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Toxicologic Pathology Oct 2023Drug-induced liver injury (DILI) remains a major concern in drug development from a patient safety perspective because it is the leading cause of acute liver failure.... (Review)
Review
Drug-induced liver injury (DILI) remains a major concern in drug development from a patient safety perspective because it is the leading cause of acute liver failure. One mechanism of DILI is altered bile acid homeostasis and involves several hepatic bile acid transporters. Functional impairment of some hepatic bile acid transporters by drugs, disease, or genetic mutations may lead to toxic accumulation of bile acids within hepatocytes and increase DILI susceptibility. This review focuses on the role of hepatic bile acid transporters in DILI. Model systems, primarily and modeling tools, such as DILIsym, used in assessing transporter-mediated DILI are discussed. Due to species differences in bile acid homeostasis and drug-transporter interactions, key aspects and challenges associated with the use of preclinical animal models for DILI assessment are emphasized. Learnings are highlighted from three case studies of hepatotoxic drugs: troglitazone, tolvaptan, and tyrosine kinase inhibitors (dasatinib, pazopanib, and sorafenib). The development of advanced models and novel biomarkers that can reliably predict DILI is critical and remains an important focus of ongoing investigations to minimize patient risk for liver-related adverse reactions associated with medication use.
Topics: Animals; Humans; Chemical and Drug Induced Liver Injury; Drug-Related Side Effects and Adverse Reactions; Bile Acids and Salts; Carrier Proteins; Membrane Glycoproteins
PubMed: 37982363
DOI: 10.1177/01926233231212255 -
Journal of Pediatric Hematology/oncology Oct 2023Advances in local control techniques, chemotherapy regimens, and imaging modalities have led to improvements in both morbidity and mortality in pediatric sarcoma...
Advances in local control techniques, chemotherapy regimens, and imaging modalities have led to improvements in both morbidity and mortality in pediatric sarcoma patients. However, approximately one-third of patients develop disease relapse and intracranial metastasis was considered rare. The incidence of sarcoma brain metastasis is thought to have increased and is associated with grim outcomes. This was a retrospective study of 3 deidentified patient charts illustrating the possibility of the central nervous system as a potential site for pediatric sarcoma relapse and investigate the patterns of such relapses. We note this is the first report of infantile fibrosarcoma brain metastasis and a rare report of sarcoma lymph node metastasis. In addition, each patient was treated with targeted therapies, including entrectinib, Ruxolitnib, and pazopanib. Caregivers in cases 2 and 3 reported new-onset neurological manifestations before identification of new brain metastasis, indicating a lag in detection of new intracranial relapse in asymptomatic sarcoma patients. We suggest implementing a brief review of systems screening tool focused on concerning neurological manifestations to screen for new brain metastasis.
Topics: Child; Humans; Retrospective Studies; Sarcoma; Fibrosarcoma; Brain Neoplasms; Recurrence
PubMed: 37526369
DOI: 10.1097/MPH.0000000000002713 -
Food and Chemical Toxicology : An... Nov 2023Parkinson's disease (PD) is characterized by motor impairments and progressive dopaminergic neuronal death in the substantia nigra (SN). Recently, the involvement of...
Parkinson's disease (PD) is characterized by motor impairments and progressive dopaminergic neuronal death in the substantia nigra (SN). Recently, the involvement of other regulated cell death (RCD) machineries has been highlighted in PD. Necroptosis is controlled by p-RIPK1, p-RIPK3, and p-MLKL and negatively regulated by caspase-8. Ferroptosis is characterized by iron overload and accumulation of reactive oxygen species. Interestingly, the molecular chaperone complex HSP90/CDC37 has been reported to directly regulate necroptosis, ferroptosis, and some PD-associated proteins. We investigated the potential anti-necroptotic and anti-ferroptotic effects of the anti-cancer drug pazopanib, uncovering the HSP90/CDC37 complex as a master RCD modulator in rotenone-induced Parkinsonism in rats. Oral administration of 15 mg/kg pazopanib to rotenone-intoxicated rats for three weeks improved motor deficits, debilitated histopathological changes, and increased striatal dopaminergic levels. Pazopanib suppressed LRRK2 and c-Abl. Pazopanib displayed an anti-necroptotic effect through inhibition of the p-RIPK1/p-RIPK3/p-MLKL pathway and activation of caspase-8. Moreover, pazopanib inhibited the ferroptotic p-VEGFR2-PKCβII-PLC-γ-ACSL-4 pathway, iron, 4-HNE, and PTGS2 while increasing GPX-4 and GSH levels. Taken together, the current research sheds light on the repositioning of pazopanib targeting HSP90/CDC37 and its multiple RCD mechanisms, which would offer a new perspective for therapeutic strategies in PD.
Topics: Rats; Animals; Rotenone; Caspase 8; Parkinsonian Disorders; Parkinson Disease; Dopamine; Ferroptosis; Molecular Chaperones; HSP90 Heat-Shock Proteins
PubMed: 37820786
DOI: 10.1016/j.fct.2023.114069 -
Cancers Oct 2023Granular cell tumors (GCT) represent 0.5% of all soft tissue sarcomas (STS), and when metastatic, they exhibit aggressive behavior and determine limited survival.... (Review)
Review
Granular cell tumors (GCT) represent 0.5% of all soft tissue sarcomas (STS), and when metastatic, they exhibit aggressive behavior and determine limited survival. Metastatic GCTs are relatively chemo-resistant; however, there is growing evidence of the benefit of using pazopanib and other targeted therapies in this histology. This is a review of the role of pazopanib and other targeted therapies in the treatment of GCTs, along with some insights on pathology and molecular biology described in GCTs. From 256 articles found in our search, 10 case-report articles met the inclusion criteria. Pazopanib was the most employed systemic therapy. The median reported time on therapy with pazopanib was seven months. Eight out of ten patients (80%) experienced disease control with pazopanib, while four out of ten (40%) patients achieved an objective RECIST response. Molecular studies suggested that antitumoral effects of pazopanib in GCT might be due to a loss-of-function of genes which consequently enhance signaling through several molecular pathways, such as SFKs, STAT5a/b, and PDGFR-β. Other reported targeted therapies for malignant GCTs included pazopanib in combination with crizotinib, which showed disease control for four months in one patient, and a PI3K inhibitor which achieved disease control for nine months in another patient. Dasatinib and megestrol were ineffective in two other different patients. Pazopanib has been demonstrated to be active in advanced GCTs and may be considered as a preferable treatment option.
PubMed: 37958362
DOI: 10.3390/cancers15215187 -
Clinical & Translational Oncology :... Dec 2023Soft tissue sarcomas (STSs) are an uncommon and heterogeneous group of tumours. Several drugs and combinations have been used in clinical practice as second-line (2L)...
BACKGROUND
Soft tissue sarcomas (STSs) are an uncommon and heterogeneous group of tumours. Several drugs and combinations have been used in clinical practice as second-line (2L) and third-line (3L) treatment. The growth modulation index (GMI) has previously been used as an exploratory efficacy endpoint of drug activity and represents an intra-patient comparison.
METHODS
We performed a real-world retrospective study including all patients with advanced STS who had received at least 2 different lines of treatment for advanced disease between 2010 and 2020 at a single institution. The objective was to study the efficacy of both 2L and 3L treatments, analysing the time to progression (TTP) and the GMI (defined as the ratio of TTP between 2 consecutive lines of therapy).
RESULTS
Eighty-one patients were included. The median TTP after 2L and 3L treatment was 3.16 and 3.06 months, and the median GMI was 0.81 and 0.74, respectively. The regimens most frequently used in both treatments were trabectedin, gemcitabine-dacarbazine, gemcitabine-docetaxel, pazopanib and ifosfamide. The median TTP by each of these regimens was 2.80, 2.23, 2.83, 4.10, and 5.00 months, and the median GMI was 0.78, 0.73, 0.67, 1.08, and 0.94, respectively. In terms of histotype, we highlight the activity (GMI > 1.33) of gemcitabine-dacarbazine in undifferentiated pleomorphic sarcoma (UPS) and in leiomyosarcoma, pazopanib in UPS, and ifosfamide in synovial sarcoma.
CONCLUSIONS
In our cohort, regimens commonly used after first-line STS treatment showed only slight differences in efficacy, although we found significant activity of specific regimens by histotype.
Topics: Humans; Ifosfamide; Retrospective Studies; Deoxycytidine; Sarcoma; Gemcitabine; Soft Tissue Neoplasms; Dacarbazine
PubMed: 37329429
DOI: 10.1007/s12094-023-03221-6 -
Current Treatment Options in Oncology Dec 2023Genetic assessment is crucial to address the correct treatment for advanced medullary thyroid cancer (MTC). Multi tyrosine kinase inhibitors (mTKIs) cabozantinib and... (Review)
Review
Genetic assessment is crucial to address the correct treatment for advanced medullary thyroid cancer (MTC). Multi tyrosine kinase inhibitors (mTKIs) cabozantinib and vandetanib are good first line options, even vandetanib prescription is currently limited to RET mutated patients. Selective RET inhibitors such as pralsetinib could be a preferred upfront treatment in case of RET mutated MTC presenting common or gatekeeper RET mutations (e.g. M918T; V804L/M). Selpercatinib, otherwise, can be prescribed as the second line after disease progression to mTKIs. The best option for subsequent lines is to consider inclusion in clinical trials or alternatively other mTKIs such as sunitinib, sorafenib, lenvatinib, or pazopanib could be evaluated. New perspectives include next-generation RET inhibitors able to overcome resistance mechanisms responsible for disease progression to standard mTKIs and RET inhibitors, and immunotherapy for MTC presenting with high tumor mutational burden.
Topics: Humans; Proto-Oncogene Proteins c-ret; Carcinoma, Neuroendocrine; Thyroid Neoplasms; Disease Progression
PubMed: 37979019
DOI: 10.1007/s11864-023-01145-5 -
Gynecologic Oncology Jul 2023Oral tyrosine kinase inhibitors (TKIs) have new indications for treatment in gynecologic malignancies. These targeted drugs have both unique and overlapping toxicities,... (Review)
Review
OBJECTIVE
Oral tyrosine kinase inhibitors (TKIs) have new indications for treatment in gynecologic malignancies. These targeted drugs have both unique and overlapping toxicities, which require careful attention and management. New combination therapies with immune-oncology agents have demonstrated promise in endometrial cancer. This review examines common adverse events associated with TKIs and provides readers with an evidence-based review on current uses and strategies for the management of these medications.
METHODS
A comprehensive review of the medical literature on TKI use in gynecologic cancer was undertaken by a committee approach. Details of each drug, its molecular target, and relevant data on both clinical efficacy and side effects were compiled and organized for clinical use. Information on drug-related secondary effects and management strategies for specific toxicities, including dose reduction and concomitant medications, were gathered.
RESULTS
TKIs can potentially offer improved response rates and durable responses for a group of patients who were previously without an effective standard second-line therapy. The combination of lenvatinib and pembrolizumab represents a more targeted approach to the drivers of endometrial cancer; however, there remains significant drug-related toxicity, and thus dose reduction and dose delay are frequently required. Toxicity management requires frequent check-ins and management strategies to help patients find the highest tolerable dose. TKIs are expensive and patient financial toxicity is as critical a measure of a drug's utility as any drug side effect. Many of these drugs have patient assistance programs, which should be fully utilized to minimize cost.
CONCLUSIONS
Future studies are needed to expand the role of TKIs into new molecularly driven groups. Attention to cost, durability of response, and long-term toxicity management is needed to ensure all eligible patients have access to treatment.
Topics: Female; Humans; Antineoplastic Agents; Endometrial Neoplasms; Treatment Outcome; Tyrosine Kinase Inhibitors
PubMed: 37207499
DOI: 10.1016/j.ygyno.2023.05.007 -
Journal of Cancer Research and Clinical... Sep 2023Description of patient characteristics, effectiveness and safety in Turkish patients treated with pazopanib for metastatic soft tissue sarcoma (STS).
AIM
Description of patient characteristics, effectiveness and safety in Turkish patients treated with pazopanib for metastatic soft tissue sarcoma (STS).
PATIENTS AND METHODS
This multicenter study is based on retrospective review of hospital medical records of patients (≥ 18 years) treated with pazopanib for non-adipocytic metastatic STS at 37 Oncology clinics across Turkey. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS) were evaluated with further analysis of data on the three most common histological subtypes (leiomyosarcoma [LMS], undifferentiated pleomorphic sarcoma [UPS], synovial sarcoma [SS]) in the cohort.
RESULTS
Data of 552 adults (57.6% women, median age: 52 years) were analyzed. DCR and ORR were 43.1% and 30.8%, respectively. Median PFS was 6.7 months and OS was 13.8 months. For LMS, UPS and SS, median PFSs were 6.1, 5.9 and 7.53 months and median OSs were 15.03, 12.87 and 12.27 months, respectively. ECOG ≥ 2 was associated with poor PFS and OS. Liver metastasis was only a factor for progression. Second-line use of pazopanib (vs. front-line) was associated with better PFS, its use beyond third line predicted worse OS. Adverse events (AE) occurred in 82.7% of patients. Most common AEs were fatigue (58.3%) and anorexia (52.3%) which were graded as ≥ 3 in 8.2% and 7.4% of patients, respectively.
CONCLUSION
Pazopanib is effective and well-tolerated in treatment of non-adipocytic metastatic STS. Its earlier use (at second-line), good performance status may result in better outcomes. Worldwide scientific collaborations are important to gain knowledge on rarer STS subtypes by conducting studies in larger patient populations.
Topics: Adult; Humans; Female; Middle Aged; Male; Retrospective Studies; Turkey; Sarcoma; Leiomyosarcoma; Indazoles; Sarcoma, Synovial; Soft Tissue Neoplasms; Neoplasms, Second Primary
PubMed: 37067546
DOI: 10.1007/s00432-023-04766-3 -
In Vivo (Athens, Greece) 2023The prognosis of metastatic and inoperable sarcomas is extremely poor, and intensive chemotherapy-based treatment is typically administered to prolong survival....
BACKGROUND/AIM
The prognosis of metastatic and inoperable sarcomas is extremely poor, and intensive chemotherapy-based treatment is typically administered to prolong survival. Currently, pazopanib, eribulin, and trabectedin are key drugs used in patients with these sarcomas. The aim of the study was to identify prognostic factors for metastatic and inoperable bone and soft tissue sarcomas.
PATIENTS AND METHODS
Clinicopathological data of 46 patients with metastatic and inoperable sarcomas treated with pazopanib, eribulin, and trabectedin between January 2013 and February 2022 at our institution were retrospectively analyzed. Age, sex, primary tumor location, adverse effects, history of doxorubicin and radiation therapy, performance status scores, maximum tumor response, and survival duration were evaluated. The significant prognostic factors were identified using Cox proportional hazards models. Moreover, the 5-year survival rate was evaluated using the Kaplan-Meier method.
RESULTS
The median survival duration after treatment was 13.3 months, where the 5-year overall survival rate was estimated to be 9.85%. Both univariate and multivariate analyses revealed significant relationships among patient prognosis, performance status, and tumor response.
CONCLUSION
Performance status scores and tumor response were significantly associated with patient prognosis. Therefore, regardless of age, sex, primary tumor location, adverse effects, and history of doxorubicin and radiation therapy, use of cutting-edge drugs, such as pazopanib, eribulin, and trabectedin, may be advantageous in patients with advanced sarcomas, if their drug response and performance status scores are good.
Topics: Humans; Trabectedin; Prognosis; Retrospective Studies; Sarcoma; Soft Tissue Neoplasms; Doxorubicin
PubMed: 37905627
DOI: 10.21873/invivo.13371