Modern Approach to Melanoma Adjuvant Treatment with Anti-PD1 Immune Check Point Inhibitors or BRAF/MEK Targeted Therapy: Multicenter Real-World Report.

BACKGROUND: The landscape of melanoma management changed as randomized trials have launched adjuvant treatment. MATERIALS AND METHODS: An analysis of data on 248 consecutive melanoma stage III and IV patients given adjuvant therapy in eight centers (February 2019 to January 2021) was conducted. RESULTS: The analyzed cohort comprised 147 melanoma patients given anti-PD1 (33% nivolumab, 26% pembrolizumab), and 101 (41%) were given dabrafenib plus trametinib (DT). The 2-year overall survival (OS), relapse-free survival (RFS), and distant-metastases-free survival (DMFS) rates were 86.7%, 61.4%, and 70.2%, respectively. The disease stage affected only the RFS rate; for stage IV, it was 52.2% (95% CI: 33.4-81.5%) vs. 62.5% (95% CI: 52.3-74.8%) for IIIA-D, p = 0.0033. The type of lymph node surgery before adjuvant therapy did not influence the outcomes. Completion of lymph node dissection cessation after positive SLNB did not affect the results in terms of RFS or OS. Treatment-related adverse events (TRAE) were associated with longer 24-month RFS, with a rate of 68.7% (55.5-84.9%) for TRAE vs. 56.6% (45.8-70%) without TRAE, p = 0.0031. For TRAE of grade ≥ 3, a significant decline in OS to 60.6% (26.9-100%; p = 0.004) was observed. CONCLUSIONS: Melanoma adjuvant therapy with anti-PD1 or DT outside clinical trials appears to be effective and comparable with the results of registration studies. Our data support a de-escalating surgery approach in melanoma treatment.

The Current Treatment Trends and Survival Patterns in Melanoma Patients with Positive Sentinel Lymph Node Biopsy (SLNB): A Multicenter Nationwide Study.

BACKGROUND: In melanoma treatment, an approach following positive sentinel lymph node biopsy (SLNB) has been recently deescalated from completion lymph node dissection (CLND) to active surveillance based on phase III trials data. In this study, we aim to evaluate treatment strategies in SLNB-positive melanoma patients in real-world practice. METHODS: Five-hundred-fifty-seven melanoma SLNB-positive patients from seven comprehensive cancer centers treated between 2017 and 2021 were included. Kaplan-Meier methods and the Cox Proportional-Hazards Model were used for analysis. RESULTS: The median follow-up was 25 months. Between 2017 and 2021, the percentage of patients undergoing CLND decreased (88-41%), while the use of adjuvant treatment increased (11-51%). The 3-year OS and RFS rates were 77.9% and 59.6%, respectively. Adjuvant therapy prolonged RFS (HR:0.69, p = 0.036)), but CLND did not (HR:1.22, p = 0.272). There were no statistically significant differences in OS for either adjuvant systemic treatment or CLND. Lower progression risk was also found, and time-dependent hazard ratios estimation in patients treated with systemic adjuvant therapy was confirmed (HR:0.20, p = 0.002 for BRAF inhibitors and HR:0.50, p = 0.015 for anti-PD-1 inhibitors). CONCLUSIONS: Treatment of SLNB-positive melanoma patients is constantly evolving, and the role of surgery is currently rather limited. Whether CLND has been performed or not, in a group of SLNB-positive patients, adjuvant systemic treatment should be offered to all eligible patients.

Real-life data of abiraterone acetate and enzalutamide treatment in post-chemotherapy metastatic castration-resistant prostate cancer in Poland.

Background: Abiraterone acetate (ABI) and Enzalutamide (ENZA) are second-generation hormone drugs that show breakthrough activity in post-chemotherapy, metastatic castration-resistant prostate cancer (mCRPC). The leading oncological and urological guidelines indicate both drugs with the same strong recommendation. There is a lack of randomized trials which compare the efficacy of ABI and ENZA. The current study aimed to compare the effectiveness of the drugs with an analysis of prognostic factors related to those drugs. Patients and methods: The study included 420 patients with docetaxel (DXL) pretreated mCRPC from seven Polish cancer centers. Patients were treated according to inclusion and exclusion criteria in the Polish national drug program (1000 mg ABI and 10 mg prednisone, n=76.2%; ENZA, 160 mg; n=23.8%). The study retrospectively analyzed the overall survival (OS), time to treatment failure (TTF), PSA 50% decline rate (PSA 50%) and selected clinic-pathological data. Results: In the study group, the median OS was 17 months (95% CI: 15.6-18.3). The median OS (26.1 vs. 15.7 mo.; p<0.001), TTF (14.2 vs. 7.6 mo.; p<0.001) and PSA 50% (87.5 vs. 56%; p<0.001) were higher in ENZA than in ABI treatment. Multivariate analysis shows that ENZA treatment and PSA nadir <17.35 ng/mL during or after DXL treatment were related to longer TTF. ENZA treatment, DXL dose ≥750 mg, PSA nadir <17.35 ng/mL during or after DXL treatment was related to longer OS. Conclusions: ENZA treatment may be related to more favorable oncological outcomes than ABI treatment in the studied Polish population of patients. A 50% decline in PSA is an indicator of longer TTF and OS. Due to the non-randomized and retrospective nature of the analysis, the current results require prospective validation.

Long-term clinical evidence of comparable efficacy and toxicity of nivolumab and pembrolizumab in advanced melanoma treatment.

Pembrolizumab and nivolumab (anty-PD-1 antibody) are commonly used for the treatment of melanoma patients. However, their efficacy and safety have never been directly compared, leaving little guidance for clinicians to select the best therapy. The study included patients with inoperable or metastatic melanoma treated in first line with anti-PD-1 immunotherapy (nivolumab or pembrolizumab). In total 1037 patients were enrolled in the study, 455 (44%) patients were treated with pembrolizumab and 582 (56%) with nivolumab. The estimated median overall survival (OS) in the pembrolizumab and nivolumab groups was 17.4 and 20.0 months [ P = 0.2323; hazard ratio (HR), 1.1; 95% confidence interval (CI), 0.94-1.28], respectively, whereas the median progression-free survival (PFS) was 5.6 and 7.5 months ( P = 0.0941; HR, 1.13; 95% CI, 0.98-1.29), respectively. The estimated 2- and 3-year OS in the pembrolizumab and nivolumab groups were 42/34% and 47/37%, respectively, and the PFS was 25/21% and 29/23%, respectively. There were 391 (49%) immune-related adverse events (irAEs) of any grade during treatment, including 133 (42%) related to pembrolizumab treatment and 258 (53%) to nivolumab treatment. A total of 72 (9.6%) irAEs were in G3 or G4, including during pembrolizumab 29 (9%) and nivolumab 48 (11%). There were no differences in OS, PFS and overall response rates between nivolumab and pembrolizumab therapy in previously untreated patients with advanced/metastatic melanoma. There were no differences in the frequency of G1/G2 or G3/G4 irAEs. The choice of treatment should be based on the preferences of the patient and the clinician.

Long-Term Real-World Outcomes and Safety of Vemurafenib and Vemurafenib + Cobimetinib Therapy in Patients with BRAF-Mutated Melanoma.

BACKGROUND: Combined treatment with BRAFi and/or MEK inhibitors (MEKi) improves outcomes in advanced melanoma patients in comparison with monotherapy. OBJECTIVE: We aim to report real-world treatment efficacy and safety of vemurafenib (V) and vemurafenib + cobimetinib (V + C) from 10 years of practice. PATIENTS AND METHODS: A total of 275 consecutive patients with unresectable or metastatic BRAF mutated melanoma started first-line V or V + C treatment between 1 October 2013 and 31 December 2020. Survival analyses were performed using the Kaplan-Meier method, and Log-rank and Chi-square tests were used for comparison between groups. RESULTS: The estimated median overall survival (mOS) was 10.3 months in the V group, and 12.3 months in the V + C group (p = 0.0005; HR = 1.58, 95% CI 1.2-2.1), although the latter group of patients had lactate dehydrogenase elevated numerically more often. Estimated median progression-free survival (mPFS) was 5.5 months in the V group, and 8.3 months in the V + C group (p = 0.0002; HR = 1.62, 95% CI 1.3-2.1). Complete response, partial response, stable disease, and progressive disease as best responses were recorded in the V/V + C groups in 7%/10%, 52%/46%, 26%/28%, and 15%/16% of patients, respectively. The numbers of patients with any grade of adverse effects were similar in both groups. CONCLUSIONS: We confirmed significant improvement in the mOS and mPFS of unresectable and/or metastatic BRAF mutated-melanoma patients treated outside clinical trials with V + C as compared with V, with no major increase in toxicity for the combination.

The Analysis of Trends in Survival for Patients with Melanoma Brain Metastases with Introduction of Novel Therapeutic Options before the Era of Combined Immunotherapy-Multicenter Italian-Polish Report.

Stage IV melanoma patients develop melanoma brain metastases (MBM) in 50% of cases. Their prognosis is improving, and its understanding outside the context of clinical trials is relevant. We have retrospectively analyzed the clinical data, course of treatment, and outcomes of 531 subsequent stage IV melanoma patients with BM treated in five reference Italian and Polish melanoma centers between 2014 and 2021. Patients with MBM after 2017 had a better prognosis, with a significantly improved median of overall survival (OS) after 2017 in the worst mol-GPA prognostic groups (mol-GPA ≤ 2): a median OS >6 months and HR 0.76 vs. those treated before 2017 (CI: 0.60−0.97, p = 0.027). In our prognostic model, mol-GPA was highly predictive for survival, and symptoms without steroid use did not have prognostic significance. Local therapy significantly improved survival regardless of the year of diagnosis (treated before or after 2017), with median survival >12 months. Systemic therapy improved outcomes when it was combined with local therapy. Local surgery was associated with improved OS regardless of the timing related to treatment start (i.e., before or after 30 days from MBM diagnosis). Local and systemic treatment significantly prolong survival for the poorest mol-GPA prognosis. Use of modern treatment modalities is justified in all mol-GPA prognostic groups.

Characteristics of Giant Nodular Melanomas in Special Locations: a Case Series and Review of the Literature.

INTRODUCTION: Nodular melanoma (NM) is a rare subtype of melanoma, responsible for more than 40% of melanoma deaths, characterized by rapid growth and high metastatic potential. Only a few case studies concerning the dermoscopic presentations of giant nodular melanoma have been reported so far. OBJECTIVES: The aim of the study was to assess dermoscopic features of giant nodular melanomas in special locations, along with their clinical and histopathologic aspects. METHODS: Among 120 patients with histopathologically confirmed melanoma treated by the Skin Cancer and Melanoma Team between September 2020 and February 2021, we identified six patients with giant nodular melanoma in special locations. We retrospectively assessed the archived dermoscopic images to determine the dermoscopic features of these tumors. RESULTS: The group consisted of six cases of giant melanoma in special locations, including the scalp (4/6) and the heel (2/6). The giant tumors were large in size (at least 5 cm in diameter). The most common dermoscopic structures in polarized light included asymmetric distribution of dermoscopic structures, the presence of structureless, multicolored zones (showing three or more colors), and the presence of white perpendicular lines or small, pink globules. CONCLUSIONS: It seems that there are no significant differences in dermoscopy between small and giant melanomas; however, further studies should be conducted on a larger scale.

Innate immune checkpoint inhibitor resistance is associated with melanoma sub-types exhibiting invasive and de-differentiated gene expression signatures.

Melanoma is a highly aggressive skin cancer, which, although highly immunogenic, frequently escapes the body's immune defences. Immune checkpoint inhibitors (ICI), such as anti-PD1, anti-PDL1, and anti-CTLA4 antibodies lead to reactivation of immune pathways, promoting rejection of melanoma. However, the benefits of ICI therapy remain limited to a relatively small proportion of patients who do not exhibit ICI resistance. Moreover, the precise mechanisms underlying innate and acquired ICI resistance remain unclear. Here, we have investigated differences in melanoma tissues in responder and non-responder patients to anti-PD1 therapy in terms of tumour and immune cell gene-associated signatures. We performed multi-omics investigations on melanoma tumour tissues, which were collected from patients before starting treatment with anti-PD1 immune checkpoint inhibitors. Patients were subsequently categorized into responders and non-responders to anti-PD1 therapy based on RECIST criteria. Multi-omics analyses included RNA-Seq and NanoString analysis. From RNA-Seq data we carried out HLA phenotyping as well as gene enrichment analysis, pathway enrichment analysis and immune cell deconvolution studies. Consistent with previous studies, our data showed that responders to anti-PD1 therapy had higher immune scores (median immune score for responders = 0.1335, median immune score for non-responders = 0.05426, p-value = 0.01, Mann-Whitney U two-tailed exact test) compared to the non-responders. Responder melanomas were more highly enriched with a combination of CD8+ T cells, dendritic cells (p-value = 0.03) and an M1 subtype of macrophages (p-value = 0.001). In addition, melanomas from responder patients exhibited a more differentiated gene expression pattern, with high proliferative- and low invasive-associated gene expression signatures, whereas tumours from non-responders exhibited high invasive- and frequently neural crest-like cell type gene expression signatures. Our findings suggest that non-responder melanomas to anti-PD1 therapy exhibit a de-differentiated gene expression signature, associated with poorer immune cell infiltration, which establishes a gene expression pattern characteristic of innate resistance to anti-PD1 therapy. Improved understanding of tumour-intrinsic gene expression patterns associated with response to anti-PD1 therapy will help to identify predictive biomarkers of ICI response and may help to identify new targets for anticancer treatment, especially with a capacity to function as adjuvants to improve ICI outcomes.

Long Term Results and Prognostic Biomarkers for Anti-PD1 Immunotherapy Used after BRAFi/MEKi Combination in Advanced Cutaneous Melanoma Patients.

(1) Background: BRAFi/MEKi are usually offered as a first line treatment for patients requiring rapid response; with elevated lactate dehydrogenase (LDH) activity, large tumor burden, and with brain metastases. The efficacy of second line therapies after BRAFi/MEKI failure is now well defined. (2) Methods: Patients treated with first line target BRAFi/MEKi therapy (vemurafenib plus cobimetinib, dabrafenib plus trametinib or encorafenib plus binimetinib); and for the second line treatment immunotherapy with programmed cell death 1 (PD-1) checkpoint inhibitors (nivolumab or pembrolizumab) with at least one cycle of second line were analyzed for survival and prognostic biomarkers. (3) Results: There were no statistically significant differences in ORR between the treatment groups with nivolumab and pembrolizumab, as well as median progression free-survival (PSF) and overall survival (OS) since the initiation of second line therapy; on nivolumab OS was 6.6 months, and on pembrolizumab 5.0 months. The greatest clinical benefit with second line immunotherapy was observed in patients with LDH ≤ ULN and <3 organ sites with metastasis at baseline. Longer OS was also noted in patients with time to PD >6 months in first line (slow progression). (4) Conclusions: Second line anti-PD1 immunotherapy is effective in BRAF-mutated melanoma patients after BRAFi/MEKi therapy failure.

Systemic treatment in patients with malignant pleural mesothelioma - real life experience.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare, aggressive malignancy of the pleural cavity linked to asbestos exposure. The combination of pemetrexed and platinum is a standard first-line therapy for malignant pleural mesothelioma. Despite some progress, almost all MPM patients experience progression after first-line therapy. The second-line treatment is still being under discussion and there are very limited data available on the second-line and subsequent treatments. METHODS: The retrospective analysis included 57 patients (16 females and 41 males) from two Polish oncological institutions treated for advanced mesothelioma between 2013 and 2019. We analysed the efficacy of first-line and second-line therapy: progression-free survival (PFS), overall survival (OS), overall response rate (ORR). RESULTS: In the first-line treatment, 55 patients received pemetrexed-based chemotherapy (PBC) and two cisplatin in monotherapy. Patients' characteristics at baseline: median age was 64.2 years, ECOG PS ≤ 1 (86.2%), epithelial histology (85.7%). Median PFS and OS were 7.6 months and 14 months, respectively. Patients with ECOG PS ≤ 1 vs > 1 had a longer median OS (14.8 months vs 9.7 months, p = 0.057). One-year OS and PFS were 60.9% and 32.0%, respectively. Disease control rate (DCR) was 82.5%. Response to first-line therapy: PFS ≥ 6 months and PFS ≥ 12 months had a significant impact on median OS. Twelve patients received second-line therapy (seven PBC and five other cytotoxic single agents: navelbine, gemcitabine, or adriamycin/vincristine/methotrexate triplet). Median PFS and OS were 3.7 months and 7.2 months, respectively. DCR was 83%. One-year OS and PFS were 37% and 16.7%, respectively. In the group receiving PBC, OS was prolonged by 4.5 months compared to the non-PBC group (6.0 months vs 10.5 months, p = 0.47). CONCLUSION: Patients who benefited from first-line therapy and had prolonged PFS at first-line and achieve PFS longer than 6 months at first-line should be offered second-line treatment. Consideration of retreatment with the same cytotoxic agent could to be a viable option when no other treatment are available.

Long-Term Outcomes of Targeted Therapy after First-Line Immunotherapy in BRAF-Mutated Advanced Cutaneous Melanoma Patients-Real-World Evidence.

BACKGROUND: Currently, limited data on targeted therapy and immunotherapy sequencing in patients with BRAF-mutant melanoma is available. Targeted therapy and immunotherapy are expected to be comparable in terms of overall survival (OS) when used as second-line therapies; therefore, understanding the characteristics of patients who completed sequential treatment is needed. METHODS: The primary objective of this study was to analyze the efficacy of BRAFi/MEKi activity as second-line therapy in patients with advanced melanoma. We also aimed to describe the clinical characteristics of patients with advanced melanoma who were treated sequentially with immunotherapy and targeted therapy. We enrolled 97 patients treated between 1st December 2015 and 31st December 2020 with first-line immunotherapy with programmed cell death 1 (PD-1) checkpoint inhibitors; and for the second-line treatment with at least one cycle of BRAFi/MEKi therapy with follow-up through 31 January 2022. RESULTS: Median OS since first-line treatment initiation was 19.9 months and 12.8 months since initiation of BRAFi/MEKi treatment. All BRAFi/MRKi combinations were similarly effective. Median progression free survival (PFS) was 7.5 months since initiation of any BRAFi/MEKi treatment. CONCLUSIONS: BRAFi/MEKi therapy is effective in the second-line in advanced and metastatic melanoma patients. For the first time, the efficacy of all BRAFi/MEKi combinations as second-line therapy is shown.

Treatment of Locally Advanced Merkel Cell Carcinoma-A Multi-Center Study.

Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer with a high risk of recurrence and poor prognosis. The treatment of locally advanced disease involves surgery and radiotherapy. To analyze real-life treatment patterns and clinical outcomes, we conducted a retrospective analysis of data from 161 MCC patients treated with curative intent in four oncological centers in Poland. The median age at diagnosis was 72 years (30-94); 49.7% were male. Lymph node (LN) involvement at diagnosis was found in 26.9% of patients. Sentinel lymph node biopsy (SLNB) was performed in 36.5% of patients (positive in 10.5%), and 51.9% of patients received perioperative treatment. The relapse rate was 38.3%. With the median follow-up of 2.3 years, the median disease-free survival (DFS) was not reached, and the 1-year rate was 65%. The negative independent risk factors for DFS were male gender, metastases in LN at diagnosis, no SLNB in patients without clinical nodal metastases, and no perioperative radiotherapy. The estimated median overall survival (OS) was 6.9 years (95% CI 4.64-9.15). The negative independent risk factors for OS were male gender, age above 70, metastases in LN at diagnosis, and no SLNB in patients without clinical nodal metastases. Our results confirm that the MCC treatment should be conducted in an experienced multidisciplinary team; however, the outcomes are still unsatisfactory.

Survival of patients with stage IIIC and IIID melanomas with nodal metastases in the light of new therapies.

Introduction: Within stage III melanoma prognosis and outcomes significantly vary. Advances in systemic therapy improved prognosis in metastatic melanoma. Adjuvant therapy in stage III significantly lowered relapses, although the effect on survival is less evident. Analysis of treatment results in stage IIIC and IIID before introduction of the modern adjuvant therapy, but after introduction of the effective systemic therapy in metastatic relapse, is needed. Aim: To analyse the clinical outcomes in patients with stage IIIC and IIID melanoma before the introduction of the novel adjuvant therapy. Material and methods: Consecutive stage IIIC and IIID melanoma patients treated in 2015-2018 in 4 reference centres in Poland were enrolled in the analysis of RFS and OS (in-transit metastases excluded). Median follow-up was 26.6 months (1.7-67.2). Results: There were 224 stage IIIC and 49 stage IIID patients. Recurrence was observed in 170 (62.2%); 102 (45.5%) deaths in stage IIIC and 28 (57.1%) in stage IIID were reported. RFS and OS were better in stage IIIC compared to stage IIID. RFS and OS in the IIIC group were 19.7 and 36.2 months, respectively, and in IIID - 8.9 and 27.8 months, respectively. Conclusions: The survival of patients with high-risk melanomas has improved in recent years, however, it is still unsatisfactory. The major changes in melanoma management related to the introduction of the adjuvant therapy require further careful observation.

Development of immunity-related adverse events correlates with baseline clinical factors, survival and response to anti-PD-1 treatment in patients with inoperable or metastatic melanoma.

BACKGROUND: The relationship between immune related adverse events (irAEs) and efficacy is not definitively proven, and data on the relationship between irAE and treatment efficacy are contradictory. MATERIAL AND METHODS: Five hundred ninety-three consecutive patients with unresectable or metastatic melanoma treated in the first line with anti-PD-1 (nivolumab or pembrolizumab) between January 2016 and December 2019 were enrolled in the study. RESULTS: Statistically significant differences were demonstrated between the group of patients without and with irAE in median OS and PFS (p < .0001 both) and also in OS between the group of patients without irAE and patients with irAE within 3, 6, and 9 months from the start of anti-PD-1 therapy (p = .0121, p = .0014, p < .0001; respectively) and PFS (p = .0369, p = .0052, p = .0001; respectively). A statistically significant relationship was demonstrated between the occurrence of irAE and the location of the primary tumor (skin vs. mucosa vs. unknown; p = .0183), brain metastasis (present vs. absent; p = .0032), other locations (present vs. absent, p = .0032), LDH (normal vs. elevated; p = .0046) and stage according to TNM (p = .0093). CONCLUSION: The occurrence of irAE was associated with longer OS, PFS, and more frequent response to treatment. IrAE occurred statistically significantly more often in patients with mucosa primary tumor, with normal LDH levels, without brain metastases, stages III, M1a, and M1b.

Differential Expression of BARD1 Isoforms in Melanoma.

Melanoma comprises <5% of cutaneous malignancies, yet it causes a significant proportion of skin cancer-related deaths worldwide. While new therapies for melanoma have been developed, not all patients respond well. Thus, further research is required to better predict patient outcomes. Using long-range nanopore sequencing, RT-qPCR, and RNA sequencing analyses, we examined the transcription of BARD1 splice isoforms in melanoma cell lines and patient tissue samples. Seventy-six BARD1 mRNA variants were identified in total, with several previously characterised isoforms (γ, φ, δ, ε, and η) contributing to a large proportion of the expressed transcripts. In addition, we identified four novel splice events, namely, Δ(E3_E9), ▼(i8), IVS10+131▼46, and IVS10▼176, occurring in various combinations in multiple transcripts. We found that short-read RNA-Seq analyses were limited in their ability to predict isoforms containing multiple non-contiguous splicing events, as compared to long-range nanopore sequencing. These studies suggest that further investigations into the functional significance of the identified BARD1 splice variants in melanoma are warranted.

Radiotherapy in the Management of Pediatric and Adult Osteosarcomas: A Multi-Institutional Cohort Analysis.

BACKGROUND: Due to the rarity of osteosarcoma and limited indications for radiotherapy (RT), data on RT for this tumor are scarce. This study aimed to investigate the utilization of RT for osteosarcomas in the recent 20 years and to identify factors related to patients' response to radiation. METHODS: We performed a retrospective analysis of patients irradiated for osteosarcoma treatment. We planned to assess differences in the utilization of RT between the periods of 2000-2010 and 2011-2020, identify the risk factors associated with local progression (LP), determine whether RT-related parameters are associated with LP, and calculate patients' survival. RESULTS: A total of 126 patients with osteosarcoma who received 181 RT treatments were identified. We found a difference in RT techniques between RT performed in the years 2000-2010 and that performed in the years 2011-2020. LP was observed after 37 (20.4%) RT treatments. Intent of RT, distant metastases, and concomitant systemic treatment affected the risk of LP. Five-year overall survival was 33% (95% confidence interval (26%-43%)). CONCLUSIONS: RT for osteosarcoma treatment has evolved from simple two-dimensional palliative irradiation into more conformal RT applied for new indications including oligometastatic and oligoprogressive disease. RT may be a valuable treatment modality for selected patients with osteosarcoma.

The analysis of 3-year adjuvant therapy with imatinib in patients with high-risk molecular profiled gastrointestinal stromal tumors (GIST) treated in routine practice.

INTRODUCTION: The real-world data on adjuvant imatinib therapy in high-risk primary GIST are scarce. METHODS: We have analysed the data of 107 consecutive patients with gastrointestinal stromal tumour (GIST) after resection treated with adjuvant imatinib (for planned 3 years with initial dose 400 mg daily, started not later than 4 months after operation) in 6 oncological centres in 2013-2018. All patients were required to have high risk of recurrence (at least 50% according to NCCN/AFIP criteria), known mutational status to exclude PDGFRA D842V mutants and KIT/PDGFRA-wild type cases from therapy without any further selection. Median follow-up time was 27 months. RESULTS: The most common primary localization of GIST was small bowel (63 patients; 59%), followed by the stomach (40 patients; 37%). The majority of GIST cases harboured exon 11 KIT mutations (88 cases, 82%), 11 cases had exon 9 KIT mutations (10%), 8 had other KIT/PDGFRA mutations potentially sensitive to imatinib. Forty patients (37%) finished 3-year adjuvant imatinib therapy as planned, 48 (45%) still continue therapy, 5 (4.5%) patients had finished adjuvant therapy prematurely due to toxicity, 6 (6%) due to disease progression on treatment and 8 (7.5%) due to other reasons. The disease relapse was detected in 19 patients, of them in 5 cases in exon 9 KIT mutants (45%), and 14 cases in patients with exon 11 KIT mutations (11%) [p < 0.01]. Estimated 4-year relapse-free survival (RFS) rate is 78%. CONCLUSIONS: The early results of adjuvant therapy with imatinib in routine practice outside clinical trials in high-risk mutation-driven GIST patients only confirm high efficacy of this therapy with better tolerability than in clinical trials. We found overrepresentation of exon 9 KIT mutants and ruptured tumors in a group of patients with disease relapse.