PDGRFA-mutant gastrointestinal stromal tumours (GISTs) in Eastern England: clinicopathological features and outcomes of 50 patients diagnosed between 2008-2021

Background PDGRFA-mutant gastrointestinal tumours (GISTs) comprise approximately 10% of GISTs and are mostly gastric. Targeted therapies against these tumours have historically been limited by tyrosine kinase inhibitor (TKI)-resistance. We reviewed the characteristics and outcome of all PDGRFA-mutant patients seen at our centre over the last 13 years. Methods All PDGRFA-mutant patients seen at the Cambridge University Hospitals NHS Foundation Trust GIST clinic from July 2008-July 2021 were retrospectively reviewed and followed up. Results: 50 PDGRFA-mutant GIST patients were diagnosed during the 13-year period. 60% were male. Median tumour size was 5 cm and the majority were epithelioid (44%) or mixed (36%) type. Commonest primary location was the gastric body (52%). In non-metastatic patients the low-risk modified AFIP risk group was the most common (65.2%). PDGFRA exon 18 (86%) were the most common PDGFRA mutations, most being imatinib resistant. None harboured a KIT mutation. 38% of cases had high KIT expression (immunohistochemistry), whilst 48% had patchy expression and 14% were negative. Most were positive for DOG1 (94%). CD34 was highly expressed in 48% of cases. 13% developed metastases during the 13-year follow-up period: liver (80%) being the commonest site. 76% of all patients underwent radical resection. 14% received TKI therapy. After a median follow-up of 55.1 months, 82% remained alive: 6 patients died from metastatic GIST; 3 from other causes. Median time to metastatic disease was 30.1 months, and median time from metastatic diagnosis to death was 18.5 months. Patients who presented with metastatic disease had the poorest survival outcome (p=0.001) Conclusion To date this is the largest single-centre European PDGRFA-mutant GIST cohort. Results highlight the generally indolent nature of PDGRFA-mutant disease (contrasted to the poor outcome of those who present with metastatic disease), male and gastric preponderance (unlike KIT-mutant GISTs), and variable KIT expression.

To Explore the Haemostatic Effect of Compression Haemostasis Using an Ultrasonic Probe under the Guidance of Ultrasound after Radial Artery Puncture

Objective. To evaluate a new haemostasis method using an ultrasound probe to compress the radial artery and haemostasis under direct vision to replace traditional manual compression of the radial artery. Methods. According to a random number table, 240 patients with gastrointestinal tumours who had undergone arterial puncture were divided into Group A (120 cases) and Group B (120 cases). In Group A, patients were under the guidance of ultrasound to confirm the vascular port, determine the compression position of the ultrasound probe, observe the degree of vascular deformation, and press the radial artery puncture port with pressure to stop bleeding under direct vision. In Group B, traditional manual compression was used. All patients received 5 min of compression for haemostasis, and haemostasis conditions were recorded after compression and 24 hours postoperatively. Results. The incidence of bleeding, haematoma, and skin ecchymosis at the puncture site after 5 minutes of compression in Group A was lower than that in Group B ( P < 0.05 ). No significant difference was found between the two groups at 24 hours after the operation ( P > 0.05 ). Conclusion. The method using an ultrasound probe to guide radial artery compression to haemostasis is better than traditional manual compression when applied for compression haemostasis after removing the radial artery catheter.

Epigenetic promoter alterations in GI tumour immune-editing and resistance to immune checkpoint inhibition

ObjectivesEpigenomic alterations in cancer interact with the immune microenvironment to dictate tumour evolution and therapeutic response. We aimed to study the regulation of the tumour immune microenvironment through epigenetic alternate promoter use in gastric cancer and to expand our findings to other gastrointestinal tumours.DesignAlternate promoter burden (APB) was quantified using a novel bioinformatic algorithm (proActiv) to infer promoter activity from short-read RNA sequencing and samples categorised into APBhigh, APBint and APBlow. Single-cell RNA sequencing was performed to analyse the intratumour immune microenvironment. A humanised mouse cancer in vivo model was used to explore dynamic temporal interactions between tumour kinetics, alternate promoter usage and the human immune system. Multiple cohorts of gastrointestinal tumours treated with immunotherapy were assessed for correlation between APB and treatment outcomes.ResultsAPBhigh gastric cancer tumours expressed decreased levels of T-cell cytolytic activity and exhibited signatures of immune depletion. Single-cell RNAsequencing analysis confirmed distinct immunological populations and lower T-cell proportions in APBhigh tumours. Functional in vivo studies using ‘humanised mice’ harbouring an active human immune system revealed distinct temporal relationships between APB and tumour growth, with APBhigh tumours having almost no human T-cell infiltration. Analysis of immunotherapy-treated patients with GI cancer confirmed resistance of APBhigh tumours to immune checkpoint inhibition. APBhigh gastric cancer exhibited significantly poorer progression-free survival compared with APBlow (median 55 days vs 121 days, HR 0.40, 95% CI 0.18 to 0.93, p=0.032).ConclusionThese findings demonstrate an association between alternate promoter use and the tumour microenvironment, leading to immune evasion and immunotherapy resistance.

Cardiotoxicity Associated with Chemotherapy Used in Gastrointestinal Tumours

Cardiotoxicity is a well-recognised side effect of cancer-related therapies with a great impact on outcomes and quality of life in the cancer survivor population. The pathogenesis of chemotherapy-induced cardiotoxicity in patients with gastrointestinal cancers involves various molecular mechanisms, and the combined use of various chemotherapies augments the risk of each drug used alone. In terms of cardiotoxicity diagnosis, novel biomarkers, such as troponins, brain natriuretic peptide (BNP), myeloperoxidases and miRNAs have been recently assessed. Echocardiography is a noninvasive imaging method of choice for the primary assessment of chemotherapy-treated patients to generally evaluate the cardiovascular impact of these drugs. Novel echocardiography techniques, like three-dimensional and stress echocardiography, will improve diagnosis efficacy. Cardiac magnetic resonance (CMR) can evaluate cardiac morphology, function and wall structure. Corroborated data have shown the importance of CMR in the early evaluation of patients with gastrointestinal cancers, treated with anticancer drugs, but further studies are required to improve risk stratification in these patients. In this article, we review some important aspects concerning the cardiotoxicity of antineoplastic drugs used in gastrointestinal cancers. We also discuss the mechanism of cardiotoxicity, the role of biomarkers and the imaging methods used in its detection.

Transvaginal Ultrasound-Guided Core Biopsy—Experiences in a Comprehensive Cancer Centre

In this paper, we report our experience of transvaginal ultrasound (TVUS)-guided core biopsies involving 303 patients referred to the gynaecological ultrasound unit of our national comprehensive cancer centre. Adequate histologic specimens were obtained in 299 patients (98.7%). The most common sites of biopsy sampling were the adnexa (29.7%), the vaginal stump or wall (13.5%), the uterus (11.6%) and the peritoneum (10.2%). Malignancy was confirmed in two-thirds of patients (201/303) and a primary malignancy was diagnosed in 111 of the 201 histologically verified malignant cases (55.2%). Interestingly, 23.9% (48/201) of malignant tumours were proven to have a non-gynaecological origin. Among them, gastrointestinal tumours occurred the most frequently (31/48 patients). Three abscesses were discovered following the biopsy procedure, resulting in a complication rate of 1%. In 94 (31%) patients, subsequent surgery allowed the comparison of the ultrasound-guided and surgically obtained histologic results. We found inaccuracy in 12 cases (12.8%), which is discussed in this paper in detail. Sensitivity, specificity, PPV and NPV to diagnose malignancy was 94.8%, 94.1%, 98.7% and 80.0%, respectively. This is the largest study reported to date about the efficacy and safety of TVUS-guided core biopsy in evaluating pelvic lesions giving rise to a suspicion of gynaecological cancer.

Long Noncoding RNA Small Nucleolar Host Gene: A Potential Therapeutic Target in Urological Cancers

The incidence of urological cancer has been gradually increasing in the last few decades. However, current diagnostic tools and treatment strategies continue to have limitations. Substantial evidence shows that long noncoding RNAs (lncRNAs) play essential roles in carcinogenesis and the progression, treatment response and prognosis of multiple human cancers, including urological cancers, gastrointestinal tumours, reproductive cancers and respiratory neoplasms. LncRNA small nucleolar RNA host genes (SNHGs), a subgroup of lncRNAs, have been found to be dysregulated in tumour cell biology. In this review, we summarize the impacts of lncRNA SNHGs in urological malignancies and the underlying mechanisms.

Role of Her-2 in Gastrointestinal Tumours beyond Gastric Cancer: A Tool for Precision Medicine

Gastrointestinal (GI) tumors account for a quarter of all the cancer burden and a third of the global cancer-related mortality. Among them, some cancers retain a dismal prognosis; therefore, newer and innovative therapies are urgently needed in priority disease areas of high-unmet medical need. In this context, HER2 could be a relevant prognostic and predictive biomarker acting as a target for specific drugs. However, if the role of HER2 has been object of investigation for several years in gastric cancer, it is not well established in other GI malignancies. The aim of this narrative review was to portray the current landscape of the potential role of HER2 as a predictive biomarker for GI tumors beyond gastric cancer. In colon cancer, the benefit from anti-HER2 therapies is less clear than in gastric neoplasms for the lack of controlled studies. Pancreatic, biliary tract adenocarcinomas and hepatocarcinoma may derive a less clear clinical benefit by using anti-HER2 agents in HER2 positive tumors. Overall, the results are promising and seem to suggest that the integration of multiple modalities of therapies can optimize the cancer care. However, further prospective trials are needed to validate the use of personalized targeted therapies in this field.