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Ein nicht kleinzelliges Lungenkarzinom (NSCLC) wird seit jeher mit einer schlechten Prognose und einer geringen Überlebensrate von bis zu 5 Jahren in Verbindung gebracht, aber der Einsatz zielgerichteter Therapien beim NSCLC hat die Behandlungsergebnisse für die Patienten in den letzten 10 Jahren verbessert. Die Entwicklung neuer zielgerichteter Therapien beschleunigt sich und damit auch der Bedarf an molekularen Tests für neue Mutationen, die als Ziele geeignet sind. Da die Komplexität der Biomarkertests beim NSCLC zunimmt, besteht ein Bedarf an Leitlinien für den Umgang mit dem im Fluss befindlichen Behandlungsstandard beim NSCLC, für pragmatische molekulare Testbedingungen und für die Optimierung des Ergebnisberichts. Eine multidisziplinäre Expertengruppe mit Vertretern aus der medizinischen Onkologie, der Pathologie und der klinischen Genetik kam über virtuelle Treffen zusammen, um Konsensusempfehlungen für Tests auf neue geeignete Zielmutationen beim NSCLC zu erarbeiten. Die Arbeitsgruppe betonte, wie wichtig es ist, alle potenziellen Zielmutationen genau und rechtzeitig zu testen, um die Behandlung der Krankheit mit gezielten Therapien zu optimieren. Daher empfiehlt das Expertengremium, dass alle möglichen Zielmutationen routinemäßig bei der Diagnose von NSCLC als Teil eines umfassenden Panels getestet werden, wobei Methoden verwendet werden sollten, die alle relevanten mutierten Zielgene erkennen können. Darüber hinaus sollten auf Wunsch des behandelnden Arztes umfassende Biomarkertests durchgeführt werden, wenn sich eine Resistenz gegen eine zielgerichtete Therapie entwickelt. Die multidisziplinäre Expertenarbeitsgruppe gab auch Empfehlungen für die Berichterstattung ab, um die nötige Klarheit und einfache Interpretation der Ergebnisse durch die behandelnden Ärzte zu gewährleisten und der raschen Entwicklung der klinischen Anwendbarkeit dieser Mutationen Rechnung zu tragen. Molekulare Tests auf alle geeigneten Zielmutationen beim NSCLC sind der Schlüssel für die Behandlungsentscheidung und den Zugang zu neuen Therapien. Diese Konsensusempfehlungen sind als Leitfaden für die weitere Optimierung der molekularen Tests auf neue geeignete Zielmutationen gedacht.

In Canada, the therapeutic management of patients with advanced non-small cell lung cancer (NSCLC) with rare actionable mutations differs between provinces, territories, and individual centres based on access to molecular testing and funded treatments. These variations, together with the emergence of several novel mesenchymal-epithelial transition (MET) factor-targeted therapies for the treatment of NSCLC, warrant the development of evidence-based consensus recommendations for the use of these agents. A Canadian expert panel was convened to define key clinical questions, review evidence, discuss practice recommendations and reach consensus on the treatment of advanced MET-altered NSCLC. Questions addressed by the panel include: 1. How should the patients most likely to benefit from MET-targeted therapies be identified? 2. What are the preferred first-line and subsequent therapies for patients with MET exon 14 skipping mutations? 3. What are the preferred first-line and subsequent therapies for advanced NSCLC patients with de novo MET amplification? 4. What is the preferred therapy for patients with advanced epidermal growth factor receptor (EGFR)-mutated NSCLC with acquired MET amplification progressing on EGFR inhibitors? 5. What are the potential strategies for overcoming resistance to MET inhibitors? Answers to these questions, along with the consensus recommendations herein, will help streamline the management of MET-altered NSCLC in routine practice, assist clinicians in therapeutic decision-making, and help ensure optimal outcomes for NSCLC patients with MET alterations.

Malignant sarcomas are rare accounting for

Small-cell lung cancer (SCLC) is highly responsive to chemotherapy (CT) and one of the few malignancies treated in hospitalized patients with poor Eastern Cooperative Oncology Group (ECOG) performance status (PS). Because of the little current information available on the outcomes experienced by hospitalized patients with SCLC receiving CT, we explored the outcomes for these patients to improve the evidence base for practice.We conducted a retrospective cohort study to evaluate patients with a diagnosis of SCLC and treated with CT during a 10-year period. Progression-free survival (PFS) and overall survival (OS) were evaluated according to site of first CT (inpatient vs. outpatient) and PS. Multivariable analysis was completed to assess for independent survival predictors.A total of 530 patients with SCLC were treated, with 82 (15%) receiving their first CT in hospital. Inpatients had a greater burden of disease and poorer PS. Neutropenia, thrombocytopenia, nephrotoxicity, and fatigue were all experienced less often by the inpatient cohort (P .001, P .001, P .001, and P = .007, respectively). For inpatients and outpatients, the OS rate at 12, 24, and 60 months was 22%, 9%, and 7% and 43%, 20%, and 9%, respectively (P .001 for all). The median PFS and OS were longer for outpatients and highly functional patients. On multivariable analysis, ECOG PS was an independent predictor of the outcome and the site of first CT was not (P = .04 and P = .49, respectively).Patients with SCLC initially treated as inpatients and those with poor functional status had shorter PFS and OS; however, some experienced long-term survival, including 5-year survival of 7% for the inpatient cohort and 5% for the ECOG PS 3-4 cohort. CT toxicities were less common in the inpatient cohort, validating that administration of CT in hospital should be considered for these patients because they could experience a meaningful long-term response to therapy.

Background: Multiple clinical trials for the treatment of advanced EGFR-mutated non-small-cell lung cancer (nsclc) have recently been reported. As a result, the treatment algorithm has changed, and many important clinical questions have been raised: (1) What is the optimal first-line treatment for patients with EGFR-mutated nsclc? (2) What is preferred first-line treatment for patients with brain metastasis? (3) What is the preferred second-line treatment for patients who received first-line first- or second-generation tyrosine kinase inhibitors (tkis)? (4) What is the preferred treatment after osimertinib? (5) What evidence do we have for treating patients whose tumours harbour uncommon EGFR mutations? Methods: A Canadian expert panel was convened to define the key clinical questions, review recent evidence, and discuss and agree on practice recommendations for the treatment of advanced EGFR-mutated nsclc. Results: The published overall survival results for osimertinib, combined with its central nervous system activity, have led to osimertinib becoming the preferred first-line treatment for patients with common EGFR mutations, including those with brain metastasis. Other agents could still have a role, especially when osimertinib is not available or not tolerated. Treatment in subsequent lines of therapy depends on the first-line therapy or on T790M mutation status. Treatment recommendations for patients whose tumours harbour uncommon EGFR mutations are guided mainly by retrospective and limited prospective evidence. Finally, the evidence for sequencing and combining tkis with chemotherapy, angiogenesis inhibitors, checkpoint inhibitors, and other new therapeutics is reviewed. Conclusions: This Canadian expert consensus statement and algorithm were driven by significant advances in the treatment of EGFR-mutated nsclc.

Immune checkpoint inhibitor&ndash, based therapies that target ctla-4, PD-1, or the PD-1 ligand PD-L1 have received approval in Canada and many parts of the world for the treatment of melanoma, renal cell cancer, urothelial cancer, classical Hodgkin lymphoma, and non-small-cell lung cancer. However only a small proportion of patients derive long-term clinical benefit. Here, we describe the biomarkers associated with the complex relationship between tumour-related immune stimulus, T cell&ndash, mediated immune response, and immune modulation of the microenvironment that can help to predict improved patient outcomes.

Background Diagnosis codes in administrative health data are routinely used to monitor trends in disease prevalence and incidence. The International Classification of Diseases (ICD), which is used to record these diagnoses, have been updated multiple times to reflect advances in health and medical research. Our objective was to examine the impact of transitions between ICD versions on the prevalence of chronic health conditions estimated from administrative health data. Methods Study data (i.e., physician billing claims, hospital records) were from the province of Manitoba, Canada, which has a universal healthcare system. ICDA-8 (with adaptations), ICD-9-CM (clinical modification), and ICD-10-CA (Canadian adaptation; hospital records only) codes are captured in the data. Annual study cohorts included all individuals 18 + years of age for 45 years from 1974 to 2018. Negative binomial regression was used to estimate annual age- and sex-adjusted prevalence and model parameters (i.e., slopes and intercepts) for 16 chronic health conditions. Statistical control charts were used to assess the impact of changes in ICD version on model parameter estimates. Hotelling’s T2 statistic was used to combine the parameter estimates and provide an out-of-control signal when its value was above a pre-specified control limit. Results The annual cohort sizes ranged from 360,341 to 824,816. Hypertension and skin cancer were among the most and least diagnosed health conditions, respectively; their prevalence per 1,000 population increased from 40.5 to 223.6 and from 0.3 to 2.1, respectively, within the study period. The average annual rate of change in prevalence ranged from -1.6% (95% confidence interval [CI]: -1.8, -1.4) for acute myocardial infarction to 14.6% (95% CI: 13.9, 15.2) for hypertension. The control chart indicated out-of-control observations when transitioning from ICDA-8 to ICD-9-CM for 75% of the investigated chronic health conditions but no out-of-control observations when transitioning from ICD-9-CM to ICD-10-CA. Conclusions The prevalence of most of the investigated chronic health conditions changed significantly in the transition from ICDA-8 to ICD-9-CM. These results point to the importance of considering changes in ICD coding as a factor that may influence the interpretation of trend estimates for chronic health conditions derived from administrative health data.

Central nervous system (CNS) metastasis will develop in 50% of small cell lung cancer (SCLC) patients throughout disease course. Development of CNS metastasis poses a particular treatment dilemma due to the accompanied cognitive changes, poor permeability of the blood-brain barrier to systemic therapy and relatively advanced state of disease. Survival of patients with untreated SCLC brain metastases is generally

Objectives: Metabolomics is a potential means for biofluid-based lung cancer detection. We conducted a non-targeted, data-driven, assessment of plasma from early-stage non-small cell lung cancer (ES-NSCLC) cases versus cancer-free controls (CFC) to explore and identify classes of metabolites for further targeted metabolomics biomarker development. Materials and Methods: Plasma from 250 ES-NSCLC cases and 250 CFCs underwent Ultra High-Performance Liquid Chromatography/Quadrupole Time-Of-Flight Mass Spectrometry (UHPLC-QTOF-MS) in positive and negative electrospray ionization (ESI) modes. Molecular feature extraction, formula generation, and find-by-ion tools annotated metabolic entities. Analysis was restricted to endogenous metabolites present in ≥80% of samples. Unsupervised hierarchical cluster analysis identified clusters of metabolites. The metabolites with the strongest correlation with the principal component of each cluster were included in logistic regression modeling to assess discriminatory performance with and without adjustment for clinical covariates. Results: 1,900 UHPLC-QTOF-MS assessments identified 1,667 and 2,032 endogenous metabolites in the ESI positive and ESI negative modes, respectively. After data filtration, 676 metabolites remained, and 12 clusters of metabolites were identified from each ESI mode. Multivariable logistic regression using the representative metabolite from each cluster revealed effective classification of cases from controls with overall diagnostic accuracy of 91% (ESI positive) and 94% (ESI negative). Metabolites of interest identified for further targeted analysis include: 1b, 3a, 12a-trihydroxy-5b-cholanoic acid, pyridoxamine 5’-phosphate, sphinganine 1-phosphate, gamma-CEHC, 20-carboxy-leukotriene B4, isodesmosine, and 18-hydroxycortisol.Conclusions: Plasma-based metabolomic detection of early-stage NSCLC appears feasible. Further metabolomics studies targeting phospholipid, steroid, and fatty acid metabolism are warranted to further develop non-invasive metabolomics-based detection of early-stage NSCLC.

Frailty impacts outcomes for patients with lung cancer, but no brief tools have been assessed in patients with metastatic disease. We evaluated the impact of the Modified Frailty Index (mFI) on clinical outcomes for patients with metastatic non-small cell lung cancer (NSCLC).We conducted a retrospective cohort study of all patients with Stage IV NSCLC diagnosed in Manitoba between 2011 and 2016 who then received first-line cytotoxic chemotherapy. We assigned mFI scores based on documented comorbidities and collected data on toxicity, progression, and survival. Descriptive statistics characterized the cohort and toxicity experienced. Kaplan-Meier methods were used to evaluate progression-free survival (PFS) and overall survival (OS), followed by multivariable Cox proportional hazards models.Our cohort of 426 (mFI 0/1-2/3+ = 175/196/55) patients, showed no significant association between higher mFI score and incidence of overall chemotherapy toxicity. Patients with mFI 0 experienced more frequent thromboses (p=0.022) and a trend towards less nausea or vomiting (p = 0.059). There was no significant difference in PFS or OS among frailty groups. Poorer performance status, number of metastatic sites, and the absence of a driver mutation were independently associated with poorer PFS and OS. Male sex and not completing chemotherapy were also associated with worse OS.This study is the first to investigate the use of the mFI as a frailty tool in patients with metastatic NSCLC receiving cytotoxic chemotherapy. The mFI does not appear to be strongly associated with treatment-related toxicities, PFS, or OS in patients with metastatic NSCLC receiving first-line cytotoxic chemotherapy.

IntroductionAdministrative health data capture diagnoses using the International Classification of Diseases (ICD), which has multiple versions over time. To facilitate longitudinal investigations using these data, we aimed to map diagnoses identified in three ICD versions – ICD-8 with adaptations (ICDA-8), ICD-9 with clinical modifications (ICD-9-CM), and ICD-10 with Canadian adaptations (ICD-10-CA) – to mutually exclusive chronic health condition categories adapted from the open source Clinical Classifications Software (CCS). MethodsWe adapted the CCS crosswalk to 3-digit ICD-9-CM codes for chronic conditions and resolved the one-to-many mappings in ICD-9-CM codes. Using this adapted CCS crosswalk as the reference and referring to existing crosswalks between ICD versions, we extended the mapping to ICDA-8 and ICD-10-CA. Each mapping step was conducted independently by two reviewers and discrepancies were resolved by consensus through deliberation and reference to prior research. We report the frequencies, agreement percentages and 95% confidence intervals (CI) from each step. ResultsWe identified 354 3-digit ICD-9-CM codes for chronic conditions. Of those, 77 (22%) codes had one-to-many mappings; 36 (10%) codes were mapped to a single CCS category and 41 (12%) codes were mapped to combined CCS categories. In total, the codes were mapped to 130 adapted CCS categories with an agreement percentage of 92% (95% CI: 86%–98%). Then, 321 3-digit ICDA-8 codes were mapped to CCS categories with an agreement percentage of 92% (95% CI: 89%–95%). Finally, 3583 ICD-10-CA codes were mapped to CCS categories; 111 (3%) had a fair or poor mapping quality; these were reviewed to keep or move to another category (agreement percentage=77% [95% CI: 69%–85%]). ConclusionsWe developed crosswalks for three ICD versions (ICDA-8, ICD-9-CM, and ICD-10-CA) to 130 clinically meaningful categories of chronic health conditions by adapting the CCS classification. These crosswalks will benefit chronic disease studies spanning multiple decades of administrative health data.

The advent of personalized therapy for non-small-cell lung carcinoma (nsclc) has improved patient outcomes. Selection of appropriate targeted therapy for patients with nsclc now involves testing for multiple biomarkers, including EGFR. EGFR mutation status is required to optimally treat patients with nsclc, and thus timely and accurate biomarker testing is necessary. However, in Canada, there are currently no standardized processes or methods in place to ensure consistent testing implementation. That lack creates challenges in ensuring that all appropriate biomarkers are tested for each patient and that the medical oncologist receives the results for making informed treatment decisions in a timely way.An expert multidisciplinary working group was convened to create consensus recommendations about biomarker testing in advanced NSCLC in Canada, with a primary focus on EGFR testing. Recognizing that there are biomarkers beyond EGFR that require timely identification, the expert multidisciplinary working group considered EGFR testing in the broader context of integration into complex lung biomarker testing. Primarily, the panel of experts recommends that all patients with nonsquamous NSCLC, regardless of stage, should undergo comprehensive reflex biomarker testing at diagnosis with targeted next-generation sequencing. The panel also considered the EGFR testing algorithm and the challenges associated with the pre-analytic, analytic, and post-analytic elements of testing. Strategies for funding testing by reducing silos of single biomarker testing for EGFR and for optimally implementing the recommendations presented here and educating oncology professionals about them are also discussed.

Immunotherapy is less effective in non-small cell lung cancer (NSCLC) with driver mutations in epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) and some may extrapolate this trend to other driver mutations. Up to 4% of NSCLC cases contain a BRAF mutation. Most BRAF mutations are V600E, and little is known about the impact of treatment in rare BRAF G469A mutations. We present a case of a patient found to have BRAF G469A mutated NSCLC. She was diagnosed with Stage IIIB NSCLC and treated with concurrent chemotherapy and radiation. Post-treatment imaging demonstrated disease progression and she was started on nivolumab, resulting in a dramatic and prolonged response which is ongoing after 76 cycles. Her substantial response and prolonged benefit suggest that BRAF-mutated NSCLC may respond better than EGFR- or ALK-driven disease to immunotherapy. Due to the rarity of specific mutations, this case adds to the limited current published literature on NSCLC harbouring a BRAF G469A mutation and suggests that immunotherapy is a reasonable treatment option.

Metabolomics analysis of blood from patients (n = 42) undergoing surgery for suspected lung cancer was performed in this study. Venous and arterial blood was collected in both Streck and Heparin tubes. A total of 96 metabolites were detected, affected by sex (n = 56), collection tube (n = 33), and blood location (n = 8). These metabolites belonged to a wide array of compound classes including lipids, acids, pharmaceutical agents, signalling molecules, vitamins, among others. Phospholipids and carboxylic acids accounted for 28% of all detected compounds. Out of the 33 compounds significantly affected by collection tube, 18 compounds were higher in the Streck tubes, including allantoin and ketoleucine, and 15 were higher in the Heparin tubes, including LysoPC(P-16:0), PS 40:6, and chenodeoxycholic acid glycine conjugate. Based on our results, it is recommended that replicate blood samples from each patient should be collected in different types of blood collection tubes for a broader range of the metabolome. Several metabolites were found at higher concentrations in cancer patients such as lactic acid in Squamous Cell Carcinoma, and lysoPCs in Adenocarcinoma and Acinar Cell Carcinoma, which may be used to detect early onset and/or to monitor the progress of the cancer patients.

Lung cancer is the leading cause of cancer-specific death among Canadians, with non-small-cell lung cancer (NSCLC) being the most common histologic variant. Despite advances in the understanding of the molecular biology of NSCLC, the survival rate for this malignancy is still poor. It is now understood that, to evade detection and immune clearance, NSCLC tumours overexpress the immunosuppressive checkpoint protein programmed death ligand 1 (PD-L1). Inhibiting the PD-1/PD-L1 axis with monoclonal antibodies has significantly changed the treatment landscape in NSCLC during the last 5 years. Despite evidence of clinical response in some patients, only approximately 20% of patients obtain any durable benefit, and many of the patients who do respond ultimately relapse with drug-resistant disease. The identification of patients who are most likely to benefit from such therapy is therefore important. In the present review, we cover the basics of the PD-1/PD-L1 axis and its clinical significance in NSCLC, biomarkers that are predictive of treatment response, relevant clinical trials of PD-1/PD-L1 blockade completed to date, and proposed mechanisms of acquired therapeutic resistance.

Lung cancer is the most common cause of cancer-related deaths worldwide with non-small cell lung cancer (NSCLC) making up most of these cases. Males have poorer overall survival compared to women following a lung cancer diagnosis. Many studies have focused on the effects of estrogen to explain higher survival rates among women, but few have looked at the effects of androgens. We describe the expression of the androgen receptor (AR) and Ki67 in lung cancer specimens in the Manitoba Tumor Bank (MTB) and correlate these factors with patient outcome. Using the MTB, we performed immunohistochemistry on lung cancer tissue to determine expression of the AR and Ki67. These were then correlated with patient outcome. Of the 136 cases, 55% were female and 55% were adenocarcinoma. AR expression was not independently associated with outcome. Ki67 was associated with a significantly higher hazard ratio for death and recurrence (HR 2.19, 95% CI 1.30-3.70; HR 1.92, 95% CI 1.07-3.46, respectively). AR expression modified the effect of Ki67 on outcome, such that when both were expressed, there was no association with recurrence or survival (HR 2.39, 95% CI 1.31-4.36 for AR- Ki67+ vs HR 1.54, 95% CI 0.44-5.37 for AR+ Ki67+). Ki67 was associated with poorer outcomes alone. AR status alone was not associated with outcome. Although the mechanism remains unclear, AR status seems to negate the association of a high Ki67 and poor outcome.

Rapid advancements in next-generation sequencing (NGS) technology have created an unprecedented opportunity to decipher the molecular profile of tumours to more effectively prevent, diagnose, and treat cancer. Oncologists now have the option to order molecular tests that can guide treatment decisions. However, to date, most oncologists have received limited training in genomics, and they are now faced with the challenge of understanding how such tests and their interpretation align with patient management. Guidance on how to effectively use NGS technology is therefore needed to aid oncologists in applying the results of genomic tests. The Canadian guideline presented here describes best practices and unmet needs related to ngs-based testing for somatic variants in oncology, including clinical application, assay and sample selection, bioinformatics and interpretation of reports performed by laboratories, patient communication, and clinical trials.

Breast cancer is one of the leading causes of cancer death in women. It is a complex and heterogeneous disease with different clinical outcomes. Stratifying patients into subgroups with different outcomes could help guide clinical decision making. In this study, we used two opposing groups of genes, Yin and Yang, to develop a prognostic expression ratio signature. Using the METABRIC cohort we identified a16-gene signature capable of stratifying breast cancer patients into four risk levels with intention that low-risk patients would not undergo adjuvant systemic therapy, intermediate-low-risk patients will be treated with hormonal therapy only, and intermediate-high- and high-risk groups will be treated by chemotherapy in addition to the hormonal therapy. The 16-gene signature for four risk level stratifications of breast cancer patients has been validated using 14 independent datasets. Notably, the low-risk group (n = 51) of 205 estrogen receptor-positive and node negative (ER+/node-) patients from three different datasets who had not had any systemic adjuvant therapy had 100% 15-year disease-specific survival rate. The Concordance Index of YMR for ER+/node negative patients is close to the commercially available signatures. However, YMR showed more significance (HR = 3.7, p = 8.7e-12) in stratifying ER+/node- subgroup than OncotypeDx (HR = 2.7, p = 1.3e-7), MammaPrint (HR = 2.5, p = 5.8e-7), rorS (HR = 2.4, p = 1.4e-6), and NPI (HR = 2.6, p = 1.2e-6). YMR signature may be developed as a clinical tool to select a subgroup of low-risk ER+/node- patients who do not require any adjuvant hormonal therapy (AHT).

Introduction Lung cancer is the leading killer cancer worldwide. There is an urgent need for easy-to-use and robust clinical gene signatures for improved prognosis and treatment prediction. Methods We used a gene expression signature termed the Yin and Yang mean ratio (YMR), which is based on two groups of genes with opposing function, to determine lung cancer prognosis. The YMR signature represents the relative state of an individual tumor on a gene expression spectrum ranging from malignancy to the normal healthy lung. The genes in the YMR signature have therefore been determined independently of survival time, which is different from previous regression models. We then leveraged the cross-platform utility of the YMR signature to optimize the signature into a smaller set of genes that validated the robustness of the signature in many independent lung cancer expression data sets. Results Four Yin and six Yang genes were optimized using 741 NSCLC cases from diverse platforms, including microarray and RNA sequencing. The 10-gene signature demonstrated significant differences in survival in eight individual independent data sets and a larger combined 1346-patient data set. When multivariate analysis taking into account other common predictors of survival was used, the 5-year recurrence-free rate of YMR ( p = 6.4 × 10 -6 , HR =1.71 [1.36–2.16]) was secondary only to stage. The YMR signature significantly separated high- and low-risk patients with stage IA or 1B adenocarcinoma and squamous cell carcinomas of all stages. The YMR signature can also predict the benefit of adjuvant chemotherapy in high-risk patients with stage I NSCLC. Conclusions The YMR signature has great potential for guiding clinical management for NSCLC, particularly early-stage disease. The signature appears more reproducible than older signatures and functions using a variety of common gene expression platforms.

Objectives Lung cancer is one of the most lethal cancers. Currently, there are no biomarkers for early detection, monitoring treatment response, and detecting recurrent lung cancer. We undertook this study to determine if 1 H magnetic resonance spectroscopy (MRS) of sputum and exhaled breath condensate (EBC), as a noninvasive tool, can identify metabolic biomarkers of lung cancer. Materials and Methods Sputum and EBC samples were collected from 20 patients, comprising patients with pathologically confirmed non-small cell lung cancer ( n = 10) and patients with benign respiratory conditions ( n = 10). Both sputum and EBC samples were collected from 18 patients; 2 patients provided EBC samples only. 1 H MR spectra were obtained on a Bruker Avance 400 MHz nuclear magnetic resonance (NMR) spectrometer. Sputum samples were further confirmed cytologically to distinguish between true sputum and saliva. Results In the EBC samples, median concentrations of propionate, ethanol, acetate, and acetone were higher in lung cancer patients compared to the patients with benign conditions. Median concentration of methanol was lower in lung cancer patients (0.028 mM) than in patients with benign conditions (0.067 mM; P = 0.028). In the combined sputum and saliva and the cytologically confirmed sputum samples, median concentrations of N -acetyl sugars, glycoprotein, propionate, lysine, acetate, and formate were lower in the lung cancer patients than in patients with benign conditions. Glucose was found to be consistently absent in the combined sputum and saliva samples (88%) as well as in the cytologically confirmed sputum samples (86%) of lung cancer patients. Conclusion Absence of glucose in sputum and lower concentrations of methanol in EBC of lung cancer patients discerned by 1 H MRS may serve as metabolic biomarkers of lung cancer for early detection, monitoring treatment response, and detecting recurrence.

Importance Mindfulness-based interventions (MBIs), grounded in mindfulness, focus on purposely paying attention to experiences occurring at the present moment without judgment. MBIs are increasingly used by patients with cancer for the reduction of anxiety, but it remains unclear if MBIs reduce anxiety in patients with cancer. Objective To evaluate the association of MBIs with reductions in the severity of anxiety in patients with cancer. Data Sources Systematic searches of MEDLINE, Embase, Cochrane Central Register of Controlled Trials, CINAHL, PsycINFO, and SCOPUS were conducted from database inception to May 2019 to identify relevant citations. Study Selection Randomized clinical trials (RCTs) that compared MBI with usual care, waitlist controls, or no intervention for the management of anxiety in cancer patients were included. Two reviewers conducted a blinded screening. Of 101 initially identified studies, 28 met the inclusion criteria. Data Extraction and Synthesis Two reviewers independently extracted the data. The Cochrane Collaboration risk-of-bias tool was used to assess the quality of RCTs, and the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline was followed. Summary effect measures were reported as standardized mean differences (SMDs) and calculated using a random-effects model. Main Outcomes and Measures Our primary outcome was the measure of severity of short-term anxiety (up to 1-month postintervention); secondary outcomes were the severity of medium-term (1 to ≤6 months postintervention) and long-term (>6 to 12 months postintervention) anxiety, depression, and health-related quality of life of patients and caregivers. Results This meta-analysis included 28 RCTs enrolling 3053 adults with cancer. None of the trials were conducted in children. Mindfulness was associated with significant reductions in the severity of short-term anxiety (23 trials; 2339 participants; SMD, −0.51; 95% CI, −0.70 to −0.33;I2 = 76%). The association of mindfulness with short-term anxiety did not vary by evaluated patient, intervention, or study characteristics. Mindfulness was also associated with the reduction of medium-term anxiety (9 trials; 965 participants; SMD, −0.43; 95% CI, −0.68 to −0.18;I2 = 66%). No reduction in long-term anxiety was observed (2 trials; 403 participants; SMD, −0.02; 95% CI, −0.38 to 0.34;I2 = 68%). MBIs were associated with a reduction in the severity of depression in the short term (19 trials; 1874 participants; SMD, −0.73; 95% CI; −1.00 to −0.46;I2 = 86%) and the medium term (8 trials; 891 participants; SMD, −0.85; 95% CI, −1.35 to −0.35;I2 = 91%) and improved health-related quality of life in patients in the short term (9 trials; 1108 participants; SMD, 0.51; 95% CI, 0.20 to 0.82;I2 = 82%) and the medium term (5 trials; 771 participants; SMD, 0.29; 95% CI, 0.06 to 0.52;I2 = 57%). Conclusions and Relevance In this study, MBIs were associated with reductions in anxiety and depression up to 6 months postintervention in adults with cancer. Future trials should explore the long-term association of mindfulness with anxiety and depression in adults with cancer and determine its efficacy in more diverse cancer populations using active controls.

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

Background Lower extremity soft tissue sarcoma treatment has evolved from primarily amputation procedures toward limb salvage. This series assesses whether soft tissue sarcoma tissue defects, extensive enough to require microsurgical reconstruction, can reliably result in preservation of ambulation, as well as objectively evaluate functional outcomes utilizing a patient-reported validated scale. It will also look at whether immediate functional muscle reconstructions and tendon transfers can be successful at restoring ambulation, potentially expanding the indications for limb salvage procedures. Methods A retrospective review of all microsurgical reconstructions for limb salvage in lower extremity sarcoma patients was completed at our institution (2009–2013). Patients were additionally asked to complete the Toronto Extremity Salvage Score(TESS) quality of life survey. Results Over a 5-year period, 23 patients (mean age: 53 years) underwent free flap reconstructions for 23 sarcomas (mean follow-up: 14 months). Seventy-eight percent of patients received neoadjuvant radiation. The thigh was the most common tumor site (61%) and three muscles were resected on average. Perforator flaps were most frequently used (61%), and functional muscle transfers or immediate tendon transfers were used in four patients. There were no flap take-backs or failures, and 22 patients achieved independent ambulation. Three patients in the series died, two from metastatic disease found postoperatively and one from local recurrence. A 74% response rate was achieved for the TESS survey, with a mean score of 83. Conclusion Microsurgical reconstruction of lower extremity sarcoma defects enables preservation of independent ambulation. Restoration of function utilizing immediate functional microsurgical reconstructions and tendon transfers should be considered.

Crizotinib is a first line treatment for patients with non-small cell lung cancer (NSCLC) harboring translocations in anaplastic lymphoma kinase (ALK). The current gold standard for determining ALK status is fluorescence in-situ hybridisation (FISH), but immunohistochemistry (IHC) is becoming increasingly popular due to lower cost. There are currently few reports on clinical outcomes with crizotinib therapy in patients who have tested negative by FISH and positive by IHC. A 53 year old lifelong non-smoking, physically active male with newly diagnosed Stage IV NSCLC presented with shortness of breath on exertion one month prior to referral. Staging CT scan failed to show a discreet lung lesion, but the left lower lobe was collapsed due to pleural effusion. Pleural fluid showed adenocarcinoma and IHC was positive for an ALK mutation, while FISH was negative. Pre-treatment PET-CT showed hypermetabolic, enlarged lymph nodes in the mediastinum and retroperitoneum. Partially due to patient concerns about cytotoxic chemotherapy toxicity, crizotinib therapy was instituted. Repeat CT conducted two months after crizotinib initiation showed a decrease in lymphadenopathy at all sites compared to the PET-CT. Furthermore, the patient showed clinical improvement, with less drainage through his PleurX catheter and stability of his excellent performance status. After 12 months on crizotinib CT showed ongoing improvement in lymphadenopathy. His bloodwork has been stable, and he denies significant drug toxicity. This case illustrates a sustained response to crizotinib therapy in a patient with an ALK translocation identified by IHC, but with negative FISH testing. The literature suggests that the population with these discordant results could be up to 19% of ALK positive NSCLC. Patients in this subgroup who are receiving crizotinib should be identified and outcome data pooled. However, in the interim, oncologists may wish to consider targeted therapy for these discordant patients.

Anaplastic lymphoma kinase (alk) is an oncogenic driver in non-small-cell lung cancer (nsclc). Chromosomal rearrangements involving the ALK gene occur in up to 4% of nonsquamous nsclc patients and lead to constitutive activation of the alk signalling pathway. ALK-positive nsclc is found in relatively young patients, with a median age of 50 years. Patients frequently have brain metastasis. Targeted inhibition of the alk pathway prolongs progression-free survival in patients with ALK-positive advanced nsclc. The results of several recent clinical trials confirm the efficacy and safety benefit of crizotinib and ceritinib in this population. Canadian oncologists support the following consensus statement: All patients with advanced nonsquamous nsclc (excluding pure neuroendocrine carcinoma) should be tested for the presence of an ALK rearrangement. If an ALK rearrangement is present, treatment with a targeted alk inhibitor in the first-line setting is recommended. As patients become resistant to first-generation alk inhibitors, other treatments, including second-generation alk inhibitors can be considered.

Breast cancer is one of the leading causes of cancer death in women. It is a complex and heterogeneous disease with different clinical outcomes. Stratifying patients into subgroups with different outcomes could help guide clinical decision making. In this study, we used two opposing groups of genes, Yin and Yang, to develop a prognostic expression ratio signature. Using the METABRIC cohort we identified a16-gene signature capable of stratifying breast cancer patients into four risk levels with intention that low-risk patients would not undergo adjuvant systemic therapy, intermediate-low-risk patients will be treated with hormonal therapy only, and intermediate-high- and high-risk groups will be treated by chemotherapy in addition to the hormonal therapy. The 16-gene signature for four risk level stratifications of breast cancer patients has been validated using 14 independent datasets. Notably, the low-risk group (n = 51) of 205 estrogen receptor-positive and node negative (ER+/node-) patients from three different datasets who had not had any systemic adjuvant therapy had 100% 15-year disease-specific survival rate. The Concordance Index of YMR for ER+/node negative patients is close to the commercially available signatures. However, YMR showed more significance (HR = 3.7, p = 8.7e-12) in stratifying ER+/node- subgroup than OncotypeDx (HR = 2.7, p = 1.3e-7), MammaPrint (HR = 2.5, p = 5.8e-7), rorS (HR = 2.4, p = 1.4e-6), and NPI (HR = 2.6, p = 1.2e-6). YMR signature may be developed as a clinical tool to select a subgroup of low-risk ER+/node- patients who do not require any adjuvant hormonal therapy (AHT).

Small-cell lung cancer (SCLC) is an aggressive lung tumor subtype with poor prognosis(1-3). We sequenced 29 SCLC exomes, 2 genomes and 15 transcriptomes and found an extremely high mutation rate of 7.4 +/- 1 protein-changing mutations per million base pairs. Therefore, we conducted integrated analyses of the various data sets to identify pathogenetically relevant mutated genes. In all cases, we found evidence for inactivation of TP53 and RB1 and identified recurrent mutations in the CREBBP, EP300 and MLL genes that encode histone modifiers. Furthermore, we observed mutations in PTEN, SLIT2 and EPHA7, as well as focal amplifications of the FGFR1 tyrosine kinase gene. Finally, we detected many of the alterations found in humans in SCLC tumors from Tp53 and Rb1 double knockout mice(4). Our study implicates histone modification as a major feature of SCLC, reveals potentially therapeutically tractable genomic alterations and provides a generalizable framework for the identification of biologically relevant genes in the context of high mutational background.