616 Rare KIT gene mutation in a recurrent GIST: Case Report

Introduction The diagnosis and treatment of Gastro-intestinal stromal tumours (GISTs) has been revolutionized by molecular pathology and targeted therapy. Description This patient was diagnosed with locally advanced gastric GIST in 2009. He was initially treated neoadjuvantly with imatinib from 2009- 2010. He underwent laparoscopic resection in 2010. Pathology showed almost complete response with only 1.5mm focus of viable tumour. He did not receive adjuvant imatinib as this was not established practice in 2010. Recurrent disease was resected in 2011. Mitotic count was 200/50hpf. Adjuvant imatinib was given for 5 years then discontinued in 2016. Imaging showed no recurrence over this time period. Molecular testing showed Kit Exon 11 mutation- this is common in GISTs and associated with response to imatinib. Recurrent disease was diagnosed 2018 with a 10x9cm mass between residual stomach and liver– he recommenced imatinib with partial response (maximal response was reached in 2020, but a new 3cm lesion was noted) He underwent further resection of the residual stomach and liver segmentectomy in 2020. Histology showed acellular areas of myxoid degeneration, indicating treatment response however viable tumour remained. Sequencing was performed. This showed the expected mutation in exon 11 but also a mutation in exon 13 of KIT- this has been shown recently to confer resistance to imatinib. Discussion Over 90% of GISTs harbour mutations in c-KIT. Recent work has demonstrated that some tumours acquire secondary mutations conferring resistance, following prolonged TKI therapy. Radiological and histopathological features correlate with such events and assist in deciding surgical management.

Peripheral blood T-cell receptor immune repertoire characterization of resectable stage IIIA non-small cell lung cancer patients receiving neo-adjuvant chemo-immunotherapy treatment from NADIM study.

9041 Background: Characterization of the peripheral blood T-cell receptor (TCR) repertoire has become a novel approach to predict the clinical benefit to anti-PD1/PDL1 therapy. However, there is lack of knowledge about the clinical relevance of TCR repertoire in terms of pathological response and clinical outcomes (PFS and OS) in chemo-immunotherapy. To answer this question we have analysed samples from the NADIM study (NCT03081689), in which resectable stage IIIA NSCLC patients were treated with neoadjuvant chemo-immunotherapy with Nivolumab. Methods: Using ION Torrent-based next-generation sequencing we have analysed TCR repertoire of peripheral blood from 30 patients receiving chemo-immunotherapy. Using 25ng of total RNA from PBMCs, clonal convergence, evenness and diversity were calculated at diagnosis (pre-treatment) and after 3 cycles of Nivolumab plus carboplatin (post-treatment). Regarding pathological responses, patients were classified in 3 groups: complete response (pCR) (0% viable tumour at the resection specimen), mayor response (pMR) ( < 10% viable tumour) and incomplete response (pIR) ( > 10% of viable tumour). At data analysis, PFS and OS median follow-up times were longer than 20 months. Results: No statistically significant differences in TCR repertoire in terms of evenness (p = 0,373), diversity (p = 0,691) or convergence (p = 0,054) between pre- and post-neoadjuvant treatment were observed. Similarly, no significant differences were observed in these metrics between pathological response groups. However, a detailed analysis of the clones showed that the percentage of frequent clones (greater than 0.1%) that increase after neoadjuvant therapy does show differences between the different pathological response groups (pIR vs pMR), being elevated in patients who presented responses greater than 90% (p = 0.0385). Regarding the clinical benefit, having this parameter higher than the median (43,90% in this cohort) is associated with a higher PFS (p = 0.0490) and OS (p = 0.078) using KM Log-rank test. Conclusions: Evenness, Diversity and Convergence derived from immune repertoire analysis do not appear to be clinically useful in the context of neoadjuvant chemo-immunotherapy in lung cancer. However, the detailed analysis of the clones seems promising. The increase of the most frequent clones after treatment seems to be associated to different clinical variables such as pathological response and PFS in these patients. Clinical trial information: NCT03081689.

Spontaneous Necrosis of a Large Choroidal Melanoma: Unusual Presentation in a 49-Year-Old Male

Purpose: To demonstrate a case of massive vitreous haemorrhage obscuring the underlying diagnosis of a large mixed-cell choroidal melanoma which had undergone spontaneous necrosis. Case Report: A 49-year-old man in good general health suddenly lost vision in his right eye due to an extensive vitreous haemorrhage 1 day after a workout at the gym. He reported good vision prior to that without any symptoms of flashes, floaters, or shadows. He was referred to the vitreoretinal department of a tertiary eye hospital, where he presented with a drop in vision to light perception only in the right phakic eye. Pars plana vitrectomy was performed in the right eye, which revealed intraoperatively massive retinal ischemia and choroidal haemorrhage, but no obvious tumour mass that could have been biopsied. The vitrectomy cassette specimen was sent for histopathology, where “ghost-like” melanoma cells were identified. The eye was subsequently enucleated, revealing an extensively necrotic and haemorrhagic choroidal melanoma of mixed cell type with only small viable tumour foci at the base and almost complete lysis of the detached retina. Conclusion: Some uveal melanomas (UMs) undergo spontaneous necrosis due to rapid growth, with the centre of the tumour outstripping its established blood supply in the “watershed area” of the eye, and becoming hypoxic with associated necrosis of intraocular structures. Such UMs are often associated with haemorrhage and/or inflammation and usually cause significant destruction of ocular tissues, resulting in enucleation as the only treatment option.

Evaluation of diffusion-weighted MRI and (18F) fluorothymidine-PET biomarkers for early response assessment in patients with operable non-small cell lung cancer treated with neoadjuvant chemotherapy

Objective: To correlate changes in the apparent diffusion coefficient (ADC) from diffusion-weighted (DW)-MRI and standardised uptake value (SUV) from fluorothymidine (18FLT)-PET/CT with histopathological estimates of response in patients with non-small cell lung cancer (NSCLC) treated with neoadjuvant chemotherapy and track longitudinal changes in these biomarkers in a multicentre, multivendor setting. Methods: 14 patients with operable NSCLC recruited to a prospective, multicentre imaging trial (EORTC-1217) were treated with platinum-based neoadjuvant chemotherapy. 13 patients had DW-MRI and FLT-PET/CT at baseline (10 had both), 12 were re-imaged at Day 14 (eight dual-modality) and nine after completing chemotherapy, immediately before surgery (six dual-modality). Surgical specimens (haematoxylin-eosin and Ki67 stained) estimated the percentage of residual viable tumour/necrosis and proliferation index. Results: Despite the small numbers,significant findings were possible. ADCmedian increased (p < 0.001) and SUVmean decreased (p < 0.001) significantly between baseline and Day 14; changes between Day 14 and surgery were less marked. All responding tumours (>30% reduction in unidimensional measurement pre-surgery), showed an increase at Day 14 in ADC75th centile and reduction in total lesion proliferation (SUVmean x proliferative volume) greater than established measurement variability. Change in imaging biomarkers did not correlate with histological response (residual viable tumour, necrosis). Conclusion: Changes in ADC and FLT-SUV following neoadjuvant chemotherapy in NSCLC were measurable by Day 14 and preceded changes in unidimensional size but did not correlate with histopathological response. However, the magnitude of the changes and their utility in predicting (non-) response (tumour size/clinical outcome) remains to be established. Advances in knowledge: During treatment, ADC increase precedes size reductions, but does not reflect histopathological necrosis.

Haematological biomarkers of pathological response on neo-adjuvant chemo-immunotherapy treatment for resectable stage IIIA non-small cell lung cancer (NSCLC) patients.

e20026 Background: PD1/PDL1 treatments have become the main therapy in advanced stages of NSCLC due to its significant increase in overall survival (OS), but recently, combination with chemotherapy in locally advanced stages is showing promising results. Many studies have described the neutrophil-to-lymphocyte ratio (NLR) and platelets-to-lymphocyte ratio (PLR) as indicator of systemic inflammation, that could be use as biomarker of response to immunotherapy. In our study, we described the effect of neoadjuvant chemo-immunotherapy in Complete Blood Count (CBC) parameters and evaluated their relationship with pathological responses. Methods: Immune cell populations of 46 resectable stage IIIA NSCLC patients treated with neo-adjuvant chemo-immunotherapy from NADIM clinical trial were analysed. Samples were extracted before initiating the neo-adjuvant treatment with nivolumab plus carboplatin and at the third cycle before patients underwent surgery. We classified patients in 3 subgroups of pathological response assessed in the resection specimen: complete response (pCR), mayor response (< 10% viable tumour) and incomplete response (> 10% viable tumour). Wilcoxon and Mann-Whitney U statistic test were used to evaluated differences between pre and post treatment and between pathological responses groups respectively. Results: From 46 patients, 5 patients did not undergo surgery, so they were excluded from the analysis. Absolute numbers (x103cells/µl) of CBC were significantly reduced after neo-adjuvant treatment in patients, leucocytes (8.80 vs 6.64), Eosinophil (0.22 vs 0.15), Monocytes (0.72 vs 0.62), Neutrophils (5.53 vs 3.53), Haemoglobin (35.82 vs 29.68), Platelets (292.44 vs 227.22), NLR (2.73 vs 1.71) and PLR (143.34 vs 115.85) except Lymphocytes (2.22 vs 2.25) and Basophils (0.06 vs 0.05). Moreover, when the analysis was done by subgroups of pathological responses, PLR variation was significantly different between pCR and incomplete response (-21.33 vs -76.98) whereas NLR and the rest of the immune populations were no different between subgroups. Conclusions: In our study, NLR is not associated to chemo-immune neo-adjuvant treatment response. Nevertheless, in our cohort a higher decrease on PLR post neo-adjuvant treatment is associated to an incomplete pathological response.

Is There a Relationship between the Stratum Corneum Thickness and That of the Viable Parts of Tumour Cells in Basal Cell Carcinoma?

Basal cell carcinoma (BCC) is an invasive epithelial skin tumour. The thickness of the outermost epidermal layer of the skin, the stratum corneum (SC), influences drug uptake and penetration into tumour and may thereby affect the response of BCC to topical treatment. The aim was to investigate a possible relationship between the thickness of the SC and that of the viable part of BCC. Histopathological evaluations of the corresponding SC and viable tumour thickness measurements of individual BCCs of different subtypes were explored. A total of 53 BCCs from 46 patients were studied. The median tumour thickness was 1.7 mm (0.8–3.0 mm), with a significant difference between subtypes (p<0.001). The SC had a median thickness of 0.3 mm (0.2–0.4 mm), with no difference between tumour subtypes (p=0.415). Additionally, no significant association between the thickness of the SC and that of the viable part of the tumour was demonstrated (p=0.381). In conclusion our results indicate that SC thickness is relatively constant in BCC.