The incremental contribution of mobile cone-beam computed tomography to the tool-lesion relationship during shape-sensing robotic-assisted bronchoscopy.

Introduction: This study aims to answer the question of whether adding mobile cone-beam computed tomography (mCBCT) imaging to shape-sensing robotic-assisted bronchoscopy (ssRAB) translates into a quantifiable improvement in the tool-lesion relationship. Methods: Data from 102 peripheral lung lesions with ≥2 sequential mCBCT orbital spins and from 436 lesions with 0-1 spins were prospectively captured and retrospectively analysed. The primary outcome was the tool-lesion relationship status across the first and the last mCBCT spins. Secondary outcomes included 1) the change in distance between the tip of the sampling tool and the centre of the lesion between the first and the last spins and 2) the per-lesion diagnostic yield. Results: Compared to lesions requiring 0-1 spins, lesions requiring ≥2 spins were smaller and had unfavourable bronchus sign and intra-operative sonographic view. On the first spin, 54 lesions (53%) were designated as non-tool-in-lesion (non-TIL) while 48 lesions (47%) were designated as TIL. Of the 54 initially non-TIL cases, 49 (90%) were converted to TIL status by the last spin. Overall, on the last spin, 96 out of 102 lesions (94%) were defined as TIL and six out of 102 lesions (6%) were defined as non-TIL (p<0.0001). The mean distance between the tool and the centre of the lesion decreased from 10.4 to 6.6 mm between the first and last spins (p<0.0001). The overall diagnostic yield was 77%. Conclusion: Targeting traditionally challenging lung lesions, intra-operative volumetric imaging allowed for the conversion of 90% of non-TIL status to TIL. Guidance with mCBCT resulted in a significant decrease in the distance between the tip of the needle to lesion centre.

Guided Bronchoscopy for the Evaluation of Pulmonary Lesions: An Updated Meta-analysis.

BACKGROUND: Guided bronchoscopy is increasingly used to diagnose peripheral pulmonary lesions (PPLs). A meta-analysis published in 2012 demonstrated a pooled diagnostic yield of 70%; however, recent publications have documented yields as low as 40% and as high as 90%. RESEARCH QUESTION: Has the diagnostic yield of guided bronchoscopy in patients with PPLs improved over the past decade? STUDY DESIGN AND METHODS: A comprehensive search was performed of studies evaluating the diagnostic yield of differing bronchoscopic technologies used to reach PPLs. Study quality was assessed using the Quality assessment of diagnostic accuracy of studies (QUADAS-2) assessment tool. Number of lesions, type of technology used, overall diagnostic yield, and yield by size were extracted. Adverse events were recorded. Meta-analytic techniques were used to summarize findings across all studies. RESULTS: A total of 16,389 lesions from 126 studies were included. There was no significant difference in diagnostic yield prior to 2012 (39 studies; 3,052 lesions; yield 70.5%) vs after 2012 (87 studies; 13,535 lesions; yield 69.2%) (P > .05). Additionally, there was no significant difference in yield when comparing different technologies. Studies with low risk of overall bias had a lower diagnostic yield than those with high risk of bias (66% vs 71%, respectively; P = .018). Lesion size > 2 cm, presence of bronchus sign, and reports with a high prevalence of malignancy in the study population were associated with significantly higher diagnostic yield. Significant (P < .0001) between-study heterogeneity was also noted. INTERPRETATION: Despite the reported advances in bronchoscopic technology to diagnose PPLs, the diagnostic yield of guided bronchoscopy has not improved.

Targeted Therapy Management in NSCLC Patients Using Cytology: Experience from a Tertiary Care Cancer Center.

BACKGROUND: Although biopsy is the gold standard for diagnosis, cytological material has often been used to assist in making a pathologic diagnosis as well as for molecular testing in certain cancers such as in the lung, cervix, and head/neck. OBJECTIVE: Our objective is to share experience from our institution in the use of cytological material in screening for epidermal growth factor receptor (EGFR) mutations in a subset of patients with non-small cell lung cancer (NSCLC). METHODS: Fine needle aspirates, pleural effusion, cell blocks of 223 NSCLC patients, where cytology suggested malignancy were screened for EGFR mutation in exons 18-21 using Scorpion(®) ARMS real-time polymerase chain reaction (PCR) technology. RESULTS: Overall, EGFR mutation was seen in 43.5 % of study samples. Deletions were highest in exon 19 (27.2 %), followed by exon 21 (15.5 %), exon 18 (5.3 %), and exon 20 (1.9 %). Chi-squared analysis revealed a significant correlation for mutation status in women compared with men (χ (2) = 5.88, p = 0.02), with exon 19 mutation predominating (χ (2) = 5.66, p = 0.02). CONCLUSION: Our results demonstrate the successful use of cytology material for molecular testing in a subset of NSCLC patients to direct their treatment.

Genomic profiling in a homogeneous molecular subtype of non-small cell lung cancer: An effort to explore new drug targets.

BACKGROUND: Patients' who are positive for kinase domain activating mutations in epidermal growth factor receptor (EGFR) gene, constitute 30-40% of non-small cell lung cancer (NSCLC), and are suitable candidates for Tyrosine Kinase Inhibitor based targeted/personalized therapy. In EGFR non-mutated subset, 8-10% that show molecular abnormalities such as EML4-ALK, ROS1-ALK, KIP4-ALK, may also derive the benefit of targeted therapy. However, 40% of NSCLC belong to a grey zone of tumours that are negative for the clinically approved biomarkers for personalized therapy. This pilot study aims to identify and classify molecular subtypes of this group to address the un-met need for new drug targets in this category. Here we screened for known/novel oncogenic driver mutations using a 46 gene Ampliseq Panel V1.0 that includes Ser/Thr/Tyr kinases, transcription factors and tumor suppressors. METHODS: NSCLC with tumor burden of at least 40% on histopathology were screened for 29 somatic mutations in the EGFR kinase domain by real-time polymerase chain reaction methods. 20 cases which were EGFR non-mutated for TK domain mutations were included in this study. DNA Quality was verified from each of the 20 cases by fluorimeter, pooled and subjected to targeted re-sequencing in the Ion Torrent platform. Torrent Suite software was used for next generation sequencing raw data processing and variant calling. RESULTS: The clinical relevance and pathological role of all the mutations/variants that include SNPs and Indels was assessed using polyphen-2/SIFT/PROVEAN/mutation assessor structure function prediction programs. There were 10 pathogenic mutations in six different oncogenes for which annotation was available in the COSMIC database; C420R mutation in PIK3CA, Q472H mutation in vascular endothelial growth factor receptor 2 (VEGFR2) (KDR), C630W and C634R in RET, K367M mutation in fibroblast growth factor receptor 2 (FGFR2), G12C in KRAS and 4 pathogenic mutations in TP53 in the DNA binding domain (E285K, R213L, R175H, V173G). CONCLUSION: Results suggest, a potential role for PIK3CA, VEGFR2, RET and FGFR2 as therapeutic targets in EGFR non-mutated NSCLC that requires further clinical validation.

Prevalence of KRAS mutations in metastatic colorectal cancer: A retrospective observational study from India.

BACKGROUND: One of the genetic alterations implicated in tumor progression in colorectal cancers (CRCs) are abnormalities in Kristen Rat Sarcoma (KRAS) gene. Evaluation of KRAS mutation status is an important prognostic factor and has predictive value in deciding first line therapy based on monoclonal antibodies such as Cetuximab and Panitumumab in metastatic CRCs. MATERIALS AND METHODS: In this retrospective study, we analyzed 7 different somatic mutations in Exon 2 of KRAS gene in 299 unselected incidental CRC patients who visited the hospital for clinical management during the period 2009-2013. Most of the tumors were primarily originating from colon and rectum; nevertheless, there were a few from rectosigmoid, sigmoid, ceacum and anal canal in the study group. Genomic DNA extracted from paraffin embedded tumor tissues was screened for 7 point mutations located in Codons 12 and 13 of KRAS gene, using Scorpions amplified refractory mutation system real time polymerase chain reaction technology. Statistical analysis was performed to assess bivariate relationship between different variables that includes: mutation status, mutation type, tumor location, tumor morphology, age and sex. RESULTS: Prevalence of mutation in Codons 12 and 13 was 42.8% in the study group. Well-differentiated tumors had significantly more mutation positivity than moderately and poorly differentiated tumors (P = 0.001). 92% of the mutations were from Codon 12 and 8% in Codon 13. Glycine to Arginine was relatively more common in rectosigmoid followed by ceacum, while Glycine to Alanine mutation was relatively more prevalent in sigmoid, followed by rectum and rectosigmoid. CONCLUSION: The results suggest a prevalence of KRAS mutation at 42.8% in Indian population indicating that this testing is very crucial for targeted therapy management in metastatic CRC in India. Further analysis on mutation status of other homologues such as NRAS and downstream partner, v-raf murine sarcoma viral oncogene homolog B1, would add value to understanding the role of anti-epidermal growth factor receptor therapy in CRC management.

Digit ratio (2D:4D) and performance in Indian swimmers.

It has been suggested that achievement in sports is correlated with a putative measure of prenatal testosterone the 2nd to 4th digit ratio (2D:4D). It has been shown that digit ratio (2D:4D) is negatively associated with prenatal testosterone, and it is also negatively associated with ability in sports. This study examined associations between 2D:4D and performance of both male and female National level Indian swimmers. Age matched non-sports personnel formed the control. Lengths of second and fourth digits were measured after scanning both hands and their ratio calculated. Our results show lower 2D:4D values in males compared to females (P < 0.05). Among male, but not female, swimmers had significantly (P < 0.05) lower 2D:4D ratio. Low 2D:4D in male swimmers suggests they are more prenatally programmed via long-lasting extra genital effects of testosterone. 2D:4D ratio could be used to identify young sports personnel who have potential to reach high levels of performance.

Epidermal growth factor receptor mutation in non-small-cell lung carcinomas: a retrospective analysis of 1036 lung cancer specimens from a network of tertiary cancer care centers in India.

BACKGROUND: Epidermal growth factor receptor (EGFR) mutation plays a vital role in the prognosis of patients with lung cancer. However, there is a dearth of studies on EGFR mutation in Indian population. In this retrospective study conducted at a network of tertiary cancer care centers across India, we evaluated the proportion of EGFR mutation in patients with non-small-cell lung carcinomas (NSCLC). MATERIALS AND METHODS: A total of 1036 cases of non-small lung cancer were assessed for EGFR mutation status using Scorpion amplified refractory mutation system real time polymerase chain reaction method from fine needle aspiration cytology core biopsy, pleural fluid and cell blocks. For a few cases, macro dissection of tumor from H and E slides was also performed for EGFR analysis. EGFR Status was assessed for the most commonly known driver mutations in Exons 18, 19, 20 and 21, which contributes to a total of 29 somatic mutations including the resistance mutation T790M. RESULTS: Around 39% of the cohort was female and 61% were male. Mutation was positive in 40.3% and negative (wild type) in 59.7%. There was 1.8% mutation in exon 18, 24.6% in exon 19, 1.6% in exon 20 and 12.8% in exon 21. 38.2% had a mutation in a single site and 1.1% had a mutation in two sites. Overall mutation was significant in females (50.5% vs. 33.9%) compared with males (χ2 = 28.3, P < 0.001). Mutation was significant in exon 21 (16.8% vs. 10.3%, χ2 = 9.44, P = 0.002) and exon 19 (30.7% vs. 20.7%, χ2 = 13.2, P < 0.001) in females compared with males. CONCLUSION: EGFR is expressed differentially/mutated in patients with NSCLC. Further studies to unravel the predictors for acquired genetic alterations of EGFR are needed.