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

BRAF mutations in sporadic colorectal carcinoma from polish patients

BRAF mutations are second to KRAS mutations in activation of the MAPK pathway in colorectal carcinoma cells. In addition to mutated KRAS, BRAF V600E mutation is associated with resistance to EGFR-targeted therapy in colorectal cancer; thus mutated BRAF might serve as a predictive factor. In this study, 163 routinely resected adenocarcinomas were screened for mutations in exons 11 and 15 of the BRAF gene. Only 6 (3.7%) tumours had a missense point mutation (G469A, D594G, G596R, K601N and twice V600E). The tumours were locally advanced with multiple metastases to lymph nodes. Mutations were associated with microsatellite instability (2 cases MSI-H, 2 cases MSI-L) and mutually exclusive with a mutated KRAS gene. In this sample set, mutations in the BRAF gene were more diverse and less frequent than usually reported

Beneficial effect of kidney transplantation from a deceased donor on severe chronic refractory intradialytic hypotension : a case report

Abstract Background Chronic refractory hypotension (IDH, intradialytic hypotension) is a rare but serious problem encountered in patients on hemodialysis. Patients with chronic hypotension are often disqualified by transplant teams from renal transplantation. This is due to the possibility of an enormous risk of ischemic complications. Case presentation We describe a 44-year old female patient with severe refractory hypotension (mean BP 60/30 mmHg, the lowest 48/28 mmHg), which appeared after bilateral laparoscopic nephrectomy of the infected kidneys. The kidney transplantation from a deceased donor, with infusion of the two pressor amines (dopamine, dobutamine) was performed without technical complications and the blood pressure measurements were 100–120/70–80 mmHg. The immunosuppression regimen was tacrolimus (TAC) + mycophenolate mophetil (MMF) and steroids (GS). Pressor amines were discontinued on the 18th day after the transplantation. Because of delayed graft function, 4 hemodialysis treatments were performed. The patient was discharged from the hospital on the 22nd day with good function of the transplanted kidney (the concentration of serum creatinine 117 μmol/l). During one-year follow-up, the patient has been remaining stable with a very good graft function (serum creatinine 84 μmol/l) and normal blood pressure (115/70 mmHg). Conclusions Proper preparation and adequate perioperative treatment allowed for safely performing kidney transplantation in the patient with severe IDH

The effects of intraoperative electron-beam radiotherapy on the incidence of postoperative complications in patients with unresectable pancreatic cancer

Wstęp. Radioterapia śródoperacyjna przy użyciu wiązki elektronów (IOERT) może przyczynić się do poprawy wyników leczenia chorych na raka trzustki. Ze względu na możliwość uszkodzenia sąsiadujących z guzem tkanek, kluczowym elementem jest ocena bezpieczeństwa proponowanego modelu postępowania. Cel pracy. Celem pracy była analiza bezpieczeństwa radioterapii śródoperacyjnej w grupie chorych z miejscowo zaawansowanym rakiem trzustki. Metodyka. Dokonano analizy przebiegu pooperacyjnego w grupie 97 chorych z miejscowo zaawansowanym, nieresekcyjnym rakiem trzustki, w tym 36 osób poddanych IOERT. Czynniki ryzyka powikłań oszacowano przy pomocy analizy jedno- i wieloczynnikowej. Wyniki. IOERT prowadził do znamiennego wydłużenia czasu trwania zabiegu operacyjnego z 165 ±47 do 222 ±55 minut (p=0,001) oraz wzrostu odsetka chorych wymagających przetoczenia krwi (z 7% do 19%; p=0,053). Powikłania pooperacyjne stwierdzono u 8 z 36 (22%) osób w grupie IOERT i 21 z 61 (34%) chorych bez napromieniania (p=0,204), a odsetek zgonów pooperacyjnych odpowiednio 3% i 8%. Zarówno częstość powikłań chirurgicznych (IOERT 11%, bez IOERT 20%; p=0,272), jak i powikłań ogólnych (IOERT 14%, bez IOERT 20%; p=0,469) była porównywalna między ocenianymi grupami. Wieloczynnikowa analiza potencjalnych czynników wpływających na przebieg pooperacyjny wykazała, że jedynymi niezależnymi czynnikami ryzyka powikłań był przedoperacyjny endoskopowy drenaż dróg żółciowych (iloraz szans 2,93; 95% CI 1,02-8,41) i wykonanie zespolenia omijającego w czasie zabiegu operacyjnego (iloraz szans 3,84; 95% CI 1,24-11,97). Wnioski. IOERT nie zwiększa w istotnym stopniu ryzyka powikłań po zabiegach operacyjnych u chorych z miejscowo nieresekcyjnym rakiem trzustki.Introduction. Intraoperative electron-beam radiotherapy (IOERT) may improve treatment results in patients with pancreatic cancer. However, due to the potential risk of damage to the tumor surrounding tissues, the key-element of the proposed treatment regimen is its safety evaluation. Aim. The aim of the study was to evaluate the safety of IOERT in patients with locally advanced, unresectable pancreatic cancer. Methods. The analysis of postoperative outcomes in 97 patients with locally advanced, unresectable pancreatic cancer, including 36 patients undergoing IOERT, was performed. Potential risk factors for postoperative morbidity were evaluated with univariate and multivariate analyses. Results. The IOERT significantly prolonged duration of surgery from 165 ±47 to 222 ±55 minutes (P=0.001) and increased the percentage of patients requiring blood transfusions (from 7% to 19%; P=0.053). Postoperative complications were found in 8 of 36 (22%) patients subjected to IOERT and 21 of 61 (34%) undergoing surgery without radiotherapy (P=0.204). Mortality rates were 3% and 8%, respectively. The incidence of surgical (IOERT 11%, no IOERT 20%; P=0.272) and general (IOERT 14%, no IOERT 20%; P=0.469) complications was similar in both groups. The multivariate analysis of potential variables influencing early postoperative outcome identified preoperative endoscopic biliary drainage (Odds Ratio 2.93; 95% CI 1.02-8.41) and enteric or biliary bypass procedure (Odds Ratio 3.84; 95% CI 1.24-11.97) as the only independent risk factors for complications. Conclusions. IOERT does not increase significantly the risk of postoperative complications in patients with locally advanced, unresectable pancreatic cancer