PDGFRA mutation

The follow-up CT scan revealed peritoneal nodules suggestive of peritoneal dissemination, and Entrectinib (a TRK inhibitor) was administered...The present case may offer new insights into the potential introduction of TRK inhibitors as treatments for GISTs with NTRK fusions. Additionally, the presence of abundant lymphoid infiltration in the present case may prompt further research into immunotherapy as a possible additional therapeutic option.

P1, N=240, Recruiting, IDRx, Inc. | N=143 --> 240

P2, N=28, Recruiting, Reema A. Patel | Not yet recruiting --> Recruiting | Trial primary completion date: Dec 2024 --> Dec 2025

Furthermore, we evaluated the sensitivity of these mutants to three FDA-approved tyrosine kinase inhibitors: imatinib, dasatinib, and avapritinib, which effectively suppressed the constitutive activity of the mutant receptors. Interestingly, K385M was reported in a few cases of brain tumors but not in MGNT. Our results provide valuable insights into the molecular mechanism underlying the activation of PDGFRα by the K385I/L mutations, highlighting their potential as actionable targets in the treatment of myxoid glioneuronal tumors.

Common differential diagnoses include leiomyoma, schwannoma, and solitary fibrous tumor. This article presents a classic GIST case and showcases relatively simple diagnostic clues for identifying similar lesions that may occur in diverse locations.

In conclusion, our findings shed light on the unique molecular complexity of PBL, unveiling its mutational landscape and potential therapeutic targets. Due to the rarity of PBL, further research with a more extensive sample size is essential to completely elucidate the mutational landscape of PBL.

P1, N=34, Terminated, Daiichi Sankyo | Completed --> Terminated; The study was terminated due to a business decision.

Despite the outstanding results of first-line imatinib in advanced GIST, resistance ultimately occurs mainly through secondary mutations in KIT/PDGFRA...However, it is now recognized that the situation is more intricate, with various factors interacting with KIT and PDGFRA, playing a crucial role in the response and resistance to treatments. Future strategies in the management of advanced GIST should integrate driver inhibition with the blockade of other molecules to enhance cell death and establish enduring responses in patients.

To the best of our knowledge, there have been only two examples of primary papillary colon carcinoma reported in the literature, and neither of them with a PDGFRA mutation. We describe one tumor and discuss its pathological features.

No abstract available

The overall biological behavior of this type of GIST is relatively inert, which is due to the low proportion of medium-high malignant GIST. The modified NIH risk stratification may not be effective in risk stratification for PDGFRA mutant GIST.

Against this background, we solve the crystal structures of avapritinib in complex with wild-type and mutant PDGFRA and stem cell factor receptor (KIT), which provide evidence and understanding of inhibitor binding and lead to the identification of a sub-pocket (Gα-pocket). We utilize this information to design, synthesize and characterize avapritinib derivatives for the determination of key pharmacophoric features to overcome drug resistance and limit potential blood-brain barrier penetration.

In conclusion, SERCA3 immunohistochemistry may be useful for the diagnosis of GIST with high confidence, when used as a third marker in parallel with KIT and DOG1. Moreover, SERCA3 immunopositivity may be particularly helpful in cases with negative or weak KIT or DOG1 staining, a situation that may be encountered de novo, or during the spontaneous or therapy-induced clonal evolution of GIST.

Moreover, mutations in Kit exon 9 and 11 are actionable, due to their response to imatinib, while mutations in PDGFRA respond to sunitinib and/or avapritinib. This allows the clinician to have an accurate picture of the genetic changes of the tumor over time. In this work, we aimed to discuss the implications of mutational testing in clinical outcomes, the methods to test ctDNA and the future challenges in the establishment of alternatives of personalized medicine.

NF1-GISTs involved multifocal spindle cell tumors in the small intestine. SDH-GISTs occurred in young patients and were multifocal in the stomach and clinically indolent.

The utility of actionable multigene panel revealed the value of a well-designed next-generation sequencing workflow in the practical use of clinical outcomes via the prediction of responsiveness to therapeutic agents or indications for novel treatment modalities in addition to prognosis estimate.

In conclusion, osseous metaplasia in GIST is a very rare event and only few cases are reported in the literature. The number of reported cases is inadequate to confirm the pathogenesis and the prognosis.

The median overall survival was 36.8 months, compared to 15.5 months for the other 450 patients (p < 0.001). We conclude that "De novo replication repair deficient glioblastoma, IDH-wildtype" represents a biologically distinct subtype in the adult population that may benefit from prospective identification and treatment with immune checkpoint blockade.

Analysis of AML with t(4; 12)(q12; p13) translocation by WGS and WTS provides detailed information that separates two subsets distinguished by distinct breakpoint cluster regions on 4q12 and PDGFRA gene expression. The clinical impact of increased PDGFRA gene expression on response to TKI and prognosis as well as the presence of additional fusion transcripts has to be evaluated in further studies.

Avapritinib showed greater antitumor activity in patients with GISTs harboring KIT ALposABPneg mutations versus KIT OTHERS, and may be considered in the former subpopulation. Patients with KIT exon 9 mutations may also benefit in ³4 line settings.

The coexistence of PDGFRA and SDHD mutations may have affected SDHB expression. Altogether, we concluded that PDGFRA mutations may play an important role in co-mutant GIST pathogenesis.

Cell viability and live cell imaging studies revealed that the loaded NGs are capable of intracellular drug release by showing similar IC values to those of the free drugs. Furthermore, multi-drug-loaded NGs were capable of overcoming BLU-285 resistance in T1-α-D842V + G680R cells, demonstrating the utility of this carrier system.

Refractory T-ALL has not been fully characterized. Alterations in PDGFRA or other targetable kinases may inform therapy for patients with refractory T-ALL who otherwise have limited treatment options. Clinical genomic profiling, in real time, is needed for fully informed therapeutic decision making.

Some patients were treated with immune checkpoint blockade (nivolumab or pembrolizumab) and survived over three years. The median overall survival for the cohort was 37.4 months (95% CI: 22-not reached), compared to 15.4 months (95% CI: 14.7-17.9) for the other 451 patients. We speculate that “de novo replication repair deficient glioblastoma, IDH-wildtype” represents a biologically distinct subtype that may benefit from prospective identification and treatment with immune checkpoint blockade.

IDH-mutant low grade astrocytomas not being treated with temozolomide or irradiation do not develop hypermutation or specific gene mutation for their natural evolution and malignant transformation.

Salvage therapy comprised re-irradiation (n=52, 43%), temozolomide (TMZ) (n=39, 32%), lomustine (n=47, 39%), and/or bevacizumab (n=22, 18%). Our study outlines the molecular factors associated with survival and response to re-irradiation in rGBM as well as, the molecular differences between primary/recurrent samples.

Genomic profiling revealed actionable targets and new therapeutic options for glioblastoma pts. A full and updated overview of patient characteristics, actionable targets and survival data will be presented at the meeting.

One patient with PDGFRA/KIT amplification developed a spontaneous EGFR gain and a secondary PDGFRA mutation in a cerebellar metastatic lesion that progressed on avapritinib therapy. In summary, we report that avapritinib, a selective, CNS penetrant small molecule inhibitor of PDGFRA has potent activity in preclinical models and produced clinical responses with good tolerability in pediatric and young adult patients with high-grade glioma, suggesting a promising role for avapritinib therapy in HGG patients.

P3, N=255, Active, not recruiting, Heikki Joensuu | Trial completion date: May 2028 --> May 2033 | Trial primary completion date: May 2028 --> May 2026

While there are numerous examples of KIT TKIs that do not inhibit FLT3 (imatinib, avapritinib, dasatinib), to date, all clinically active FLT3 TKIs (quizartinib, gilteritinib, midostaurin, sorafenib) fail to spare KIT inhibition...Compared to FF-10101 and gilteritinib, BGS-2456 exhibited the least amount of hematologic toxicity, facilitating in vitro proliferation and differentiation of normal hematopoietic progenitor cells even at 100x EC50 concentration against Molm14 cells... This is the first description of a potent and exquisitely specific FLT3 inhibitor that spares KIT inhibition and displays no myelosuppression in vitro at >100x EC50 concentration. The potent inhibitory effects of BGS-2456 on both D835Y and F691L mutants support its promise as a best-in-class TKI for the treatment of FLT3-mutant AML. Efforts to molecularly dissect the basis of the high degree of selectivity of BGS-2456 are ongoing.

ConclusionPDGFRA/B expression in tumour cells of therapy-resistant ALK-positive ALCL patients can discriminate genetically and functionally distinct lymphoma subgroups that are directly related to long-term treatment response to kinase inhibitor imatinib. Our data suggests that significant imatinib responses may be achieved in more than 80% of chemotherapy-resistant ALK+ ALCL cases.

We report a case of GISTs associated with NF1 that showed a jejunal origin, multifocal development and few mitotic figures. The recurrence risk, survival prognosis and need for adjuvant chemotherapy, particularly in cases where the initial GIST exhibits a very indolent pathology in NF1-related GISTs, remain to be elucidated.

This is the first report of successful laparoscopic-thoracoscopic surgery for a patient with familial gastric GISTs accompanied with a large esophageal diverticulum.

P1/2, N=67, Recruiting, Blueprint Medicines Corporation | Initiation date: Apr 2023 --> Sep 2023

One model is characterized by an imatinib-resistant PDGFRA exon 18 p.D842V mutation... We are expanding our established platform of well-characterized GIST PDX models, that were proven to serve as an excellent tool for preclinical drug testing and tumor biology studies. The platform is available for cooperative projects with academic and commercial partners.

We prospectively investigate whether the amount of mutant ctDNA at different timepoints is informative concerning risk of relapse, response to neoadjuvant therapy, progression-free and overall survival. Furthermore, we study secondary mutations in ctDNA at relapse to investigate the impact of clonal heterogeneity and further possibilities for risk stratification (proteomics, radiomics). Currently, the study is initiated in Lübeck, Mannheim, Berlin-Buch and Bad Saarow and is recruiting.

Transarterial radioembolisation, followed by systemic gemcitabine/cisplatin therapy induced long-term remission...Therefore, due to the progressive hepatocellular component, the patient received atezolizumab/bevacizumab with induced tumor devascularization and AFP normalization. However, after six months, the therapy was changed to FOLFIRI due to progressive disease with lung, liver and lymph node involvement and an increase in CA19-9... In 2020, a 50-year-old male patient presented to our department with weight loss and pain in the right upper abdomen. CT and MRI imaging of the liver showed a 20-cm diffusely growing tumour involving all liver segments and multiple satellite lesions. Histologic examination confirmed the diagnosis of a poorly differentiated cHCC-CCA.

No abstract available

Emerging evidence shows that ripretinib is superior to sunitinib as second-line treatment for KIT exon 11-mutated GISTs due to its activity against highly heterogeneous frequently occurring secondary mutations. This review summarizes current data on the use of ripretinib to treat advanced imatinib-resistant GISTs. We also propose future research directions to improve the precision of targeted GIST treatment.

Thus, the results represent an up-and-coming innovation in the practical field of digital pathology and fundamental questions of glioma carcinogenesis.

Secondary objectives were to assess (1) patients' outcome in terms of time to next treatment (TNT) for each line of systemic treatment, (2) patients' overall survival (OS), (3) evolution of patients' treatment modalities and OS according to treatment access: <2002 (pre-imatinib approval), 2002-2006 (pre-sunitinib approval), 2006-2014 (pre-regorafenib approval), post 2014, and (4) the impact of clinical trials and LR procedures on TNT and OS in the metastatic setting. In multivariate analysis, age, AFIP Miettinen classification, mutational status, surgery of the primary tumor, participation in a clinical trial in the first line and LR procedure to metastatic sites were associated with longer TNT in the first line, whereas age, mitotic index, mutational status, surgery of the primary tumor and LR procedure to metastatic sites were associated with longer OS. This real-life study advocates for early reference of metastatic GIST patients to expert centers to orchestrate the best access to future innovative clinical trials together with LR strategies and further improve GIST patients' survival.