The Blueprint (BP) Programmed Death Ligand 1 (PD-L1) Immunohistochemistry Comparability Project is a pivotal academic/professional society and industrial collaboration to assess the feasibility of ...harmonizing the clinical use of five independently developed commercial PD-L1 immunohistochemistry assays. The goal of BP phase 2 (BP2) was to validate the results obtained in BP phase 1 by using real-world clinical lung cancer samples.
BP2 were conducted using 81 lung cancer specimens of various histological and sample types, stained with all five trial-validated PD-L1 assays (22C3, 28-8, SP142, SP263, and 73-10); the slides were evaluated by an international panel of pathologists. BP2 also assessed the reliability of PD-L1 scoring by using digital images, and samples prepared for cytological examination. PD-L1 expression was assessed for percentage (tumor proportional score) of tumor cell (TC) and immune cell areas showing PD-L1 staining, with TCs scored continuously or categorically with the cutoffs used in checkpoint inhibitor trials.
The BP2 results showed highly comparable staining by the 22C3, 28-8 and SP263 assays; less sensitivity with the SP142 assay; and higher sensitivity with the 73-10 assay to detect PD-L1 expression on TCs. Glass slide and digital image scorings were highly concordant (Pearson correlation >0.96). There was very strong reliability among pathologists in TC PD-L1 scoring with all assays (overall intraclass correlation coefficient ICC = 0.86–0.93), poor reliability in IC PD-L1 scoring (overall ICC = 0.18–0.19), and good agreement in assessing PD-L1 status on cytological cell block materials (ICC = 0.78–0.85).
BP2 consolidates the analytical evidence for interchangeability of the 22C3, 28-8, and SP263 assays and lower sensitivity of the SP142 assay for determining tumor proportion score on TCs and demonstrates greater sensitivity of the 73-10 assay compared with that of the other assays.
Background
Several studies have investigated the diagnostic accuracy of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) for pancreatic lesions, but they have included only limited ...patient populations. This study aimed to clarify the diagnostic accuracy of EUS-FNA in a large number of pancreatic lesions, and to describe the factors that influence it.
Methods
From March 1997 to May 2010, 944 consecutive patients who had undergone EUS-FNA for pancreatic solid lesions were evaluated retrospectively. Factors affecting EUS-FNA accuracy were then analyzed.
Results
A total of 996 solid pancreatic lesions were sampled by EUS-FNA. The overall sampling adequacy and diagnostic accuracy of these lesions were 99.3 % (989/996) and 91.8 % (918/996), respectively. The sensitivity and specificity for differentiating malignant from benign lesions were 91.5 % (793/867) and 97.7 % (126/129), respectively. The diagnostic performance was significantly higher when both cytological and cell-block examinations were carried out than with only cytological examination. In multivariate analysis, final diagnosis, location of lesion, lesion size, availability of on-site cytopathological evaluation, and experience of EUS-FNA procedure were independent factors affecting the accuracy of EUS-FNA. On-site cytopathological evaluation and lesion size were found to be the most weighted factors affecting diagnostic accuracy.
Conclusions
EUS-FNA for pancreatic solid lesions yielded a high accuracy and low complication rate. Both cytological and cell-block preparations and on-site cytopathological evaluation contributed to improve the accuracy. The diagnostic ability of EUS-FNA was less for smaller lesions, and repeated procedures may be needed if malignancy is suspected.
Background
The heterotopic submucosal gland (HSG) is a common incidental finding in gastrectomy specimens. The majority of HSGs are small incidental lesions, which are also known as gastritis cystica ...profunda. However, larger lesions may appear as an inverted growth of well-organized mucosa referred to as gastric inverted polyps.
Methods
To determine whether genetic alterations are involved in HSG development, we analyzed 63 gastric HSG lesions using targeted next-generation sequencing and immunohistochemistry.
Results
Histologically, HSG lesions consistently had areas of pyloric gland differentiation with variable extent of foveolar differentiation. Although the background mucosa showed intestinal metaplasia in most cases (98%), intestinal-type epithelium was seen in only one HSG lesion (2%). Sequencing analysis identified activating
KRAS
,
BRAF
,
CTNNB1
, and
GNAS
mutations in 34 (54%), 1 (2%), 1 (2%), and 7 (11%) lesions, respectively. HSG lesions harboring a
KRAS
mutation were more likely to present extensive foveolar differentiation (
P
= 0.013) and absence of parietal cells (
P
= 0.0081). Five HSG lesions had a dysplastic component, and concordant genetic alterations were detected between the non-dysplastic and dysplastic areas of two lesions that were successfully analyzed. Immunohistochemical staining demonstrated diffuse expression of mutant KRAS protein in lesions with the most common genetic alteration,
KRAS
G12D.
Conclusions
Our study demonstrated that a major proportion of HSGs were proliferative lesions associated with oncogenic mutations, with more than half of lesions harboring activating
KRAS
mutations.
Epidermal growth factor receptor (EGFR) exon 20 insertion mutations (Exon20ins) account for 4-12% of all EGFR mutations in non-small cell lung cancer (NSCLC) patients. Data on the differences in ...clinical characteristics between patients with Exon20ins and major mutations (M-mut) such as exon 19 deletion and L858R are limited. We retrospectively reviewed advanced NSCLC patients with EGFR mutations, who were treated with systemic therapy between January 2011 and December 2019. We identified 23 patients with Exon20ins and 534 patients with M-mut. In Exon20ins patients, the median age was 60 (range 27-88) years, and females and never-smokers were predominant. Clinical characteristics were similar in the two groups. In Exon20ins patients, 17 patients received platinum doublet as first-line therapy, and the overall response rate (ORR) and median progression-free survival (mPFS) were 11.8% and 8.9 months. Additionally, seven patients received conventional EGFR-tyrosine kinase inhibitors (TKIs), and eight patients anti-PD-1 antibodies in any-line therapy. ORR and mPFS of EGFR-TKIs and anti-PD-1 antibodies were 0%, 2.2 months and 25%, 3.1 months, respectively. Overall survival was significantly shorter in Exon20ins patients than in M-mut patients (29.3 vs. 43.4 months, p = 0.04). The clinical outcomes in Exon20ins patients were not satisfactory compared to M-mut patients.
There is a dearth of knowledge about the pathogenesis of premalignant lung lesions, especially for atypical adenomatous hyperplasia (AAH), the only known precursor for the major lung cancer subtype ...adenocarcinoma (LUAD). In this study, we performed deep DNA and RNA sequencing analyses of a set of AAH, LUAD, and normal tissues. Somatic
variants were found in AAHs from 5 of 22 (23%) patients, 4 of 5 of whom had matched LUAD with driver
mutations.
mutations were present in AAHs from 4 of 22 (18%) of patients.
mutations in AAH were only found in ever-smokers and were exclusive to
-mutant cases. Integrative analysis revealed profiles expressed in
-mutant cases (
) and
-mutant cases (
) of AAH, or common to both sets of cases (suppressed
). Gene sets associated with suppressed antitumor (Th1;
) and elevated protumor (
) immune signaling were enriched in AAH development and progression. Our results reveal potentially divergent
or
pathways in AAH as well as immune dysregulation in the pathogenesis of this premalignant lung lesion.
.
The EML4 (echinoderm microtubule-associated protein-like 4)-ALK (anaplastic lymphoma kinase) fusion-type tyrosine kinase is an oncoprotein found in 4 to 5% of non-small-cell lung cancers, and ...clinical trials of specific inhibitors of ALK for the treatment of such tumors are currently under way. Here, we report the discovery of two secondary mutations within the kinase domain of EML4-ALK in tumor cells isolated from a patient during the relapse phase of treatment with an ALK inhibitor. Each mutation developed independently in subclones of the tumor and conferred marked resistance to two different ALK inhibitors. (Funded by the Ministry of Health, Labor, and Welfare of Japan, and others.).
Aims
Molecular targeted therapy against EGFR kinase domain mutations has been successfully established for lung cancer. These mutations have now also been reported in head and neck tumours, ...particularly in inverted sinonasal papillomas (ISPs). The aim of this study was to clarify the spectrum of EGFR mutations in head and neck squamous cell carcinomas and papillomas.
Methods and results
We examined EGFR mutations in 288 head and neck squamous cell carcinomas and 58 head and neck papillomas or polyps. EGFR mutations were detected in 24 (30%) of 80 sinonasal squamous cell carcinomas (SNSCCs) and in 19 (90%) of 21 ISPs. Notably, 15 (88%) of 17 SNSCCs that developed along with ISPs harboured EGFR mutations in both components, whereas EGFR mutations were detected in nine (14%) of 63 SNSCCs without any papilloma component. Analysis to detect other known driver oncogene mutations – KRAS, BRAF and HER2 – was also performed; none of these mutations was detected in SNSCCs. The other 208 non‐sinonasal carcinomas and 37 non‐ISP head and neck papillomas or polyps did not harbour EGFR mutations.
Conclusions
Taken together with the specific involvement of EGFR mutations in ISP, a molecular benign lesion trail suggests that 26 (33%) of 80 SNSCCs developed in association with an ISP. SNSCCs with EGFR mutations may be biologically distinct among head and neck cancers.
The discovery in 2004 of activating mutations in the EGFR gene opened the era of personalized medicine in thoracic oncology. Treatment with drugs that target EGFR typically results in dramatic tumour ...response compared with conventional chemotherapy in patients with non-small-cell lung cancer. Subsequently, newer driver oncogenes such as ALK, ROS1 and RET have been discovered. Nevertheless, surgery has become safer and less invasive in the past 10-15 years. In the era of personalized medicine, thoracic surgeons have to think about their evolving roles. In this article, we discuss four topics relevant to this issue. Firstly, the value of surgical specimens as opposed to biopsy specimens for further understanding tumour biology is discussed. Secondly, extended indication of surgery in the era of targeted therapy is considered. Thirdly, in clinical trials that examine neoadjuvant therapy in patients selected by appropriate biomarkers, the important role of surgeons is highlighted. Finally, the possibility of personalizing the surgical procedure itself according to lung cancer subtypes defined by biomarkers is reviewed.
Abstract
Background
The Oncomine™ Dx Target Test based on next-generation sequencing has been approved for the screening of oncogenic mutations in advanced non-small-cell lung cancer patients.
...Methods
We assessed the tissue sample factors that affect the success rate of Oncomine™ Dx Target Test companion diagnostics and the feasibility of using biopsy specimens for Oncomine™ Dx Target Test companion diagnostics in advanced non-small-cell lung cancer patients.
Results
Ninety-nine biopsy samples were subjected to genetic testing using the Oncomine™ Dx Target Test companion diagnostics to detect v-raf murine sarcoma viral oncogene homologue B1 mutations (Cohort 1), and 136 biopsy samples were examined using Oncomine™ Dx Target Test companion diagnostics for the detection of multiple oncogenic mutations (Cohort 2) between July 2018 and April 2020. We retrospectively collected clinical and pathological data, including tissue size and tumour cell content. The success rate was 77% (76/99) in Cohort 1 and 93% (127/136) in Cohort 2. In Cohort 1, the success rate was significantly associated with the tumour cell content: the success rate was 63% for samples with a tumour cell content of <20%, whereas it was 83% for samples with a tumour cell content of 20% or higher (P = 0.0446). The tissue size also affected the success rate: a success rate of 57% was obtained for tissue sizes <4 mm2, whereas a success rate of 95% was obtained for tissue sizes of 4 mm2 or larger (P < 0.0001). In Cohort 2, the success rate was 100% when tumour specimens with a tissue size of 4 mm2 or larger were used.
Conclusions
Tissue size and tumour cell content were significantly associated with the success rate of Oncomine™ Dx Target Test companion diagnostics.
We identified both tumour cell content (20% or more) and tissue sample size (4 mm2 or more) affected the success rate of Oncomine™ Dx Target Test in patients with advanced non-small-cell lung cancer.
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