Avapritinib in advanced gastrointestinal stromal tumor: case series and review of the literature from a tertiary care center in India.
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ABSTRACT:
SUBMITTER: Verma S
PROVIDER: S-EPMC8015663 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background:Gastrointestinal stromal tumors (GISTs) extremely and rarely metastasize to the skin, and such metastases have not been well characterized. Methods:Retrospective analysis of clinicopathological data of patients with skin metastasis of a GIST (SM-GIST) admitted to Xiangya Hospital (Changsha, Hunan, China) and literature review were conducted. Results:Including our 4 cases, a total of 17 cases have been reported to date. The mean age of the patients was 55.4 years (29~70 years) and there was not sex predominance (male 10 and female 7). Primary tumors were often located in the stomach (n=9), duodenum (n=2) and small bowel (n=2). Meanwhile, SM-GIST mainly occurred in head and face (n=6), extremities (n=6), followed by abdomen wall (n=5), back (n=3) and chest (n=2). Mutation analysis revealed that the frequency of wild-type GIST (WT-GIST), exon 9, 11 and 13 mutations was 6, 1, 4 and 1, respectively. The average time to SM-GIST was 4.22 years, specifically 4.59 years in gastric and 3.8 years in non-gastric. Moreover, for the resection only group (including chemotherapy), such average time was 3.63 years, while for the combined group (resection and tyrosine kinase inhibitors (TKIs)), it was about 4.74 years. The mean survival was approximately 6.2 years. However, after the diagnosis of SM-GIST, survival was only about 1.69 years. Conclusion:SM-GIST is a rare malignant condition. Non-gastric GIST, surgery without TKIs, high invasiveness and tumor burden, and molecular subtype (mutation in exon 9, 11 and wild-type) may be conducive to the development of SM-GIST. Additionally, it is also a sign of poor prognosis.
| S-EPMC7455533 | biostudies-literature
Project description:BackgroundMost gastrointestinal stromal tumors (GIST) driven by KIT or platelet-derived growth factor receptor A (PDGFRA) mutations develop resistance to available tyrosine kinase inhibitor (TKI) treatments. NAVIGATOR is a two-part, single-arm, dose escalation and expansion study designed to evaluate safety and antineoplastic activity of avapritinib, a selective, potent inhibitor of KIT and PDGFRA, in patients with unresectable or metastatic GIST.Materials and methodsEligible patients were 18 years or older with histologically or cytologically confirmed unresectable GIST and Eastern Cooperative Oncology Group performance status ≤2 and initiated avapritinib at 300 mg or 400 mg once daily. Primary endpoints were safety in patients who initiated avapritinib at 300 mg or 400 mg once daily and overall response rate (ORR) in patients in the safety population with three or more previous lines of TKI therapy.ResultsAs of November 16, 2018, in the safety population (n = 204), the most common adverse events (AEs) were nausea (131 [64%]), fatigue (113 [55%]), anemia (102 [50%]), cognitive effects (84 [41%]), and periorbital edema (83 [41%]); 17 (8%) patients discontinued due to treatment-related AEs, most frequently confusion, encephalopathy, and fatigue. ORR in response-evaluable patients with GIST harboring KIT or non-D842V PDGFRA mutations and with at least three prior therapies (n = 103) was 17% (95% confidence interval [CI], 10-25). Median duration of response was 10.2 months (95% CI, 7.2-10.2), and median progression-free survival was 3.7 months (95% CI, 2.8-4.6).ConclusionAvapritinib has manageable toxicity with meaningful clinical activity as fourth-line or later treatment in some patients with GIST with KIT or PDGFRA mutations.Implications for practiceIn the NAVIGATOR trial, avapritinib, an inhibitor of KIT and platelet-derived growth factor receptor A tyrosine kinases, provided durable responses in a proportion of patients with advanced gastrointestinal stromal tumors (GIST) who had received three or more prior therapies. Avapritinib had a tolerable safety profile, with cognitive adverse events manageable with dose interruptions and modification in most cases. These findings indicate that avapritinib can elicit durable treatment responses in some patients with heavily pretreated GIST, for whom limited treatment options exist.
| S-EPMC8018324 | biostudies-literature
Project description:Background:Plasmablastic lymphoma (PBL) is an aggressive subtype of mature B-cell non-Hodgkin lymphoma. Given its rarity, there remains a lack of clinicopathological data to guide its management, particularly on Asian patients. Methods:We conducted a retrospective chart review of 10 patients diagnosed with PBL at the National Cancer Centre Singapore and performed a literature review of similar studies on Asian cohorts. Results:Most patients were male (n = 9), with median age at diagnosis of 55 years (range, 33 - 91 years). Seven (70%) patients were considered to be immunocompromised. In the overall cohort, the median overall survival (OS) was 19.4 months with 5-year survival estimates given at 60% and 36% for OS and progression-free survival (PFS), respectively. At diagnosis, patients with HIV/AIDS (n = 5) were younger compared to others (median, 43 vs. 61 years; P = 0.0278), had greater number of nodal site involvement (median, 6 vs. 0; P = 0.0333), and higher international prognostic index (IPI) scores (P = 0.034 for trend). Amongst different chemotherapy used, etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin (EPOCH)-based regimens (n = 6) elicited prominent complete response rates (83%) and led to durable responses even in the setting of advanced stage, high-risk IPI score and immunodeficiency. Conclusions:In conclusion, our study describes the features of PBL in an Asian cohort and highlights disease features unique to HIV-associated PBL.
| S-EPMC7430862 | biostudies-literature
Project description:BackgroundSyphilis infections are increasing globally. Lower gastrointestinal syphilis (LGIS) is a rare manifestation of early syphilis transmitted through anal sexual contact. Misdiagnosis of LGIS as inflammatory bowel disease may result from clinician underawareness.MethodsWe searched the literature for articles describing cases of LGIS, and identified additional cases diagnosed within our institution. Data were extracted from the articles and medical records and analyzed to provide a summative account.ResultsFifty-four cases of LGIS were identified in 39 articles published between 1958 and 2020. Eight additional cases were diagnosed at our institution between 2011 and 2020, totaling 62 cases. All cases were described in men and transwomen aged 15-73 years. Fifty (93%) individuals reported having sex with men. In 26 cases (52%), the individuals were human immunodeficiency virus (HIV) coinfected. LGIS presented most commonly with hematochezia (67%) and anal pain (46%). The most common physical examination findings were rectal mass (38%), lymphadenopathy (31%), and rash (26%). Nontreponemal titers ranged from 1:2 to 1:1024. Of the 52 cases in which endoscopy was reported, 22 (42%) showed anorectal mass and 18 (35%) showed anorectal ulcer. In 44 cases (75%), histopathology revealed a chronic inflammatory infiltrate with a prominent lymphocyte component (45%) and/or plasma cells (36%). Seventy-eight percent of specimens to which a tissue stain was applied were positive for spirochetes.ConclusionsLGIS should be suspected in men and transwomen presenting with a lower gastrointestinal symptom or mucosal abnormality. A sexual history must be elicited and guide testing. Misdiagnosis can delay treatment and threatens patient and public health.
| S-EPMC8494075 | biostudies-literature
Project description:Retroperitoneal gastrointestinal tumor is the rarest subtype among 3 subtypes of extragastrointestinal tumors, which are uncommon stromal tumors. We herein report a case of a 55-year-old man with retroperitoneal gastrointestinal tumor detected by magnetic resonance imaging and confirmed by postoperative histology and immunohistochemistry.
| S-EPMC7415774 | biostudies-literature
Project description:BackgroundVertebral osteomyelitis is a serious condition that requires prompt diagnosis to avoid delays in proper management. There is no well-defined gold standard for diagnosis. We describe the current diagnostic approach at our institution, with a focus on the yield of image-guided vertebral biopsy.MethodsWe performed a single-centre 10-year retrospective case series, including adults with imaging suggestive of vertebral osteomyelitis/discitis, with either positive blood cultures, and/or a vertebral biopsy. We defined positive histopathology as our gold standard for test characteristic evaluation of biopsy cultures.ResultsOut of 694 patients identified, 221 met our inclusion criteria, and 173/221 (78.2%) patients underwent a spinal biopsy. Of those patients with biopsies, 113 (65%) had received antibiotics within 2 weeks preceding their evaluation. Six of 43 (13.9%) bone specimens were positive by culture, while 66/152 (43.4%) of disc specimens were culture positive. Forty-seven of 84 (55.9%) histopathology (bone or disc) specimens were diagnostic for osteomyelitis/discitis. The sensitivity of bone and disk culture were 30.0% and 56.0%, respectively, with specificities of 92.8% and 75.0%, respectively. Twenty-three (13.4%) patients had repeat biopsies, including 10 bone specimens and 14 disc specimens, and 11 (47.8%) specimens had histopathology performed which diagnosed an additional 3/23 patients (13% additional diagnostic yield).ConclusionsCulture of percutaneous biopsy of disc resulted in the highest diagnostic yield. Histopathology added to the diagnostic yield in culture-negative specimens. Histopathologic evaluation of bone had better yield than bone culture. A repeat biopsy can add to the diagnostic yield.
| S-EPMC8860156 | biostudies-literature
Project description:BackgroundAvapritinib, a novel inhibitor of KIT/PDGFRA, is approved in the U.S. for the treatment of adults with PDGFRA exon 18-mutant unresectable or metastatic gastrointestinal stromal tumors (U/M GISTs). We assessed the safety of avapritinib and provide evidence-based guidance on management of avapritinib-associated adverse events (AEs), including cognitive effects and intracranial bleeding.Materials and methodsWe performed a post hoc analysis of data from a two-part, single-arm dose escalation/expansion phase I study (NAVIGATOR; NCT02508532) in patients with U/M GISTs treated with oral avapritinib 30-600 mg once daily. The primary endpoints were safety and tolerability; the impact of dose modification (interruption and/or reduction) on progression-free survival (PFS) was a secondary endpoint. Efficacy analyses were limited to patients who started avapritinib at 300 mg (approved dose).ResultsOf 250 patients enrolled in the study, 74.0% presented with KIT mutation and 24.8% presented with PDGFRA exon 18-mutation; 66.8% started avapritinib at 300 mg. The most common treatment-related AEs (any grade) were nausea (59.2%), fatigue (50.0%), periorbital edema (42.0%), anemia (39.2%), diarrhea (36.0%), vomiting (36.0%), and increased lacrimation (30.8%). No treatment-related deaths occurred. Among 167 patients starting on 300 mg avapritinib, all-cause cognitive effects rate (grade 1-2) was 37.0% in all patients and 52.0% in patients ≥65 years. Cognitive effects improved to a lower grade more quickly with dose modification (1.3-3.1 weeks) than without (4.9-7.6 weeks). Median PFS was 11.4 months with dose modification and 7.2 months without.ConclusionTolerability-guided dose modification of avapritinib is an effective strategy for managing AEs in patients with GISTs.Implications for practiceEarly recognition of adverse events and tailored dose modification appear to be effective approaches for managing treatment-related adverse events and maintaining patients on avapritinib. Dose reduction does not appear to result in reduced efficacy. Patients' cognitive function should be assessed at baseline and monitored carefully throughout treatment with avapritinib for the onset of cognitive adverse events. Dose interruption is recommended at the first sign of any cognitive effect, including grade 1 events.
| S-EPMC8018323 | biostudies-literature
Project description:Management of gastrointestinal stromal tumors (GISTs) has been revolutionized by the identification of activating mutations in KIT and PDGFRA and clinical application of RTK inhibitors in advanced disease. Stratification of GISTs into molecularly defined subsets provides insight into clinical behavior and response to approved targeted therapies. Although these RTK inhibitors are effective in most GISTs, resistance remains a significant clinical problem. Development of effective treatment strategies for refractory GISTs requires identification of novel targets to provide additional therapeutic options. Global kinome profiling has the potential to identify critical signaling networks and reveal protein kinases essential in GISTs. Using multiplexed inhibitor beads and mass spectrometry, we explored the majority of the kinome in GIST specimens from the 3 most common molecular subtypes (KIT mutant, PDGFRA mutant, and succinate dehydrogenase deficient) to identify kinase targets. Kinome profiling with loss-of-function assays identified an important role for G2/M tyrosine kinase, Wee1, in GIST cell survival. In vitro and in vivo studies revealed significant efficacy of MK-1775 (Wee1 inhibitor) in combination with avapritinib in KIT mutant and PDGFRA mutant GIST cell lines as well as notable efficacy of MK-1775 as a monotherapy in the engineered PDGFRA mutant line. These studies provide strong preclinical justification for the use of MK-1775 in GIST.
| S-EPMC7934848 | biostudies-literature
Project description: Not available
| S-EPMC10917280 | biostudies-literature
Project description:PurposeGastrointestinal stromal tumor (GIST) is associated with increased risk of additional cancers. In this study, synchronous GIST, and peritoneal mesothelioma (PM) were characterized to evaluate the relationship between these two cancers.MethodsA retrospective chart review was conducted for patients diagnosed with both GIST and PM between July 2010 and June 2021. Patient demographics, past tumor history, intraoperative reports, cross-sectional imaging, peritoneal cancer index (PCI) scoring, somatic next-generation sequencing (NGS) analysis, and histology were reviewed.ResultsOf 137 patients who underwent primary GIST resection from July 2010 to June 2021, 8 (5.8%) were found to have synchronous PM, and 4 patients (50%) had additional cancers and/or benign tumors. Five (62.5%) were male, and the median age at GIST diagnosis was 57 years (range: 45-76). Seventy-five percent of GISTs originated from the stomach. Of the eight patients, one patient had synchronous malignant mesothelioma (MM), and the remaining had well-differentiated papillary mesothelioma (WDPM), which were primarily located in the region of the primary GIST (89%). The median PCI score was 2 in the WDPM patients. NGS of GIST revealed oncogenic KIT exon 11 (62.5%), PDGFRA D842V (25%), or SDH (12.5%) mutations, while NGS of the MM revealed BAP1 and PBRM1 alterations.ConclusionsOne in 17 GIST patients undergoing resection in this series have PM, which is significantly higher than expected if these two diseases were considered as independent events. Our results indicate that synchronous co-occurrence of GIST and PM is an underrecognized finding, suggesting a possible relationship that deserves further investigation.
| S-EPMC10226389 | biostudies-literature