Search

Soft tissue sarcomas are rare cancers and most cases are metastatic at the time of diagnosis. Although the chances of survival are good with surgical treatment in the early stages, systemic treatment in the advanced stages is only associated with a survival duration of ~12 months. Alterations in the anaplastic lymphoma kinase (ALK) gene are becoming increasingly recognized as pan-cancer indicators in solid tumors. However, little is known regarding the molecular spectrum of ALK-positive histiocytosis. Molecular treatments, including ALK inhibitors, are potential treatment options. The present case report describes an aggressive ALK-positive soft tissue sarcoma with intracardiac metastases and severe leukocytosis responding to ALK inhibitors. The patient initially responded to crizotinib but required alectinib due to central nervous system progression. The patient has shown a near-complete response and remained stable for 2 years; however, there has been recent lymph node progression. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the clinical significance of subtyping (type 1 vs 2) of papillary renal cell carcinoma (PRCC) in patients treated with targeted therapy, as well as the concordance, sensitivity and positive predictive value (PPV) of local review pathology review. Methods: Patients with advanced refractory PRCC were randomised to receive sunitinib or cabozantinib, crizotinib or savolitinib, stratified by PRCC subtype (type 1, type 2, or not otherwise specified [NOS]/mixed) by local review. Central review was retrospectively conducted by three expert genitourinary pathologists who independently reviewed cases. The sensitivity and PPV of local review were estimated and outcomes [objective response rate (ORR), progression‐free survival (PFS)] were summarised for treatment groups stratified by subtypes by central review. Results: Amongst the 147 patients reviewed, the prevalence of individual subtypes varied by local or central review (type 1: 17.7% vs 29.3%; type 2: 53.1% vs 45.6%; NOS/mixed: 29.3% vs 25.2%), respectively. Individual cases were frequently reclassified and local pathology review demonstrated low sensitivity (type 1: 48%, 95% confidence interval [CI] 33, 65; type 2: 67%, 95% CI 55, 78; NOS/mixed: 43%, 95% CI 27, 61). The PPVs of local review were 80%, 57.7% and 37% for type 1, 2 and NOS/mixed, respectively. Compared to sunitinib, cabozantinib demonstrated improved PFS for both type 1 and type 2 PRCC subgroups (7.4 vs 9.0 and 2.9 vs 5.6 months, respectfully) as well as higher ORR. Conclusions: The PRCC subtype assignment did not identify a subset of patients with greater clinical benefit from cabozantinib, with significant discordance between local and central review. Our findings confirm the limited clinical value of pathological subtyping of metastatic PRCC, in line with the recent World Health Organisation 2022 guidelines. Patient summary: In this study, categorising papillary renal cell carcinoma into type 1 or 2 subtypes showed limited concordance between central and local pathological review and did not enrich for patients more likely to benefit from cabozantinib in the S1500 PAPMET trial. [ABSTRACT FROM AUTHOR]

Background Hypertrophic scarring is a disease of abnormal skin fibrosis caused by excessive fibroblast proliferation. Existing drugs have not achieved satisfactory therapeutic effects. Objectives To explore the molecular pathogenesis of hypertrophic scars and screen effective drugs for their treatment. Methods Existing human hypertrophic scar RNA sequencing data were utilized to search for hypertrophic scar-related gene modules and key genes through weighted gene co-expression network analysis (WGCNA). Candidate compounds were screened in a compound library. Potential drugs were screened by molecular docking and verified in human hypertrophic scar fibroblasts and a mouse mechanical force hypertrophic scar model. Results WGCNA showed that hypertrophic scar-associated gene modules influence focal adhesion, the transforming growth factor (TGF)-β signalling pathway and other biologic pathways. Integrin β1 (ITGB1) is the hub protein. Among the candidate compounds obtained by computer virtual screening and molecular docking, crizotinib, sorafenib and SU11274 can inhibit the proliferation and migration of human hypertrophic scar fibroblasts and profibrotic gene expression. Crizotinib had the best effect on hypertrophic scar attenuation in mouse models. At the same time, mouse ITGB1 small interfering RNA can also inhibit mouse scar hyperplasia. Conclusions ITGB1 and TGF-β signalling pathways are important for hypertrophic scar formation. Crizotinib could be a potential treatment drug for hypertrophic scars. [ABSTRACT FROM AUTHOR]

BACKGROUND: Tyrosine kinase inhibitors, as well as other types of small-molecule cancer drugs, can cause severe cardiotoxicity. OBJECTIVE: To perform a heart safety re-evaluation by observing the effects of antitumor drugs on isolated heart electrocardiograph, cardiac action potential and associated ion channels and cytotoxicity. METHODS: Extracorporeal cardiac perfusion was given to the isolated rabbit heart using Langendorff perfusion: Sunitinib (0.3, 3, 10 μmol/L), Crizotinib (0.3, 1, 3 μmol/L), and Doxorubicin (1, 30 μmol/L) were perfused sequentially for 120 minutes to record electrocardiograph and left ventricular pressure. A blank control group was set for comparison. Manual patch clamp was used to record the effects of Crizotinib, Sunitinib, Doxorubicin on hERG, Cav1.2, Nav1.5 channel currents and action potential in human induced pluripotent stem cell derived cardiomyocytes. Adenosine triphosphate level in human induced pluripotent stem cell derived cardiomyocytes was detected by CellTiter-Glo luminescent cell viability assay. RESULTS AND CONCLUSION: Isolated rabbit heart using Langendorff perfusion: Compared with the blank ontrol group, Sunitinib and Crizotinib at ≥ 3 μmol/L decreased heart rate (P < 0.01) and prolonged QT/QTc interval (P < 0.01), and reduced left ventricular pressure to different extents. Manual patch clamp recording: Compared with the blank control group, Sunitinib and Crizotinib at 3 μmol/L inhibited the activities of hERG, Nav1.5 and Cav1.2 channels and significantly prolonged the duration of action potential (P < 0.01). According to the analysis of the test article, the difference between the labeled concentration and the measured concentration of the recovered solution was not significant. Cell viability assays: Compared with the blank control group, adenosine triphosphate content in human induced pluripotent stem cell derived cardiomyocytes significantly decreased after treatment with Sunitinib (IC50=4.64 μmol/L), Doxorubicin (IC50=4.21 μmol/L) and Crizotinib (IC50=2.87 μmol/L), indicating that cell viability significantly decreased (P < 0.01). To conclude, this study successfully established an early cardiac safety evaluation method for antitumor drugs, which provides good support and help for the subsequent development of antitumor drugs. [ABSTRACT FROM AUTHOR]

Small molecular kinase inhibitors play a key role in modern cancer therapy. Protein kinases are essential mediators in the growth and progression of cancerous tumors, rendering involved kinases an increasingly important target for therapy. However, kinase inhibitors are almost insoluble in water because of their hydrophobic aromatic nature, often lowering their availability and pharmacological efficacy. Direct drug functionalization with polar groups represents a simple strategy to improve the drug solubility, availability, and performance. Here, we present a strategy to functionalize secondary amines with oligoethylene glycol (OEG) phosphate using a one‐pot synthesis in three exemplary kinase inhibiting drugs Ceritinib, Crizotinib, and Palbociclib. These OEG‐prodrug conjugates demonstrate superior solubility in water compared to the native drugs, with the solubility increasing up to 190‐fold. The kinase inhibition potential is only slightly decreased for the conjugates compared to the native drugs. We further show pH dependent hydrolysis of the OEG‐prodrugs which releases the native drug. We observe a slow release at pH 3, while the conjugates remain stable over 96 h under physiological conditions (pH 7.4). Using confocal microscopy, we verify improved cell uptake of the drug‐OEG conjugates into the cytoplasm of HeLa cells, further supporting our universal solubility approach. [ABSTRACT FROM AUTHOR]

Non‐small‐cell lung cancer (NSCLC) accounts for the majority of lung cancer cases worldwide, with a significant proportion of patients harbouring actionable oncogenic alterations. Among these alterations, the ROS1 rearrangement represents a distinct subset with therapeutic implications. Here, we present the case of a 52‐year‐old man diagnosed with advanced NSCLC harbouring the ROS1 fusion gene. Despite the initial poor response to conventional chemotherapy, the patient exhibited an exceptional and sustained response to crizotinib, with a progression‐free survival of 94 months and complete metabolic response on PET scan. This case underscores the importance of molecular profiling in guiding treatment decisions and highlights the efficacy of targeted therapies for ROS1‐positive NSCLC. [ABSTRACT FROM AUTHOR]

The discovery of epinephrine (adrenaline) and its subsequent implications in medicine owes significant contributions to Cybulski across different centuries, who, in 1894, was pivotal in identifying the adrenal medulla's role in blood pressure regulation and naming the active substance "nadnerczyna", known today as adrenaline. His work demonstrated the adrenal glands' critical function in the body's regulatory mechanisms beyond the nervous system. Cybulski's groundbreaking research laid foundational knowledge for future endocrinological studies and pharmaceutical advancements. In the late 20th century, Andruszkiewicz collaborated with Silverman at Northwestern University to develop pregabalin, the active ingredient in Lyrica. Their innovative synthesis of gamma-aminobutyric acid derivatives led to a significant advancement in treating epilepsy, neuropathic pain, and fibromyalgia. Andruszkiewicz's expertise in organic chemistry and enzymology was crucial in this collaborative effort, resulting in the successful development and commercialization of Lyrica. Additionally, Mroczkowski's leadership at Pfizer contributed to the development of crizotinib, a notable anaplastic lymphoma kinase and proto-oncogene 1 tyrosine-protein kinase inhibitor used to treat specific types of non-small cell lung cancer. Her work exemplifies the continuing influence of Polish researchers in pioneering drug discovery and advancing therapeutic treatments over the past three centuries. These contributions highlight Poland's significant role in global pharmaceutical innovations and medical research. [ABSTRACT FROM AUTHOR]

Introduction: Inflammatory myofibroblastic tumors (IMTs) are intermediate-grade lesions that frequently recur and rarely metastasize. There are currently no guidelines on the management of bladder IMTs. This systematic review aims to describe the clinical presentation and compare the management options for bladder IMTs. Methods: A PubMed/Medline search was conducted, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, using the following Mesh terms: ('inflammatory myofibroblastic') AND ('tumor') OR ('tumor') AND ('bladder') AND ('case report'). A total of 75 case reports were included in the analysis. Results: The mean age of the patients was 36 years. 65 of the cases initially presented with hematuria. 68 of the tumors stained positive for anaplastic lymphoma kinase, and 20 invaded the muscularis. Patients underwent either transurethral resection of the bladder tumor (TURBT) only (34), TURBT followed by complementary partial cystectomy (16), or TURBT followed by radical cystectomy (4). 36 and 9 of the cases underwent partial and radical cystectomy after the initial diagnosis, respectively. Cystectomies were performed using an open (74), laparoscopic (14), robotic-assisted (10), or unknown (2) approach. At a mean follow-up of 14 months, the recurrence and metastasis rates were about 9 and 4, respectively. In addition, we present the case of a 49-year-old woman with a bladder IMT who underwent TURBT followed by laparoscopic partial cystectomy. The patient remains tumor free postoperatively (follow-up period of 12 months). Conclusion: A complete surgical excision of the bladder IMT is crucial for the optimal management of these cases. Proper differentiation of this tumor from sarcoma or leiomyosarcoma leads to the best outcomes., Author(s): Lory Hage [1]; Michael A O'Donnell [2]; Mohamad Abou Chakra (corresponding author) [2]; Amel Kime [3]; Mathilde Sibony [3]; Michaël Peyromaure [1]; Igor Duquesne [1] INTRODUCTION Inflammatory myofibroblastic tumors [...]

Epithelioid inflammatory myofibroblastic sarcoma, a variant of the inflammatory myofibroblastic tumor, is a rare tumor that is not well described in the radiologic literature. We present a case of a 14-year-old male adolescent who presented with fever, fatigue, and weight loss symptoms and was found to have an abdominal mass on contrast enhanced CT. Initial differentials included lymphoma, pheochromocytoma, desmoid, and sarcoma, and pathological evaluation revealed an epithelioid inflammatory myofibroblastic sarcoma. The mass was separate from the surrounding structures of the left upper abdomen with unique radiologic features not previously described in the literature. Prior literature examples of epithelioid inflammatory myofibroblastic sarcoma described a heterogenous, enhancing lobulated mass, and our case was a lobulated, avidly enhancing homogenous mass on CT with surrounding inflammation and avid uptake on PET/CT. In addition to the imaging features, we describe the surgical findings, the pathologic features of the tumor, and the oncologic treatment of this patient. This case highlights the importance of including rare tumors such as epithelioid inflammatory myofibroblastic sarcoma as a potential differential consideration of an avidly enhancing homogenous abdominal mass in an adolescent.