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Context.--The addition of cetuximab to first-line chemotherapy substantially prolonged survival in patients with advanced non-small cell lung cancer whose tumors expressed high levels of epidermal growth factor receptor (EGFR; immunohistochemistry score of ≥200 on a scale of 0-300). Objective.--To evaluate the interobserver reproducibility of this EGFR immunohistochemistry scoring system, based on both the tumor cell membrane staining intensity (graded 0-3+) and the percentage of cells staining at each intensity. Design.--In parts 1 (initial feasibility study) and 2 of this 2-part round robin test, sections of different non-small cell lung cancer tissue microarrays were stained in a central reference laboratory. Following reference evaluation, EGFR expression in 30 selected tumor cores was characterized in serial sections by lung cancer pathology specialists. The reproducibility of scoring by different raters was assessed. Analysis of between-rater agreement was based on the allocation of EGFR immunohistochemistry scores into low- (<200) and high- (≥200) EGFR expression groups. Results.--After discussion with raters of the issues impacting reproducibility identified in part 1 and following adjustment of processes, part 2 of the round robin test showed a high interobserver agreement in EGFR immunohistochemistry scoring, with an overall concordance rate of 90.9% and a mean coefficient of 0.812. Specimens with a reference EGFR immunohistochemistry score of lower than 200 and of 200 or higher showed mean concordance rates of 94.7% and 85.6%, respectively. Conclusions.--After appropriate training, assessing EGFR expression by this immunohistochemistry-based method allowed a highly reproducible allocation of non- small cell lung cancers into clinically relevant high- or low-EGFR expression groups. [ABSTRACT FROM AUTHOR]

The article presents a case study of the never smoker 62-year-old woman who was admitted due to the possible hydroxycarbamide-induced pneumonitis. It states that the woman experienced months of non-productive cough and increasing breathlessness on exertion. It mentions that prior to her ailment, she was administered to take hydroxycarbamide 500 mg daily for 12 years. In conclusion, it declares that the patient suffered from hydroxycarbamide-induced pneumonitis because it was seen in lung biopsy.

A case study of a 20-year-old woman presented with haematemesis and diagnosed with pulmonary chondromas.

• KRAS is the most commonly mutated oncogene in advanced NSCLC in Western countries. • KRAS G12C is the most common KRAS variant at ∼13% of NSCLC cases overall. • Approved RAS GTPase inhibitors transform KRASG12C into a predictive biomarker. • Real-world studies show significant geographic variation in KRAS G12C prevalence. • Prospective studies required to ascertain significance of co-mutations (STK11 / KEAP1) KRAS is the most commonly mutated oncogene in advanced, non-squamous, non-small cell lung cancer (NSCLC) in Western countries. Of the various KRAS mutants, KRAS G12C is the most common variant (~40%), representing 10–13% of advanced non-squamous NSCLC. Recent regulatory approvals of the KRASG12C-selective inhibitors sotorasib and adagrasib for patients with advanced or metastatic NSCLC harboring KRAS G12C have transformed KRAS into a druggable target. In this review, we explore the evolving role of KRAS from a prognostic to a predictive biomarker in advanced NSCLC, discussing KRAS G12C biology, real-world prevalence, clinical relevance of co-mutations, and approaches to molecular testing. Real-world evidence demonstrates significant geographic differences in KRAS G12C prevalence (8.9–19.5% in the US, 9.3–18.4% in Europe, 6.9–9.0% in Latin America, and 1.4–4.3% in Asia) in advanced NSCLC. Additionally, the body of clinical data pertaining to KRAS G12C co-mutations such as STK11 , KEAP1, and TP53 is increasing. In real-world evidence, KRAS G12C -mutant NSCLC was associated with STK11, KEAP1, and TP53 co-mutations in 10.3–28.0%, 6.3–23.0%, and 17.8–50.0% of patients, respectively. Whilst sotorasib and adagrasib are currently approved for use in the second-line setting and beyond for patients with advanced/metastatic NSCLC, testing and reporting of the KRAS G12C variant should be included in routine biomarker testing prior to first-line therapy. KRAS G12C test results should be clearly documented in patients' health records for actionability at progression. Where available, next-generation sequencing is recommended to facilitate simultaneous testing of potentially actionable biomarkers in a single run to conserve tissue. Results from molecular testing should inform clinical decisions in treating patients with KRAS G12C -mutated advanced NSCLC. [ABSTRACT FROM AUTHOR]

Aortic valve stenosis is the most common valve disease in the western world. Central to the pathogenesis of this disease is the growth of new blood vessels (angiogenesis) within the aortic valve allowing infiltration of immune cells and development of intra-valve inflammation. Identifying the cellular mediators involved in this angiogenesis is important as this may reveal new therapeutic targets which could ultimately prevent the progression of aortic valve stenosis. Aortic valves from patients undergoing surgery for aortic valve replacement or dilation of the aortic arch were examined both ex vivo and in vitro. We now demonstrate that the anti-angiogenic protein, soluble fms-like tyrosine kinase 1 (sFlt1), a non-signalling soluble receptor for vascular endothelial growth factor, is constitutively expressed in non-diseased valves. sFlt-1 expression was, however, significantly reduced in aortic valve tissue from patients with aortic valve stenosis while protein markers of hypoxia were simultaneously increased. Exposure of primary-cultured valve interstitial cells to hypoxia resulted in a decrease in the expression of sFlt-1. We further reveal using a bioassay that siRNA knock-down of sFlt1 in valve interstitial cells directly results in a pro-angiogenic environment. Finally, incubation of aortic valves with sphingosine 1-phosphate, a bioactive lipid-mediator, increased sFlt-1 expression and inhibited angiogenesis within valve tissue. In conclusion, this study demonstrates that sFlt1 expression is directly correlated with angiogenesis in aortic valves and the observed decrease in sFlt-1 expression in aortic valve stenosis could increase valve inflammation, promoting disease progression. This could be a viable therapeutic target in treating this disease. [Display omitted] • sFlt1, an anti-angiogenic protein, is downregulated in patients with aortic valve stenosis. • Hypoxia downregulates sFlt1 expression in human aortic valvular interstitial cells. • sFlt1 is essential for maintaining avascularity in the aortic valve. • The endogenous lipid mediator, sphingosine 1-phosphate, can inhibit blood vessel growth in human aortic valves. • Sphingosine 1-phosphate can increase sFlt1 expression in the aortic valve. [ABSTRACT FROM AUTHOR]

A 44-year-old woman who had recently been on immunosuppressive therapy presented with malaise, cough, fever, weight loss, lymphadenopathy, severe hypercalcaemia and a paratracheal mass on imaging. The initial impression was of disseminated malignancy, and lymphoma was suspected. A mediastinal biopsy showed a mycobacterial spindle cell pseudotumour containing acid and alcohol fast bacilli (AAFB). Sputum microscopy demonstrated AAFBs, confirmed as Mycobacterium tuberculosis complex by PCR. Prolonged culture grew Mycobacterium microti, an organism often associated with disease in small rodents and llamas. M microti isolates from postmortem samples of an alpaca at a nearby farm were genetically indistinguishable. Although the patient had not visited the farm, concurrent illness in her adopted stray cat suggested a possible zoonotic connection. The patient responded to antituberculous therapy, and rehydration and pamidronate for hypercalcaemia. We believe the hypercalcaemia was caused by a similar mechanism to raised calcium levels sometimes seen in tuberculosis. [ABSTRACT FROM AUTHOR]

• ROS1 was assessed in a retrospective cohort of surgically resected NSCLC. • ROS1 was correlated to outcome variables/results from previous biomarker projects. • ROS1 IHC by SP384 clone is useful for exclusion of ROS1 gene fusion negative cases. ROS1 fusion is a relatively low prevalence (0.6–2.0%) but targetable driver in lung adenocarcinoma (LUAD). Robust and low-cost tests, such as immunohistochemistry (IHC), are desirable to screen for patients potentially harboring this fusion. The aim was to investigate the prevalence of ROS1 fusions in a clinically annotated European stage I-III LUAD cohort using IHC screening with the in vitro diagnostics (IVD)-marked clone SP384, followed by confirmatory molecular analysis in pre-defined subsets. Resected LUADs constructed in tissue microarrays, were immunostained for ROS1 expression using SP384 clone in a ready-to-use kit and Ventana immunostainers. After external quality control, analysis was performed by trained pathologists. Staining intensity of at least 2+ (any percentage of tumor cells) was considered IHC positive (ROS1 IHC +). Subsequently, ROS1 IHC + cases were 1:1:1 matched with IHC0 and IHC1 + cases and subjected to orthogonal ROS1 FISH and RNA-based testing. The prevalence of positive ROS1 expression (ROS1 IHC +), defined as IHC 2+/3+, was 4 % (35 of 866 LUADs). Twenty-eight ROS1 IHC + cases were analyzed by FISH/RNA-based testing, with only two harboring a confirmed ROS1 gene fusion, corresponding to a lower limit for the prevalence of ROS1 gene fusion of 0.23 %. They represent a 7 % probability of identifying a fusion among ROS1 IHC + cases. Both confirmed cases were among the only four with sufficient material and H-score ≥ 200, leading to a 50 % probability of identifying a ROS1 gene fusion in cases with an H-score considered strongly positive. All matched ROS1 IHC- (IHC0 and IHC1 +) cases were also found negative by FISH/RNA-based testing, leading to a 100 % probability of lack of ROS1 fusion for ROS1 IHC- cases. The prevalence of ROS1 fusion in an LUAD stage I-III European cohort was relatively low. ROS1 IHC using SP384 clone is useful for exclusion of ROS1 gene fusion negative cases. [ABSTRACT FROM AUTHOR]

Several observations indicate that protein expression analysis by immunohistochemistry (IHC) remains relevant in individuals with non-small-cell lung cancer (NSCLC) when considering targeted therapy, as an early step in diagnosis and for therapy selection. Since the advent of next-generation sequencing (NGS), the role of IHC in testing for NSCLC biomarkers has been forgotten or ignored. We discuss how protein-level investigations maintain a critical role in defining sensitivity to lung cancer therapies in oncogene- and non-oncogene-addicted cases and in patients eligible for immunotherapy, suggesting that IHC testing should be reconsidered in clinical practice. We also argue how a panel of IHC tests should be considered complementary to NGS and other genomic assays. This is relevant to current clinical diagnostic practice but with potential future roles to optimize the selection of patients for innovative therapies. At the same time, strict validation of antibodies, assays, scoring systems, and intra- and interobserver reproducibility is needed. [Display omitted] • Molecular abnormalities in patients with NSCLC with adenocarcinoma histology are now targets for treatment. • Since the advent of NGS, the role of IHC in testing for NSCLC biomarkers has been forgotten or ignored. • Protein-level investigations maintain a critical role in defining sensitivity to lung cancer therapies. • A panel of IHC tests should be considered complementary to NGS and other genomic assays, to optimize the patients selection. • Strict validation of antibodies, assays, scoring systems, and intra- and interobserver reproducibility is needed. [ABSTRACT FROM AUTHOR]

• Routine molecular testing in stage I–III NSCLC has not been required to date. • However, targeted agents are undergoing trials in adjuvant and neoadjuvant settings. • Adjuvant osimertinib was recently approved for EGFR m (ex19del/L858R) resected NSCLC. • Molecular testing in stage I–III NSCLC will be necessary in the near future. • We discuss opportunities/challenges of integrating molecular testing into practice. Precision medicine in non-small cell lung cancer (NSCLC) is a rapidly evolving area, with the development of targeted therapies for advanced disease and concomitant molecular testing to inform clinical decision-making. In contrast, routine molecular testing in stage I–III disease has not been required, where standard of care comprises surgery with or without adjuvant or neoadjuvant chemotherapy, or concurrent chemoradiotherapy for unresectable stage III disease, without the integration of targeted therapy. However, the phase 3 ADAURA trial has recently shown that the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), osimertinib, reduces the risk of disease recurrence by 80% versus placebo in the adjuvant setting for patients with stage IB–IIIA EGFR mutation-positive NSCLC following complete tumor resection with or without adjuvant chemotherapy, according to physician and patient choice. Treatment with adjuvant osimertinib requires selection of patients based on the presence of an EGFR-TKI sensitizing mutation. Other targeted agents are currently being evaluated in the adjuvant and neoadjuvant settings. Approval of at least some of these other agents is highly likely in the coming years, bringing with it in parallel, a requirement for comprehensive molecular testing for stage I–III disease. In this review, we consider the implications of integrating molecular testing into practice when managing patients with stage I–III non-squamous NSCLC. We discuss best practices, approaches and challenges from pathology, surgical and oncology perspectives. [ABSTRACT FROM AUTHOR]