Feasibility of a multiparametric MRI protocol for imaging biomarkers associated with neoadjuvant radiotherapy for soft tissue sarcoma

OBJECTIVE: Soft tissue sarcoma (STS) is a rare malignancy with a 5 year overall survival rate of 55%. Neoadjuvant radiotherapy is commonly used in preparation for surgery, but methods to assess early response are lacking despite pathological response at surgery being predictive of overall survival, local recurrence and distant metastasis. Multiparametric MR imaging (mpMRI) is used to assess response in a variety of tumours but lacks a robust, standardised method. The overall aim of this study was to develop a feasible imaging protocol to identify imaging biomarkers for further investigation. METHODS: 15 patients with biopsy-confirmed STS suitable for pre-operative radiotherapy and radical surgery were imaged throughout treatment. The mpMRI protocol included anatomical, diffusion-weighted and dynamic contrast-enhanced imaging, giving estimates of apparent diffusion coefficient (ADC) and the area under the enhancement curve at 60 s (iAUC(60)). Histological analysis of resected tumours included detection of CD31, Ki67, hypoxia inducible factor and calculation of a hypoxia score. RESULTS: There was a significant reduction in T1 at visit 2 and in ADC at visit 3. Significant associations were found between hypoxia and pre-treatment iAUC(60), pre-treatment ADC and mid-treatment iAUC(60). There was also statistically significant association between mid-treatment ADC and Ki67. CONCLUSION: This work showed that mpMRI throughout treatment is feasible in patients with STS having neoadjuvant radiotherapy. The relationships between imaging parameters, tissue biomarkers and clinical outcomes warrant further investigation. ADVANCES IN KNOWLEDGE: mpMRI-based biomarkers have good correlation with STS tumour biology and are potentially of use for evaluation of radiotherapy response

Primary glomus tumour of the pituitary gland: diagnostic challenges of a rare and potentially aggressive neoplasm

From Springer Nature via Jisc Publications RouterHistory: received 2020-06-05, rev-recd 2020-08-14, accepted 2020-08-24, registration 2020-09-02, pub-electronic 2020-09-12, online 2020-09-12, pub-print 2021-05Publication status: PublishedFunder: University of ManchesterAbstract: Primary non-neuroendocrine tumours of the pituitary gland and sella are rare lesions often challenging to diagnose. We describe two cases of clinically aggressive primary glomus tumour of the pituitary gland. The lesions occurred in a 63-year-old male and a 30-year-old female who presented with headache, blurred vision and hypopituitarism. Neuroimaging demonstrated large sellar and suprasellar tumours invading the surrounding structures. Histologically, the lesions were characterised by angiocentric sheets and nests of atypical cells that expressed vimentin, smooth muscle actin and CD34. Perivascular deposition of collagen IV was also a feature. Case 2 expressed synaptophysin. INI-1 (SMARCB1) expression was preserved. Both lesions were mitotically active and demonstrated a Ki-67 labelling index of 30%. Next-generation sequencing performed in case 1 showed no mutations in the reading frame of 37 commonly mutated oncogenes, including BRAF and KRAS. Four pituitary glomus tumours have previously been reported, none of which showed features of malignant glomus tumour. Similar to our two patients, three previous examples displayed aggressive behaviour

The hypoxia marker CAIX is prognostic in the UK phase III VorteX-Biobank cohort: an important resource for translational research in soft tissue sarcoma

BACKGROUND: Despite high metastasis rates, adjuvant/neoadjuvant systemic therapy for localised soft tissue sarcoma (STS) is not used routinely. Progress requires tailoring therapy to features of tumour biology, which need exploration in well-documented cohorts. Hypoxia has been linked to metastasis in STS and is targetable. This study evaluated hypoxia prognostic markers in the phase III adjuvant radiotherapy VorteX trial. METHODS: Formalin-fixed paraffin-embedded tumour biopsies, fresh tumour/normal tissue and blood were collected before radiotherapy. Immunohistochemistry for HIF-1α, CAIX and GLUT1 was performed on tissue microarrays and assessed by two scorers (one pathologist). Prognostic analysis of disease-free survival (DFS) used Kaplan-Meier and Cox regression. RESULTS: Biobank and outcome data were available for 203 out of 216 randomised patients. High CAIX expression was associated with worse DFS (hazard ratio 2.28, 95% confidence interval: 1.44-3.59, P<0.001). Hypoxia-inducible factor-1α and GLUT1 were not prognostic. Carbonic anhydrase IX remained prognostic in multivariable analysis. CONCLUSIONS: The VorteX-Biobank contains tissue with linked outcome data and is an important resource for research. This study confirms hypoxia is linked to poor prognosis in STS and suggests that CAIX may be the best known marker. However, overlap between single marker positivity was poor and future work will develop an STS hypoxia gene signature to account for tumour heterogeneity

Female immunity protects from cutaneous squamous cell carcinoma

PURPOSE: Cancer susceptibility and mortality are higher in males, and the mutational and transcriptomic landscape of cancer differs by sex. The current assumption is that men are at higher risk of epithelial cancers as they expose more to carcinogens and accumulate more damage than women. We present data showing women present less aggressive primary cutaneous squamous cell carcinoma (cSCC) and early strong immune activation. METHODS: We explored clinical and molecular sexual disparity in immunocompetent and immunosuppressed primary cSCC patients (N=738, N=160), advanced stage cSCC (N=63, N=20) and FVB/N mice exposed to equal doses of DMBA, as well as in human keratinocytes by whole exome, bulk and single cell RNA sequencing. RESULTS: We show cSCC is more aggressive in men, and immunocompetent women develop mild cSCC, later in life. To test if sex drives disparity, we exposed male and female mice to equal doses of carcinogen, and found males present more aggressive, metastatic cSCC than females. Critically, females activate cancer immune-related expression pathways and CD4 and CD8 T cell infiltration independently of mutations, a response that is absent in prednisolone treated animals. In contrast, males increase the rate of mitosis and proliferation in response to carcinogen. Women’s skin and keratinocytes also activate immune-cancer fighting pathways and immune cells at ultraviolet radiation-damaged sites. Critically, a compromised immune system leads to high-risk, aggressive cSCC specifically in women. CONCLUSIONS: This work shows the immune response is sex biased in cSCC, and highlights female immunity offers greater protection than male immunity