Analysis of reliability of different risk classifications for assessment of relapses of gastrointestinal stromal tumors (GIST) — the impact of primary tumor genotyping

Background. Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Radical surgery is the primary treatment for GIST. Unfortunately, 40–50% of patients relapse, mainly due to hepatic and peritoneal metastases. Currently, the treatment of choice for locally advanced, inoperable or metastatic GIST is the use of tyrosine kinase inhibitors, including imatinib. GISTs are a group of tumors with various morphological, pathological and molecular features as well as different clinical courses, therefore their biological course is difficult to determine. Nevertheless, we currently have 5 classifications that assess the risk of relapse after surgery. The aim of this study was to analyze prognostic factors with regard to the risk of recurrence and overall survival, and to compare the clinical reliability of the recurrence risk classifications developed so far with an attempt to present a new classification including the genotype of primary GIST. Patients and methods. The material consisted of a group of 697 patients with primary GIST treated with the intention to cure, collected prospectively as part of the GIST clinical registry, Department of Melanoma and Soft Tissue and Bone Sarcomas, Maria Sklodowska-Curie National Research Institute of Oncology in Warsaw. All patients were classified based on 5 existing recurrence risk classifications. Univariate and multivariate analysis were performed for disease-free survival (DFS) and overall survival (OS). The relationships of the following factors with DFS and OS were assessed: sex, age, primary tumor mutational status, primary tumor location, primary tumor size, number of mitoses/50 HPF, surgical margins and the presence of tumor rupture. The next analysis concerned the comparison of the accuracy of existing recurrence risk classifications. The analysis was performed using ROC curves and a new classification model was proposed including mutation analysis as well as factors such as gender and age for selected existing recurrence risk assessment models. Results. Univariate and multivariate analyses showed statistical significance of variables such as male sex (P = 0.02), mitotic index 5–10/50 HPF and &gt; 10/50 HPF (P &lt; 0.001), primary tumor size 5–10 cm and &gt; 10 cm (P &lt; 0.001), primary tumor location outside of the stomach (P &lt; 0.001), R1 surgery (P &lt; 0.001), tumor rupture (P &lt; 0.001), and the presence of mutations in the KIT gene exon 11 including deletion 557–558 and the KIT gene exon 9 (P = 0.009) as negative prognostic factors affecting disease recurrence. Five-year disease-free survival rate was 57.3%. Median DFS was 76 months. Negative prognostic factors for OS are: age &lt; 40 (P = 0.045), mitotic index 5–10/50 and &gt; 10/50 HPF (P &lt; 0.001), primary tumor size 5–10 cm and &gt; 10 cm (P &lt; 0.001), R1 surgery and tumor rupture (P &lt; 0.001). All existing recurrence risk classifications showed prognostic value for assessing differences in DFS and OS, no significant differences were found between individual recurrence risk classifications. In addition, the reliability of all these classifications was improved by adding gender, age and mutation status. The value added of mutation status for better risk assessment was most significant when used in intermediate risk groups according to different classifications (P &lt; 0.01). Conclusion. All current GIST recurrence risk classifications allow for reliable assessment of recurrence risk. Mutations involving deletions (557–558) in the KIT gene exon 11 are most often present in the group at high risk of recurrence. Patients with confirmed mutations in the PDGFRA gene exon 18 and wild-type genotype have a favorable prognostic effect. The reliability of existing classifications for assessing the risk of relapse after GIST resection can be improved by adding mutation status, especially in groups at intermediate risk of relapse, which should facilitate therapeutic decisions in the context of adjuvant therapy.Background. Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Radical surgery is the primary treatment for GIST. Unfortunately, 40–50% of patients relapse, mainly due to hepatic and peritoneal metastases. Currently, the treatment of choice for locally advanced, inoperable or metastatic GIST is the use of tyrosine kinase inhibitors, including imatinib. GISTs are a group of tumors with various morphological, pathological and molecular features as well as different clinical courses, therefore their biological course is difficult to determine. Nevertheless, we currently have 5 classifications that assess the risk of relapse after surgery. The aim of this study was to analyze prognostic factors with regard to the risk of recurrence and overall survival, and to compare the clinical reliability of the recurrence risk classifications developed so far with an attempt to present a new classification including the genotype of primary GIST. Patients and methods. The material consisted of a group of 697 patients with primary GIST treated with the intention to cure, collected prospectively as part of the GIST clinical registry, Department of Melanoma and Soft Tissue and Bone Sarcomas, Maria Sklodowska-Curie National Research Institute of Oncology in Warsaw. All patients were classified based on 5 existing recurrence risk classifications. Univariate and multivariate analysis were performed for disease-free survival (DFS) and overall survival (OS). The relationships of the following factors with DFS and OS were assessed: sex, age, primary tumor mutational status, primary tumor location, primary tumor size, number of mitoses/50 HPF, surgical margins and the presence of tumor rupture. The next analysis concerned the comparison of the accuracy of existing recurrence risk classifications. The analysis was performed using ROC curves and a new classification model was proposed including mutation analysis as well as factors such as gender and age for selected existing recurrence risk assessment models. Results. Univariate and multivariate analyses showed statistical significance of variables such as male sex (P = 0.02), mitotic index 5–10/50 HPF and > 10/50 HPF (P 10 cm (P 10/50 HPF (P 10 cm (P < 0.001), R1 surgery and tumor rupture (P < 0.001). All existing recurrence risk classifications showed prognostic value for assessing differences in DFS and OS, no significant differences were found between individual recurrence risk classifications. In addition, the reliability of all these classifications was improved by adding gender, age and mutation status. The value added of mutation status for better risk assessment was most significant when used in intermediate risk groups according to different classifications (P < 0.01). Conclusion. All current GIST recurrence risk classifications allow for reliable assessment of recurrence risk. Mutations involving deletions (557–558) in the KIT gene exon 11 are most often present in the group at high risk of recurrence. Patients with confirmed mutations in the PDGFRA gene exon 18 and wild-type genotype have a favorable prognostic effect. The reliability of existing classifications for assessing the risk of relapse after GIST resection can be improved by adding mutation status, especially in groups at intermediate risk of relapse, which should facilitate therapeutic decisions in the context of adjuvant therapy

First step to eradication of Poa annua L. from Point Thomas Oasis (King George Island, South Shetlands, Antarctica)

Poa annua, an alien species reported from the Antarctic continent and many Antarctic and sub-Antarctic islands, was accidentally introduced in the vicinity of the Polish Antarctic Station H. Arctowski. Recently the species has been found entering native plant communities. In almost 30 years it dispersed over 250 m from the site it was first observed and can therefore be considered invasive. We report the first steps to eradicate the species following the initial research to quantify the biology, ecology and genetics of the species. After detailed mapping of all 1439 tussocks located in the Arctowski Station area we removed 314 tussocks closest to a moss carpet formation (native plant community of high conservation value). All of the 49 tussocks growing in the Ecology Glacier forefield were removed. It is the biggest alien plant eradication act conducted so far in Antarctica. We plan to continue the eradication process and monitor the eradicated sites. This will provide valuable information on impacts and issuesrelated to removal of alien species in the maritime Antarctic and will help in informing future decisions on management of other plant invasions in the region. Given the increasing human traffic to the Antarctic and the associated risks of invasion our results will be important not only for Arctowski but also for the whole Antarctic region

Avelumab use in Merkel cell carcinoma treatment

Avelumab is a programmed death-ligand 1 (PD-L1) blocking human IgG1 lambda monoclonal antibody. It was the first immunotherapy to be approved for the treatment of MCC. In March 2017, the FDA granted accelerated approval to avelumab for the treatment of adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (MCC) –irrespective of prior therapy. In July 2017, the European Medicines Agency (EMA) recommended the approval of avelumab as a monotherapy for the treatment of adult patients with metastatic Merkel cell carcinoma (mMCC). Approvals were based on the efficacy and safety demonstrated in JAVELIN Merkel 200 (NCT02155647), a multi-center, open-label, single-arm, phase II clinical trial [1]. Part A of the study consisted of patients treated in the second line with metastatic, chemotherapy-refractory MCC. Part B consisted of systemic treatment-naive patients who received avelumab as a first-line treatment for metastatic or distally recurrent MCC. In the first line the ORR is 39.7%. Durable responses lasting at least 6 months were observed and the majority of responses are observed early with the median time to response of 6.1 week. PFS rate at 6 and 12 months are 41% and 31%, respectively. Median OS is 20.3 months. The OS rate at 1 year is 60%

Avelumab use in Merkel cell carcinoma treatment

Avelumab is a programmed death-ligand 1 (PD-L1) blocking human IgG1 lambda monoclonal antibody. It was the first immunotherapy to be approved for the treatment of MCC. In March 2017, the FDA granted accelerated approval to avelumab for the treatment of adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (MCC) irrespective of prior therapy. In July 2017, the European Medicines Agency (EMA) recommended the approval of avelumab as a monotherapy for the treatment of adult patients with metastatic Merkel cell carcinoma (mMCC). Approvals were based on the efficacy and safety demonstrated in JAVELIN Merkel 200 (NCT02155647), a multi-center, open-label, single-arm, phase II clinical trial [1]. Part A of the study consisted of patients treated in the second line with metastatic, chemotherapy-refractory MCC. Part B consisted of systemic treatment-naive patients who received avelumab as first-line treatment for metastatic or distally recurrent MCC. In the first line the ORR is 39.7%. Durable responses lasting at least 6 months were observed and the majority of responses are observed earlywith the median time to response of 6.1 week. PFS rate at 6 months and at 12 months are 41% and 31%, respectively. Median OS is 20.3 months. The OS rate at 1 year is 60%

Analiza oceny wiarygodności różnych systemów klasyfikacji ryzyka związanych z nawrotami nowotworów podścieliskowych przewodu pokarmowego (GIST) — wpływ genotypowania guza pierwotnego

Wstęp. Nowotwory podścieliskowe przewodu pokarmowego (GIST) są najczęstszymi nowotworami pochodzenia mezenchymalnego przewodu pokarmowego. Podstawowym sposobem leczenia GIST jest radykalne leczenie chirurgiczne. Niestety u 40–50% pacjentów dochodzi do nawrotu choroby, głównie pod postacią przerzutów do wątroby i do otrzewnej. GIST stanowią grupę nowotworów o różnych cechach morfologiczno-patologicznych oraz molekularnych i różnym przebiegu klinicznym, dlatego ich przebieg biologiczny jest trudny do określenia. Niemniej, dysponujemy obecnie 5 klasyfikacjami, które oceniają ryzyko nawrotu choroby po pierwotnym leczeniu chirurgicznym. Cele niniejszej pracy obejmują analizę czynników rokowniczych w odniesieniu do ryzyka nawrotu choroby i przeżyć całkowitych oraz porównanie wiarygodności klinicznej opracowanych dotychczas klasyfikacji oceny ryzyka nawrotu z próbą przedstawienia nowej klasyfikacji, uwzględniającej genotyp pierwotnego GIST. Materiał i metody. Materiał stanowiła grupa 697 chorych na pierwotny GIST leczonych z intencją wyleczenia, zgromadzona prospektywnie w Klinice Nowotworów Tkanek Miękkich, Kości i Czerniaków Narodowego Instytutu Onkologii. Wszystkich chorych sklasyfikowano na podstawie 5 istniejących klasyfikacji ryzyka nawrotu. Przeprowadzono analizę jedno- i wieloczynnikową dla takich parametrów jak czas wolny od nawrotu choroby (DFS) oraz czas przeżycia całkowitego (OS). Oceniono zależność wymienionych parametrów od następujących czynników: płeć, wiek, lokalizacja, status mutacji w guzie pierwotnym, wielkość guza pierwotnego, liczba mitoz/50 HPF, marginesy chirurgiczne oraz pęknięcie guza. Kolejna analiza dotyczyła porównania dokładności istniejących klasyfikacji oceny ryzyka nawrotu. Analizę przeprowadzono za pomocą krzywych ROC i zaproponowano nowy model klasyfikacyjny z uwzględnieniem analizy mutacji, jak również takich czynników jak płeć i wiek dla wybranych spośród istniejących już modeli oceny ryzyka nawrotu. Wyniki. Analiza jedno- i wieloczynnikowa wykazała istotność statystyczną następujących zmiennych: płeć męska (p = 0,02), indeks mitotyczny 5–10/50 HPF i &gt; 10/50 HPF (p &lt; 0,001), wielkość 5–10 cm i &gt; 10 cm (p &lt; 0,001), lokalizacja poza żołądkiem (p &lt; 0,001), resekcja R1 (p &lt; 0,001), pęknięcie guza (p &lt; 0,001) i obecność mutacji genu KIT w eksonie 11, obejmującej delecję 557–558, oraz genu KIT w eksonie 9 (p = 0,009) jako negatywnych czynników prognostycznych mających wpływ na DFS. Pięcioletnie przeżycia bez nawrotu choroby w badanej grupie wynosiły 57,3%. Mediana DFS wyniosła 76 miesięcy. Negatywne czynniki prognostyczne dla OS to: wiek &lt; 40 lat (p = 0,045), indeks mitotyczny 5–10/50 HPF i &gt; 10/50 HPF (p &lt; 0,001), pierwotny rozmiar guza 5–10 cm i &gt; 10 cm (p &lt; 0,001), operacja R1 lub pęknięcie guza (p &lt; 0,001). Wszystkie istniejące klasyfikacje ryzyka wykazały wartość prognostyczną do oceny różnic w DFS i OS, nie znaleziono istotnych różnic między poszczególnymi klasyfikacjami oceny ryzyka nawrotu. Ponadto poprawiono wiarygodność wszystkich tych klasyfikacji, dodając płeć/wiek i status mutacji. Wartość dodana statusu mutacji dla lepszej oceny ryzyka była najbardziej znacząca, gdy zastosowano ją w grupach pośredniego ryzyka według różnych klasyfikacji (p &lt; 0,01). Wnioski. Wszystkie obecnie stosowane klasyfikacje oceny ryzyka nawrotu GIST pozwalają na wiarygodną ocenę ryzyka nawrotu. Mutacje obejmujące delecje 557–558 w eksonie 11 genu KIT są najczęściej obecne w grupie o wysokim ryzyku nawrotu. Chorzy, u których potwierdzono obecność mutacji w eksonie 18 genu PDGFRA oraz wild-type, cechują się lepszym rokowaniem. Wiarygodność istniejących klasyfikacji do oceny ryzyka nawrotu choroby po resekcji GIST można poprawić, dodając status mutacji, szczególnie w grupach o pośrednim ryzyku nawrotu, co powinno ułatwić podjęcie decyzji terapeutycznych w kontekście leczenia uzupełniającego

Treatment of Gastrointestinal Stromal Tumors (GISTs): A Focus on Younger Patients

Gastrointestinal stromal tumors (GISTs) originate from Cajal’s cells and are the most common mesenchymal neoplasms of the gastrointestinal tract. GISTs in young adults, i.e., patients before the age of 40, are rare and differ from those in older patients and GISTs in children in terms of the molecular and clinical features, including the location and type of mutations. They often harbor other molecular abnormalities than KIT and PDGFRA mutations (wild-type GISTs). The general principles of therapeutic management in young patients are the same as in the elderly. Considering some differences in molecular abnormalities, molecular testing should be the standard procedure to allow appropriate systemic therapy if needed. The optimal treatment strategy should be established by a multidisciplinary team experienced in sarcoma treatment. The impact of treatment on the quality of life and daily activities, including the impact on work, pregnancy, and fertility, in this patient population should be especially taken into consideration

The Outcome of Targeted Therapy in Advanced Gastrointestinal Stromal Tumors (Gist) with Non-Exon 11 Kit Mutations

GIST is the most common mesenchymal tumour of gastrointestinal tract arising from mutation of KIT or PDGFRA gene. Surgery is the primary method of treatment, however a targeted therapy with imatinib is necessary due to recurrence. The aim of the study was to evaluate efficacy of the targeted chemotherapy in advanced gastrointestinal stromal tumours with non-exon 11 KIT mutations. Material and methods. Data from 279 patients with advanced GIST treated with imatinib between 2001 and 2011 were analysed in the study. Exon 11 KIT mutation was found in 192 patients (68.7%), non-exon 11 KIT mutation was found in 87 patients (31.3%): this group included lack of mutation - wild-type, exon 9 KIT mutations, exon 18 PDGFRA D842V mutations, non-D842V PDGFRA mutations as well as non-exon 9 and 11 KIT mutations. Analysis of progression-free survival and overall survival were done for the entire group of patients and for patients with particular mutations, and then effects on progression-free survival and overall survival of such factors as sex, age, imatinib dose were evaluated. Results. Occurrence of non-exon 11 KIT mutation increases the risk of disease progression by 20% in comparison to the presence of exon 11 KIT mutation, however it does not increase the risk of patient’s death. Percentage of 5-year progression-free survivals is the greatest in the case of PDGFRA mutation other than D842V mutation. Percentage of 5-year survivals in case of the presence of D842V PDGFRA mutation is more than twice worse than in the case of the other mutations. Lesion location in the gastrointestinal tract affected the risk of death, with the greatest percentage of 5-year survival for lesions located in the stomach. Such factors as sex, age at diagnosis (<50, ≥50 years) and imatinib dose did not affect the risk of disease progression and the risk of patient’s death. Conclusions. The ratio of overall survival of patients with advanced GIST with a mutation other than exon 11 KIT mutation treated with imatinib is similar to the ratio of overall survival of patients with GIST with exon 11 KIT mutation. An exception is the group of patients with GIST in whom the presence of D842V PDGFRA mutation was found. In general, longer survival has been found in patients with GIST located in the stomach in comparison to the small intestine or other less frequent locations. Percentage of 5-year progression-free survivals is the greatest in the case of PDGFRA mutation other than D842V mutation