Noninvasive Detection of Clinically Significant Prostate Cancer Using Circulating Tumor Cells.

PURPOSE: Prostate specific antigen testing results in unnecessary biopsy and over diagnosis with consequent overtreatment. Tissue biopsy is an invasive procedure associated with significant morbidity. More accurate noninvasive or minimally invasive diagnostic approaches should be developed to avoid unnecessary prostate biopsy and over diagnosis. We investigated the potential of using circulating tumor cell analysis in cancer diagnosis, particularly to predict clinically significant prostate cancer in prebiopsy cases. MATERIALS AND METHODS: We enrolled 155 treatment naïve patients with prostate cancer and 98 before biopsy for circulating tumor cell enumeration. RNA was extracted from circulating tumor cells of 184 patients for gene expression analysis. The Kruskal-Wallis and Spearman rank tests, multivariate logistic regression and the random forest method were applied to assess the association of circulating tumor cells with aggressive prostate cancer. RESULTS: Of patients with localized prostate cancer 54% were scored as having positive circulating tumor cells, which was associated with a higher Gleason score (p=0.0003), risk group (p <0.0001) and clinically significant prostate cancer (p <0.0001). In the prebiopsy group a positive circulating tumor cell score combined with prostate specific antigen predicted clinically significant prostate cancer (AUC 0.869). A 12-gene panel prognostic for clinically significant prostate cancer was also identified. When combining the prostate specific antigen level, the circulating tumor cell score and the 12-gene panel, the AUC of clinically significant prostate cancer prediction was 0.927. Adding those data to cases with available multiparametric magnetic resonance imaging data significantly increased prediction accuracy (AUC 0.936 vs 0.629). CONCLUSIONS: Circulating tumor cell analysis has the potential to significantly improve patient stratification by prostate specific antigen and/or multiparametric magnetic resonance imaging for biopsy and treatment.

Clinical evaluation of the efficacy of limbus artificial intelligence software to augment contouring for prostate and nodes radiotherapy.

OBJECTIVES: To determine if Limbus, an artificial intelligence (AI) auto-contouring software, can offer meaningful time savings for prostate radiotherapy treatment planning. METHODS: Three clinical oncologists recorded the time taken to contour prostate and seminal vesicles, lymph nodes, bladder, rectum, bowel, and femoral heads on CT scans for 30 prostate patients (15 prostate, 15 prostate and nodes). Limbus 1.6.0 was used to generate these contours on the 30 CT scans. The time taken by the oncologists to modify individual Limbus contours was noted and compared with manual contouring times. The geometric similarity of Limbus and expert contours was assessed using the Dice Similarity Coefficient (DSC), and the dosimetric impact of using un-edited Limbus organs at risk contours was studied. RESULTS: Limbus reduced the time to produce clinically acceptable contours by 26 minutes for prostate and nodes patients and by 13 minutes for the prostate only patients. DSC values of greater than 0.7 were calculated for all contours, demonstrating good initial agreement. A dosimetric study showed that 5 of the 20 plans optimized using unmodified AI structures required unnecessary compromise of PTV coverage, highlighting the importance of expert review. CONCLUSIONS: Limbus offers significant time saving and has become an essential part of our clinical practice. ADVANCES IN KNOWLEDGE: This article is the first to include bowel and lymph nodes when assessing potential time savings using Limbus software. It demonstrates that Limbus can be used as an aid for prostate and node radiotherapy treatment planning.

Simulation as an effective means of preparing trainees for active participation in MDT meetings.

Introduction: Cancer multi-disciplinary team (MDT) meetings are an important component of consultant workload, however previous literature has suggested trainees are not satisfied with their current curriculum in preparing for MDT working. Methods: This educational pilot assessed whether multi-speciality simulated scenarios with pre-defined learning objectives, could prepare specialist registrars for interacting within an MDT. Participants completed pre- and post-questionnaires assessing a number of areas including: current experience of training, confidence presenting patients and whether the course would alter future practice. Results: Trainee confidence increased significantly from a mean of 5 to 7 (mean to nearest whole number, p < 0.01). Trainees rated the session highly for utility and altering their future practice (mean scores of 9 for both respectively, out of 10). Conclusion: Simulation has shown success in other multidisciplinary teaching, however to our knowledge there are no cancer specific training programmes. Our results highlight a potential gap in UK specialist training, and suggest simulation may be beneficial in preparing trainees to present in MDT meetings.

The essentials of acute oncology.

The general medical physician will often encounter patients who develop acute complications of their cancer diagnosis or anti-cancer treatment. Here we provide an overview of emergency solid tumour oncology to guide the initial management of these patients.

The potential of using circulating tumour cells and their gene expression to predict docetaxel response in metastatic prostate cancer.

Background: Docetaxel improves overall survival (OS) in castration-resistant prostate cancer (PCa) (CRPC) and metastatic hormone-sensitive PCa (mHSPC). However, not all patients respond due to inherent and/or acquired resistance. There remains an unmet clinical need for a robust predictive test to stratify patients for treatment. Liquid biopsy of circulating tumour cell (CTCs) is minimally invasive, can provide real-time information of the heterogeneous tumour and therefore may be a potentially ideal docetaxel response prediction biomarker. Objective: In this study we investigate the potential of using CTCs and their gene expression to predict post-docetaxel tumour response, OS and progression free survival (PFS). Methods: Peripheral blood was sampled from 18 mCRPC and 43 mHSPC patients, pre-docetaxel treatment, for CTC investigation. CTCs were isolated using the epitope independent Parsortix® system and gene expression was determined by multiplex RT-qPCR. We evaluated CTC measurements for post-docetaxel outcome prediction using receiver operating characteristics and Kaplan Meier analysis. Results: Detection of CTCs pre-docetaxel was associated with poor patient outcome post-docetaxel treatment. Combining total-CTC number with PSA and ALP predicted lack of partial response (PR) with an AUC of 0.90, p= 0.037 in mCRPC. A significantly shorter median OS was seen in mCRPC patients with positive CTC-score (12.80 vs. 37.33 months, HR= 5.08, p= 0.0005), ≥3 total-CTCs/7.5mL (12.80 vs. 37.33 months, HR= 3.84, p= 0.0053), ≥1 epithelial-CTCs/7.5mL (14.30 vs. 37.33 months, HR= 3.89, p= 0.0041) or epithelial to mesenchymal transitioning (EMTing)-CTCs/7.5mL (11.32 vs. 32.37 months, HR= 6.73, p= 0.0001). Significantly shorter PFS was observed in patients with ≥2 epithelial-CTCs/7.5mL (7.52 vs. 18.83 months, HR= 3.93, p= 0.0058). mHSPC patients with ≥5 CTCs/7.5mL had significantly shorter median OS (24.57 vs undefined months, HR= 4.14, p= 0.0097). In mHSPC patients, expression of KLK2, KLK4, ADAMTS1, ZEB1 and SNAI1 was significantly associated with shorter OS and/or PFS. Importantly, combining CTC measurements with clinical biomarkers increased sensitivity and specificity for prediction of patient outcome. Conclusion: While it is clear that CTC numbers and gene expression were prognostic for PCa post-docetaxel treatment, and CTC subtype analysis may have additional value, their potential predictive value for docetaxel chemotherapy response needs to be further investigated in large patient cohorts.

The Identification of Plasma Exosomal miR-423-3p as a Potential Predictive Biomarker for Prostate Cancer Castration-Resistance Development by Plasma Exosomal miRNA Sequencing.

Castration-resistant prostate cancer (CRPC) is the major cause of death from prostate cancer. Biomarkers to improve early detection and prediction of CRPC especially using non-invasive liquid biopsies could improve outcomes. Therefore, we investigated the plasma exosomal miRNAs associated with CRPC and their potential for development into non-invasive early detection biomarkers for resistance to treatment. RNA-sequencing, which generated approximately five million reads per patient, was performed to identify differentially expressed plasma exosomal miRNAs in 24 treatment-naive prostate cancer and 24 CRPC patients. RT-qPCR was used to confirm the differential expressions of six exosomal miRNAs, miR-423-3p, miR-320a, miR-99a-5p, miR-320d, miR-320b, and miR-150-5p (p = 7.3 × 10-8, 0.0020, 0.018, 0.0028, 0.0013, and 0.0058, respectively) firstly in a validation cohort of 108 treatment-naive prostate cancer and 42 CRPC patients. The most significant differentially expressed miRNA, miR-423-3p, was shown to be associated with CRPC with area under the ROC curve (AUC) = 0.784. Combining miR-423-3p with prostate-specific antigen (PSA) enhanced the prediction of CRPC (AUC = 0.908). A separate research center validation with 30 treatment-naive and 30 CRPC patients also confirmed the differential expression of miR-423-3p (p = 0.016). Finally, plasma exosomal miR-423-3p expression in CRPC patients was compared to 36 non-CRPC patients under androgen depletion therapy, which showed significantly higher expression in CRPC than treated non-CRPC patients (p < 0.0001) with AUC = 0.879 to predict CRPC with no difference between treatment-naive and treated non-CRPC patients. Therefore, our findings demonstrate that a number of plasma exosomal miRNAs are associated with CRPC and miR-423-3p may serve as a biomarker for early detection/prediction of castration-resistance.

Encephalopathy secondary to capecitabine chemotherapy: a case report and discussion.

INTRODUCTION: Capecitabine is an oral prodrug of 5-fluorouracil (5-FU) chemotherapy and is licensed for the treatment of breast and gastrointestinal cancers. Multifocal inflammatory leukoencephalopathy has been associated with intravenous 5-FU, but only a few cases of capecitabine-induced encephalopathy have been reported. SETTING: We describe here a case of encephalopathy following administration of Epirubicin/ Cisplatin/Capecitabine chemotherapy, review those cases previously described and suggest recommendations for management. RESULTS: Symptoms of neurotoxicity from 5-FU and capecitabine usually include confusion, ataxia, nystagmus, dysarthria, sensory loss, and memory loss. Withdrawal of the drug generally leads to improvement of symptoms and steroids are of only questionable benefit. CONCLUSION: Patients on fluouropyrimidine drugs with new neurological symptoms should be investigated with brain MRI scan and the drug should be withdrawn until symptoms resolve. Dihydropyrimidine dehydrogenase deficiency should be excluded and ideally an alternative chemotherapy regime sought. We would encourage reporting of such incidences to gain a clearer picture of the incidence and optimal management.

Optimal management of cancer treatment-induced bone loss: considerations for elderly patients.

Hormone manipulation, commonly used in breast and prostate cancer, can result in significant bone loss. In multiple myeloma (MM), corticosteroids play an important role in therapy but increase the risk of fracture over that expected for any given bone mineral density. These adverse effects on the skeletal system are particularly relevant in the elderly population, in whom osteoporosis can significantly affect not only quality of life but also survival. The associated health and social care costs are becoming increasingly important. Screening with dual energy x-ray absorptiometry (DXA) scans and lifestyle advice on smoking, alcohol and dietary intake are essential parts of the management of patients with cancer treatment-induced bone loss. The value of exercise also cannot be underestimated. A careful drug review should be carried out to eliminate agents that may potentially exacerbate bone toxicity. Therapies to address bone toxicities include bisphosphonates, which have been shown to play an increasingly important role in preventing declines in bone health. The issues of compliance when oral agents are used should not be underestimated. Renal toxicity and osteonecrosis of the jaw are relevant toxicities, especially in the elderly. Cardiac toxicity has not been proven, but there is evidence to suggest that the suppression of bone turnover seen with some, although not all, bisphosphonates is not reversed following cessation of treatment. The implications of this finding need to be borne in mind when treating elderly patients. The possibility of atypical fractures in patients taking bisphosphonates also needs to be given consideration, although this remains a rare complication. Recently, the receptor activator of nuclear factor-κB ligand (RANKL) ligand antibody denosumab has been shown to be of value in fracture prevention, and its subcutaneous route of administration offers a potential advantage. Oncologists should also remember that tamoxifen, which has little effect on bone integrity, remains a useful drug for breast cancer patients. A multidisciplinary approach involving the hospital specialist, general practitioner, nurse and, most importantly, the patient, family and carers should ensure that the maximal benefit is received from the anti-cancer treatment, with minimal cost to the patient. As cancer cure rates increase, late toxicity is increasingly relevant and challenging. The skeletal system warrants more research to maximize the care of all our patients, especially the elderly, who may be most at risk.