Real-World Outcomes of Patients with Advanced Epidermal Growth Factor Receptor-Mutated Non-Small Cell Lung Cancer in Canada Using Data Extracted by Large Language Model-Based Artificial Intelligence.

Real-world evidence for patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC) in Canada is limited. This study's objective was to use previously validated DARWENTM artificial intelligence (AI) to extract data from electronic heath records of patients with non-squamous NSCLC at University Health Network (UHN) to describe EGFR mutation prevalence, treatment patterns, and outcomes. Of 2154 patients with NSCLC, 613 had advanced disease. Of these, 136 (22%) had common sensitizing EGFR mutations (cEGFRm; ex19del, L858R), 8 (1%) had exon 20 insertions (ex20ins), and 338 (55%) had EGFR wild type. One-year overall survival (OS) (95% CI) for patients with cEGFRm, ex20ins, and EGFR wild type tumours was 88% (83, 94), 100% (100, 100), and 59% (53, 65), respectively. In total, 38% patients with ex20ins received experimental ex20ins targeting treatment as their first-line therapy. A total of 57 patients (36%) with cEGFRm received osimertinib as their first-line treatment, and 61 (39%) received it as their second-line treatment. One-year OS (95% CI) following the discontinuation of osimertinib was 35% (17, 75) post-first-line and 20% (9, 44) post-second-line. In this real-world AI-generated dataset, survival post-osimertinib was poor in patients with cEGFR mutations. Patients with ex20ins in this cohort had improved outcomes, possibly due to ex20ins targeting treatment, highlighting the need for more effective treatments for patients with advanced EGFRm NSCLC.

EndoBridge 2023: highlights and pearls.

EndoBridge 2023 took place on October 20-22, 2023, in Antalya, Turkey. Accredited by the European Council, the 3-day scientific program of the 11th Annual Meeting of EndoBridge included state-of-the-art lectures and interactive small group discussion sessions incorporating interesting and challenging clinical cases led by globally recognized leaders in the field and was well attended by a highly diverse audience. Following its established format over the years, the program provided a comprehensive update across all aspects of endocrinology and metabolism, including topics in pituitary, thyroid, bone, and adrenal disorders, neuroendocrine tumors, diabetes mellitus, obesity, nutrition, and lipid disorders. As usual, the meeting was held in English with simultaneous translation into Russian, Arabic, and Turkish. The abstracts of clinical cases presented by the delegates during oral and poster sessions have been published in JCEM Case Reports. Herein, we provide a paper on highlights and pearls of the meeting sessions covering a wide range of subjects, from thyroid nodule stratification to secondary osteoporosis and from glycemic challenges in post-bariatric surgery to male hypogonadism. This report emphasizes the latest developments in the field, along with clinical approaches to common endocrine issues. The 12th annual meeting of EndoBridge will be held on October 17-20, 2024 in Antalya, Turkey.

Prevention of allergic reactions during oxaliplatin desensitization through inhibition of Bruton tyrosine kinase.

BACKGROUND: Acute infusion reactions to oxaliplatin, a chemotherapeutic used to treat gastrointestinal cancers, are observed in about 20% of patients. Rapid drug desensitization (RDD) protocols often allow the continuation of oxaliplatin in patients with no alternative options. Breakthrough symptoms, including anaphylaxis, can still occur during RDD. OBJECTIVE: Our aim was to evaluate whether pretreatment with acalabrutinib, a Bruton tyrosine kinase inhibitor, can prevent anaphylaxis during RDD in a patient sensitized to oxaliplatin. METHODS: A 52-year-old male with locally advanced gastric carcinoma developed anaphylaxis during his fifth cycle of oxaliplatin. As he required 6 additional cycles to complete his curative-intent treatment regimen, he underwent RDD to oxaliplatin but still developed severe acute reactions. The risks and benefits of adding acalabrutinib before and during RDD were reviewed, and the patient elected to proceed. RESULTS: With acalabrutinib taken before and during the RDD, the patient was able to tolerate oxaliplatin RDD without complication. Consistent with its mechanism of action, acalabrutinib completely blocked the patient's positive skin prick response to oxaliplatin. Acalabrutinib did not alter the percentage of circulating basophils (1.24% vs 0.98%) before the RDD but did protect against basopenia (0.74% vs 0.09%) after the RDD. Acalabrutinib was associated with a drastic reduction in the ability of basophils to upregulate CD63 in vitro following incubation with oxaliplatin (0.11% vs 2.38%) or polyclonal anti-human IgE antibody (0.08% vs 44.2%). CONCLUSIONS: Five doses of acalabrutinib, 100 mg, orally twice daily starting during the evening 2 days before and continuing through RDD allowed a sensitized patient to receive oxaliplatin successfully and safely.

Safety and feasibility of establishing an adjuvant hepatic artery infusion program.

BACKGROUND: Hepatic artery infusion (HAI) is less frequently used in the adjuvant setting for resectable colorectal liver metastasis (CRLM) due to concerns regarding toxicity. Our objective was to evaluate the safety and feasibility of establishing an adjuvant HAI program. METHODS: Patients who underwent HAI pump placement between January 2019 and February 2023 for CRLM were identified. Complications and HAI delivery were compared between patients who received HAI in the unresectable and adjuvant settings. RESULTS: Of 51 patients, 23 received HAI for unresectable CRLM and 28 in the adjuvant setting. Patients with unresectable CRLM more commonly had bilobar disease (n = 23/23 vs n = 18/28, p < 0.01) and more preoperative liver metastases (median 10 [IQR 6-15] vs 4 [IQR 3-7], p < 0.01). Biliary sclerosis was the most common complication (n = 2/23 vs n = 4/28); however, there were no differences in postoperative or HAI-specific complications. In the most recent two years, 0 patients in the unresectable group vs 2 patients in the adjuvant group developed biliary sclerosis. All patients were initiated on HAI with no difference in treatment times or dose reductions. CONCLUSION: Adjuvant HAI is safe and feasible for patients with resectable CRLM. HAI programs can carefully consider including patients with resectable CRLM if managed by an experienced multidisciplinary team with quality assurance controls in place.

Inspiring New Science to Guide Healthcare in Turner Syndrome: Rationale, design, and methods for the InsighTS Registry.

Inspiring New Science to Guide Healthcare in Turner Syndrome (InsighTS) Registry is a national, multicenter registry for individuals with Turner syndrome (TS) designed to collect and store validated longitudinal clinical data from a diverse cohort of patients with TS. Herein, we describe the rationale, design, and approach used to develop the InsighTS registry, as well as the demographics of the initial participants to illustrate the registry's diversity and future utility. Multiple stakeholder groups have been involved from project conceptualization through dissemination, ensuring the registry serves the priorities of the TS community. Key features of InsighTS include recruitment strategies to facilitate enrollment of participants that appropriately reflect the population of individuals with TS receiving care in the US, clarity of data ownership and sharing, and sustainability of this resource. The registry gathers clinical data on diagnosis, treatment, comorbidities, health care utilization, clinical practices, and quality of life with the goal of improving health outcomes for this population. Future directions include multiple patient-centered clinical-translational research projects that will use the InsighTS platform. This thorough and thoughtful planning will ensure InsighTS is a valuable and sustainable resource for the TS community for decades to come.

Association of Circulating Tumor DNA Testing Before Tissue Diagnosis With Time to Treatment Among Patients With Suspected Advanced Lung Cancer: The ACCELERATE Nonrandomized Clinical Trial.

Importance: Liquid biopsy has emerged as a complement to tumor tissue profiling for advanced non-small cell lung cancer (NSCLC). The optimal way to integrate liquid biopsy into the diagnostic algorithm for patients with newly diagnosed advanced NSCLC remains unclear. Objective: To evaluate the use of circulating tumor DNA (ctDNA) genotyping before tissue diagnosis among patients with suspected advanced NSCLC and its association with time to treatment. Design, Setting, and Participants: This single-group nonrandomized clinical trial was conducted among 150 patients at the Princess Margaret Cancer Centre-University Health Network (Toronto, Ontario, Canada) between July 1, 2021, and November 30, 2022. Patients referred for investigation and diagnosis of lung cancer were eligible if they had radiologic evidence of advanced lung cancer prior to a tissue diagnosis. Interventions: Patients underwent plasma ctDNA testing with a next-generation sequencing (NGS) assay before lung cancer diagnosis. Diagnostic biopsy and tissue NGS were performed per standard of care. Main Outcome and Measures: The primary end point was time from referral to treatment initiation among patients with advanced nonsquamous NSCLC using ctDNA testing before diagnosis (ACCELERATE [Accelerating Lung Cancer Diagnosis Through Liquid Biopsy] cohort). This cohort was compared with a reference cohort using standard tissue genotyping after tissue diagnosis. Results: Of the 150 patients (median age at diagnosis, 68 years [range, 33-91 years]; 80 men [53%]) enrolled, 90 (60%) had advanced nonsquamous NSCLC. The median time to treatment was 39 days (IQR, 27-52 days) for the ACCELERATE cohort vs 62 days (IQR, 44-82 days) for the reference cohort (P < .001). Among the ACCELERATE cohort, the median turnaround time from sample collection to genotyping results was 7 days (IQR, 6-9 days) for plasma and 23 days (IQR, 18-28 days) for tissue NGS (P < .001). Of the 90 patients with advanced nonsquamous NSCLC, 21 (23%) started targeted therapy before tissue NGS results were available, and 11 (12%) had actionable alterations identified only through plasma testing. Conclusions and Relevance: This nonrandomized clinical trial found that the use of plasma ctDNA genotyping before tissue diagnosis among patients with suspected advanced NSCLC was associated with accelerated time to treatment compared with a reference cohort undergoing standard tissue testing. Trial Registration: ClinicalTrials.gov Identifier: NCT04863924.

Implantable Collamer Lens Use in a Spaceflight Participant During Short Duration Spaceflight.

BACKGROUND: The purpose of this report is to document the first use of a single piece, posterior chamber phakic implantable collamer lens (ICL) with a central port in the right eye (OD) of a spaceflight participant (SFP) during a 12-d Soyuz mission to the International Space Station (ISS). We also briefly document the stability of a pre-existing pachychoroid pigment epitheliopathy (PPE) in the macula of his left eye (OS) during this mission.CASE REPORT: Ocular examination, including refraction, slit lamp examination, macular examination by optical coherence tomography (OCT), and tonometry were performed before and after his mission and he was questioned regarding visual changes during each portion of his flight.DISCUSSION: We documented no change in ICL position during his spaceflight. He reported stable vision during liftoff, entry into microgravity, 12 d on the ISS, descent, and landing. Our results suggest that the modern ICL with a central port is stable, effective, and well tolerated during short duration spaceflight. His PPE also remained stable during this mission as documented by OCT.Gibson CR, Mader TH, Lipsky W, Brown DM, Jennings R, Law J, Sargsyan A, Brunstetter T, Danilichev SN, Maezawa Y. Implantable collamer lens use in a spaceflight participant during short duration spaceflight. Aerosp Med Hum Perform. 2023; 94(1):48-50.

Pharmacological Relief of Acute Urinary Retention in a Remote Environment.

BACKGROUND: In spaceflight, acute urinary retention (AUR) could develop as a sequela of medication use, urinary tract infection, urolithiasis, or intentional urine holding. While AUR is generally treated with bladder decompression, urinary catheterization could be difficult operationally in terms of training and proficiency, supplies, and lack of space or privacy. This report discusses a case in which tamsulosin and lorazepam were used successfully on an offshore ship while awaiting medical evacuation, a situation that could arise in remote locations where aerospace operations are conducted.CASE REPORT: A 52-yr-old man with hypertension and obstructive sleep apnea but no formal diagnosis of benign prostatic hyperplasia was unable to urinate for over 16 h while on a deep-sea fishing vessel approximately 200 nmi offshore. By phone, the physician providing remote medical direction diagnosed AUR in the setting of possible infection and prescribed acetaminophen, ciprofloxacin, and a trial of tamsulosin as the ship did not have any medical personnel trained to perform urinary catheterization and there were no catheter supplies available. Lorazepam was later added for anxiolysis and potential smooth muscle relaxation. Within 1 h of initial medication administration, the patient successfully voided a large quantity of urine, which tested positive for infection by urine dipstick. The patient was continued on antibiotics and evacuated to a medical facility onshore for further management.DISCUSSION: Pharmacological treatment could be considered as a temporizing measure where operational constraints limit the ability to perform urinary catheterization to relieve acute urinary retention.Law J, Cardy V. Pharmacological relief of acute urinary retention in a remote environment. Aerosp Med Hum Perform. 2023; 94(2):90-93.

Plasma-first: accelerating lung cancer diagnosis and molecular profiling through liquid biopsy.

Introduction: Molecular profiling of tumor tissue is the gold standard for treatment decision-making in advanced non-small cell lung cancer (NSCLC). Results may be delayed or unavailable due to insufficient tissue, prolonged wait times for biopsy, pathology assessment and testing. We piloted the use of plasma testing in the initial diagnostic workup for patients with suspected advanced lung cancer. Methods: Patients with ⩽15 pack-year smoking history and suspected advanced lung cancer referred to the lung cancer rapid diagnostic program underwent plasma circulating-tumor DNA testing using a DNA-based mutation panel. Tissue testing was performed per standard of care, including comprehensive next-generation sequencing (NGS). The primary endpoint was time from diagnostic program referral to cancer treatment in stage IV NSCLC patients (Cohort A) compared to a contemporary cohort not enrolled in the study (Cohort B) and an historical pre-COVID cohort referred to the program between 2018 and 2019 (Cohort C). Results: From January to June 2021, 20 patients were enrolled in Cohort A; median age was 70.5 years (range 33-87), 70% were female, 55% Caucasian, 85% never smokers, and 75% were diagnosed with NSCLC. Seven had actionable alterations detected in plasma or tissue (4/7 concordant). Fusions, not tested in plasma, were identified by immunohistochemistry for three patients. Mean result turnaround time was 17.8 days for plasma NGS and 23.6 days for tissue (p = 0.10). Mean time from referral to treatment initiation was significantly shorter in cohort A at 32.6 days (SD 13.1) versus 62.2 days (SD 31.2) in cohort B and 61.5 days (SD 29.1) in cohort C, both p < 0.0001. Conclusion: Liquid biopsy in the initial diagnostic workup of patients with suspected advanced NSCLC can lead to faster molecular results and shorten time to treatment even with smaller DNA panels. An expansion study using comprehensive NGS plasma testing with faster turnaround time is ongoing (NCT04862924).

The economic value of liquid biopsy for genomic profiling in advanced non-small cell lung cancer.

Background: Liquid biopsy (LB) can detect actionable genomic alterations in plasma circulating tumor circulating tumor DNA beyond tissue testing (TT) alone in advanced non-small cell lung cancer (NSCLC) patients. We estimated the cost-effectiveness of adding LB to TT in the Canadian healthcare system. Methods: A cost-effectiveness analysis was conducted using a decision analytic Markov model from the Canadian public payer (Ontario) perspective and a 2-year time horizon in patients with treatment-naïve stage IV non-squamous NSCLC and ⩽10 pack-year smoking history. LB was performed using the comprehensive genomic profiling Guardant360™ assay. Standard of care TT for each participating institution was performed. Costs and outcomes of molecular testing by LB + TT were compared to TT alone. Transition probabilities were calculated from the VALUE trial (NCT03576937). Sensitivity analyses were undertaken to assess uncertainty in the model. Results: Use of LB + TT identified actionable alterations in more patients, 68.5 versus 52.7% with TT alone. Use of the LB + TT strategy resulted in an incremental cost savings of $3065 CAD per patient (95% CI, 2195-3945) and a gain in quality-adjusted life-years of 0.02 (95% CI, 0.01-0.02) versus TT alone. More patients received chemo-immunotherapy based on TT with higher overall costs, whereas more patients received targeted therapy based on LB + TT with net cost savings. Major drivers of cost-effectiveness were drug acquisition costs and prevalence of actionable alterations. Conclusion: The addition of LB to TT as initial molecular testing of clinically selected patients with advanced NSCLC did not increase system costs and led to more patients receiving appropriate targeted therapy.

Postoperative Packing of Perianal Abscess Cavities (PPAC2): randomized clinical trial.

BACKGROUND: Perianal abscess is common. Traditionally, postoperative perianal abscess cavities are managed with internal wound packing, a practice not supported by evidence. The aim of this randomized clinical trial (RCT) was to assess if non-packing is less painful and if it is associated with adverse outcomes. METHODS: The Postoperative Packing of Perianal Abscess Cavities (PPAC2) trial was a multicentre, RCT (two-group parallel design) of adult participants admitted to an NHS hospital for incision and drainage of a primary perianal abscess. Participants were randomized 1:1 (via an online system) to receive continued postoperative wound packing or non-packing. Blinded data were collected via symptom diaries, telephone, and clinics over 6 months. The objective was to determine whether non-packing of perianal abscess cavities is less painful than packing, without an increase in perianal fistula or abscess recurrence. The primary outcome was pain (mean maximum pain score on a 100-point visual analogue scale). RESULTS: Between February 2018 and March 2020, 433 participants (mean age 42 years) were randomized across 50 sites. Two hundred and thirteen participants allocated to packing reported higher pain scores than 220 allocated to non-packing (38.2 versus 28.2, mean difference 9.9; P < 0.0001). The occurrence of fistula-in-ano was low in both groups: 32/213 (15 per cent) in the packing group and 24/220 (11 per cent) in the non-packing group (OR 0.69, 95 per cent c.i. 0.39 to 1.22; P = 0.20). The proportion of patients with abscess recurrence was also low: 13/223 (6 per cent) in the non-packing group and 7/213 (3 per cent) in the packing group (OR 1.85, 95 per cent c.i. 0.72 to 4.73; P = 0.20). CONCLUSION: Avoiding abscess cavity packing is less painful without a negative morbidity risk. REGISTRATION NUMBER: ISRCTN93273484 (https://www.isrctn.com/ISRCTN93273484). REGISTRATION NUMBER: NCT03315169 (http://clinicaltrials.gov).

Perianal abscess is a common, painful condition due to infection and swelling around the anus caused by blockage of the anal glands. The treatment of perianal abscess has stayed the same for over 50 years. An operation is performed under general anaesthetic to cut the skin and drain the infection. This is followed by continued internal dressing (packing) of the remaining cavity (hole) until the skin has healed over. Packing changes are needed multiple times a week for several weeks. Packing is the accepted treatment as it is believed to reduce the chance of the abscess coming back, and also reduces the chance of perianal fistula forming. There are no medical studies to support this idea. Perianal fistula (an abnormal passage between the skin around the anus, and the inside of the anal canal or rectum) is a long-term condition, which causes pain, and pus (and sometimes faeces) discharge, and often needs another operation (or multiple operations) to fix it. This trial was performed to demonstrate if no packing of a perianal abscess would result in a reduction of pain, with no increase in unwanted abscess recurrences and fistulas, in comparison to the standard treatment of packing. The trial recruited 433 people, who were randomly chosen to enter one of two groups; one to have their wound packed and the other to have no packing of the wound. After being discharged from hospital following surgery, the patients attended or were visited by a community nurse for the dressing to be changed or wound packed. Each patient provided information on pain from their wound, including worst pain each day and pain before, during, and after the changing of their dressing or packing. This and other information was gathered for the first 10 days after surgery and periodically until 6 months after surgery. The no-packing group experienced much less pain than the packing group. There was no difference in abscess recurrence and fistula formation between the non-packing and packing groups. The findings demonstrate that no packing of perianal abscess wounds after drainage operation is the best treatment.

Upfront Next Generation Sequencing in Non-Small Cell Lung Cancer.

In advanced non-small cell lung cancer (NSCLC), patients with actionable genomic alterations may derive additional clinical benefit from targeted treatment compared to cytotoxic chemotherapy. Current guidelines recommend extensive testing with next generation sequencing (NGS) panels. We investigated the impact of using a targeted NGS panel (TruSight Tumor 15, Illumina) as reflex testing for NSCLC samples at a single institution. Molecular analysis examined 15 genes for hotspot mutation variants, including AKT1, BRAF, EGFR, ERBB2, FOXL2, GNA11, GNAQ, KIT, KRAS, MET, NRAS, PDGFRA, PIK3CA, RET and TP53 genes. Between February 2017 and October 2020, 1460 samples from 1395 patients were analyzed. 1201 patients (86.1%) had at least one variant identified, most frequently TP53 (47.5%), KRAS (32.2%) or EGFR (24.2%). Among these, 994 patients (71.3%) had clinically relevant variants eligible for treatment with approved therapies or clinical trial enrollment. The incremental cost of NGS beyond single gene testing (EGFR, ALK) was CAD $233 per case. Reflex upfront NGS identified at least one actionable variant in more than 70% of patients with NSCLC, with minimal increase in testing cost. Implementation of NGS panels remains essential as treatment paradigms continue to evolve.

Automating Access to Real-World Evidence.

Introduction: Real-world evidence is important in regulatory and funding decisions. Manual data extraction from electronic health records (EHRs) is time-consuming and challenging to maintain. Automated extraction using natural language processing (NLP) and artificial intelligence may facilitate this process. Whereas NLP offers a faster solution than manual methods of extraction, the validity of extracted data remains in question. The current study compared manual and automated data extraction from the EHR of patients with advanced lung cancer. Methods: Previously, we extracted EHRs from 1209 patients diagnosed with advanced lung cancer (stage IIIB or IV) between January 2015 and December 2017 at Princess Margaret Cancer Centre (Toronto, Canada) using the commercially available artificial intelligence engine, DARWEN (Pentavere, Ontario, Canada). For comparison, 100 of 333 patients that received systemic therapy were randomly selected and clinical data manually extracted by two trained abstractors using the same accepted gold standard feature definitions, including patient, disease characteristics, and treatment data. All cases were re-reviewed by an expert adjudicator. Accuracy and concordance between automated and manual methods are reported. Results: Automated extraction required considerably less time (<1 day) than manual extraction (∼225 person-hr). The collection of demographic data (age, sex, diagnosis) was highly accurate and concordant with both methods (96%-100%). Accuracy (for either extraction approach) and concordance were lower for unstructured data elements in EHR, such as performance status, date of diagnosis, and smoking status (NLP accuracy: 88%-94%; Manual accuracy: 78%-94%; concordance: 71%-82%). Concurrent medications (86%-100%) and comorbid conditions (96%-100%), were reported with high accuracy and concordance. Treatment details were also accurately captured with both methods (84%-100%) and highly concordant (83%-99%). Detection of whether biomarker testing was performed was highly accurate and concordant (96%-98%), although detection of biomarker test results was more variable (accuracy 84%-100%, concordance 84%-99%). Features with syntactic or semantic variation requiring clinical interpretation were extracted with slightly lower accuracy by both NLP and manual review. For example, metastatic sites were more accurately identified through NLP extraction (NLP: 88%-99%; manual: 71%-100%; concordance: 70%-99%) with the exception of lung and lymph node metastases (NLP: 66%-71%; manual: 87%-92%; concordance: 58%) owing to analogous terms used in radiology reports not being included in the accepted gold standard definition. Conclusions: Automated data abstraction from EHR is highly accurate and faster than manual abstraction. Key challenges include poorly structured EHR and the use of analogous terms beyond the accepted gold standard definition. The application of NLP can facilitate real-world evidence studies at a greater scale than could be achieved with manual data extraction.

Impact on blood loss and transfusion rates following administration of tranexamic acid in major oncological abdominal and pelvic surgery: A systematic review and meta-analysis.

BACKGROUND AND OBJECTIVES: Major bleeding and receiving blood products in cancer surgery are associated with increased postoperative complications and worse outcomes. Tranexamic acid (TXA) reduces blood loss and improves outcomes in various surgical specialities. We performed a systematic review and meta-analysis to investigate TXA use on blood loss in elective abdominal and pelvic cancer surgery. METHODS: A literature search was performed for studies comparing intravenous TXA versus placebo/no TXA in patients undergoing major elective abdominal or pelvic cancer surgery. RESULTS: Twelve articles met the inclusion criteria, consisting of 723 patients who received TXA and 659 controls. Patients receiving TXA were less likely to receive a red blood cell (RBC) transfusion (p < 0.001, OR 0.4 95% CI [0.25, 0.63]) and experienced less blood loss (p < 0.001, MD -197.8 ml, 95% CI [-275.69, -119.84]). The TXA group experienced a smaller reduction in haemoglobin (p = 0.001, MD -0.45 mmol/L, 95% CI [-0.73, -0.18]). There was no difference in venous thromboembolism (VTE) rates (p = 0.95, OR 0.98, 95% CI [0.46, 2.08]). CONCLUSIONS: TXA use reduced blood loss and RBC transfusion requirements perioperatively, with no significant increased risk of VTE. However, further studies are required to assess its benefit for cancer surgery in some sub-specialities.

Integrating comprehensive genomic sequencing of non-small cell lung cancer into a public healthcare system.

OBJECTIVES: Standard molecular testing for patients with stage IV non-small cell lung cancer (NSCLC) in the Canadian publicly funded health system includes single gene testing for EGFR, ALK, and ROS-1. Comprehensive genomic profiling (CGP) may broaden treatment options for patients. This study examined the impact of CGP in a publicly funded health system. METHODS: Consenting patients with stage IV NSCLC without known targetable alterations underwent CGP on diagnostic samples. Patients that had progressed on targeted therapy were also eligible. The CGP assay was a hybrid capture next generation sequencing (NGS) panel (Oncomine Comprehensive Assay Version 3, ThermoFisher). The number of actionable alterations, changes in treatment, clinical trial eligibility and costs as a result of CGP were evaluated and patient willingness-to-pay. RESULTS: Of 182 screened patients,134 (74%) had successful CGP testing. Twenty percent had received prior targeted therapy. Incremental actionable alterations were identified in 31% of patients. The most common novel targets identified were mutations in ERBB2 (exon 20 insertions), MET (exon 14 skipping) and KRAS (G12C). At data cut off (31/12/2020), 16% of patients had a change in treatment as a result of CGP. Additional clinical trial options were identified for 75% of patients. The incremental direct laboratory cost for CGP beyond public reimbursement for single gene tests was $747 CAD/case. CONCLUSION: CGP identifies additional actionable targets beyond single gene tests with a direct impact on patient treatment and increased clinical trial eligibility. These benefits highlight the value of CGP in patients with NSCLC in public health systems.

The financial impact of cancer care on renal cancer patients.

INTRODUCTION Advances in novel treatment options may render renal cell cancer (RCC) patients susceptible to the financial toxicity (FT) of cancer treatment, and the factors associated with FT are unknown. MATERIALS AND METHODS: Eligible patients were ≥ 18 years old and had a diagnosis of stage IV RCC for at least 3 months. Patients were recruited from Princess Margaret Cancer Centre and Sunnybrook Odette Cancer Centre (Toronto, Canada). FT was assessed using the validated Comprehensive Score for Financial Toxicity (COST) instrument, a 12-question survey scored from 0-44, with lower scores reflecting worse FT. Patient and treatment characteristics, out-of-pocket costs (OOP) and private insurance coverage (PIC) were collected. Factors associated with worse FT (COST score < 21) were determined. RESULTS: Sixty-five patients were approached and 80% agreed to participate (n = 52). The median age was 62 (44-88); 20% were female (n = 10); 43% were age ≥ 65 (n = 22); 63% were Caucasian (n = 31). Median COST score was 20.5 (3-44). Factors associated with worse FT were age < 65 (OR 9.5, p = 0.007), high OOP (OR 4.4, p = 0.04) and receiving treatment off clinical trial (in comparison to being on surveillance or on clinical trial) (OR 5.9, p = 0.03), when adjusting for other factors in multivariable logistic regression. However, there was no correlation between annual income or PIC and FT. CONCLUSION: Financial toxicity in the RCC population is more significant in younger patients and those on treatment outside of a clinical trial. Financial aid should be offered to these at-risk patients to optimize adherence to life prolonging RCC treatments.

Reflex ROS1 IHC Screening with FISH Confirmation for Advanced Non-Small Cell Lung Cancer-A Cost-Efficient Strategy in a Public Healthcare System.

ROS1 rearrangements are identified in 1-2% of lung adenocarcinoma cases, and reflex testing is guideline-recommended. We developed a decision model for population-based ROS1 testing from a Canadian public healthcare perspective to determine the strategy that optimized detection of true-positive (TP) cases while minimizing costs and turnaround time (TAT). Eight diagnostic strategies were compared, including reflex single gene testing via immunohistochemistry (IHC) screening, fluorescence in-situ hybridization (FISH), next-generation sequencing (NGS), and biomarker-informed (EGFR/ALK/KRAS wildtype) testing initiated by pathologists and clinician-initiated strategies. Reflex IHC screening with FISH confirmation of positive cases yielded the best results for TAT, TP detection rate, and cost. IHC screening saved CAD 1,000,000 versus reflex FISH testing. NGS was the costliest reflex strategy. Biomarker-informed testing was cost-efficient but delayed TAT. Clinician-initiated testing was the least costly but resulted in long TAT and missed TP cases, highlighting the importance of reflex testing. Thus, reflex IHC screening for ROS1 with FISH confirmation provides a cost-efficient strategy with short TAT and maximizes the number of TP cases detected.

Correction: Variation in early number skills and mathematics achievement: Implications from cognitive profiles of children with or without Turner syndrome.

[This corrects the article DOI: 10.1371/journal.pone.0239224.].

Karyotype is associated with timing of ovarian failure in women with Turner syndrome.

OBJECTIVE: To characterize the age of ovarian failure in Turner Syndrome (TS) patients by karyotype. METHODS: Retrospective cohort study of individuals with TS at an academic university hospital. Subjects were seen in TS Clinic at UNC Hospital between 2014 and 2018. Individuals were analyzed by karyotype category (45X, 45X/46XX mosaicism, miscellaneous) and percentage of 45X cells. Age at follicle-stimulating hormone> 30 was defined as the age at loss of ovarian function. RESULTS: A total of 79 patients were identified after excluding individuals with unknown ovarian function and those with Y chromosome material. Thirty-eight percent were 45X monosomic, 62% were 45X/46XX mosaic or miscellaneous karyotypes. Fifty-five of 79 (70%) patients had evidence of ovarian failure, median age of failure 11 years (IQR: 4,12). Ovarian failure was more prevalent among individuals with 45X karyotype (100%). The median age of ovarian failure for 45X patients (n=30) was 10 years old, which is significantly younger than other karyotypes (n=49), with a median of 15 years, p<0.01. Linear regression analysis found that 1 percentage point increase in 45X cells in the peripheral karyotype is associated with a 0.09 year decrease in age of ovarian failure (p value=0.01). Only 9% of individuals were referred for fertility counseling. CONCLUSIONS: There is a lower prevalence of ovarian failure among individuals with mosaic TS karyotypes, and referral rate for fertility counseling of patients with TS is low. These findings are in line with published literature. The finding that percentage of 45X cells in peripheral karyotype is associated with earlier age of ovarian failure is novel and warrants further investigation in a larger prospective cohort.

Changes to care delivery at nine international pediatric diabetes clinics in response to the COVID-19 global pandemic.

BACKGROUND: Pediatric diabetes clinics around the world rapidly adapted care in response to COVID-19. We explored provider perceptions of care delivery adaptations and challenges for providers and patients across nine international pediatric diabetes clinics. METHODS: Providers in a quality improvement collaborative completed a questionnaire about clinic adaptations, including roles, care delivery methods, and provider and patient concerns and challenges. We employed a rapid analysis to identify main themes. RESULTS: Providers described adaptations within multiple domains of care delivery, including provider roles and workload, clinical encounter and team meeting format, care delivery platforms, self-management technology education, and patient-provider data sharing. Providers reported concerns about potential negative impacts on patients from COVID-19 and the clinical adaptations it required, including fears related to telemedicine efficacy, blood glucose and insulin pump/pen data sharing, and delayed care-seeking. Particular concern was expressed about already vulnerable patients. Simultaneously, providers reported 'silver linings' of adaptations that they perceived as having potential to inform care and self-management recommendations going forward, including time-saving clinic processes, telemedicine, lifestyle changes compelled by COVID-19, and improvements to family and clinic staff literacy around data sharing. CONCLUSIONS: Providers across diverse clinical settings reported care delivery adaptations in response to COVID-19-particularly telemedicine processes-created challenges and opportunities to improve care quality and patient health. To develop quality care during COVID-19, providers emphasized the importance of generating evidence about which in-person or telemedicine processes were most beneficial for specific care scenarios, and incorporating the unique care needs of the most vulnerable patients.