Metastatic Gastrointestinal Stromal Tumors Research Articles

Early response evaluation using 18F-FDG-PET/CT does not influence management of patients with metastatic gastrointestinal stromal tumors (GIST) treated with palliative intent.

The aim of this study was to investigate the impact of 18F-FDG-PET/CT on treatment decision making in metastatic gastrointestinal stromal tumor (GIST) patients. This study retrospectively evaluated 18F-FDG-PET/CT scans to monitor response of metastatic GIST patients treated with palliative intent. Data from the Dutch GIST Registry was used. Early scans (<10 weeks after start of treatment) and late scans (>10 weeks after start of treatment) were scored on the impact in change of treatment. Sixty-one PET/CT scans were performed for treatment evaluation in 39 patients with metastatic GIST of which 36 were early scans and 25 were late scans. Early PET/CT scans led to a change in management in 5.6% of patients and late PET/CT scans led to a change in management in 56% of patients. Change in management was more often seen after scans with lack of metabolic response (48% vs. 11% in scans with metabolic response, p=0.002). Neither metabolic response nor change in treatment were more often seen in patients with KIT mutations compared to patients with non-KIT mutations (metabolic response 65% KIT vs. 46% non-KIT, p=0.33, and change in management 28% KIT vs. 21% non-KIT, p=0.74). 18F-FDG-PET/CT is not recommended for early response evaluation in an unselected patient population with metastatic GIST, since it does not influence treatment decisions. 18F-FDG-PET/CT, however, can be useful for late response assessment, especially in case of indeterminate CT results.

A rare case of extraluminally pedunculated gastrointestinal stromal tumor with postoperative metastasis to pancreas

The gastrointestinal stromal tumor (GIST) is the most common type of sarcomatous tumor of the gastrointestinal tract. Many GISTs appear as submucosal tumors with intraluminal protrusion. GISTs with malignant features have a high risk of postoperative recurrence or metastasis, usually to the liver or peritoneum. We present a case of gastric GIST with double rarities: arising completely extraluminally with a pedicle and postoperative metastasis to the pancreas. A woman in her seventies diagnosed with a large extraluminal gastric GIST underwent complete removal of the tumor. Nine months later, a solitary metastatic tumor in the pancreas was detected. Imatinib controlled metastasis well for four years before the tumor became resistant. The patient then had a partial pancreatectomy with splenectomy. She is currently free from recurrence. We genetically analyzed the primary and metastatic GISTs and found known mutations related to poor prognosis and imatinib resistance.

Assessment of Adherence to Imatinib and Health-Related Quality of Life Among Patients with Gastrointestinal Stromal Tumor: A Cross-Sectional Study in an Oncology Clinic in Malaysia.

PurposeTo evaluate the rate and predictors of non-adherence to imatinib in gastrointestinal stromal tumor (GIST) patients, as well as to compare the difference in health-related quality of life (HRQOL) between adherent and non-adherent patients.Patients and MethodsA cross-sectional study at the Oncology Clinic, Hospital Kuala Lumpur was conducted from March to August 2018. All patients with metastatic and/or unresectable GIST aged ≥18 years old and on at least 3 months of imatinib were included. Adherence to imatinib was assessed using the 10-item validated Medication Compliance Questionnaire, with a score of <100% indicating non-adherence. Non-adherence predictors were determined by multiple logistic regressions. HRQOL was evaluated by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). The difference in the mean HRQOL scores between adherent and non-adherent groups was determined by multivariate analysis of variance.ResultsA total of 89 patients were enrolled, of which 49 (55.1%) were considered non-adherent. The significant predictors of non-adherence were age (adjusted odds ratio [OR] 0.93; CI 0.89–0.98; P = 0.007), presence of nausea and vomiting (OR 5.63; CI 1.25–25.27; P = 0.024), and presence of comorbidities (OR 4.56; CI 1.44–14.40; P = 0.010). Patients who were in the adherent group showed significantly better score in overall HRQOL, F (15, 73) = 2.09, P < 0.02; Pillai’s trace = 0.3, partial eta squared = 0.30.ConclusionNon-adherence to long-term treatment with imatinib among patients with GIST should not be underestimated. Significant predictors of non-adherence among this population are younger age, presence of nausea and vomiting, as well as comorbidities. Patients with good adherence portrayed better HRQOL.

Postpartum diagnosis of a recurrent metastatic gastrointestinal stromal tumor

Background: Gastrointestinal stromal tumors are rare in pregnancy, and typically present in the second trimester present with size-greater-than-dates, abdominal pain, or nonspecific symptoms. Case: A 31-year-old gravida 1 female presented in the postpartum period with weight loss, cachexia, an abdominal mass, and persistent unexplained tachycardia. She was found to have a recurrent metastatic gastrointestinal stromal tumor and pulmonary emboli. She was anticoagulated and treated with neoadjuvant imatinib therapy with excellent initial response. Unfortunately, she died one year later due to complications of her disease and treatment. Conclusion: Malignancy should be considered in a pregnant woman with size-greater-than-dates or with an abdominal mass, especially when associated with unexplained weight loss and a history of a gastrointestinal stromal tumor, as the recurrence rate is high without continued maintenance therapy. Delivery at 35 to 37 weeks is recommended, and involvement of a multidisciplinary team improves outcomes.

Avapritinib in unresectable or metastatic gastrointestinal stromal tumor with PDGFRA exon 18 mutation: safety and efficacy

ABSTRACT Introduction Avapritinib (formerly known as BLU-285) is an orally available type I tyrosine kinase inhibitor that, in 2020, obtained regulatory approval for the treatment of patients with gastrointestinal stromal tumors (GISTs) harboring a primary mutation in PDGFRA exon 18, including the PDGFRA D842V mutation. Areas covered Herein, we comprehensively review the available efficacy and safety data on avapritinib, with the final goal of providing practical knowledge to both sarcoma and community-based oncologists for the correct management of this rare GIST subpopulation with this novel therapy. Expert opinion The approval of avapritinib in GIST is a milestone in precision oncology, as this is the first agent ever demonstrating unequivocal antitumoral activity in GIST driven by the multi-resistant PDGFRA D842V mutation. The safety profile is manageable and tolerability-guided dose adjustment is recommended to manage treatment-related adverse events without compromising efficacy. Based on its unprecedented activity, avapritinib should be considered as first-line therapy for GIST patients harboring this mutation. We strongly recommend to determine KIT/PDGFRA genotype in order to identify the different GIST molecular subtypes and guide treatment decision.

Immunohistochemical features of gastrointestinal stromal tumors and the role of expression of p16ink4A, Ki-67, VEGF and MMP-9 in their behavior

Aim: to clarify the prognostic value of cytoplasmic p16ink4A, VEGF, MMP-9 and Ki-67 expressions in gastrointestinal stromal tumors (GISTs) and connection of different levels of these markers expression with aggressive transformation of GISTs. Materials and methods. Our study included 36 samples of primary tumors and 10 relapses of GIST and metastases in liver after primary combined treatment (surgery and chemotherapy with imatinib). The immunohistochemical study was performed with 4 primary antibodies: Ki-67, p16ink4A, VEGF and MMP-9. We used formalin fixed and paraffin embedded (FFPE) tissue samples for immunohistochemical study. Results. In our study we showed significant connection between levels of cytoplasmic expression of p16ink4A in primary GISTs and such markers of tumor aggressive behaviour as Ki-67, MMP-9 and VEGF (Fisher’s exact P-value = 0.000753; 0.000101 and 0.000048 respectively). Between cytoplasmic expression of p16ink4A and VEGF and also between p16ink4A and MMP-9 strong direct correlation was found (γ = 0.829, P &lt; 0.05 and rs = 0.961, P &lt; 0.05 respectively). The correlation between expression of Ki-67 and p16ink4A was also direct and strong (rs = 0.754, P &lt; 0.05), but with some exclusions, that’s why this correlation needs further investigation in larger groups with preciser molecular analysis. Analysis of metastatic GISTs samples showed prominent levels of MMP-9 and VEGF expression. Conclusions. Our study has shown very important role of cytoplasmic expression of p16ink4A in GIST as one of the markers of aggressive behavior, which can be used in complex with other markers for more accurate prognosis of GISTs progression. Prominent levels of MMP-9 and VEGF expression in metastatic GISTs can be a marker of resistance to imatinib. So probably evaluation of MMP-9 and VEGF expression can be used as a tool for correct choice of chemotherapy for patients with GISTs.

A Rare Case of a Giant Locally Advanced Stromal Tumor of the Stomach Made Resectable by Imatinib

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the digestive tract. Most gastrointestinal soft tissue neoplasms, previously classified as leiomyomas, leiomyoblastomas, schwannomas or leiomyosarcomas, are now classified as GISTs on the basisof histology, molecular study and immunohistochemistry. They originate from the stem cells which differentiate toward the pacemaker cell (Interstitial cell of Cajal). Prognostic factors have been identified for GISTs,they include the tumor size and the mitotic rate. Surgery is the standard treatment for resectable GISTs. Metastatic and inoperable GISTs should consider medication with tyrosine kinase inhibitor (imatinib mesylate), which inhibits the c-kit receptor. We present the case of a locally advanced giant stromal tumor that became resectable after neoadjuvant chemotherapy with Imatinib; our work shows the importance of this molecule which can modify tumor status and surgical prognosis in locally advanced or metastatic GISTs.

Standard versus personalized schedule of regorafenib in metastatic gastrointestinal stromal tumors: a retrospective, multicenter, real-world study

BackgroundDespite its proven activity as third-line treatment in gastrointestinal stromal tumors (GIST), regorafenib can present a poor tolerability profile which often leads to treatment modifications and transient or permanent discontinuation; thus, in clinical practice physicians usually adopt various dosing and interval schedules to counteract regorafenib-related adverse events and avoid treatment interruption. The aim of this real-world study was to investigate the efficacy and safety of personalized schedules of regorafenib in patients with metastatic GIST, in comparison with the standard schedule (160 mg daily, 3-weeks-on, 1-week-off).Patients and methodsInstitutional registries across seven Italian reference centers were retrospectively reviewed and data of interest retrieved to identify patients with GIST who had received regorafenib from February 2013 to January 2021. The Kaplan–Meier method was used to estimate survival and the log-rank test to make comparisons.ResultsOf a total of 152 patients with GIST, 49 were treated with standard dose, while 103 received personalized schedules. At a median follow-up of 36.5 months, median progression-free survival was 5.6 months [95% confidence interval (CI) 3.73-11.0 months] versus 9.7 months (95% CI 7.9-14.5 months) in the standard-dose and the personalized schedule groups, respectively [hazard ratio (HR) 0.51; 95% CI 0.34-0.75; P = 0.00052]. Median overall survival was 16.6 months (95% CI 14.1-21.8 months) versus 20.5 months (95% CI 15.0-25.4 months), respectively (HR 0.75; 95% CI 0.49-1.22; P = 0.16).ConclusionsRegorafenib-personalized schedules are commonly adopted in daily clinical practice of high-volume GIST expert centers and correlate with significant improvement of therapeutic outcomes. Therefore, regorafenib treatment optimization in patients with GIST may represent the best strategy to maximize long-term therapy.

Inhibition of PI3K and MAPK pathways along with KIT inhibitors as a strategy to overcome drug resistance in gastrointestinal stromal tumors.

Activating mutations in KIT/PDGFRA receptor tyrosine kinases drive gastrointestinal stromal tumors (GIST). KIT/PDGFRA inhibitors, such as imatinib do not evoke an effective cytocidal response, leaving room for quiescence and development of multiple secondary resistance mutations. As the majority of the secondary resistance clones activate PI3K and MAPK pathways, we investigated whether combined targeting of KIT/PI3K/MAPK (KPM) pathways overcomes drug resistance and quiescence in GIST cells. We monitored the proliferation of imatinib–sensitive and–resistant GIST cell lines after treating them with various combinations of drugs to inhibit KPM pathways. Cytocidal response was evaluated through proliferation, apoptosis and colony outgrowth assays. Combined inhibition of KPM signaling pathways using a KPM inhibitor cocktail decreased the survival of drug-resistant GIST cells and dramatically reduced their proliferation. Downstream pathway analysis showed that the residual PI3K/MAPK signaling observed after KIT inhibitor treatment plays a role in mediating quiescence and drug resistance. The KPM inhibitor cocktail with sunitinib or regorafenib effectively induced apoptosis and prevented colony outgrowth after long-term drug removal, suggesting that it can be used as an effective strategy against quiescence and drug resistance in metastatic GIST.

Early and Next-Generation KIT/PDGFRA Kinase Inhibitors and the Future of Treatment for Advanced Gastrointestinal Stromal Tumor.

The majority of gastrointestinal stromal tumors (GIST) harbor an activating mutation in either the KIT or PDGFRA receptor tyrosine kinases. Approval of imatinib, a KIT/PDGFRA tyrosine kinase inhibitor (TKI), meaningfully improved the treatment of advanced GIST. Other TKIs subsequently gained approval: sunitinib as a second-line therapy and regorafenib as a third-line therapy. However, resistance to each agent occurs in almost all patients over time, typically due to secondary kinase mutations. A major limitation of these 3 approved therapies is that they target the inactive conformation of KIT/PDGFRA; thus, their efficacy is blunted against secondary mutations in the kinase activation loop. Neither sunitinib nor regorafenib inhibit the full spectrum of KIT resistance mutations, and resistance is further complicated by extensive clonal heterogeneity, even within single patients. To combat these limitations, next-generation TKIs were developed and clinically tested, leading to 2 new USA FDA drug approvals in 2020. Ripretinib, a broad-spectrum KIT/PDGFRA inhibitor, was recently approved for the treatment of adult patients with advanced GIST who have received prior treatment with 3 or more kinase inhibitors, including imatinib. Avapritinib, a type I kinase inhibitor that targets active conformation, was approved for the treatment of adults with unresectable or metastatic GIST harboring a PDGFRA exon 18 mutation, including PDGFRA D842V mutations. In this review, we will discuss how resistance mutations have driven the need for newer treatment options for GIST and compare the original GIST TKIs with the next-generation KIT/PDGFRA kinase inhibitors, ripretinib and avapritinib, with a focus on their mechanisms of action.

GMP-compliant production of [68Ga]Ga-NeoB for positron emission tomography imaging of patients with gastrointestinal stromal tumor

Background[68Ga]Ga-NeoB is a novel DOTA-coupled Gastrin Releasing Peptide Receptor (GRPR) antagonist with high affinity for GRPR and good in vivo stability. This study aimed at (1) the translation of preclinical results to the clinics and establish the preparation of [68Ga]Ga-NeoB using a GMP conform kit approach and a licensed 68Ge/68Ga generator and (2) to explore the application of [68Ga]Ga-NeoB in patients with gastrointestinal stromal tumors (GIST) before and/or after interventional treatment (selective internal radiotherapy, irreversible electroporation, microwave ablation).ResultsValidation of the production and quality control of [68Ga]Ga-NeoB for patient use had to be performed before starting the GMP production. Six independent batches of [68Ga]Ga-NeoB were produced, all met the quality and sterility criteria and yielded 712 ± 73 MBq of the radiotracer in a radiochemical purity of > 95% and a molar activity of 14.2 ± 1.5 GBq/μmol within 20 min synthesis time and additional 20 min quality control. Three patients (2 females, 1 male, 51–77 yrs. of age) with progressive gastrointestinal stromal tumor metastases in the liver or peritoneum not responsive to standard tyrosine kinase inhibitor therapy underwent both [68Ga]Ga-NeoB scans prior and after interventional therapy. Radiosynthesis of 68Ga-NeoB was performed using a kit approach under GMP conditions. No specific patient preparation such as fasting or hydration was required for [68Ga]Ga-NeoB PET/CT imaging. Contrast-enhanced PET/CT studies were performed. A delayed, second abdominal image after the administration of the of [68Ga]Ga-NeoB was acquired at 120 min post injection.ConclusionsA fully GMP compliant kit preparation of [68Ga]Ga-NeoB enabling the routine production of the tracer under GMP conditions was established for clinical routine PET/CT imaging of patients with metastatic GIST and proved to adequately visualize tumor deposits in the abdomen expressing GRPR. Patients could benefit from additional information derived from [68Ga]Ga-NeoB diagnosis to assess the presence of GRPR in the tumor tissue and monitor antitumor treatment.

Abstract 1482: M4645 is a potent and highly selective inhibitor of disease relevant cKIT mutations for the treatment of metastatic or recurrent GIST

Abstract Oncogenic mutations in cKIT in exons 9 and 11 are the main driver of gastrointestinal stromal tumors (GIST). Imatinib is standard of care in 1L in unresectable metastatic or recurrent GIST, yet secondary resistance mutations in exons 13/14 and 17/18 of the cKIT kinase domain frequently arise limiting efficacy. Currently approved 2L and 3L therapies sunitinib and regorafenib target these mutations only to some extent and show limited clinical benefit. Even with the recent approval of ripretinib as 4L treatment, a high unmet medical need remains for patients with imatinib resistance mutations in exon13/14. M4645 was designed to particularly inhibit the frequent V654A resistance mutation in exon 13 of cKIT. Based on cKIT inhibitor scaffolds identified within the Merck compound collection, a 3,5,6-substituted indazole-lead was discovered. Substituent optimization in the 5- and 6-positions of the core scaffold resulted in highly selective kinase inhibitors. Through variation at the 3-position, potency and physicochemical properties were optimized, resulting in the candidate molecule M4645 which combined potency, kinase selectivity, and solubility with a good safety profile. The excellent kinase selectivity could be rationalized by the crystal structure of cKIT V654A mutant kinase domain in complex with M4645. M4645 showed potent inhibition of cKIT autophosphorylation and of downstream P-ERK1/2 and P-AKT signaling in cell lines bearing activating and resistance mutations of cKIT. Dose-dependent inhibition of cKIT activation was demonstrated in a GIST xenograft model expressing the cKIT resistance mutation V654A in exon 13. Strong antitumor activity was observed in cell line and patient-derived GIST xenograft models with this imatinib resistance mutation. Compared to imatinib, M4645 induced prolonged anti-tumor response in a GIST model with a primary activating mutation of cKIT. In summary, the favorable profile and strong antitumor activity, particularly in GIST models expressing the V654A resistance mutation, suggests superiority of M4645 compared to currently available &amp;gt; 2L treatment options for unresectable metastatic or recurrent GIST patients. Citation Format: Nina Linde, Andreas Blum, Dieter Dorsch, Ulrich Graedler, Michael Busch, Nina Glaser, Carl Petersson, Aaron Ruff, Eva Sherbetjian, Christina Esdar. M4645 is a potent and highly selective inhibitor of disease relevant cKIT mutations for the treatment of metastatic or recurrent GIST [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1482.

Abstract LB031: Plasma based metabolic profiling in metastatic gastrointestinal stromal tumors (GIST)

Abstract Background: Discovery of oncogenic mutations as targets for cancer therapy revolutionized treatment of GIST and other cancers. However, nearly all patients ultimately progress, which emphasizes the need for development of new tools to assess cancer prognosis and factors associated with benefit of cancer therapies. Altered metabolism is a hallmark of cancer, enabling tumors to proliferate, survive and metastasize. By measuring the complete set of metabolites in an individual (metabolome) it is possible to identify biomarkers that correlate with disease status, prognosis, and therapeutic response. Methods: We performed untargeted NMR and MS-based machine learning metabolomic analysis (Olaris, Waltham, MA) of serial plasma samples collected at baseline and during experimental systemic therapies in 39 patients with advanced/metastatic GIST. Results were compared to clinical outcomes. Results: In serial plasma samples from 39 patients with advanced/metastatic GIST using untargeted NMR and MS-based machine learning (ML) metabolomic analysis, we identified metabolic signatures to build Biomarker-of-Response (BoR) ML models that could accurately differentiate patients with response, intrinsic and adaptive resistance to experimental systemic therapies. The BoR ML model also correlated with tumor growth or tumor reduction in patients with response, intrinsic and adaptive resistance. Finally, we identified metabolic pathways associated with response and resistance. Conclusions: Comprehensive metabolomic profiling of serially collected plasma is feasible and detects metabolic signatures associated with therapeutic response in advanced GIST. Citation Format: Chandrashekhar Honrao, Srihari Raghavendra Rao, Nathalie Teissier, S. Greg Call, Elizabeth M. ODay, Filip Janku. Plasma based metabolic profiling in metastatic gastrointestinal stromal tumors (GIST) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB031.

SO-12 Updated safety, efficacy, and PK results from an open-label, multicenter, phase I/II study of avapritinib in Chinese patients with unresectable or metastatic gastrointestinal stromal tumors

More than 85% of gastrointestinal stromal tumors (GIST) patients (pts) have tumors associated with KIT/PDGFRA mutations. Avapritinib is a potent, selective, small-molecule, KIT/PDGFRA inhibitor and has been approved in the US for pts with GIST harboring PDGFRA exon 18 mutation. However, these pts have no standard of care in China. This abstract reports safety, efficacy, and PK results of avapritinib in Chinese pts.

Rhabdoid Signet- Ring Mixed Cell Subtype Gastrointestinal Stromal Tumor from the Stomach - Pathohistological and Immunohistochemical Analysis, Differential Diagnosis, Prognosis and Complex Treatment

We present rarely diagnosed extremely malignant rhabdoid signet- ring mixed cell subtype gastrointestinal stromal tumor (GIST) from the stomach in a man of 67 years. This is a third rhabdoid histological phenotype GIST posted in the English medical literature. The diagnosis is placed after a pathochistological and immunohistochemical analysis of the lung biopsy material. The purpose of this presentation is to discuss the difficulty early diagnostics, the prognosis of this extremely malignant GIST, the differential pathohistological and immunohistochemical diagnosis with other benign and malignant tumors. The diagnosis of a GISTs is directly related to treatment with a tyrosine kinase inhibitor (Imatinib), which is indicated for inoperable and metastatic GIST.

Metastatic Liver Tumors in Surgical Pathology: Impact of Contemporary Diagnostic and Therapeutic Paradigms in a Tertiary Care Center.

We analyzed metastatic liver tumors received in the department of pathology in a tertiary care center over a 3-year period. There were 509 metastatic liver tumors; counterintuitively, there were as many resections (235 cases) as biopsies (274 cases). This unexpected finding reflects contemporaneous organ-specific paradigms for diagnosis and management of metastatic liver disease in oncologic practice, and the association of our practice with a National Cancer Institute-designated comprehensive cancer center with expertise and specialization in liver surgery. We receive a large number of resections for metastatic liver tumors because metastasectomy from a variety of primary tumors is associated with improved overall, and in many instances, disease-free, long-term survival. Metastatic colorectal carcinomas, metastatic neuroendocrine tumors, and metastatic gastrointestinal stromal tumors constituted 78% of resections because the largest body of literature and cumulative experience exists for these lesions. In contrast, breast carcinomas and pancreatic carcinomas, which are the next common metastatic liver tumors were biopsied but rarely resected, because metastasectomy is not the standard of care for these tumors. Immunohistochemistry was performed in less than a quarter of the total number of cases (23%), because the primary tumor site was known in the vast majority of cases. Of the 42 cases with unknown primary tumor, it was elucidated in 50% of the cases by immunohistochemical and clinical work-up. Of the cases with known primary tumor, immunohistochemistry was performed mostly in metastatic breast, colon, and lung carcinomas. In these cases, biomarker analyses provided additional information relevant to clinical management.

Polydatin Reduces Cardiotoxicity and Enhances the Anticancer Effects of Sunitinib by Decreasing Pro-Oxidative Stress, Pro-Inflammatory Cytokines, and NLRP3 Inflammasome Expression.

Renal cell carcinoma (RCC) represents the main renal tumors and are highly metastatic. Sunitinib, a recently-approved, multi-targeted Tyrosine Kinases Inhibitor (TKi), prolongs survival in patients with metastatic renal cell carcinoma and gastrointestinal stromal tumors, however a dose related cardiotoxicity was well described. Polydatin (3,4’,5-trihydroxystilbene-3-β-d-glucoside) is a monocrystalline compound isolated from Polygonum cuspidatum with consolidated anti-oxidant and anti-inflammatory properties, however no studies investigated on its putative cardioprotective and chemosensitizing properties during incubation with sunitinib. We investigated on the effects of polydatin on the oxidative stress, NLRP3 inflammasome and Myd88 expression, highlighting on the production of cytokines and chemokines (IL-1β, IL-6, IL-8, CXCL-12 and TGF-β) during treatment with sunitinib. Exposure of cardiomyocytes and cardiomyoblasts (AC-16 and H9C2 cell lines) and human renal adenocarcinoma cells (769‐P and A498) to polydatin combined to plasma-relevant concentrations of sunitinib reduces significantly iROS, MDA and LTB4 compared to only sunitinib-treated cells (P<0.001). In renal cancer cells and cardiomyocytes polydatin reduces expression of pro-inflammatory cytokines and chemokines involved in myocardial damages and chemoresistance and down-regulates the signaling pathway of NLRP3 inflammasome, MyD88 and NF-κB. Data of the present study, although in vitro, indicate that polydatin, besides reducing oxidative stress, reduces key chemokines involved in cancer cell survival, chemoresistance and cardiac damages of sunitinib through downregulation of NLRP3-MyD88 pathway, applying as a potential nutraceutical agent in preclinical studies of preventive cardio-oncology.

Lentinan as a natural stabilizer with bioactivities for preparation of drug–drug nanosuspensions

Lentinan is a natural β–glucan with various bioactivities and is combined with chemotherapy drugs for cancer treatment. Regorafenib is an oral multi-kinase inhibitor approved by FDA for treatment of metastatic colorectal cancer, advanced hepatocellular carcinoma, and metastatic gastrointestinal stromal tumors. Regorafenib has poor water solubility and multiple toxicities. We report drug–drug nanosuspensions of regorafenib and lentinan. Results of dynamic light scattering and scanning electron microscopy showed that the mean particle size of the regorafenib–lentinan nanosuspensions was approximately 200 nm and was uniformly distributed. Transmission electron microscopy findings indicated that lentinan stabilized the nanosuspensions by steric manner. Hydrogen bonds and hydrophobic interactions were found between regorafenib and lentinan by molecular dynamics simulation. The results of cytotoxicity assay and pharmacokinetics study in rats showed that the regorafenib–lentinan nanosuspensions reduced the toxicity and enhanced the in vitro anticancer activity and oral bioavailability of regorafenib. Lentinan as a natural stabilizer has the potential using for drug nanosuspensions. Drug–drug nanosuspensions are a new form of combination therapies that can reduce the number of drugs taken by patients and improve their compliance.

Rapid Progression of Coronary Atherosclerosis in Patients Taking an Oral Antitumor, Multikinase Receptor Inhibitor.

Rapid Progression of Coronary Atherosclerosis in Patients Taking an Oral Antitumor, Multikinase Receptor Inhibitor.

Fulminant liver failure in a patient treated with Sunitinib for metastatic gastrointestinal stromal tumor

Fulminant liver failure in a patient treated with Sunitinib for metastatic gastrointestinal stromal tumor