•Immune checkpoint inhibitors are the most promising treatment for advanced NSCLC.•Primary and acquired resistance to immune checkpoint inhibitors is common.•We examined biopsies taken from sites of ...acquired resistance or mixed responses.•Transformation from NSCLC to SCLC was identified as a mechanism of resistance.
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death world-wide. Immune checkpoint inhibitors (ICI) have become the most promising type of treatment in oncology in general, and significantly so in NSCLC. Limited data is available about mechanisms of primary resistance. Data is lacking about mechanisms involved in acquired resistance or mixed responses in NSCLC. We aimed to identify mechanisms of resistance by studying biopsies taken from sites of secondary progression.
We identified all cases of NSCLC that have received ICI for advanced disease in our institute. Of these cases, those that have demonstrated acquired resistance or mixed responses, and have underwent a biopsy from a progressive lesion were analyzed. Selected specimens were subjected to next-generation sequencing (NGS; Oncomine™ Solid Tumour Fusion Transcript Kit).
Out of 664 lung cancer cases, 249 were NSCLC that have received ICI. Of these, eight cases matched our search criteria. Two of them demonstrated transformation to small cell lung cancer (SCLC; 2/8, 25%). NGS verified a common origin to a matched pre-treatment NSCLC specimen and an on-treatment progressive SCLC specimen. In two cases no tumor cells were found and in the remaining four the pathology was similar to the initial biopsy. In one of the cases of SCLC transformation platinum-etoposide chemotherapy was administered, with short-term benefit only and further disease progression.
Mechanisms of acquired resistance to ICI include SCLC transformation. Repeat biopsies of progressing lesions after initial response or in cases of mixed response can shed light on mechanisms of resistance.
Abstract Objective The clinical significance of vertebral osteomyelitis and infectious endocarditis co-infection is unclear. This study investigates the rate, clinical features, and outcome of ...vertebral osteomyelitis with and without concomitant infectious endocarditis. Methods A retrospective study of all cases of osteomyelitis with spinal imaging (n = 176), from January 2007 to April 2013, that were diagnosed as vertebral osteomyelitis. Sixty-two patients with spontaneous vertebral osteomyelitis were identified after excluding postsurgical, decubitus ulcers and spinal metastases. Seventeen (27%) were identified with concomitant infectious endocarditis. Results All patients presented with back pain and 59% were diagnosed with infectious endocarditis subsequent to vertebral osteomyelitis. Distinguishing features among the co-infection group include the increased use of transesophageal echocardiography (94% vs 58%, P = .004), predisposing cardiac conditions (59% vs 16%, P = .001), and Gram-positive bacteremia, of which Streptococcus sp. and Enterococcus sp. were more common (35% vs 11%, P = .026). Adverse neurologic events were increased significantly in the co-infection group (59% vs 22%, P = .006). On transesophageal echocardiography, 88% of co-infection patients had highly mobile vegetations, 9 of which measured 10 mm or more. The overall mortality was 41% and 29% in the co-infection and lone vertebral osteomyelitis groups, respectively ( P = .356). One-year mortality was identical for both groups at 24% ( P = .999), and higher than previously reported (11.3% for lone vertebral osteomyelitis). Conclusions Patients with vertebral osteomyelitis, in whom infectious endocarditis is not excluded, are at increased risk for adverse neurologic events and mortality. The prompt diagnosis of infectious endocarditis, and associated high-risk features that may benefit from surgical intervention, require early evaluation by transesophageal echocardiography.
MicroRNAs (miRNAs) belong to a class of noncoding, regulatory RNAs that is involved in oncogenesis and shows remarkable tissue specificity. Their potential for tumor classification suggests they may ...be used in identifying the tissue in which cancers of unknown primary origin arose, a major clinical problem. We measured miRNA expression levels in 400 paraffin-embedded and fresh-frozen samples from 22 different tumor tissues and metastases. We used miRNA microarray data of 253 samples to construct a transparent classifier based on 48 miRNAs. Two-thirds of samples were classified with high confidence, with accuracy >90%. In an independent blinded test-set of 83 samples, overall high-confidence accuracy reached 89%. Classification accuracy reached 100% for most tissue classes, including 131 metastatic samples. We further validated the utility of the miRNA biomarkers by quantitative RT-PCR using 65 additional blinded test samples. Our findings demonstrate the effectiveness of miRNAs as biomarkers for tracing the tissue of origin of cancers of unknown primary origin.
To evaluate the prevalence of metastatic tumors involving the myocardium and study their presentation in order to increase awareness to their existence.
Pathological reports from Sheba Medical Center ...(Israel, January 1, 2010 through December 31, 2015) and medical records from The Institute for Cardiovascular Diseases of Vojvodina, Sremska Kamenica (Serbia, 23 years period) were screened for cases of metastatic cardiac tumors. Medical, radiological and pathological data of identified cases was retrieved and reviewed.
Out of thousands of registered cardiac surgeries we found less than a dozen cases of metastatic cardiac tumors classified as melanoma, carcinomas of lung, colon and kidney and sarcomas of uterine origin. We found that metastatic cardiac tumors comprised 15.8% of all the cardiac tumors.
Metastatic cardiac tumors are extremely rare. As new diagnostic technologies and improved survival of oncological patients may increase the incidence of metastatic cardiac tumors in the future, awareness to their existence and knowledge of their presentation are key factors in their timely recognition.
Systemic lupus erythematosus (SLE) comprise a diverse range of clinical manifestations. To date, more than 30 single gene causes of lupus/lupus like syndromes in humans have been identified. In the ...clinical setting, identifying the underlying molecular diagnosis is challenging due to phenotypic and genetic heterogeneity.
We employed whole exome sequencing (WES) in patients presenting with childhood-onset lupus with severe and/or atypical presentations to identify cases that are explained by a single-gene (monogenic) cause.
From January 2015 to June 2018 15 new cases of childhood-onset SLE were diagnosed in Edmond and Lily Safra Children's Hospital. By WES we identified causative mutations in four subjects in five different genes: C1QC, SLC7A7, MAN2B1, PTEN and STAT1. No molecular diagnoses were established on clinical grounds prior to genetic testing.
We identified a significant fraction of monogenic SLE etiologies using WES and confirm the genetic locus heterogeneity in childhood-onset lupus. These results highlight the importance of establishing a genetic diagnosis for children with severe or atypical lupus by providing accurate and early etiology-based diagnoses and improving subsequent clinical management.
Purpose: Brain metastases affect 25% of patients with non–small cell lung cancer (NSCLC). We hypothesized that the expression of genes
in primary NSCLC tumors could predict brain metastasis and be ...used for identification of high-risk patients, who may benefit
from prophylactic therapy.
Experimental Design: The expression of 12 genes was measured by real-time quantitative reverse transcriptase PCR in 142 frozen NSCLC tissue samples.
Univariate and multivariate Cox regression analysis was used to analyze the correlation between gene expression and the occurrence
of brain metastasis. Immunohistochemistry on independent samples was used to verify the findings.
Results: A score based on the expression levels of three genes, CDH2 (N-cadherin), KIFC1 , and FALZ , was highly predictive of brain metastasis in early and advanced lung cancer. The probability of remaining brain metastasis–free
at 2 years after diagnosis was 90.0 ± 9.5% for patients with stage I/stage II tumors and low score compared with 62.7 ± 12%
for patients with high score ( P < 0.01). In patients with more advanced lung cancer, the brain metastasis–free survival at 24 months was 89% for patients
with low score compared with only 37% in patients with high score ( P < 0.02). These results were confirmed by immunohistochemical detection of N-cadherin in independent cohort of primary NSCLC.
Conclusions: The expression levels of three genes in primary NSCLC tumors may be used to identify patients at high risk for brain metastasis
who may benefit from prophylactic therapy to the central nervous system.
The definitive identification of malignant pleural mesothelioma (MPM) has significant clinical implications, yet other malignancies often involve the lung pleura, confounding the diagnosis of MPM. In ...the absence of accurate markers, MPM can be difficult to distinguish from peripheral lung adenocarcinoma and metastatic epithelial cancers. MicroRNA expression is tissue-specific and highly informative for identifying tumor origin. We identified microRNA biomarkers for the differential diagnosis of MPM and developed a standardized microRNA-based assay. Formalin-fixed, paraffin-embedded samples of 33 MPM and 210 carcinomas were used for assay development. Using microarrays, we identified microRNAs differentially expressed between MPM and various carcinomas. Hsa-miR-193–3p was overexpressed in MPM, while hsa-miR-200c and hsa-miR-192 were overexpressed in peripheral lung adenocarcinoma and carcinomas that frequently metastasize to lung pleura. We developed a standardized diagnostic assay based on the expression of these microRNAs. The assay reached a sensitivity of 100% and a specificity of 94% in a blinded validation set of 68 samples from the lung and pleura. This diagnostic assay can provide a useful tool in the differential diagnosis of MPM from other malignancies in the pleura.
Partial gain of chromosome arm 17q is an abundant aberrancy in various cancer types such as lung and prostate cancer with a prominent occurrence and prognostic significance in neuroblastoma--one of ...the most common embryonic tumors. The specific genetic element/s in 17q responsible for the cancer-promoting effect of these aberrancies is yet to be defined although many genes located in 17q have been proposed to play a role in malignancy. We report here the characterization of a naturally-occurring, non-reciprocal translocation der(X)t(X;17) in human lung embryonal-derived cells following continuous culturing. This aberrancy was strongly correlated with an increased proliferative capacity and with an acquired ability to form colonies in vitro. The breakpoint region was mapped by fluorescence in situ hybridization (FISH) to the 17q24.3 locus. Further characterization by a custom-made comparative genome hybridization array (CGH) localized the breakpoint within the Bromodomain PHD finger Transcription Factor gene (BPTF), a gene involved in transcriptional regulation and chromatin remodeling. Interestingly, this translocation led to elevation in the mRNA levels of the endogenous BPTF. Knock-down of BPTF restricted proliferation suggesting a role for BPTF in promoting cellular growth. Furthermore, the BPTF chromosomal region was found to be amplified in various human tumors, especially in neuroblastomas and lung cancers in which 55% and 27% of the samples showed gain of 17q24.3, respectively. Additionally, 42% percent of the cancer cell lines comprising the NCI-60 had an abnormal BPTF locus copy number. We suggest that deregulation of BPTF resulting from the translocation may confer the cells with the observed cancer-promoting phenotype and that our cellular model can serve to establish causality between 17q aberrations and carcinogenesis.
A 27-year-old female white-collar worker was diagnosed in 1998 with mesothelioma eight and one-half years following first exposure as a bystander to debris in a site in which asbestos-containing ...building materials were being dismantled and rebuilding work took place. Prodromal back pain had been present for a year and a half. She underwent extrapleural pneumectomy and received an intrapleural infusion of cisplatin post-operatively. Exposure to asbestos was verified by contemporary reports and lung biopsy, which demonstrated asbestos bodies and microscopic interstitial fibrosis -conforming evidence for asbestosis. The patient is alive and well 12 years after diagnosis and 14 years after onset of symptoms. The combination of an extremely short latency period and long survival following occupational exposure to asbestos dust is unique.
AimsTo analyse microRNA (miR)-21 distribution and expression at the cellular level in non-small cell lung cancer (NSCLC). MiR-21 is an oncogenic microRNA overexpressed in NSCLC. In previous studies, ...overexpression of miR-21 was evaluated from the tumour bulk by quantitative reverse transcription PCR with results expressed on average across the entire cell population.MethodsWe used in situ hybridisation and immunohistochemistry to assess the correlation between miR-21 levels and the expression of markers that may be possible targets (epidermal growth factor reaction) or may be involved in its upregulation (phosphatase and tensin homolog (PTEN), p53). The Pearson’s χ2 tests was used to assess correlation with clinicopathological data and with miR-21 expression both in tumour and tumour stroma.ResultsCytoplasmic staining and expression of Mir-21 were detected in the tumours and in associated stromal cells. Expression was highest in the stroma immediately surrounding the tumour cells and decreased as the distance from the tumour increased. No expression of miR-21 was found in normal lung parenchyma and a significant association was found between tumour localised miR-21 and PTEN.ConclusionsPresence of miR-21 in both cell tumour and stromal compartments of NSCLC and the relationship with PTEN confirms miR-21 as a microenvironment signalling molecule, possibly inducing epithelial mesenchymal transition and invasion by targeting PTEN in the stromal compartment possibly through exosomal transport. In situ immunohistochemical studies such as ours may help shed light on the complex interactions between miRNAs and its role in NSCLC biology.
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