Implementing Next-Generation Sequencing Process Changes to Increase Capacity and Improve Timeliness of Molecular Biomarker Profiling for Lung Cancer Patients.

BACKGROUND: Faced with expansion of molecular tumor biomarker profiling, the molecular genetics laboratory at Kingston Health Science Centre experienced significant pressures to maintain the provincially mandated 2-week turnaround time (TAT) for lung cancer (LC) patients. We used quality improvement methodology to identify opportunities for improved efficiencies and report the impact of the initiative. METHODS: We set a target of reducing average TAT from accessioning to clinical molecular lab report for LC patients. Process measures included percentage of cases reaching TAT within target and number of cases. We developed a value stream map and used lean methodology to identify baseline inefficiencies. Plan-Do-Study-Act cycles were implemented to streamline, standardize, and automate laboratory workflows. Statistical process control (SPC) charts assessed for significance by special cause variation. RESULTS: A total of 257 LC cases were included (39 baseline January-May 2021; 218 post-expansion of testing June 2021). The average time for baseline TAT was 12.8 days, peaking at 23.4 days after expansion of testing, and improved to 13.9 days following improvement interventions, demonstrating statistical significance by special cause variation (nonrandom variation) on SPC charts. CONCLUSIONS: The implementation of standardized manual and automated laboratory processes improved timeliness of biomarker reporting despite the increasing volume of testing at our center.

Diagnostic Yield for Cancer and Diagnostic Accuracy of Computed Tomography-guided Core Needle Biopsy of Subsolid Pulmonary Lesions.

PURPOSE: We aimed to determine the diagnostic yield for cancer and diagnostic accuracy of computed tomography-guided core needle biopsy (CTNB) in subsolid pulmonary lesions. MATERIALS AND METHODS: Fifty-two biopsies of 52 subsolid lesions in 51 patients were identified from a database of 912 lung biopsies and analyzed for the diagnostic yield for cancer and diagnostic accuracy of core CTNB diagnosis as well as complication rates. RESULTS: When indeterminate biopsy results were included in the analysis, the diagnostic yield for cancer was 80.8% and the diagnostic accuracy of core needle biopsy was 84.6% (n=52). It was 85.7% and 91.7%, respectively, when indeterminate results were excluded (n=48) and 82.4% and 82.4%, respectively, for biopsies with surgical confirmation (n=17). Attenuation was statistically significant for diagnostic yield for cancer (P=0.028) and diagnostic accuracy of core needle biopsy (P=0.001) when the indeterminate results were excluded (n=48). Attenuation and size were not statistically significant for diagnostic yield for cancer and diagnostic accuracy of needle biopsy (n=52), and size was not statistically significant for either when the indeterminate results were excluded. These results were achieved without any major complications as per the Society of Interventional Radiology Standards of Practice. CONCLUSIONS: CTNB offers a high yield in establishing a histopathologic diagnosis of subsolid pulmonary lesions, with both ground-glass and solid-predominance. The pure ground-glass category of lesions requires further research to determine the true diagnostic yield and diagnostic accuracy of core needle biopsies.

The histology of human right atrial tissue in patients with high-risk Obstructive Sleep Apnea and underlying cardiovascular disease: A pilot study.

BACKGROUND: Obstructive Sleep Apnea (OSA) results in intermittent hypoxia leading to atrial remodeling, which, among other things, facilitates development of atrial fibrillation. While much data exists on the macrostructural changes in cardiac physiology induced by OSA, there is a lack of studies looking for histologic changes in human atrial tissue induced by OSA which might lead to the observed macrostructural changes. METHODS: A case control study was performed. Patients undergoing coronary artery bypass grafting (CABG) were evaluated for OSA and categorized as high-risk or low-risk. The right atrial tissue samples were obtained during CABG and both microscopic histological analysis and Sirius Red staining were performed. RESULTS: 18 patients undergoing CABG were included; 10 high-risk OSA and 8 low-risk OSA in evenly matched populations. No statistically significant difference between the two groups was observed in amount of myocytolysis (p = 0.181), nuclear hypertrophy (p = 0.671), myocardial inflammation (p = n/a), amyloid deposition (p = n/a), or presence of thrombi (p = n/a), as measured through routine H&E staining. As well, no statistically significant difference in interstitial and epicardial collagen was observed, as measured by Sirius Red staining (for total tissue: p = 0.619: for myocardium: p = 0.776). CONCLUSIONS: In this pilot study there were no observable histological differences in human right atrial tissue from individuals at high- and low-risk for OSA. Further investigation would be required for more definitive results.

Isolated anterior urethral recurrence of prostatic adenocarcinoma.

Isolated anterior urethral metastases from prostate cancer are rare. The pathogenesis of this form of loco-regional recurrence may be related to spread by instrumentation-induced implantation and could potentially then be associated with a better prognosis than metastatic disease secondary to a more malignant phenotype. We report a case of a 68-year-old man with high-risk prostate cancer, diagnosed at transurethral resection of prostate, who was originally treated with combination external beam radiotherapy and hormonal therapy. He re-presented 4 years after his original diagnosis with recurrent gross hematuria and cystourethroscopic biopsies of anterior urethral polyps revealing isolated recurrent prostatic adenocarcinoma. We present our this case and review the literature.

Fer protein-tyrosine kinase promotes lung adenocarcinoma cell invasion and tumor metastasis.

UNLABELLED: Epidermal growth factor receptor (EGFR) is frequently amplified or mutated in non-small cell lung cancer (NSCLC). Although Fer protein-tyrosine kinase signals downstream of EGFR, its role in NSCLC tumor progression has not been reported. Here, Fer kinase was elevated in NSCLC tumors compared to normal lung epithelium. EGFR signaling in NSCLC cells fosters rapid Fer activation and increased localization to lamellipodia. Stable silencing of Fer in H1299 lung adenocarcinoma cells (Fer KD) caused impaired EGFR-induced lamellipodia formation compared to control cells. Fer KD NSCLC cells showed reduced Vav2 tyrosine phosphorylation that was correlated with direct Fer-mediated phosphorylation of Vav2 on tyrosine-172, which was previously reported to increase the guanine nucleotide exchange factor activity of Vav2. Indeed, Fer KD cells displayed defects in Rac-GTP localization to lamellipodia, cell migration, and cell invasion in vitro. To test the role of Fer in NSCLC progression and metastasis, control and Fer KD cells were grown as subcutaneous tumors in mice. Although Fer was not required for tumor growth, Fer KD tumor-bearing mice had significantly fewer numbers of spontaneous metastases. Combined, these data demonstrate that Fer kinase is elevated in NSCLC tumors and is important for cellular invasion and metastasis. IMPLICATIONS: Fer protein-tyrosine kinase is a potential therapeutic target in metastatic lung cancer. Mol Cancer Res; 11(8); 952-63. ©2013 AACR.

Composite paraganglioma-ganglioneuroma of the urinary bladder: a rare neoplasm causing hemodynamic crisis at tumour resection.

A 64-year-old man presented with gross painless hematuria. Cystoscopy revealed a submucosal bladder neck mass covered by normal urothelium. During transurethral resection, the patient developed hemodynamic crisis including sinus bradycardia. Histopathologic examination revealed a primary bladder composite paraganglioma-ganglioneuroma (CPG). The patient underwent partial cystectomy and is symptom-free after one year. Bladder CPGs are extremely rare neoplasms that may result in life-threatening catecholamine secretion, especially during tumour manipulation. These tumours require complete surgical excision and should be included in the differential diagnosis of any solitary bladder mass covered by normal urothelium, especially when there is a history of hypertension or micturition attacks.

Synchronous ipsilateral renal cell carcinoma and urothelial carcinoma of the renal pelvis.

Renal cell carcinoma (RCC) and urothelial carcinoma of the upper urinary tract are not uncommon urological malignancies. Their simultaneous occurrence in a patient is, however, extraordinarily rare. We report the case of a patient who underwent laparoscopic nephrectomy for suspected RCC. Preoperative imaging was suspicious for renal pelvic involvement, which was confirmed upon bivalving the fresh specimen at the time of surgery, with the discovery of a separate urothelium-based lesion. We discuss this rare occurrence and our management approach.

Augmenting detection of prostate cancer in transrectal ultrasound images using SVM and RF time series.

We propose a novel and accurate method based on ultrasound RF time series analysis and an extended version of support vector machine classification for generating probabilistic cancer maps that can augment ultrasound images of prostate and enhance the biopsy process. To form the RF time series, we record sequential ultrasound RF echoes backscattered from tissue while the imaging probe and the tissue are stationary in position. We show that RF time series acquired from agar-gelatin-based tissue mimicking phantoms, with difference only in the size of cell-mimicking microscopic glass beads, are distinguishable with statistically reliable accuracies up to 80.5%. This fact indicates that the differences in tissue microstructures affect the ultrasound RF time series features. Based on this phenomenon, in an ex vivo study involving 35 prostate specimens, we show that the features extracted from RF time series are significantly more accurate and sensitive compared to two other established categories of ultrasound-based tissue typing methods. We report an area under receiver operating characteristic curve of 0.95 in tenfold cross validation and 0.82 in leave-one-patient-out cross validation for detection of prostate cancer.

Urachal malignant fibrous histiocytoma: a case report and review of the literature.

Pathologic processes involving the urachus are usually related to inflammatory or sinofistular conditions. Neoplasms rarely arise within this structure, and when they do occur, they are typically epithelial, with mucinous adenocarcinoma being the most common. Mesenchymal lesions, both benign and malignant, have rarely been described in this location. We report the case of a 66-year-old white man who presented with a primary urachal malignant fibrous histiocytoma and died of metastatic disease 20 months after the initial diagnosis. This is an unusual case of malignant fibrous histiocytoma arising in a urachal remnant.

The role of hepatocyte growth factor (scatter factor) in epithelial-mesenchymal transition and breast cancer.

North American women have a one in eight lifetime risk of developing breast cancer, and approximately one in three women with breast cancer will die of metastases. We, and others, have recently shown that high levels of expression of hepatocyte growth factor (HGF) and its receptor Met are associated with invasive human breast cancer and may be causally linked to metastasis. This high level of HGF and Met expression has been considered as a possible indicator of earlier recurrence and shortened survival in breast cancer patients. In contrast, HGF expression (but not Met) is strongly suppressed in normal breast epithelial cells. HGF and Met are therefore candidate targets for therapeutic intervention in the treatment of breast cancer. We have recently demonstrated that sustained activation or hyper-activation of c-Src and Stat3, which occurs in invasive breast cancer, can stimulate strong expression of HGF in carcinoma cells. In contrast, transient induction of Stat3 occurs in normal epithelium and promotes mammary tubulogenesis. We hypothesize that increased autocrine HGF-Met signaling is a critical downstream function of c-Src-Stat3 activation in mammary tumorigenesis. Future studies will identify novel Stat3 consensus sites that regulate HGF promoter activity and HGF expression preferentially in carcinoma cells and could lead to novel therapeutic drugs that specifically block HGF expression in mammary carcinoma cells, and which could be used in combined treatments to abrogate metastasis.