Transcriptome analysis reveals upregulation of immune response pathways at the invasive tumour front of metastatic seminoma germ cell tumours

Background Testicular germ cell tumours (TGCTs) have a high metastasis rate. However, the mechanisms related to their invasion, progression and metastasis are unclear. Therefore, we investigated gene expression changes that might be linked to metastasis in seminomatous testicular germ cell tumour (STGCT) patients. Methods Defined areas [invasive tumour front (TF) and tumour centre (TC)] of non-metastatic (with surveillance and recurrence-free follow-up >2 years) and metastatic STGCTs were collected separately using laser capture microdissection. The expression of 760 genes related to tumour progression and metastasis was analysed using nCounter technology and validated with quantitative real-time PCR and enzyme-linked immunosorbent assay. Results Distinct gene expression patterns were observed in metastatic and non-metastatic seminomas with respect to both the TF and TC. Comprehensive pathway analysis showed enrichment of genes related to tumour functions such as inflammation, angiogenesis and metabolism at the TF compared to the TC. Remarkably, prominent inflammatory and cancer-related pathways, such as interleukin-6 (IL-6) signalling, integrin signalling and nuclear factor-κB signalling, were significantly upregulated in the TF of metastatic vs non-metastatic tumours. Conclusions IL-6 signalling was the most significantly upregulated pathway in metastatic vs non-metastatic tumours and therefore could constitute a therapeutic target for future personalised therapy. In addition, this is the first study showing intra- and inter-tumour heterogeneity in STGCT.

Kallikrein-Related Peptidase 6 Is Associated with the Tumour Microenvironment of Pancreatic Ductal Adenocarcinoma

As cancer-associated factors, kallikrein-related peptidases (KLKs) are components of the tumour microenvironment, which represents a rich substrate repertoire, and considered attractive targets for the development of novel treatments. Standard-of-care therapy of pancreatic cancer shows unsatisfactory results, indicating the need for alternative therapeutic approaches. We aimed to investigate the expression of KLKs in pancreatic cancer and to inhibit the function of KLK6 in pancreatic cancer cells. KLK6, KLK7, KLK8, KLK10 and KLK11 were coexpressed and upregulated in tissues from pancreatic cancer patients compared to normal pancreas. Their high expression levels correlated with each other and were linked to shorter survival compared to low KLK levels. We then validated KLK6 mRNA and protein expression in patient-derived tissues and pancreatic cancer cells. Coexpression of KLK6 with KRT19, αSMA or CD68 was independent of tumour stage, while KLK6 was coexpressed with KRT19 and CD68 in the invasive tumour area. High KLK6 levels in tumour and CD68+ cells were linked to shorter survival. KLK6 inhibition reduced KLK6 mRNA expression, cell metabolic activity and KLK6 secretion and increased the secretion of other serine and aspartic lysosomal proteases. The association of high KLK levels and poor prognosis suggests that inhibiting KLKs may be a therapeutic strategy for precision medicine.

A retrospective analysis of the factors associated with increased risk of readmission within 30 days following primary transurethral resection of bladder tumour

Background Transurethral resection of bladder tumour (TURBT) is associated with a perioperative morbidity of 5-10% which can lead to unplanned readmissions. In this study, we aim to identify factors that lead to an increased risk of unplanned readmissions within 30 days of primary TURBT. Methods A retrospective study was conducted to identify patients who had their primary TURBT at our institute from 2011-2019. The clinico-demographic factors, history of smoking, intake of anti-platelet drugs, co-morbidities, tumour size (< 3 cm or > 3cm), multifocality and histopathological type were abstracted. The patients who had a readmission were identified and reasons for admission were recorded. Results A total of 435 patients were identified. The median age was 66 years. There were 378 (86.9%) males, 110 (25.3%) had history of smoking and 37 (8.5%) had history of intake of an anti-platelet agent. In the cohort 166 (38.2%) were diabetic, 239 (54.9%) were hypertensive, 72 (16.6%) had COPD, 78 (7.9%) had hypothyroidism. A total of 206 (47.4%) had a tumour of >3cm, multifocality was seen in 140 (32.2%) while muscle invasive tumour was present in 161 (37%) patients. A total of 22 (5.06%) had re-admissions within 30 days with hematuria being the commonest etiology. On the univariate and multivariate analysis, history of smoking ( p=0.006 and 0.008, respectively) or intake of anti-platelet agents (p<0.001 and <0.001, respectively) were significantly associated with increased unplanned readmission. Conclusion Our study revealed smoking and intake of anti-platelet agents as the factors leading to increased risk of unplanned readmissions.

Sacral Chordoma: A Pitfall in Surgical Management

Chordomas are rare primary, locally invasive tumour of the bone which derived from notochordal remnants. Currently, the mainstay of treatment of chordomas is surgical resection. Despite the clear advantages of adequate surgical margin, the locally advanced nature of chordomas makes wide resection of the tumour difficult as they are often in close proximity with the surrounding vital organs. The published literatures of sacral chordomas mainly focus on the approach of surgery, reconstruction post-resection, long-term survival and reports on successful surgical resection. We report a case which highlights the pitfall in the surgical management of a sacral chordoma. Our patient developed delayed bowel perforation which may be associated with the sacrum osteotomy. Keywords: chordoma; sacrum; surgery; pitfall; outcome.

Prognostic values of L-type amino acid transporter 1 and CD98hc expression in breast cancer

AimsL-type amino acid transporter 1 (LAT1) is a major Na+-independent neutral amino acid transporter, forming a complex with CD98hc. The aim of this study is to investigate the significance of LAT1 and CD98hc in invasive breast cancer.MethodsLAT1 and CD98hc expression was immunohistochemically assessed in 280 invasive breast cancers and analysed for association with clinicopathological features.ResultsHigh levels of LAT1 and CD98hc were observed in triple-negative breast cancers (TNBCs) possessing negative immunoreactivity with oestrogen receptor, progesterone receptor and human epidermal growth factor receptor 2, compared with non-TNBCs (NTNBCs), and were associated with lymph-node metastasis and higher nuclear grade. The high-LAT1-expression group showed a poor prognosis in NTNBC and TNBC, however, high-CD98hc-expression group showed a poor prognosis only in NTNBC. LAT1 and CD98hc expression could be the prognostic factors in univariate analyses, but not in multivariate analyses. Further, we found that invasive tumour components showed higher LAT1 and CD98hc expression than non-invasive tumour components.ConclusionsLAT1 and CD98hc may possess prognostic values in invasive breast cancer. LAT1 may be linked with cancer cell activities and disease progression in breast cancer.

Weakly-Supervised Classification of HER2 Expression in Breast Cancer Haematoxylin and Eosin Stained Slides

Human epidermal growth factor receptor 2 (HER2) evaluation commonly requires immunohistochemistry (IHC) tests on breast cancer tissue, in addition to the standard haematoxylin and eosin (H&E) staining tests. Additional costs and time spent on further testing might be avoided if HER2 overexpression could be effectively inferred from H&E stained slides, as a preliminary indication of the IHC result. In this paper, we propose the first method that aims to achieve this goal. The proposed method is based on multiple instance learning (MIL), using a convolutional neural network (CNN) that separately processes H&E stained slide tiles and outputs an IHC label. This CNN is pretrained on IHC stained slide tiles but does not use these data during inference/testing. H&E tiles are extracted from invasive tumour areas segmented with the HASHI algorithm. The individual tile labels are then combined to obtain a single label for the whole slide. The network was trained on slides from the HER2 Scoring Contest dataset (HER2SC) and tested on two disjoint subsets of slides from the HER2SC database and the TCGA-TCIA-BRCA (BRCA) collection. The proposed method attained 83.3 % classification accuracy on the HER2SC test set and 53.8 % on the BRCA test set. Although further efforts should be devoted to achieving improved performance, the obtained results are promising, suggesting that it is possible to perform HER2 overexpression classification on H&E stained tissue slides.

The efficacy and safety of EN BLOC resection in non-muscle-invasive bladder cancer

In surgical treatment of non-muscle-invasive bladder cancer (BC) the en bloc resection technique – removal of tumour in a single piece with the subjacent muscle (detrusor) – is becoming more widely used. The objective of this review was to assess the oncological efficacy (relapse incidence) and safety (of peri- and post-operative complications) of this technique for various tumour sizes. This systematic review was written in accordance with the PRISMA criteria. The relevant literature published over the past 20 years was chosen in two databases (Medline and Scopus) with the use of the search query “en bloc” and “bladder cancer”. We selected publications that assessed the efficacy and safety of en bloc resection of the bladder wall with non-muscle-invasive tumour, and also publications comparing the efficacy of en bloc резекции resection with that of transurethral resection (TUR) of the bladder. Based on analysis of 18 studies (1592 patients after en bloc resection), the following conclusions were made: the incidence of BC relapses after en bloc resection of the bladder wall (with non-muscle-invasive tumour) is significantly lower than after conventional TUR of the bladder; a practically 100-percent presence of muscle fibers is found in the histological tumour specimen; the frequency of peri- and post-operative complications in en bloc resection is significantly lower as compared with classical TUR; the choice of a power source does not influence the oncological outcomes, but laser en bloc resection is safer than electrical; extraction of tumours with sizes up to 2-3 cm is possible in one piece; tumours of larger diameters should be preliminary fragmented in the bladder cavity; comparison of tumours of various diameters did not reveal any statistical differences between the oncological outcomes of patients. The technique of en bloc resection of the bladder wall with non-muscle-invasive tumour is effective and safe for removal of smaller tumours (~ to 2 cm); as some authors point out, it is also effective in larger tumours but there are no literature evidence sufficient for such an. Key words: systematic review, en bloc resection, non-muscle-invasive bladder cancer