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1.
J Clin Oncol ; 39(28): 3128-3139, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34343033

RESUMO

PURPOSE: Primary or secondary mutations in KIT or platelet-derived growth factor receptor alpha (PDGFRA) underlie tyrosine kinase inhibitor resistance in most GI stromal tumors (GISTs). Avapritinib selectively and potently inhibits KIT- and PDGFRA-mutant kinases. In the phase I NAVIGATOR study (NCT02508532), avapritinib showed clinical activity against PDGFRA D842V-mutant and later-line KIT-mutant GIST. VOYAGER (NCT03465722), a phase III study, evaluated efficacy and safety of avapritinib versus regorafenib as third-line or later treatment in patients with unresectable or metastatic GIST. PATIENTS AND METHODS: VOYAGER randomly assigned patients 1:1 to avapritinib 300 mg once daily (4 weeks continuously) or regorafenib 160 mg once daily (3 weeks on and 1 week off). Primary end point was progression-free survival (PFS) by central radiology per RECIST version 1.1 modified for GIST. Secondary end points included objective response rate, overall survival, safety, disease control rate, and duration of response. Regorafenib to avapritinib crossover was permitted upon centrally confirmed disease progression. RESULTS: Four hundred seventy-six patients were randomly assigned (avapritinib, n = 240; regorafenib, n = 236). Median PFS was not statistically different between avapritinib and regorafenib (hazard ratio, 1.25; 95% CI, 0.99 to 1.57; 4.2 v 5.6 months; P = .055). Overall survival data were immature at cutoff. Objective response rates were 17.1% and 7.2%, with durations of responses of 7.6 and 9.4 months for avapritinib and regorafenib; disease control rates were 41.7% (95% CI, 35.4 to 48.2) and 46.2% (95% CI, 39.7 to 52.8). Treatment-related adverse events (any grade, grade ≥ 3) were similar for avapritinib (92.5% and 55.2%) and regorafenib (96.2% and 57.7%). CONCLUSION: Primary end point was not met. There was no significant difference in median PFS between avapritinib and regorafenib in patients with molecularly unselected, late-line GIST.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias Gastrointestinais/tratamento farmacológico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Compostos de Fenilureia/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Proto-Oncogênicas c-kit/antagonistas & inibidores , Pirazóis/administração & dosagem , Piridinas/administração & dosagem , Pirróis/administração & dosagem , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Triazinas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Ásia , Austrália , Progressão da Doença , Esquema de Medicação , Europa (Continente) , Feminino , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/mortalidade , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/mortalidade , Tumores do Estroma Gastrointestinal/secundário , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , América do Norte , Compostos de Fenilureia/efeitos adversos , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas c-kit/genética , Pirazóis/efeitos adversos , Piridinas/efeitos adversos , Pirróis/efeitos adversos , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Fatores de Tempo , Triazinas/efeitos adversos
2.
J Surg Oncol ; 124(7): 1128-1135, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34324197

RESUMO

BACKGROUND AND OBJECTIVES: This study aimed to characterize the efficacy of neoadjuvant imatinib in rectal gastrointestinal stromal tumors (GISTs) and the prognostic characteristics of patients after surgery. METHODS: Patients with rectal GISTs who received neoadjuvant imatinib between 2000 and 2019 were selected from 11 large-scale tertiary hospitals in China. The best response to neoadjuvant imatinib was assessed. Propensity score matching (PSM) was conducted to reduce confounders. Recurrence free survival (RFS) and overall survival (OS) were estimated using Kaplan-Meier method. RESULTS: Of the 100 patients, 75, 18, and 7 had a partial response (PR), stable disease (SD), and progressive disease (PD), respectively. The median tumor size decreased from 5 cm before treatment to 4 cm after treatment (p < 0.001). A total of 31 patients underwent genetic testing after surgery; 23 of patients with exon 11 mutation had PR and 2 had SD. One of the patients with exon 9 mutation had PR, 2 had SD, and 1 had PD. Two patients with the wild type GIST had PD. A total of 86 patients underwent surgery of which 85 underwent complete resection; 72 underwent anal preservation and 40 underwent local excision (LE). After PSM, patients who received neoadjuvant therapy had higher rates of LE (p = 0.001) and anal preservation (p = 0.033) than those of patients without neoadjuvant therapy. The median follow-up time was 37 months. Nine patients experienced recurrence and one patient died. The 3-year RFS and OS rates were 95.0% and 100%, respectively. After PSM, we found that there was no significant difference in RFS between patients who received or did not receive neoadjuvant therapy (p = 0.623). Univariate analysis showed postneoadjuvant tumor size (p = 0.469) and mitotic count (p = 0.294) were not associated with the RFS in patients who received neoadjuvant imatinib. CONCLUSIONS: Neoadjuvant imatinib can shrink rectal GIST size, increasing the possibility of complete resection and anal preservation. Further studies are warranted to understand the long-term outcomes of rectal GISTs in patients receiving neoadjuvant imatinib.


Assuntos
Tumores do Estroma Gastrointestinal/mortalidade , Mesilato de Imatinib/uso terapêutico , Terapia Neoadjuvante , Neoplasias Retais/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Feminino , Seguimentos , Tumores do Estroma Gastrointestinal/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Prognóstico , Neoplasias Retais/terapia , Estudos Retrospectivos
3.
Sultan Qaboos Univ Med J ; 21(2): e237-e243, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34221471

RESUMO

Objectives: This study aimed to report the clinicopathological features, management and long-term outcomes of patients with gastrointestinal stromal tumours (GISTs) in Oman. Methods: This retrospective study was conducted on patients treated for GIST between January 2003 and December 2017 at three tertiary referral centres in Muscat, Oman. All patients with confirmed histopathological diagnoses of GIST and followed-up at the centres during this period were included. Relevant information was retrieved from hospital records until April 2019. Results: A total of 44 patients were included in the study. The median age was 55.5 years and 56.8% were female. The most common primary site of disease was the stomach (63.6%) followed by the jejunum/ileum (18.2%). Two patients (4.5%) had c-Kit-negative, discovered on GIST-1-positive disease. A total of 24 patients (54.5%) presented with localised disease and eight (33.3%) were classified as being at high risk of relapse. Patients with metastatic disease received imatinib in a palliative setting, whereas those with completely resected disease in the intermediate and high-risk groups were treated with adjuvant imatinib. Of the six patients (13.6%) with progressive metastatic disease, of which four had mutations on exon 11 and one on exon 9, while one had wild-type disease. Overall, rates of progression-free survival and overall survival (OS) at 100 months were 77.4% and 80.4%, respectively. Rates of OS for patients with localised and metastatic disease were 89.9% and 80.2%, respectively. Conclusion: The presenting features and outcomes of patients with GISTs in Oman were comparable to those reported in the regional and international literature.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Gastrointestinais/tratamento farmacológico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Mesilato de Imatinib/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Idoso , Quimioterapia Adjuvante , Feminino , Neoplasias Gastrointestinais/mortalidade , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/mortalidade , Tumores do Estroma Gastrointestinal/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Omã/epidemiologia , Proteínas Proto-Oncogênicas c-kit/uso terapêutico , Estudos Retrospectivos , Taxa de Sobrevida , Estados Unidos/epidemiologia
5.
J Immunol Res ; 2021: 6647292, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33681387

RESUMO

There are multiple tumor-infiltrating lymphocytes (TILs) and relevant immune checkpoints existing in gastrointestinal stromal tumor (GIST), which provides opportunities and rationales for developing effective immunotherapies. Recent studies have suggested that checkpoint TIM-3/Gal-9 plays a pivotal role on immune response in multiple tumors, similar to the PD-1/PD-L1, emerging as a potential therapeutic target. However, their functions in GIST are unrevealed. Hence, the expression of immune checkpoints TIM-3 and Gal-9, as well as the infiltration of CD8+ T cells and NK cells, is described in 299 cases of GIST specimens. The results showed that TIM-3 and Gal-9 are mainly expressed in TILs, rarely in tumor cells. Expression levels of TIM-3 and Gal-9 significantly differ in varying risks of GIST and exert opposite distribution trends. Indicated by prognosis analysis, high TIM-3 expression of TILs was associated with improved outcome, while low expression levels of TIM-3 in combination with low amounts of CD8+ and CD56+ TILs predict extremely poor survival. The integrated analysis of TIM-3+, CD8+, and CD56+ TILs as one biomarker is a reliable independent predictor of prognosis. In conclusion, low densities of TIM-3+ TILs are associated with poor survival, and integrated immune biomarkers lead to superior predictors of GIST prognosis.


Assuntos
Tumores do Estroma Gastrointestinal/etiologia , Tumores do Estroma Gastrointestinal/metabolismo , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos T Citotóxicos/metabolismo , Adulto , Idoso , Biomarcadores Tumorais , Feminino , Tumores do Estroma Gastrointestinal/mortalidade , Tumores do Estroma Gastrointestinal/patologia , Humanos , Imuno-Histoquímica , Linfócitos do Interstício Tumoral/imunologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Citotóxicos/imunologia , Carga Tumoral
6.
BMC Cancer ; 21(1): 291, 2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33740926

RESUMO

BACKGROUND: Avapritinib, a potent inhibitor of KIT and platelet-derived growth factor receptor A (PDGFRA) tyrosine kinases, has demonstrated unprecedented clinical activity in PDGFRA D842V-mutant gastrointestinal stromal tumors (GIST). METHODS: This retrospective analysis compared efficacy of avapritinib in patients enrolled in the NAVIGATOR phase 1 trial (NCT02508532) with the efficacy of other tyrosine kinase inhibitors (TKIs) in patients with unresectable/metastatic PDGFRA D842V-mutant GIST enrolled in a retrospective natural history study (Study 1002). The primary endpoint was overall survival (OS) from the start of reference treatment (avapritinib for NAVIGATOR patients or first-line TKI for treatment of unresectable/metastatic GIST for Study 1002 patients); the secondary endpoint was progression-free survival (PFS). Adjusted Kaplan-Meier survival curves were compared by Cox regression. RESULTS: Fifty-six (NAVIGATOR) and 19 (Study 1002) patients with PDGFRA D842V-mutant GIST were evaluated; of the 56 patients from NAVIGATOR, a subgroup of patients treated with either 300 mg (recommended phase 2 dose) or 400 mg (maximum tolerated dose) avapritinib starting dose (n = 38) were analyzed separately. Patient characteristics were adjusted for imbalances by propensity score between the study groups. Inverse probability of treatment weighting-adjusted Kaplan-Meier analysis of OS showed median OS was not reached for NAVIGATOR patients treated with any of the avapritinib doses tested and was 12.6 months for Study 1002 patients; OS rate at 6/48 months was 100%/63% in NAVIGATOR and 56%/17% in Study 1002 (P = 0.0001). In the 300/400 mg subgroup, adjusted OS rates at 6/36 months were 100%/73 and 68%/20% in Study 1002 (P = 0.0016). Adjusted median PFS was 29.5 months in NAVIGATOR and 3.4 months in Study 1002. CONCLUSIONS: In this indirect, retrospective analysis, avapritinib demonstrated more durable survival outcomes compared with other TKIs in patients with unresectable/metastatic PDGFRA D842V-mutant GIST. TRIAL REGISTRATION: The NAVIGATOR trial was registered at ClinicalTrials.gov as per July 2015, Identifier: NCT02508532 .


Assuntos
Tumores do Estroma Gastrointestinal/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Pirazóis/administração & dosagem , Pirróis/administração & dosagem , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Triazinas/administração & dosagem , Ensaios Clínicos Fase I como Assunto , Feminino , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/mortalidade , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Pirazóis/efeitos adversos , Pirróis/efeitos adversos , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Estudos Retrospectivos , Triazinas/efeitos adversos
7.
Eur J Surg Oncol ; 47(7): 1668-1674, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33581967

RESUMO

BACKGROUND: The surgical approaches and resection extent for rectal gastrointestinal stromal tumors (GISTs) are controversial due to the low incidence of this disease. A multicenter retrospective cohort study was conducted to compare the postoperative and oncologic outcomes of local excision (LE) and radical resection (RR) in patients with low rectal GIST. PATIENTS AND METHODS: The medical records of rectal GIST patients from 11 large-scale medical centers in China (January 2000-December 2019) were reviewed. All patients were divided into either the LE group or the RR group. Propensity score matching (PSM) was conducted to reduce confounders. RESULTS: A total of 280 patients with low rectal GIST were enrolled. After PSM, 144 patients were included (72 in each group). The LE group showed a higher anal preservation rate (100.0% vs. 76.4%, P < 0.001), shorter operation time (77.1 ± 68.4 min vs. 159.1 ± 83.6 min, P < 0.001), fewer complications (8.3% vs. 22.2%, P = 0.021) and shorter postoperative hospital stay (4.9 ± 4.1 d vs. 10.7 ± 8.1 d, P < 0.001) than the RR group. There was no significant difference in recurrence-free survival (RFS) between the RR and LE groups among patients with tumors ≤2 cm (P = 0.220), and the RR group had a superior RFS than the LE group in patients with tumors >2 cm (P = 0.046). CONCLUSIONS: LE resulted in improved postoperative outcomes and comparable oncological safety with a low rectal GIST of ≤2 cm. However, for patients with a low rectal GIST of >2 cm, RR might be a more appropriate option with better RFS.


Assuntos
Procedimentos Cirúrgicos do Sistema Digestório/métodos , Tumores do Estroma Gastrointestinal/cirurgia , Neoplasias Retais/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , China , Feminino , Tumores do Estroma Gastrointestinal/mortalidade , Humanos , Tempo de Internação/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Pontuação de Propensão , Neoplasias Retais/mortalidade , Taxa de Sobrevida
8.
Eur J Cancer ; 145: 132-142, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33465704

RESUMO

BACKGROUND: PDGFRA D842V mutations occur in 5-10% of gastrointestinal stromal tumours (GISTs), and previously approved tyrosine kinase inhibitors (TKIs) are inactive against this mutation. Consequently, patients have a poor prognosis. We present an updated analysis of avapritinib efficacy and long-term safety in this patient population. METHODS: NAVIGATOR (NCT02508532), a two-part, open-label, dose-escalation/dose-expansion phase I study, enrolled adult patients with unresectable GISTs. Patients with PDGFRA D842V-mutant GIST were a prespecified subgroup within the overall safety population, which included patients who received ≥1 avapritinib dose. Primary end-points were overall response rate (ORR) and avapritinib safety profile. Secondary end-points were clinical benefit rate (CBR), duration of response (DOR) and progression-free survival (PFS). Overall survival (OS) was an exploratory end-point. RESULTS: Between 7 October 2015 and 9 March 2020, 250 patients enrolled in the safety population; 56 patients were included in the PDGFRA D842V population, 11 were TKI-naïve. At data cut-off, median follow-up was 27.5 months. Safety profile was comparable between the overall safety and PDGFRA D842V populations. In the PDGFRA D842V population, the most frequent adverse events were nausea (38 [68%] patients) and diarrhoea (37 [66%]), and cognitive effects occurred in 32 (57%) patients. The ORR was 91% (51/56 patients). The CBR was 98% (55/56 patients). The median DOR was 27.6 months (95% confidence interval [CI]: 17.6-not reached [NR]); median PFS was 34.0 months (95% CI: 22.9-NR). Median OS was not reached. CONCLUSION: Targeting PDGFRA D842V-mutant GIST with avapritinib resulted in an unprecedented, durable clinical benefit, with a manageable safety profile. Avapritinib should be considered as first-line therapy for these patients.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Gastrointestinais/tratamento farmacológico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Pirróis/uso terapêutico , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Triazinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Feminino , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/mortalidade , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/mortalidade , Tumores do Estroma Gastrointestinal/secundário , Humanos , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Pirazóis/efeitos adversos , Pirróis/efeitos adversos , Fatores de Tempo , Triazinas/efeitos adversos
9.
Cancer Sci ; 112(3): 1262-1274, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33393143

RESUMO

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the human gastrointestinal tract. In this study, we performed single-cell RNA sequencing (RNA-seq) on intra- and peri-tumor tissues from GIST patients with the aim of discovering the heterogeneity of tumor cells in GIST and their interactions with other cells. We found four predominating cell types in GIST tumor tissue, including T cells, macrophages, tumor cells, and NK cells. Tumor cells could be clustered into two groups: one was highly proliferating and associated with high risk of metastasis, the other seemed "resting" and associated with low risk. Their clinical relevance and prognostic values were confirmed by RNA-seq of 65 GIST samples. T cells were the largest cell type in our single-cell data. Two groups of CD8+ effector memory (EM) cells were in the highest clonal expansion and performed the highest cytotoxicity but were also the most exhausted among all T cells. A group of macrophages were found polarized to possess both M1 and M2 signatures, and increased along with tumor progression. Cell-to-cell interaction analysis revealed that adipose endothelial cells had high interactions with tumor cells to facilitate their progression. Macrophages were at the center of the tumor microenvironment, recruiting immune cells to the tumor site and having most interactions with both tumor and nontumor cells. In conclusion, we obtained an overview of the GIST microenvironment and revealed the heterogeneity of each cell type and their relevance to risk classifications, which provided a novel theoretical basis for learning and curing GISTs.


Assuntos
Tumores do Estroma Gastrointestinal/patologia , Macrófagos/patologia , Linfócitos T Citotóxicos/patologia , Microambiente Tumoral/imunologia , Idoso , Comunicação Celular , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/imunologia , Tumores do Estroma Gastrointestinal/mortalidade , Humanos , Imuno-Histoquímica , Macrófagos/imunologia , Masculino , Pessoa de Meia-Idade , RNA-Seq , Análise de Célula Única , Linfócitos T Citotóxicos/imunologia
10.
PLoS One ; 16(1): e0245153, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33411849

RESUMO

BACKGROUND & AIMS: Progranulin (PGRN) is known to promote tumorigenesis and proliferation of several types of cancer cells. However, little is known about the clinicopathological features of patients with gastrointestinal stromal tumors (GISTs) with regard to PGRN expression. METHODS: A retrospective analysis was performed on patients with GISTs who underwent curative surgical resection between 2007 and 2017. PGRN expression was evaluated by immunohistochemical (IHC) analysis and semi-quantitatively categorized (no expression, 0; weak, 1+; moderate, 2+; strong, 3+). Tumors with a staining intensity of 2+ or 3+ were considered high PGRN expression. RESULTS: Fifty-four patients were analyzed; 31 patients (57%) were male. The median age at surgery was 60 years (range, 33-79), and the most common primary site was the stomach (67%). Thirty-five patients (65%) had spindle histology; 42 patients (78%) were separated as a high-risk group according to the modified National Institutes of Health (NIH) classification. High PGRN-expressing tumors were observed in 27 patients (50%), had more epithelioid/mixed histology (68% vs. 32%; p = 0.046), and KIT exon 11 mutations (76% vs. 24%; p = 0.037). Patients with high PGRN-expressing tumors had a worse recurrence-free survival (RFS) (36% of 5-year RFS) compared to those with low PGRN-expressing tumors (96%; p<0.001). Multivariate analysis showed that high PGRN expression and old age (>60 years) were independent prognostic factors for poor RFS. CONCLUSIONS: High PGRN-expressing GISTs showed more epithelioid/mixed histology and KIT exon 11 mutations. PGRN overexpression was significantly associated with poor RFS in patients with GISTs who underwent curative resection.


Assuntos
Neoplasias Gastrointestinais , Tumores do Estroma Gastrointestinal , Regulação Neoplásica da Expressão Gênica , Proteínas de Neoplasias/biossíntese , Progranulinas/biossíntese , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Neoplasias Gastrointestinais/metabolismo , Neoplasias Gastrointestinais/mortalidade , Neoplasias Gastrointestinais/patologia , Neoplasias Gastrointestinais/cirurgia , Tumores do Estroma Gastrointestinal/metabolismo , Tumores do Estroma Gastrointestinal/mortalidade , Tumores do Estroma Gastrointestinal/patologia , Tumores do Estroma Gastrointestinal/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida
11.
Dtsch Med Wochenschr ; 146(3): 157-161, 2021 02.
Artigo em Alemão | MEDLINE | ID: mdl-33513648

RESUMO

Soft tissue sarcomas are rare tumors that represent a major challenge due to varying clinical presentations and often interdisciplinary treatment concepts. Gold standard for the treatment of localized resectable soft tissue sarcomas is complete surgical removal. So far, multimodality treatment does not represent a clininal standard. However, several newer analyses and studies suggest that a subgroup of patients seems to derive an overall survival benefit from perioperative chemotherapy. In metastatic soft tissue sarcoma systemic therapy is the treatment of choice. Most active drugs are the anthracyclines and ifosfamide. Combination chemotherapy has improved both response rate and progression-free survival at the costs of increased toxicity in comparison to single agent therapy but without impact on overall survival in first-line therapy. In pretreated patients, treatment options consist of trabectedin, pazopanib, gemcitabine plus docetaxel or DTIC, and eribulin. Recent data have shown that histiotype-specific treatment options including targeted therapy represent a major improvement for several sarcoma subtypes.In GIST, imatinib is the gold standard for patients with advanced or metastatic disease. In imatinib refractory or intolerant patients, sunitinib in an individualized treatment schedule is recommended. Regorafenib has been approved for third-line therapy. Recently, avapritinib has been approved for treatment of patients with the so far resistant D842V mutation in the PDGFRA exon 18. Ripretinib has shown very promising activity in forth and further lines of therapy and is already approved in the US. The use of adjuvant imatinib therapy in patients with completely resected localized GIST with a high risk of recurrence has significantly improved overall survival with a treatment duration of 3 years. These results have now been confirmed with a 10 years follow-up analysis.


Assuntos
Antineoplásicos , Tumores do Estroma Gastrointestinal , Sarcoma , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/mortalidade , Tumores do Estroma Gastrointestinal/cirurgia , Humanos , Mesilato de Imatinib/administração & dosagem , Mesilato de Imatinib/efeitos adversos , Mesilato de Imatinib/uso terapêutico , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/uso terapêutico , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Piridinas/uso terapêutico , Sarcoma/tratamento farmacológico , Sarcoma/mortalidade , Sarcoma/cirurgia , Sunitinibe/administração & dosagem , Sunitinibe/efeitos adversos , Sunitinibe/uso terapêutico
12.
Pancreatology ; 21(1): 246-252, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33281059

RESUMO

OBJECTIVES: To investigate the frequency of imatinib-induced pancreatic complications and determine whether these are survival prognostic factors in patients with gastrointestinal stromal tumor (GIST). METHODS: This retrospective multicenter study included patients with histopathologically diagnosed GIST treated with imatinib who underwent computed tomography (CT) within 100 days before (pretreatment CT) and 500 days after (post-treatment CT) imatinib initiation (January 2004-December 2019). Forty-eight patients (63.0 ± 12.1 years, 30 men) were included. Two blinded radiologists independently measured pancreatic volumes. Pancreatic volume on pretreatment CT was compared with that of the control (within 1 year prior to pretreatment CT) and the first two post-treatment CTs using paired t-tests. Thresholds for pancreatic hypertrophy and atrophy were defined using a log-rank test. The prognostic importance of pancreatic hypertrophy was further analyzed using multivariate Cox proportional hazard regression models. RESULTS: Pancreatic volume was significantly higher for the first post-treatment CT than pretreatment CT (71.5 cm3 vs. 67.4 cm3, P = .027), whereas no significant difference was observed between the pretreatment and control CTs. Optimal thresholds for pancreatic hypertrophy and atrophy were defined as an 22% increase and 30% decrease and found in 20 and three patients, respectively. Pancreatic hypertrophy was significantly associated with reduced survival [hazard ratio = 2.9 (95% confidence interval, 1.3-6.5), P = .0088]. No patients showed serum lipase elevation, nor were they suspected of having acute pancreatitis. CONCLUSION: There was frequent asymptomatic pancreatic swelling in patients with GIST after imatinib treatment, and a ≥22% increase in pancreatic volume was a predictor of reduced survival.


Assuntos
Antineoplásicos/efeitos adversos , Neoplasias Gastrointestinais/complicações , Tumores do Estroma Gastrointestinal/complicações , Mesilato de Imatinib/efeitos adversos , Pâncreas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Atrofia , Feminino , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/mortalidade , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/mortalidade , Humanos , Hipertrofia , Mesilato de Imatinib/uso terapêutico , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Análise de Sobrevida
13.
J Surg Res ; 260: 462-466, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33272594

RESUMO

BACKGROUND: FABP3 is a member of the fatty acid-binding protein (FABP) family, whose role in various cancers has been reported in the past. However, little is known about the role that FABP3 plays in gastrointestinal stromal tumors (GISTs). METHODS: FABP3 expression was analyzed in 119 patients with GISTs using immunohistochemistry and tissue microarrays to interrogate the relationship between expression and prognosis. Kaplan-Meier analysis was used to calculate patient survival rates using complete follow-up data and to evaluate the potential prognostic value of FABP3 using Cox regression analysis. RESULTS: FABP3-positive signals were detected as brown particles located in the cytoplasm using immunohistochemistry. Among the 119 tissue samples, we observed high FABP3 expression in 64 and low or negative expression in 55. Immunohistochemical analyses suggested that FABP3 expression was significantly correlated with tumor size (P = 0.006), mitotic index (P = 0.016), gross classification (P = 0.048), and AFIP-Miettinen risk classification (P = 0.007). Multiple logistic regression analysis showed that the expression of FABP3 was significantly associated with tumor size (P = 0.021). Kaplan-Meier survival curves showed that patients with GISTs with low expression of FABP3 and classified with a very low to moderate AFIP-Miettinen risk had better prognosis. Multivariate analysis further showed that high expression of FABP3 (P = 0.017) was significantly associated with poor 5-year overall survival. CONCLUSIONS: High FABP3 expression has a prognostic value for patients with GISTs.


Assuntos
Biomarcadores Tumorais/metabolismo , Proteína 3 Ligante de Ácido Graxo/metabolismo , Neoplasias Gastrointestinais/diagnóstico , Tumores do Estroma Gastrointestinal/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Neoplasias Gastrointestinais/metabolismo , Neoplasias Gastrointestinais/mortalidade , Tumores do Estroma Gastrointestinal/metabolismo , Tumores do Estroma Gastrointestinal/mortalidade , Humanos , Imuno-Histoquímica , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Prognóstico , Análise de Sobrevida , Análise Serial de Tecidos
14.
J Surg Oncol ; 123(2): 432-438, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33169386

RESUMO

BACKGROUND OBJECTIVES: The impact of tumor necrosis as a prognostic factor in gastrointestinal stromal tumor (GISTs) is still debated. The objective was to determine whether tumor necrosis is an independent risk factor for survival in patients with GISTs. METHODS: Patients undergoing surgery for primary GIST from March 2003 to October 2018 at two sarcoma referral centers were retrospectively identified. Patients who received neoadjuvant imatinib were excluded. Multivariable Cox regression models were produced, to assess whether tumor necrosis was an independent predictor of either overall or recurrence-free survival. RESULTS: Forty-one out of 195 (21.0%) patients had tumor necrosis. Tumor necrosis was associated with a significantly higher modified National Institute of Health risk score, with 29 out of 41 (70.7%) patients with necrosis classified as high risk, compared to 52 out of 153 (34.0%) without (p < .001). Tumor necrosis was found to be independently predictive of recurrence-free survival (hazard ratio: 5.26, 95% CI: 2.62-10.56, p < .001) on multivariable analysis. At 5 years, 44.3% of patients with necrosis had either died or developed recurrence, compared to 9.9% of those without. CONCLUSION: Tumor necrosis is an independent predictor of recurrence-free survival in patients with operable GISTs. It should be routinely reported by pathologists, and used by clinicians when counseling patients and deciding on adjuvant therapy.


Assuntos
Procedimentos Cirúrgicos do Sistema Digestório/mortalidade , Neoplasias Gastrointestinais/mortalidade , Tumores do Estroma Gastrointestinal/mortalidade , Necrose , Recidiva Local de Neoplasia/mortalidade , Idoso , Feminino , Seguimentos , Neoplasias Gastrointestinais/patologia , Neoplasias Gastrointestinais/cirurgia , Tumores do Estroma Gastrointestinal/patologia , Tumores do Estroma Gastrointestinal/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
15.
Updates Surg ; 73(1): 179-186, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33146889

RESUMO

Tumours of the small intestine are rare and account for about 5% of gastrointestinal tract neoplasms. The angle of Treitz (AT) could be defined as the intestinal loop comprised between the third duodenal portion and the first 10 cm of jejunum. A gold standard surgical treatment for AT neoplasm has not yet been well defined. This paper is focused on a very rare disease and at the best of our knowledge this is the largest case series in the literature about the Laparoscopic Segmental Resection (LSR) of AT tumours. Using a prospectively collected database, all data of consecutive patients, from January 2007 to May 2019, who underwent LSR for AT tumours at two different institutions were analysed. Patients' demographics, intra and post-operative data, 30-day mortality and overall survival were collected. A total of 16 patients were retrieved from our database. The mean operative time was 206,5 ± 79 min. Conversion to open surgery was needed in two cases due to tumor size and, respectively, invasion of the transverse colon which required a multivisceral resection. The mean distal and proximal resection margins were 7.4 ± 2.2 and 3.9 ± 1.2 cm. The median number of harvested nodes was 9 ± 3. Pathological diagnosis was GIST in 11 cases, adenocarcinoma in 4 and sarcoma in 1 case. In conclusion, in experienced hands, LSR appears to be a safe and effective treatment option for tumours of the AT. Prospective studies are needed to confirm these findings.


Assuntos
Adenocarcinoma/cirurgia , Duodeno/cirurgia , Endoscopia Gastrointestinal/métodos , Neoplasias Gastrointestinais/cirurgia , Tumores do Estroma Gastrointestinal/cirurgia , Jejuno/cirurgia , Laparoscopia/métodos , Sarcoma/cirurgia , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Colo Transverso/patologia , Estudos de Viabilidade , Feminino , Neoplasias Gastrointestinais/mortalidade , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/mortalidade , Tumores do Estroma Gastrointestinal/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Duração da Cirurgia , Doenças Raras , Estudos Retrospectivos , Sarcoma/mortalidade , Sarcoma/patologia , Taxa de Sobrevida , Resultado do Tratamento
16.
J Laparoendosc Adv Surg Tech A ; 31(7): 772-778, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33155875

RESUMO

Background and Objectives: Robotic wedge resection for gastrointestinal stromal tumors (GISTs) located in the stomach offers remarkable advantages, especially for lesions in unfavorable places. Although promising, long-term oncological results associated with this surgical procedure are poorly represented in literature. We present our experience of robotic wedge resection with gastrotomy for challenging gastric GISTs, in terms of both surgical outcomes and long-term oncological results. Methods: From April 2014 to February 2020, all consecutive patients affected by unfavorably located gastric GISTs (based on the Privette/Al-Thani classification system) underwent robotic wedge resection. Clinicopathological, surgical, and long-term oncological results were retrospectively analyzed. Results: Seventeen patients underwent full-thickness gastric wedge resection with primary robot-sewn closure of the defect. In 64.7% of cases, the lesion was ≥5 cm in diameter. No conversion nor tumor rupture were recorded and complete R0 resection was achieved in all cases. Median hospital stay was 5 days (range 3-18). At a median follow-up of 46 months (range 7-67), the disease-free survival rate and the overall survival rate were 94.1% and 82.3%, respectively. Conclusions: Robotic wedge resection with gastrotomy and robotic-sewn suture is a safe and feasible procedure for GISTs located in unfavorable anatomic positions, without compromising oncological outcomes.


Assuntos
Gastrectomia/métodos , Tumores do Estroma Gastrointestinal/cirurgia , Procedimentos Cirúrgicos Robóticos/métodos , Neoplasias Gástricas/cirurgia , Estômago/cirurgia , Adulto , Idoso , Estudos de Viabilidade , Gastrectomia/mortalidade , Tumores do Estroma Gastrointestinal/mortalidade , Tumores do Estroma Gastrointestinal/patologia , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Duração da Cirurgia , Estudos Retrospectivos , Procedimentos Cirúrgicos Robóticos/mortalidade , Estômago/patologia , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Taxa de Sobrevida , Resultado do Tratamento
17.
Am Surg ; 87(3): 450-457, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33026232

RESUMO

BACKGROUND: The aim of this study was to conduct a meta-analysis comparing the safety and feasibility of laparoscopic versus open resection for gastric gastrointestinal stromal tumors (GISTs) larger than 5 cm. METHOD: We searched the Cochrane Library, PubMed, and Embase for relevant articles. Randomized and nonrandomized clinical trials were identified and included in this study. Searching for related articles on large GIST (>5 cm) for laparoscopic resection (laparoscopic group [LAPG]) and open resection (open group [OG]), RevMan 5.3 was used for data analysis, comparing 2 groups of operation time, intraoperative blood loss, complications, length of hospital stay, recurrence rate, disease-free survival, and overall survival. RESULTS: Seven studies including 440 patients were identified for the meta-analysis. Meta-analysis revealed that LAPG had less bleeding, shorter postoperative hospital stay, and a better 5-year disease-free survival. There was no significant difference between LAPG and OG in operation time, postoperative complications, recurrence rate, and overall survival. CONCLUSION: Laparoscopic resection of large (>5 cm) GIST is safe and feasible and has the advantages of less intraoperative blood loss and fast postoperative recovery, with a good outcome in the recent oncology.


Assuntos
Neoplasias Gastrointestinais/cirurgia , Tumores do Estroma Gastrointestinal/cirurgia , Laparoscopia , Perda Sanguínea Cirúrgica/estatística & dados numéricos , Estudos de Viabilidade , Neoplasias Gastrointestinais/mortalidade , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/mortalidade , Tumores do Estroma Gastrointestinal/patologia , Humanos , Tempo de Internação/estatística & dados numéricos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle , Análise de Sobrevida , Resultado do Tratamento , Carga Tumoral
18.
Am J Surg ; 221(3): 549-553, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33371951

RESUMO

BACKGROUND: Few studies evaluate the relationships between surgical approach, histologic margin, and overall survival in gastrointestinal stromal tumor. We test the hypothesis that margin positive resection is associated with compromised overall survival. METHODS: We queried the National Cancer Data Base to identify patients undergoing resections for gastrointestinal stromal tumors ≤3 cm in size between 2010 and 2015. Multivariable logistic regression was used to identify factors associated with positive microscopic margins on final pathology. Cox proportional hazard methods were used to evaluate factors associated with overall survival. RESULTS: 2064 patients met inclusion criteria; 135 (6.5%) had a microscopically positive surgical margin. On multivariable regression, minimally invasive approach was not associated with risk of a positive margin (OR 1.06 95% CI [0.71, 1.59]). On Cox analysis, positive margin status was not associated with OS (R1: 1.03, CI [0.46-2.31], reference R0). CONCLUSIONS: Positive microscopic surgical margins are not associated with compromised overall survival in patients undergoing resection of small gastrointestinal stromal tumors. Minimally invasive surgical approaches do not compromise oncologic outcomes in these cases.


Assuntos
Neoplasias Gastrointestinais/mortalidade , Neoplasias Gastrointestinais/cirurgia , Tumores do Estroma Gastrointestinal/mortalidade , Tumores do Estroma Gastrointestinal/cirurgia , Margens de Excisão , Idoso , Bases de Dados Factuais , Feminino , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/patologia , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida
19.
Expert Opin Investig Drugs ; 30(2): 143-152, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33252274

RESUMO

Introduction: Discovery of oncogenic mutations in the KIT and PDGFRA tyrosine kinase receptor was a crucial step for the development of tyrosine kinase inhibitors (TKIs). Since then, GIST became a model for the development of molecular-targeted therapy, which led to dramatically improved median overall survival of advanced GIST. Still, further progress is needed after third-line or for TKI resistant mutations. Areas covered: In this review, after a brief introduction on imatinib, sunitinib, and regorafenib, an overview of TKIs that was evaluated beyond these drugs is provided, with a main focus on the novel approved TKIs. Expert opinion: Combination therapies have thus far not fulfilled their promise in GIST, nor did immunotherapy. Increased understanding of GIST and advances in the development of molecular-targeted drugs led to the introduction of ripretinib and avapritinib. Furthermore, NTRK inhibitors became available for ultrarare NTRK fusions. Solutions for NF1 and BRAF mutated and SDH-deficient GIST are still to be awaited. This all underlines the need for adequate molecular profiling of high-risk GISTs before treatment is started. Possibly by using circulating tumor DNA in the future, targeting resistance mutations with specific drugs along the course of the disease would be easier, avoiding multiple tumor biopsies.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Gastrointestinais/tratamento farmacológico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Animais , Antineoplásicos/efeitos adversos , Resistencia a Medicamentos Antineoplásicos , Neoplasias Gastrointestinais/enzimologia , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/mortalidade , Tumores do Estroma Gastrointestinal/enzimologia , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/mortalidade , Humanos , Mesilato de Imatinib/efeitos adversos , Mesilato de Imatinib/uso terapêutico , Terapia de Alvo Molecular , Mutação , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Piridinas/efeitos adversos , Piridinas/uso terapêutico , Transdução de Sinais , Sunitinibe/efeitos adversos , Sunitinibe/uso terapêutico , Resultado do Tratamento
20.
Surgery ; 169(2): 419-425, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32863011

RESUMO

BACKGROUND: Although tumor size and mitotic rate are established prognostic factors for worse survival in patients undergoing surgical resection for gastric gastrointestinal stromal tumors, the impact of microscopic margins, or R1 resection, is not completely established. METHODS: Patients who received no neoadjuvant therapy and underwent surgical resection for stage I to III gastric gastrointestinal stromal tumors were identified from the 2010 to 2013 National Cancer Database and divided into 2 cohorts, R0 and R1 resections. Cox proportional hazards ratio and Kaplan Meier survival estimates were utilized to analyze 5-y overall survival. RESULTS: Of 2,084 patients, those with R1 resection (57, 2.7%) were more likely to have tumors >10 cm (28.1% vs 11.9%, odds ratio 3.51, P = .017) and stage III disease (26.3% vs 11.2%, odds ratio 2.26, P = .047). Although margin status was associated with higher risk tumors, it was not associated with receipt of adjuvant therapy. After multivariate Cox regression, R1 and R0 patients did not have a difference in 5-y overall survival (82.5% vs 88.6%, hazards ratio 1.26, P = .49). When stratified by stage of disease, there remained no difference in survival across all stages when comparing R1 and R0 patients. CONCLUSION: Positive microscopic margins are uncommon but do not appear to impact survival outcomes in patients with resected localized gastric gastrointestinal stromal tumors.


Assuntos
Gastrectomia/estatística & dados numéricos , Tumores do Estroma Gastrointestinal/cirurgia , Margens de Excisão , Recidiva Local de Neoplasia/epidemiologia , Neoplasias Gástricas/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Bases de Dados Factuais/estatística & dados numéricos , Feminino , Tumores do Estroma Gastrointestinal/diagnóstico , Tumores do Estroma Gastrointestinal/mortalidade , Tumores do Estroma Gastrointestinal/patologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Índice Mitótico , Recidiva Local de Neoplasia/prevenção & controle , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Estômago/patologia , Estômago/cirurgia , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Carga Tumoral , Estados Unidos/epidemiologia , Adulto Jovem
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