scholarly journals Targeting extracellular and juxtamembrane FGFR2 mutations in chemotherapy-refractory cholangiocarcinoma

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Michael Bitzer ◽  
Stephan Spahn ◽  
Sepideh Babaei ◽  
Marius Horger ◽  
Stephan Singer ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Response To Treatment ◽  
Gene Fusions ◽  
Potential Treatment ◽  
Promising Candidate ◽  
Recommended Treatment ◽  
Tumor Boards ◽  
Functional Consequences ◽  
Selection For ◽  
A Current

AbstractIntrahepatic cholangiocarcinoma (iCCA) has emerged as a promising candidate for precision medicine, especially in the case of activating FGFR2 gene fusions. In addition to fusions, a considerable fraction of iCCA patients reveals FGFR2 mutations, which might lead to uncontrolled activation of the FGFR2 pathway but are mostly of unknown functional significance. A current challenge for molecular tumor boards (MTB) is to predict the functional consequences of such FGFR2 alterations to guide potential treatment decisions. We report two iCCA patients with extracellular and juxtamembrane FGFR2 mutations. After in silico investigation of the alterations and identification of activated FGFR2 downstream targets in tumor specimens by immunohistochemistry and transcriptome analysis, the MTB recommended treatment with an FGFR-inhibiting tyrosine kinase inhibitor. Both patients developed a rapidly detectable and prolonged partial response to treatment. These two cases suggest an approach to characterize further detected FGFR2 mutations in iCCA to enable patients´ selection for a successful application of the FGFR -inhibiting drugs.

Molecular Targeting of Platelet-Derived Growth Factor B by Imatinib Mesylate in a Patient With Metastatic Dermatofibrosarcoma Protuberans

2002 ◽  
Vol 20 (17) ◽  
pp. 3586-3591 ◽  
Author(s):  
Brian P. Rubin ◽  
Scott M. Schuetze ◽  
Janet F. Eary ◽  
Thomas H. Norwood ◽  
Sohail Mirza ◽  
...  
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Imatinib Mesylate ◽  
Kinase Inhibitor ◽  
Dermatofibrosarcoma Protuberans ◽  
Response To Therapy ◽  
Platelet Derived Growth Factor ◽  
Response To Treatment ◽  
Resected Specimen ◽  
Factor B

PURPOSE: Dermatofibrosarcoma protuberans is caused by activation of the platelet-derived growth factor B (PDGFB) receptor, a transmembrane tyrosine kinase. We investigated the response of dermatofibrosarcoma protuberans to the tyrosine kinase inhibitor imatinib mesylate. PATIENTS AND METHODS: A patient with unresectable, metastatic dermatofibrosarcoma protuberans received imatinib mesylate (400 mg bid). Response to therapy was assessed by [18F]fluorodeoxyglucose (FDG) positron emission tomography, magnetic resonance imaging, and histopathologic and immunohistochemical evaluation. RESULTS: The patient was treated for 4 months with imatinib mesylate. The hypermetabolic uptake of FDG fell to background levels within 2 weeks of treatment, and the tumor volume shrank by over 75% during the 4 months of therapy, allowing for resection of the mass. There was no residual viable tumor in the resected specimen, indicating a complete histologic response to treatment with imatinib mesylate. CONCLUSION: Imatinib mesylate is highly active in dermatofibrosarcoma protuberans. The dramatic response seen in this patient demonstrates that inhibition of PDGFB receptor tyrosine kinase activity can significantly impact viability of at least one type of solid tumor.

scholarly journals Új célzott terápiás lehetőség az onkológiában: tropomiozin receptor-tirozin-kináz gátlók

2021 ◽  
Vol 162 (34) ◽  
pp. 1362-1369
Author(s):  
Edina Kiss ◽  
Zsuzsanna Pápai
Keyword(s):  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
First Generation ◽  
Kinase Inhibitor ◽  
Disease Free Survival ◽  
Diagnostic Methods ◽  
Molecular Diagnostic ◽  
Precision Oncology ◽  
Gene Fusions ◽  
Trk Inhibitors

Összefoglaló. A molekuláris diagnosztikai módszerek folyamatos fejlődésének köszönhetően egyre több onkogén genetikai eltérést azonosítanak. A neurotrofikus tropomiozin receptor-tirozin-kináz (NTRK-) génfúziók fontos precíziós onkológiai célpontok, melyek mindhárom NTRK-génben előfordulhatnak, onkogén-hajtóerőként viselkednek. A génfúziók különböző molekuláris diagnosztikai módszerekkel azonosíthatók, melyek közül a legpontosabb, legköltségesebb és legidőigényesebb meghatározást az újgenerációs szekvenálási technika jelenti. A tropomiozin receptor-tirozin-kináz (TRK-) fúziós fehérjék szelektív gátlása személyre szabott onkológiai kezelési lehetőséget jelent a tumor típusától, lokalizációjától és a beteg életkorától függetlenül. Az első generációs TRK-gátlók gyors, hatékony és tartós daganatellenes hatást biztosítanak kimutatott NTRK-fúzió-pozitív daganatok esetén, alacsony mellékhatásprofil mellett. Az első generációs TRK-gátlók mellett jelentkező ’on target’ rezisztenciát a második generációs TRK-gátlók oldják fel. Szekvenciális tirozin-kináz-inhibitor-kezeléssel tartós betegségmentes túlélés érhető el. Orv Hetil. 2021; 162(34): 1362–1369. Summary. Due to the continuous development of molecular diagnostic methods, more and more oncogenic genetic abnormalities are being identified. Neurotrophic tropomyosin receptor tyrosine kinase (NTRK) gene fusions are important precision oncology targets that can occur in all three NTRK genes and act as oncogenic drivers. Gene fusions can be identified by a variety of molecular diagnostic technologies, of which next-generation sequencing is the most accurate, costly and time-consuming determination. Selective inhibition of tropomyosin receptor tyrosine kinase (TRK) fusion proteins represents a personalized oncology treatment option regardless of tumour type, localization and patient age. First-generation TRK inhibitors provide rapid, efffective and long-lasting antitumor activity in NTRK fusion-positive tumors with a low side-effect profile. On target resistance to first-generation TRK inhibitors is resolved by second-generation TRK inhibitors. Durable disease-free survival can be achieved with sequential tyrosine kinase inhibitor therapies. Orv Hetil. 2021; 162(34): 1362–1369.

scholarly journals Pazopanib in Primary Cardiac Angiosarcoma of the Right Atrium: A Case Report

2016 ◽  
Vol 9 (2) ◽  
pp. 363-367 ◽  
Author(s):  
Sophie Schur ◽  
Rainer Hamacher ◽  
Thomas Brodowicz
Keyword(s):  
Receptor Tyrosine Kinase ◽  
Multidisciplinary Approach ◽  
Kinase Inhibitor ◽  
Response To Treatment ◽  
Conventional Chemotherapy ◽  
Cardiac Angiosarcoma ◽  
Dismal Prognosis ◽  
Heart Tumors ◽  
The Right ◽  
Severe Hypersensitivity Reaction

Primary heart tumors are an extremely rare oncological entity with primary cardiac sarcomas usually representing 20% of all primary cardiac tumorous lesions [Shanmugam: Eur J Cardiothorac Surg 2006;29: 925–932; Orlandi et al.: J Thorac Oncol 2010;5: 1483–1489]. Angiosarcoma is the most prevalent histology and despite a multidisciplinary approach tends to have a dismal prognosis [Shanmugam: Eur J Cardiothorac Surg 2006;29: 925–932; Fury et al.: Cancer J 2005;11: 241–247]. Based on the prevailing literature, we report a 48-year-old woman diagnosed with primary metastatic cardiac angiosarcoma who showed a severe hypersensitivity reaction to conventional chemotherapy with taxanes but an excellent response to treatment with the multitargeted receptor tyrosine kinase inhibitor pazopanib.

Pharmacokinetics (PK) and efficacy of sunitinib in patients with metastatic renal cell carcinoma (mRCC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 4531-4531 ◽  
Author(s):  
B. E. Houk ◽  
M. Amantea ◽  
R. J. Motzer ◽  
M. D. Michaelson ◽  
B. I. Rini ◽  
...  
Keyword(s):  
Clinical Response ◽  
Tumor Volume ◽  
Kinase Inhibitor ◽  
Plasma Concentrations ◽  
Response To Treatment ◽  
Response Relationship ◽  
Multiple Tumor ◽  
Exposure Response ◽  
Phase Ii Studies ◽  
Population Pk

4531 Background: Sunitinib malate (SU11248) is an oral, multi-targeted tyrosine kinase inhibitor of VEGFR, PDGFR, KIT, FLT3, and RET. Clinical studies have demonstrated efficacy of sunitinib in patients with multiple tumor types including two phase II studies in mRCC, where second-line monotherapy with sunitinib showed a response rate of greater than 40% by RECIST, with an additional ≥25% of pts exhibiting prolonged stable disease. A population PK analysis was performed to assess the exposure-response relationship between PK and tumor volume changes, clinical response, and time to tumor progression (TTP) in these two mRCC studies. Methods: In these two studies, 169 patients with mRCC were treated with sunitinib 50 mg/day for 4 weeks, followed by a 2-week off period (Schedule 4/2). Response to treatment was assessed by measuring tumor volume. Clinical response was assessed using RECIST and TTP using logistic regression and Kaplan-Meier survival analysis. A previously described population PK model of sunitinib and its primary active metabolite SU12662 was updated using additional data from three trials, including the two RCC trials. Using the model and trough plasma concentrations, steady-state AUCs of sunitinib plus SU12662 were estimated for each mRCC patient and tested as a predictor of response. Results: PK profiles were evaluable for 149 patients in the two mRCC trials. Plasma clearance (CL) decreased by an average of 28% in mRCC patients relative to healthy volunteers. Covariates, such as gender, age, and ECOG score also affected CL, however all of these changes were less than the estimated inter-individual variability in CL of 43%. Improved clinical response and longer TTPs were associated with greater AUCs. Within 12 weeks of treatment, mean tumor volume decreased by 24–32% in each trial. Conclusions: Individual patient exposures to sunitinib and SU12662 can be predicted with sparse concentration measurements using population PK analysis, and an exposure-response relationship is evident in mRCC. Dose adjustment is not warranted based upon any evaluated covariate. Over the first 12 weeks of treatment at 50 mg daily on Schedule 4/2, increased exposure was associated with improved clinical response and decreased tumor volumes. [Table: see text]

Pilot study of dovitinib in patients with VHL disease.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 587-587 ◽  
Author(s):  
Patrick Glen Pilie ◽  
Surena F. Matin ◽  
Ashley Henriksen Woodson ◽  
Valerie D. Marcott ◽  
Shelly Bird ◽  
...  
Keyword(s):  
Pilot Study ◽  
Kinase Inhibitor ◽  
Pilot Trial ◽  
Stopping Rule ◽  
Response To Treatment ◽  
Pancreatic Cysts ◽  
Inherited Disease ◽  
Patients Âgés ◽  
Vhl Disease ◽  
Efficacy Profile

587 Background: Von Hippel-Lindau (VHL) is an autosomal dominant inherited disease occurring in 1 in 35,000 births. Individuals with germline mutations in the VHL gene may phenotypically express a variety of lesions including hemangioblastomas (HBs), pancreatic cysts, renal cysts, and renal cell carcinomas (RCC). Previous studies have shown differentially increased FGFR3 levels in HBs compared to RCC. In this pilot trial, we investigated the safety and efficacy profile of TKI 258 (dovitinib), a tyrosine kinase inhibitor of VEGF and FGF receptors, in VHL related lesions, focusing on HBs. Methods: A MDACC IRB-approved protocol planned to enroll 25 subjects who had genetically confirmed VHL disease or clinical diagnosis of VHL, and measurable HBs with no immediate risk of needing intervention. Dovitinib 500mg/day was given in a 4 week cycle on 5 day on/2 day off schedule. In the absence of adverse events (AE), treatment lasted 6 cycles or until disease progression. Evaluation of response to treatment was done every 8 weeks including imaging, laboratory, and clinical evaluation. The trial design used a continuous Bayesian stopping rule based on toxicities that resulted in discontinuation of dovitinib and another for lack of efficacy. Signed informed consent completed on all patients enrolled. Results: Trial stopped after six patients enrolled due to toxicity stopping rule. Patients’ ages ranged 18-61 with 5/6 being male. With regards to safety, 6/6 subjects had at least one AE with the most common AEs being rash, diarrhea, and fatigue including a grade 3 AE (severe rash) in one patient. 1/6 was stopped due to noncompliance, 1/6 stopped due to progression, 3/6 stopped due to side effects despite dose reduction, and 1/6 completed full six cycles at full dose. Best response in 6/6 subjects was stable disease (SD) in HBs. Conclusions: This pilot study of dovitinib in patients with VHL disease with measureable HBs did not show a favorable safety or efficacy profile for this dose and schedule. Half of the patients discontinued the drug due to AEs before study completion, and the best achieved response was SD. Further investigation into alternative scheduling and other FGFR inhibitors in the treatment of HBs is warranted given the strong pre-clinical data. Clinical trial information: NCT01266070.

Phase IIa safety and efficacy of milciclib, a pan-cyclin dependent kinase inhibitor, in unresectable, sorafenib-refractory or -intolerant hepatocellular carcinoma patients.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16711-e16711
Author(s):  
Erica Villa ◽  
Fabio Piscaglia ◽  
Rabit Geva ◽  
George Dalecos ◽  
George Papatheodoridis ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Checkpoint Inhibitors ◽  
Primary Objective ◽  
Response To Treatment ◽  
Cyclin Dependent Kinase ◽  
Advanced Hcc ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Secondary Endpoints

e16711 Background: Current hepatocellular carcinoma (HCC) therapeutics, tyrosine kinase inhibitors (TKI) and checkpoint inhibitors (CI), provide limited improvement in overall survival, suggesting the need to identify drugs with broad-spectrum mechanisms of action, used alone or in combination with a TKI or CI. Milciclib, a pan cyclin dependent kinase inhibitor, exhibited anti-cancer activity in refractory solid malignancy patients. The primary objective of this trial was to evaluate safety and tolerability of milciclib in sorafenib-refractory or intolerant advanced HCC patients. Methods: Single arm and multi-center study in advanced HCC patients was conducted in Italy, Greece and Israel. Milciclib was administered orally for up to 6 cycles. Each cycle consisted of 100mg milciclib daily for 4d on/3d off/week for 4 weeks. Safety assessment was the primary endpoint and secondary endpoints included progression free survival (PFS), time to progression (TTP) and clinical benefit rate (CBR). Results: A total of 31 patients were enrolled and 28 were evaluable for efficacy, of which 14 (50%) completed 6-months of treatment. Milciclib was well-tolerated with manageable toxicities. Eighteen of 31 treated patients had drug-related adverse events (AEs) with most frequent (≥5%) occurrence of drug-related diarrhea, nausea, asthenia, fatigue, retinal hemorrhage, rash and myalgia. No drug-related deaths were recorded. Nine of 14 patients (64%) continued treatment under Compassionate Use after study completion. Seven patients received milciclib until 9, 9, 10, 11, 13, 13 and 16 months. The remaining 2 patients are in the 16th month of treatment. Clinical response to treatment, assessed by mRECIST (independent radiological review), is shown in the Table. Both median TTP and PFS were 5.9 months. Conclusions: Milciclib, acting via a new mechanism, was safe, well-tolerated and met primary and secondary endpoints with 61% CBR. These promising clinical data warrant further evaluation of milciclib. Clinical trial information: NCT03109886 . [Table: see text]

A Recessed-Gate In0.52Al0.48As/n+-In0.53Ga0.47As Misfet

1988 ◽  
Vol 144 ◽  
Author(s):  
Jesús A. del Alamo ◽  
Takashi Mizutani
Keyword(s):  
High Performance ◽  
Current Gain ◽  
Device Performance ◽  
Promising Candidate ◽  
Gate Structure ◽  
Source Resistance ◽  
Heavily Doped ◽  
Recessed Gate ◽  
Improve Device ◽  
A Current

ABSTRACTScaling of the In0.52Al0.48As insulator thickness of In0.52Al0.48As/n+-In0.53Ga0.47As MIStype FET's is experimentally found to result in a drastic drop of performance below 200 Å. This is demonstrated to arise from an increase in the sheet resistance of the extrinsic portions of the device that accompanies insulator scaling. In order to solve this problem, a recessed-gate dopedchannel MISFET with a very thin (300 Å) n+-In0.53Ga0.47As cap layer has been fabricated. A 1.5 μm long gate device showed a transconductance of 285 mS/mm and a current-gain cut-off frequency of 19.4 GHz. This result proves the ability of a thin n+-In0.53Ga0.47As cap to reduce source resistance and improve device performance. The fabricated recessed-gate structure is a promising candidate for high-performance scaled MIS-type FET's based on thin, heavily-doped In0.53Gav0.47 As channels.

scholarly journals Evaluation of Ruxolitinib versus Best Available Therapy in Treating Primary Myelofibrosis

2021 ◽  
Author(s):  
Kawa M. Hasan ◽  
Ahmed Y. Elmeshhadany ◽  
Nazar P. Shabila
Keyword(s):  
Overall Survival ◽  
Kinase Inhibitor ◽  
Laboratory Data ◽  
Primary Myelofibrosis ◽  
Risk Groups ◽  
Janus Kinase ◽  
Response To Treatment ◽  
International Prognostic Scoring System ◽  
Janus Kinase Inhibitor ◽  
Treatment Groups

Objectives: Ruxolitinib is a Janus kinase inhibitor (JAK) that is approved for the treatment of myelofibrosis. The therapeutic protocol has changed after the introduction of Ruxolitinib. The aim of this study was to evaluate the effectiveness of Ruxolitinib and to compare it with best available therapy in patients with primary myelofibrosis. Methods: In this retrospective study, 72 patients with primary myelofibrosis were scrutinized in the period from 2012 to 2018 at Nanakali hemato-oncology teaching center, Erbil, Iraqi Kurdistan. The patients were divided into 2 cohorts, 26 of them were treated with Ruxolitinib and 46 others received best available therapy. The patients’ characteristics, their response to treatment, and the outcomes were evaluated. The efficacy of treatment in both arms was compared. Results: The majority our studied patients (46, 63.8%) were in the high and intermediate-2 risk groups according to international prognostic scoring system. At time of diagnosis, there were no noticeable differences in the clinical characteristics and laboratory data among the Ruxolitinib and best available treatment groups of patients. Ruxolitinib was found to be effective in reducing the size of spleen and improving the overall survival when compared to best available treatment group (p<0.001, p= 0.008 respectively). The patients’ performance state had a significant effect on the overall survival in both treatment groups (p=0.003). Conclusion: Ruxolitinib has a significant role in reduction of spleen size, and potentially affect the survival outcomes in patients with myelofibrosis. Keywords: Ruxolitinib, Myelofibrosis, Splenomegaly, Outcomes.

Predictors of response to augmentation treatment in patients with treatment-resistant depression: A systematic review

2019 ◽  
Vol 33 (11) ◽  
pp. 1323-1339 ◽  
Author(s):  
Rachael W Taylor ◽  
Lindsey Marwood ◽  
Ben Greer ◽  
Rebecca Strawbridge ◽  
Anthony J Cleare
Keyword(s):  
Response Prediction ◽  
Early Response ◽  
Subsequent Treatment ◽  
Response To Treatment ◽  
Treatment Resistant Depression ◽  
Treatment Resistant ◽  
Recommended Treatment ◽  
Predictors Of Response ◽  
Resistant Depression ◽  
Pre Treatment

Background: Treatment-resistant depression is an important contributor to the global burden of depression. Antidepressant augmentation is a recommended treatment strategy for treatment-resistant patients, but outcomes remain poor. Identifying factors that are predictive of response to augmentation treatments may improve outcomes. Aims: This review aimed to synthesise the existing literature examining predictors of response to augmentation treatments in patients who had insufficiently responded to initial treatment. Methods: A systematic search was conducted identifying 2241 unique manuscripts. 24 examining predictors of outcome to pharmacological or psychological augmentation treatment were included in this review. Results: Atypical antipsychotics were the most frequently assessed treatment class (nine studies), closely followed by mood stabilisers (eight studies). Only one eligible psychological augmentation study was identified. Early response to treatment (week 2) was the best-supported predictor of subsequent treatment outcome, reported by six studies. Many predictor variables were only assessed by one report and others such as pre-treatment severity yielded contradictory results, both within and across treatment classes. Conclusions: This review highlights the importance of early response as a predictor of pharmacological augmentation outcome, with implications for both the monitoring and treatment of resistant unipolar patients. Further replication is needed across specific interventions to fully assess the generalisability of this finding. However, the clear lack of consistent evidence for other predictive factors both within and across treatments, and the scarce examination of psychological augmentation, demonstrates the need for much more research of a high quality if response prediction is to improve outcomes for patients with treatment-resistant depression.

scholarly journals The Radiologist’s Role in a Breast Multidisciplinary Tumor Board

2020 ◽  
Vol 2 (4) ◽  
pp. 372-381
Author(s):  
Steven J Rockoff ◽  
Meghan R Flanagan ◽  
Janice N Kim ◽  
Kalyan Banda ◽  
Kristine E Calhoun ◽  
...  
Keyword(s):  
Breast Conservation ◽  
Staging System ◽  
Breast Conservation Therapy ◽  
Cancer Staging ◽  
Response To Treatment ◽  
Accelerated Partial Breast Irradiation ◽  
Tumor Board ◽  
Partial Breast Irradiation ◽  
Tumor Boards ◽  
Multidisciplinary Tumor Board

Abstract Breast multidisciplinary tumor boards (MTBs) play an important role in determining treatment. This article serves as a guide for the radiologist participating in a breast MTB, as the information presented at MTB can significantly influence treatment plans and dictate future steps for further patient work-up. Multidisciplinary tumor board preparation involves a careful review of the patient’s history while gathering all relevant imaging studies, and reinterpreting them when appropriate. Presented images should be carefully selected, annotated, and displayed clearly before providing final recommendations for localization and incompletely assessed findings. Anatomic staging factors from the AJCC Breast Cancer Staging System, such as tumor size and degree of suspected skin involvement, should be described. In addition, there are many other types of information that the treatment specialists want to know. The surgeon is interested in anatomic information that will help them decide whether breast conservation therapy is feasible or if local structures, such as the nipple, can be spared. The radiation oncologist may need to know whether accelerated partial breast irradiation is feasible or if postmastectomy radiation therapy is indicated. The medical oncologist is looking for factors that may provide an indication for neoadjuvant therapy and ensuring there is a reliable follow-up method for evaluating the response to treatment, such as comparative MRI. Additionally, all specialists need to know the extent of suspected nodal involvement. By clearly and comprehensively presenting this information to the rest of the MTB team, the radiologist provides a vital contribution that guides treatment and ensures adherence to clinical guidelines.

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