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Up to 50% of patients with non-small cell lung cancer (NSCLC) develop brain metastasis (BM), yet the study of BM genomics has been limited by tissue access, incomplete clinical data, and a lack of comparison with paired extracranial specimens. Here we report a cohort of 233 patients with resected and sequenced (MSK-IMPACT) NSCLC BM and comprehensive clinical data. With matched samples (47 primary tumor, 42 extracranial metastatic), we showed CDKN2A/B deletions and cell cycle pathway alterations to be enriched in the BM samples. Meaningful clinico-genomic correlations were noted, namely EGFR alterations in leptomeningeal disease (LMD) and MYC amplifications in multifocal regional brain progression. Patients who developed early LMD frequently had uncommon, multiple, and persistently detectable EGFR driver mutations. The distinct mutational patterns identified in BM specimens compared to other tissue sites suggest specific biologic underpinnings of intracranial progression.

KRAS G12C inhibitors, such as sotorasib, have rapidly moved through clinical development and are poised to transform care of patients with KRAS G12C mutant cancers, in particular non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). Clinical efficacy is achieved in NSCLC as a single agent and in CRC in combination with anti-EGFR monoclonal antibodies, however, secondary resistance impairs the effects of KRAS G12C blockade. In this work, we sought to determine the mechanisms of acquired resistance to concomitant KRAS-EGFR inhibition. In cell lines, patient-derived xenograft, and patient samples, a heterogeneous pattern of putative resistance alterations expected primarily to prevent inhibition of ERK signalling by drug can be detected at progression. Serial analysis of patient blood samples on treatment demonstrates that most of these alterations are detected at a low frequency that does not increase substantially and sometimes disappears over time, with the exception of KRAS G12C amplification which rises in step with tumour marker levels and clinical progression. Here we show that a CRC cell line that acquired resistance to sotorasib-cetuximab combination through KRAS G12C amplification became addicted to these agents and undergoes oncogene-induced senescence upon drug withdrawal. Accordingly, the KRAS G12C signal in circulating DNA from relapsed patients harbouring G12C amplification rapidly recedes upon treatment holiday. These data indicate that KRAS G12C amplification is a recurrent resistance mechanism to KRAS-EGFR co-inhibition and suggest a potential therapeutic vulnerability, whereby therapies that target this senescence response at drug withdrawal may overcome resistance to KRAS G12C-EGFR inhibition.

This paper investigates the impact of tax variables and subsidy policy on real house prices, controlling for fundamental variables. The results show that the equilibrium price of housing is negatively associated with income tax rates, but positively associated with real construction costs, real land prices and the investor share in the market. House price fluctuations around their long‐run equilibrium are positively related to construction costs, land prices, and income, but negatively with income taxes. Negative gearing provisions have ambiguous effects, while stamp duty rates lack significance for house price movements on average. [ABSTRACT FROM AUTHOR] email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Introduction: Gallbladder carcinomas (GBC) are rare and aggressive neoplasms. Previous studies in small GBC cohorts have suggested potential molecular alterations associated with poor prognosis, however, a comprehensive understanding of the recurrent genetic events in this cancer type is very limited. In this study, we aim to characterize in detail the recurrent molecular alterations in GBC and their association with pathologic and clinical characteristics. Material and Methods: We studied the prevalence of somatic mutations and copy number alterations (CNA) in n=244 GBC samples (54% primary, 56% metastatic), collected from 2014 to 2021, and sequenced with the targeted NGS panel MSK-IMPACT. We assessed the correlation of the recurrent genomic variants with several pathologic (e.g., T stage, N stage, grade, histologic subtypes) and clinical characteristics (e.g., clinical stage) using Fisher's exact test. We also used Cox Proportional-Hazards modeling to assess the correlation between genetic variants and patient overall survival (OS). Results: The most common histologic subtypes in this GCB cohort included adenocarcinomas NOS (83%), carcinomas with squamous differentiation (9%), high-grade carcinomas (4%), and carcinomas with neuroendocrine differentiation (3%). Most patients were diagnosed with stage IV (65%) and stage III (11%) disease at the time of biopsy/resection, and the mean OS survival was 29.4 months. The most commonly mutated genes were TP53 (59%), SMAD4 (21%), ARID1A (19%), PIK3CA (10%), KRAS (7%), and ERBB2 (7%). Potentially recurrent oncogenic CNAs included deep deletions in CDKN2A (14%) and CDKN2B (14%), and amplifications in MDM2 (12%), ERBB2 (10%), CCNE1 (9%), MYC (7%), and KRAS (7%). RB1, PBRM1, and CTNNB1 variants were more common in cases with neuroendocrine differentiation, whereas alterations in IKZF1 and AGO2 were enriched in cases with squamous differentiation. The most significant event associated with shorted OS was chromosome 12q13-15 amplification i.e., CDK4 p=0.03 HR=2 [95% CI 1-3.6] and MDM2 p=0.05 HR=1.6 [1-2.5], which associated with a median OS of 20 months (vs. 34 months in the wild-type). Genomic variants associated with longer OS included ERBB2 (p=0.006 HR=0.2 [0.06-0.6]), KMT2C (p=0.03 HR=0.2 [0.1-0.9]) and KMT2D (p=0.01 HR=0.2 [0.04-0.7]) mutations, and CDK12 amplification (p=0.04 HR=0.4 [0.2-0.96]). Although ERBB2 amplification was not associated with prognosis, co-amplification of CDK12 and ERBB2 (chromosome 17q12) was frequently observed (Pearson correlation r=0.8). Conclusions: This large-scale genomic analysis reveals recurrent genomic events potentially associated with prognosis in GBC, including single nucleotide variants in ERBB2, KMT2C, and KMT2D, in addition to CNAs in chromosome 12q13-15 and 17q12 regions. This effort will continue to include a detailed analysis of recurrent structural variants, loss of heterozygosity loci, and analysis of the microbiota in this GBC cohort. Citation Format: Nicolas A. Giraldo, Abhinita Mohanty, Chad Vanderbilt, Rose Brannon, Ryma Benayed, Efsevia Vakiani, Ghassan Abou-Alfa, James Harding, Imane El Dika, Nikolaus Schultz, Bob Li, Michael F. Berger, Marc Ladanyi, Eileen O'Reilly, William Jarnagin, Olca Basturk, Maria Arcila. Molecular characterization of gallbladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 82.

Using an alternative measure for abnormal trading volume, this article examines the role of volume shock in the generation of stock returns. We find a strong high volume effect at both portfolio and individual stock levels. A strategy that buys stocks experiencing high volume shocks and sells stocks experiencing low volume shocks generates positive returns up to 12 months after formation. The effect is robust after controlling for other stock characteristics that are known to affect stock returns. Our results show that trading volume becomes relatively higher after high volume shocks. Moreover, the relation between volume shocks and stock returns is stronger for stocks that previously failed to catch investors' attention. This finding is consistent with the view that abnormal trading volume proxies for unobserved attention-grabbing events. However, we find no evidence that volume shocks are priced.

Contradictory results are documented in the literature regarding which type of mutual fund has superior performance; an Islamic or conventional mutual fund. Due to the relative short history of the Islamic mutual funds' industry, prior literature has inevitably relied on a small sample size with a short sample period. With the longest applicable sample period, this study represents one of the most recent attempts to address this conflicting evidence. We find there is no clear cut over performance by Islamic mutual funds against their conventional peers across the three financial crises in our sample period, with the exception of the most recent global financial crisis, where Islamic mutual funds generally outperformed their conventional counterparts. We further find that Islamic funds significantly outperformed conventional funds in the riskiest asset class, equity, one year before and during the global financial crisis. We further reveal that the modified value at risk for Islamic mutual funds was significantly lower than their conventional peers during the global financial crisis. This seems to indicate that Islamic mutual funds have better risk management compared to conventional peers.

This research offers fresh evidence supporting the pervasiveness of the momentum effect. Two decades after the momentum profitability firstly documented by Jegadeesh and Titman (1993), yet little research has been specifically devised for the momentum profitability on Shari'ah compliant stocks. We assess the momentum profitability over the Shari'ah compliant stocks in a Malaysian setting. We find evidence of strong return persistence as far as toward four-year holding period. Interestingly, no significant momentum returns are found among the conventional stocks. Upon further exploration we find neither an industry-driven momentum effect nor the small size firms can account for the momentum returns. Using return persistency formation criteria, we further find that underreaction seems to well fit in explaining this unique long lasting momentum profitability.

N-of-1 trials provide a mechanism for making evidence-based treatment decisions for an individual patient. They use key methodological elements of group clinical trials to evaluate treatment effectiveness in a single patient, for situations that cannot always accommodate large-scale trials: rare diseases, comorbid conditions, or in patients using concurrent therapies. Improvement in the reporting and clarity of methods and findings in N-of-1 trials is essential for reader to gauge the validity of trials and to replicate successful findings. A Consolidated Standards of Reporting Trials (CONSORT) extension for N-of-1 trials (CENT 2015) provides guidance on the reporting of individual and series of N-of-1 trials. CENT provides additional guidance for 14 of the 25 items of the CONSORT 2010 checklist, recommends a diagram for depicting an individual N-of-1 trial, and modifies the CONSORT flow diagram to address the flow of a series of N-of-1 trials. The rationale, development process, and CENT 2015 checklist and diagrams are reported in this document.

We confirm the negative relation between short-selling risk and stock returns in the US. We estimate a measure of dynamic short-selling risk in Australia and find a similar negative relation in Australia. The negative relation is more pronounced amongst small Australian stocks, but is absent in large Australian stocks. Australian stocks have lower equity loan supply and short interest, but higher equity loan fees and longer loan length than US stocks. The higher variation in equity loan utilization rate and loan characteristics in Australian stocks possibly contribute to their higher short-selling risk compared to their US counterparts.

It is well documented that past winning stocks continue to outperform past losing stocks in numerous equity markets. However, existing Australian evidence on the momentum effect is contradictory and limited, partly due to differences in empirical designs, sample periods and stock populations. We assess the momentum profitability over the most eligible stocks which are constituents of the S&P/ASX200 index. These stocks represent the principal equity investment universe for institutional investors and managed funds due to their sufficient size and liquidity which make the momentum trading strategies practical and implementable. By incorporating the short-selling ban during the global financial crisis, we find evidence of return persistence. The momentum effect is most pronounced amongst winning stocks for longer holding periods. Upon further exploration we find that neither an industry-driven momentum effect nor common risk factors can fully account for the momentum effect.

It is widely accepted that some firms' attributes or characteristics, such as a firm's size or book-to-market ratio, attract premiums in terms of average returns, which is a pervasive phenomenon not restricted to just a few individual markets. However, the way to derive these premiums by sorting firms based on their characteristics that are known to be associated with share returns, is not without controversy. This study takes a totally different approach by adopting a novel Self-Organizing Maps approach to cluster share returns first and identify the attributable factors afterwards. It finds eminent presence of the value effect in the Chinese A-shares market. It also finds that two other firm attributes, ROA and cash-flow-to-price, also have explanatory power over share returns. Liquidity and the ratio of tradable to total shares, which are often used to proxy corporate governance, show little evidence of explaining share return dispersion. Surprisingly, a “reversed” size effect is reported in this study.

Purpose Ever since the publication of the original Jegadeesh and Titman (1993) study, momentum effect has been tested vigorously to validate its pervasiveness for different time periods and across different markets. In spite of numerous out-of-sample tests, there is one apparent alibi – little research has been devised for steady increasing of Shari’ah compliant stocks. Methodology/approach This study is to examine the momentum strategy returns in a global Shari’ah compliant stock setting. Findings It finds strong presence of stock momentum returns for Pakistan and Malaysia. And the momentum returns are neither driven by industry momentum nor by the small size stocks. Though no momentum profits are found for the portfolios formed by global Shari’ah compliant stocks, this seems to be largely due to return reversal for the small size Shari’ah compliant stocks. Originality/value The strong presence of momentum profits for relatively large Shari’ah compliant stocks is a desirable trait as it indicates that the momentum trading strategies are practical and implementable.

A firm’s book equity is a measure of the value held by a firm’s ordinary shareholders. Increasingly, it is being reported as a negative number. Because a firm’s limited liability structure means that shareholders cannot have negative value, negative book equity has no obvious interpretation. Consequently, both practitioners and academics typically omit such stocks in their analysis. While these stocks are small in number, they are disproportionately represented in extreme growth–value sectors and, therefore, can have an impact on applications where value is defined in terms of book equity. The authors propose a new approach that classifies negative book equity stocks across the growth–value spectrum by considering how close their returns correspond to those of stocks that fit more obviously into these classifications. They find that this new value factor, which includes negative book equity stock, is economically and statistically different from the old value factor that excludes such stocks. Although they illustrate how this approach can be used to classify negative book equity stock, the approach is quite general and may be used whenever particular accounting data are unavailable or otherwise suspect.

N-of-1 trials are a useful tool for clinicians who want to determine the effectiveness of a treatment in a particular individual. The reporting of N-of-1 trials has been variable and incomplete, hindering their usefulness in clinical decision making and by future researchers. This document presents the CONSORT (Consolidated Standards of Reporting Trials) extension for N-of-1 trials (CENT 2015). CENT 2015 extends the CONSORT 2010 guidance to facilitate the preparation and appraisal of reports of an individual N-of-1 trial or a series of prospectively planned, multiple, crossover N-of-1 trials. CENT 2015 elaborates on 14 items of the CONSORT 2010 checklist, totalling 25 checklist items (44 sub-items), and recommends diagrams to help authors document the progress of one participant through a trial or more than one participant through a trial or series of trials, as applicable. Examples of good reporting and evidence based rationale for CENT 2015 checklist items are provided.

The stage of a patient's cancer at diagnosis is essential to predict the prognosis and plan the treatment. Since 2008, stage data have been collected on all Ontario patients with breast, colorectal, lung and prostate cancers and are linked to other data collected by Cancer Care Ontario. Here, an analysis of such data is presented. How it can be used to assess the value of screening programs, inform resource allocation, evaluate compliance with treatment guidelines, compare survival trends and enhance the spectrum of cancer control activities across the province is demonstrated. International comparisons can also be made.

A 2-stage acceleration theory for luminous flux depreciation testing at LED lamp/luminaire level is developed to reduce the test time from 6,000 hours to less than 2,000 hours. Such an acceleration theory is based on the exponential decay model and Arrhenius acceleration equation. Three key parameters, namely, activation energy, operating junction temperature, and accelerated testing junction temperature are obtained from massive proven LM80 data sets, nominal junction design temperature, and maximum allowed ambient temperature in operating conditions. A “master curve” that describes the minimum requirement of the luminous decay is defined, and the curve is associated with a certain design junction temperature. Such a design junction temperature matches the maximum junction temperature where LM80 data are enveloped in the master curve. The corresponding acceleration test procedures have been established by considering the currently available measurement capabilities. Considerable amount of representative lamp/luminaire samples, which directly came from market, have been tested to validate the theory. The results show that the proposed accelerated lifetime test is equivalent to the current 6000h test. In addition, the newly developed accelerated test can eliminate those products with either poor LED sources, or poor system thermal design, or poor electronics system (including driver system) that cannot sustain sufficient temperature storage period.

It is widely accepted that the presence of some of the firm’s attributes or characteristics attracting premiums in terms of average returns is pervasive and not restricted to a few individual markets. However, the way to derive these premiums by sorting firms based on their characteristics that are known associated with share returns is not without controversy. This chapter takes a different approach by adopting a novel Multi Self-Organising Maps to cluster shares first and then identify fundamental factors afterwards. It finds that firm’s size and book-to-market ratio attributes do have explanatory power over share average returns. There is also lack of evidence for other factors in explaining the share average returns.

A firm's book equity is a measure of the value held by a firm's ordinary shareholders. Increasingly, it is being reported as a negative number. Since the firm's limited liability structure means that shareholders' value cannot be negative value, negative book equity has no obvious interpretation. Consequently, both practitioners and academics typically omit such stocks. While these stocks are small in number they are disproportionately represented in extreme value/growth sectors, and therefore can have an impact on applications where value is defined in terms of book equity. We propose a new approach that classifies negative book equity stocks across the value/growth spectrum by considering how close their returns correspond to stocks that fit more obviously into these classifications. We find that this new value factor, which includes negative book equity stock, is economically and statistically different from the old value factor that excludes such stocks. Although we illustrate how this approach can be used to classify negative book equity stock, the approach is quite general and may be used whenever particular accounting data are unavailable or otherwise suspect.