted from chart review. The impact of health states, treatment type, toxicities, and clinical variables on HUS were evaluated. RESULTS: Between 2014 and 2018, a total of 260 patients completed 994 encounters. Across treatment groups, patients with disease progression had lower HUS compared to controlled disease (0.771 vs 0.803; P = .01). Patients predominantly received gefitinib as the first-line EGFR tyrosine kinase inhibitor (TKI) (n = 157, mean-HUS = 0.798), whereas osimertinib (n = 62, mean-HUS = 0.806) and chemotherapy (n = 38, mean-HUS = 0.721) were more likely used in subsequent treatment lines. In longitudinal analysis, TKIs retained high HUS (>0.78) compared to chemotherapy (HUS < 0.74). There were no differences between the frequency or severity of toxicity scores in patients receiving gefitinib compared to osimertinib; however, TKI therapy resulted in fewer toxicities than chemotherapy (P < .05), with the exception of worse diarrhea and skin rash (P < .001). Severity in toxicities inversely correlated with HUS (P < .001). Clinico-demographic factors significantly affecting HUS included age, Eastern Cooperative Oncology Group Performance Score (ECOG PS), disease state, treatment group, and metastatic burden. CONCLUSIONS: In a real-world EGFRm population, patients treated with gefitinib or osimertinib had similar HUS and toxicities, scores which were superior to chemotherapy. Health utility scores inversely correlated with patient-reported toxicity scores. In the era of targeted therapies, future economic analyses should incorporate real-world HUS.

Distribution gaps in cataract surgery care and impact on seniors across Ontario.

OBJECTIVE: To assess recent cataract service delivery across communities of all sizes in Ontario. DESIGN: Retrospective analysis of health records. PARTICIPANTS: All Ontario Health Insurance Plan users. METHODS: Raw physician Ontario Health Insurance Plan claims data for cataract surgery (E140A, E214A) from April 1, 2009, to March 31, 2014, were extracted from the Ontario Ministry of Health and Long-Term Care (MOHLTC) IntelliHealth database. Cataract surgery claims data were sorted by sex, by age, and by Ontario's 444 municipalities based on patient residence. Cataract surgery distribution was examined by population centre: Large Urban (≥100 000 persons), Medium (30 000-99 999 persons), Small (1000-29 999 persons), and Rural (<1000 persons) as defined by Statistics Canada. Wait times were extracted from the MOHLTC wait times database. Cataract surgery rate (CSR), defined as the number of cataract surgeries performed per million, was calculated. RESULTS: Cataract surgery volumes remained unchanged from 2010 to 2014. Mean patient age was 71.6 ± 10 years. Patients lived in large urban (63%), medium (15%), small (21%), and rural (0.6%) communities. Mean wait times increased by 28% to 68.5 days, and 90th percentile wait times increased by 44% to 154.3 days. A reduction in CSR was observed among seniors aged 65-74 years (-10%) and 75+ years (-16%). Rural communities showed the largest decline (-19%). Among seniors aged ≥75 years, CSR declined the most for those living in rural communities (-25%). CONCLUSIONS: Adjusting the current government policy of zero-growth in cataract surgery volumes will support growing demands for cataract care in our aging population.

Lymphatic vessels identified in failed corneal transplants with neovascularisation.

BACKGROUND: Corneal transplant failure with neovascularisation is a leading indication for full-thickness grafts in patients. Lymphangiogenesis is implicated in the pathology of graft failure, and here we systematically evaluate failed human corneal transplants with neovascularisation for the presence of lymphatic vessels. METHODS: Nine failed grafts with neovascularisation, based on H&E staining with subsequent immunoperoxidase staining for CD31, a blood vessel marker, were selected. Lymphatics were investigated by immunohistochemical and immunofluorescence approaches using podoplanin as a lymphatic marker. In two of nine cases, fluorescence in situ hybridisation (FISH) was used for detection of lymphatic mRNAs including podoplanin, VEGFR-3 and LYVE-1. All immunofluorescence and FISH samples were compared with positive and negative controls and visualised by confocal microscopy. RESULTS: Corneal neovascularisation was established in all cases by H&E and further confirmed by CD31 immunoreactive profiles. Immunohistochemistry for the podoplanin antibody was positive in all cases and showed morphologies ranging from distinct luminal structures to elongated profiles. Simultaneous immunofluorescence using CD31 and podoplanin showed lymphatic vessels distinct from blood vessels. Podoplanin immunofluorescence was noted in seven of nine cases and revealed clear lumina of varying sizes, in addition to lumen-like and elongated profiles. The presence of lymphatic mRNA was confirmed by FISH studies using a combination of at least two of podoplanin, VEGFR-3 and LYVE-1 mRNAs. CONCLUSIONS: The consistent finding of lymphatic vessels in failed grafts with neovascularisation implicates them in the pathogenesis of corneal transplant failure, and points to the lymphatics as a potential new therapeutic target.

New trends in corneal transplants at the University of Toronto.

OBJECTIVE: To assess trends in surgical procedures and indications for all corneal transplants performed at the University of Toronto. DESIGN: Retrospective cross-sectional study. PARTICIPANTS: One thousand one hundred and four consecutive corneal transplants performed at the Kensington Eye Institute (KEI). METHODS: Demographic, clinical, and pathological data retrieved from the Ophthalmic Pathology Laboratory on all corneal transplants performed at the KEI from January 2014 to December 2016. RESULTS: Over 3 years, partial-thickness lamellar keratoplasties were performed in 880 cases (80%) while full-thickness penetrating keratoplasties (PKP) accounted for 224 cases (20%). Leading causes of corneal transplant were Fuchs' dystrophy (42%), graft failure (17%), bullous keratopathy (15%), and keratoconus (15%). Graft failure (40%) and keratoconus (31%) were the leading causes for PKP. Descemet's membrane endothelial keratoplasty (DMEK) accounted for 37% of cases, Descemet's stripping automated endothelial keratoplasty (DSAEK) for 30%, and deep anterior lamellar keratoplasty (DALK) for 13%. By 2016, partial-thickness procedures had increased by 10%, accounting for 85% of all procedures. In addition, DMEK increased by 26%, DSAEK decreased by 13%, and PKP decreased by 11%. Fuchs' dystrophy remained the leading indication for DMEK (67%) and DSAEK (42%) procedures. In 2016, 73% of DALK procedures were for the treatment of keratoconus. CONCLUSIONS: Partial-thickness corneal transplants now account for 85% of all current graft procedures, and DMEK has emerged as the procedure of choice. Graft failure continues to be the leading indication for full-thickness grafts. Longitudinal studies are needed to determine whether these new trends persist and their future impact on graft failures.

A decade of surgical eye removals in Ontario: a clinical-pathological study.

OBJECTIVE: To assess patient demographics, clinical indications, and pathologic causes of surgically removed eyes over a decade in Ontario (Canada) and to identify areas of ocular disease management needing more attention. DESIGN: Retrospective cross-sectional study. PARTICIPANTS: The surgically removed eyes of 713 consecutive mainly adult patients from 2004 to 2013. METHODS: Demographic, clinical, and pathologic data were collected on all eyes received by the University of Toronto Ophthalmic Pathology Laboratory from 2004 to 2013. RESULTS: Of the 713 eyes removed, enucleations accounted for 60% of cases, eviscerations for 39% of cases, and exenteration for 1% of cases. The most common clinical indications for surgical eye removal were blind painful eye (37%), neoplasm (35%), and trauma (6%). The leading pathologic causes of eye removal were neoplasm (36%), glaucoma (21%), infection or inflammation (17%), and trauma (16%). Glaucoma-related findings were the most common pathologic findings observed (38%), regardless of the primary cause. CONCLUSIONS: A blind painful eye and neoplasms were the most commonly documented indications prior to removal of the eye. Common pathologies included glaucoma, neoplasms, infection/inflammation, and trauma. However, regardless of the primary cause, glaucoma-related pathologies were the most common pathologic findings. Refractory eye disease and pain continue to be important reasons for removal of eyes among patients in Ontario. More effective and targeted management strategies are needed to reduce the need for this radical eye surgery of last resort.

Mechanism of Amyloidogenesis of a Bacterial AAA+ Chaperone.

Amyloids are fibrillar protein superstructures that are commonly associated with diseases in humans and with physiological functions in various organisms. The precise mechanisms of amyloid formation remain to be elucidated. Surprisingly, we discovered that a bacterial Escherichia coli chaperone-like ATPase, regulatory ATPase variant A (RavA), and specifically the LARA domain in RavA, forms amyloids under acidic conditions at elevated temperatures. RavA is involved in modulating the proper assembly of membrane respiratory complexes. LARA contains an N-terminal loop region followed by a ß-sandwich-like folded core. Several approaches, including nuclear magnetic resonance spectroscopy and molecular dynamics simulations, were used to determine the mechanism by which LARA switches to an amyloid state. These studies revealed that the folded core of LARA is amyloidogenic and is protected by its N-terminal loop. At low pH and high temperatures, the interaction of the N-terminal loop with the folded core is disrupted, leading to amyloid formation.

Assembly principles of a unique cage formed by hexameric and decameric E. coli proteins.

A 3.3 MDa macromolecular cage between two Escherichia coli proteins with seemingly incompatible symmetries-the hexameric AAA+ ATPase RavA and the decameric inducible lysine decarboxylase LdcI-is reconstructed by cryo-electron microscopy to 11 Å resolution. Combined with a 7.5 Å resolution reconstruction of the minimal complex between LdcI and the LdcI-binding domain of RavA, and the previously solved crystal structures of the individual components, this work enables to build a reliable pseudoatomic model of this unusual architecture and to identify conformational rearrangements and specific elements essential for complex formation. The design of the cage created via lateral interactions between five RavA rings is unique for the diverse AAA+ ATPase superfamily.