Rhomboid intercostal block in a modified radical mastectomy and axillary curettage patient; A new indication for novel interfascial block (original) (raw)
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Translational lung cancer research, 2023
Background: The use of immunotherapy targeting the programmed cell death protein-1 (PD-1) and its ligand (PD-L1) has provided new hope for patients with non-small cell lung cancer (NSCLC). However, good biomarkers are needed to identify which patients will benefit from the treatment. In this study, we investigated if circulating tumor DNA (ctDNA) could predict response to pembrolizumab. Methods: Plasma samples from patients with NSCLC treated with pembrolizumab were collected immediately before and after one or two cycles of treatment. ctDNA was isolated and analyzed using targeted next-generation sequencing with a lung cancer gene panel. Results: Mutations were detected in ctDNA in 83.93% of patients before treatment initiation. High blood tumor mutational burden (bTMB), measured as the number of different mutations per Mb panel, correlated to longer progression-free survival (PFS) (10.45 vs. 2.30 months) and overall survival (OS) (21.80 vs. 12.20 months), whereas no predictive value was found in the number of mutant molecules per mL of plasma. The absence of mutations just after treatment initiation correlated with improved PFS (20.25 vs. 4.18 months) and OS (28.93 vs. 15.33 months). High bTMB before treatment was associated with a decreasing ctDNA level after treatment initiation. Importantly, a subgroup of patients experienced an increase in the ctDNA level after treatment initiation, and this correlated with inferior PFS (2.19 vs. 11.21 months) and OS (7.76 vs. 24.20 months). All patients in the subgroup with increased ctDNA level progressed within 10 months. Conclusions: Monitoring of ctDNA contains vital information about response to therapy, where the bTMB and the dynamics in the initial part of treatment are particularly important for response. Increasing ctDNA levels after treatment initiation are significantly correlated with inferior survival.
Cancer discovery, 2017
Genomic intratumor heterogeneity (ITH) may be associated with postsurgical relapse of localized lung adenocarcinomas. Recently, mutations, through generation of neoantigens were shown to alter tumor immunogenicity through T cell responses. Here, we performed sequencing of the T cell receptor (TCR) in 45 tumor regions from 11 localized lung adenocarcinomas and observed substantial intratumor differences in T cell density and clonality with the majority of T cell clones restricted to individual tumor regions. TCR ITH positively correlated with predicted neoantigen ITH, suggesting that spatial differences in the T cell repertoire may be driven by distinct neoantigens in different tumor regions. Finally, a higher degree of TCR ITH was associated with an increased risk of postsurgical relapse and shorter disease-free survival, suggesting a potential clinical significance of T cell repertoire heterogeneity.
Using DNA sequencing data to quantify T cell fraction and therapy response
Nature, 2021
The immune microenvironment influences tumour evolution and can be both prognostic and predict response to immunotherapy 1,2. However, measuring tumour infiltrating lymphocytes (TILs) is restricted by lack of appropriate data. Whole exome sequencing (WES) of DNA is frequently performed to calculate tumour mutational burden and identify actionable mutations. Here we develop a method for T cell fraction estimation from WES samples, utilising a signal from T cell receptor excision circle (TRECs) loss during VDJ recombination of the T cell receptor alpha (TCRA) gene. This score significantly correlates with orthogonal TIL estimates and is agnostic to sample type. Blood TCRA T cell fraction is higher in females and correlates with both tumour immune infiltrate and presence of bacterial sequencing reads. Tumour TCRA T cell fraction is prognostic in lung adenocarcinoma and using a meta-analysis of immunotherapy-treated tumours, we show that this score predicts immunotherapy response, providing value beyond tumour mutational burden. Applying this score to a multi-sample pancancer cohort revealed high diversity in immune infiltration within tumours. Subclonal loss of 12q24.31-32, encompassing SPPL3, was associated with reduced TCRA T cell fraction. Our method, T cell ExTRECT (T cell Exome TREC Tool), quantifies the T cell infiltrate of WES samples. Here we propose a method for the estimation of the T cell fraction present in a WES sample. This method utilises a somatic copy number-based signal from VDJ recombination and the loss of TRECs. We explore the underlying features which predict T cell infiltrate in tumours and blood and evaluate determinants of immune heterogeneity within tumours. Finally, we demonstrate that our estimated T cell fraction can be used as a predictor of clinical response to CPI therapy. Results Inferring T cell fraction from WES data T cell diversity, which is required for immune system recognition of foreign antigens, is a product of VDJ recombination, where segments within the T cell receptor genes recombine. The alpha chain of the T cell receptor is encoded by the TCRA gene (also known as TRA) and the result of VDJ recombination is the excision of unselected gene segments from TCRA as TRECs, with the T cell undergoing a deletion event within TCRA. Tools to infer cancer somatic copy number alteration (SCNA) 6-9 rely on the read depth ratio (RDR), reflecting the log of the ratio of reads between the tumour sample and its matched control (e.g. buffy coat in a centrifuged blood sample). Deviation in the RDR from zero is assumed to reflect a tumour SCNA. However, within TCRA this assumption does not hold; a deviance in the RDR may reflect T cell specific deletion events and SCNA tools may thus erroneously infer tumour SCNA. Indeed, in the TRACERx100 cohort multiple SCNA within TCRA were inferred in 165/327 tumour regions (Extended Data Fig. 1a). The RDR deviated the most within segments frequently included within TRECs (Extended Data Fig. 1b-c). This suggests that most detected SCNAs within TCRA reflect a signal of relative T cell content rather than cancer SCNAs.
A Prospective Study of Circulating Tumor DNA to Guide Matched Targeted Therapy in Lung Cancers
JNCI: Journal of the National Cancer Institute
Background: Liquid biopsy for plasma circulating tumor DNA (ctDNA) next-generation sequencing (NGS) is commercially available and increasingly adopted in clinical practice despite a paucity of prospective data to support its use. Methods: Patients with advanced lung cancers who had no known oncogenic driver or developed resistance to current targeted therapy (n ¼ 210) underwent plasma NGS, targeting 21 genes. A subset of patients had concurrent tissue NGS testing using a 468-gene panel (n ¼ 106). Oncogenic driver detection, test turnaround time (TAT), concordance, and treatment response guided by plasma NGS were measured. All statistical tests were two-sided. Results: Somatic mutations were detected in 64.3% (135/210) of patients. ctDNA detection was lower in patients who were on systemic therapy at the time of plasma collection compared with those who were not (30/70, 42.9% vs 105/140, 75.0%; OR ¼ 0.26, 95% CI ¼ 0.1 to 0.5, P < .001). The median TAT of plasma NGS was shorter than tissue NGS (9 vs 20 days; P < .001). Overall concordance, defined as the proportion of patients for whom at least one identical genomic alteration was identified in both tissue and plasma, was 56.6% (60/106, 95% CI ¼ 46.6% to 66.2%). Among patients who tested plasma NGS positive, 89.6% (60/ 67; 95% CI ¼ 79.7% to 95.7%) were also concordant on tissue NGS and 60.6% (60/99; 95% CI ¼ 50.3% to 70.3%) vice versa. Patients who tested plasma NGS positive for oncogenic drivers had tissue NGS concordance of 96.1% (49/51, 95% CI ¼ 86.5% to 99.5%), and directly led to matched targeted therapy in 21.9% (46/210) with clinical response. Conclusions: Plasma ctDNA NGS detected a variety of oncogenic drivers with a shorter TAT compared with tissue NGS and matched patients to targeted therapy with clinical response. Positive findings on plasma NGS were highly concordant with tissue NGS and can guide immediate therapy; however, a negative finding in plasma requires further testing. Our findings support the potential incorporation of plasma NGS into practice guidelines.
Prognostic value of quantitative ctDNA levels in non small cell lung cancer patients
Oncotarget, 2018
Circulating tumor DNA (ctDNA) levels correlate well with tumor bulk. In this paper we aim to estimate the prognostic value of the dynamic quantification of ctDNA levels. A total of 251 serial plasma samples from 41 non-small-cell lung cancer patients who carried an activating EGFR mutation were analysed by digital PCR. For survival analysis, ctDNA levels were computed as a time-dependent covariate. Dynamic ctDNA measurements had prognostic significance (hazard ratio for overall survival and progression free survival according to p.T790M mutant allele frequency; 2.676 and 2.71 respectively;< 0.05). In the same way, patients with p.T790M-negative or unchanging or decreasing plasma levels of sensitizing EGFR mutation were 12 and 4.8 times more likely to maintain response or stable disease, respectively, than patients in which the opposite occurred (< 0.05).On average, the p.T790M mutation was detected in plasma 51 days before the assessment of progression disease by CT-scan. Fina...
Pathology and Oncology Research
Background: Observation of anticancer therapy effect by monitoring of minimal residual disease (MRD) is becoming an important tool in management of non-small cell lung cancer (NSCLC). The approach is based on periodic detection and quantification of tumor-specific somatic DNA mutation in circulating tumor DNA (ctDNA) extracted from patient plasma. For such repetitive testing, complex liquid-biopsy techniques relying on ultra-deep NGS sequencing are impractical. There are other, cost-effective, methods for ctDNA analysis, typically based on quantitative PCR or digital PCR, which are applicable for detecting specific individual mutations in hotspots. While such methods are routinely used in NSCLC therapy prediction, however, extension to cover broader spectrum of mutations (e.g., in tumor suppressor genes) is required for universal longitudinal MRD monitoring.Methods: For a set of tissue samples from 81 NSCLC patients we have applied a denaturing capillary electrophoresis (DCE) for in...
Purpose:Accurate response assessment during neoadjuvant systemic treatment (NST) poses a clinical challenge. Therefore, a minimally invasive assessment of tumor response based on cell-free circulating tumor DNA (ctDNA) may be beneficial to guide treatment decisions.Experimental Design:We profiled 93 genes in tissue from 193 patients with early breast cancer. Patient-specific assays were designed for 145 patients to track ctDNA during NST in plasma. ctDNA presence and levels were correlated with complete pathological response (pCR) and residual cancer burden (RCB) as well as clinicopathologic characteristics of the tumor to identify potential proxies for ctDNA release.Results:At baseline, ctDNA could be detected in 63/145 (43.4%) patients and persisted in 25/63 (39.7%) patients at mid-therapy (MT) and 15/63 (23.8%) patients at the end of treatment. ctDNA detection at MT was significantly associated with higher RCB (OR = 0.062; 95% CI, 0.01–0.48; P = 0.0077). Of 31 patients with detec...
Cancers, 2021
Despite the success of immunotherapies in lung cancer, development of new biomarkers for patient selection is urgently needed. This study aims to explore minimally invasive approaches to characterize circulating T cell receptor beta chain (TCR-β) repertoire in a cohort of advanced non-small cell lung cancer (NSCLC) patients treated with first-line pembrolizumab. Peripheral blood samples were obtained at two time points: i) pretreatment (PRE) and ii) first response assessment (FR). Next-generation sequencing (NGS) was used to analyze the hypervariable complementary determining region 3 (CDR3) of TCR-β chain. Richness, evenness, convergence, and Jaccard similarity indexes plus variable (V) and joining (J)-gene usage were studied. Our results revealed that increased richness during treatment was associated with durable clinical benefit (DCB; p = 0.046), longer progression-free survival (PFS; p = 0.007) and overall survival (OS; p = 0.05). Patients with Jaccard similarity index ≥0.0605 ...
Clinical Cancer Research, 2021
Purpose: Accurate response assessment during neoadjuvant systemic treatment (NST) poses a clinical challenge. Therefore, a minimally invasive assessment of tumor response based on cell-free circulating tumor DNA (ctDNA) may be beneficial to guide treatment decisions. Experimental Design: We profiled 93 genes in tissue from 193 patients with early breast cancer. Patient-specific assays were designed for 145 patients to track ctDNA during NST in plasma. ctDNA presence and levels were correlated with complete pathological response (pCR) and residual cancer burden (RCB) as well as clinicopathologic characteristics of the tumor to identify potential proxies for ctDNA release. Results: At baseline, ctDNA could be detected in 63/145 (43.4%) patients and persisted in 25/63 (39.7%) patients at mid-therapy (MT) and 15/63 (23.8%) patients at the end of treatment. ctDNA detection at MT was significantly associated with higher RCB (OR = 0.062; 95% CI, 0.01–0.48; P = 0.0077). Of 31 patients with ...