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Treatment options for patients with advanced neuroendocrine tumors (NETs) are limited. Preclinical and early clinical evidence suggest that cabozantinib and temozolomide may exert synergistic antitumor activity. We performed an open-label, single-arm, phase 2 study (NCT04893785) to assess the safety and efficacy of cabozantinib and metronomic temozolomide in patients with advanced, progressive, well-differentiated NETs of gastroenteropancreatic, pulmonary or unknown origin. Patients received cabozantinib 40 mg daily and temozolomide 100 mg/m 2 /day one week on/one week off. The primary endpoint was overall response rate (ORR) by blinded local review. Secondary endpoints included progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR), duration of response (DOR) and safety. Of the 37 patients enrolled, 14 harbored gastrointestinal NETs, 12 pancreatic NETs, 9 lung NETs and 2 NETs of unknown primary. Neoplasms were classified as G1, G2 or G3 in 9, 24 and 4 cases respectively. While all enrolled patients were assessable for toxicity, 33 met the criteria for per protocol assessment of efficacy. The ORR was 15% (95% CI, 5-31%) and did not meet the primary endpoint. However, after a median follow-up of 19.2 months, the CBR was 100% (95% CI, 89.5-100%) and the median PFS was 28.5 months (95% CI, 16.8-28.5 months). The median OS was not reached, with a 3-year OS rate of 68.5% ( ± 9.1%). The median DOR was 19.5 months. Lymphopenia (16%), thrombocytopenia (11%), diarrhea (8%) and colitis (8%) emerged as the most frequent grade ≥3 treatment-related adverse events. No treatment-related deaths were recorded. Deficiency of O⁶-methylguanine–DNA methyltransferase (MGMT) and c-MET expression were associated with response. The proportion of the patients benefitting of the treatment and its safety profile justify larger, controlled studies to further investigate the added role of combining cabozantinib with metronomic temozolomide. ClinicalTrials.gov identifier: NCT04893785. Treatment options for patients with advanced neuroendocrine tumors (NETs) are limited. Here this group reports a single-arm, phase 2 trial assessing the safety and efficacy of cabozantinib and metronomic temozolomide in patients with advanced, progressive, well-differentiated NETs of gastroenteropancreatic, pulmonary or unknown origin.

Background Pazopanib, a multi-targeted tyrosine kinase inhibitor, is employed in the treatment of various malignancies, including metastatic non-adipocytic soft tissue sarcoma. Methods This systematic review and meta-analysis adhered to PRISMA guidelines to evaluate the efficacy and toxicity of pazopanib monotherapy in treating sarcomas. A comprehensive search of PubMed/MEDLINE and Scopus/ELSEVIER databases was conducted, covering the period from 2009 to 2025. The included studies were evaluated for quality using the MINORS, Newcastle-Ottawa Scale, and RoB2 tools. The spectrum of toxicities and responses in sarcoma types was described. A meta-analysis was performed to compare the efficacy of pazopanib with non-placebo treatments, using both fixed-effect and random-effect models to calculate pooled hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS). Results A total of 40 studies were included, encompassing a wide range of study designs and quality. The analysis revealed variable objective response rates (ORR) across different sarcoma types, with the highest ORRs by RECIST observed in desmoid tumors (37.0%) and alveolar soft part sarcoma (35.5%). Common toxicities included hypertension, liver function test abnormalities, and fatigue, with significant variability in dose reductions and treatment interruptions across studies. The pooled HRs for PFS and OS were 1.10 (95% CI: 0.69–1.25) and 0.99 (95% CI: 0.63–1.35), respectively, indicating no significant advantage of non-placebo treatments respect to pazopanib. Conclusions Pazopanib demonstrated histology-specific efficacy in sarcomas, with a manageable toxicity profile. Furthermore, it does not appear inferior to non-placebo interventions, highlighting the need for further comparative studies to clarify its role in the therapeutic landscape of advanced sarcomas.

Pheochromocytomas (PCCs) and Paragangliomas (PGLs), commonly known as PPGLs to include both entities, are rare neuroendocrine tumors that may arise in the context of hereditary syndromes or be sporadic. However, even among sporadic PPGLs, identifiable somatic alterations in at least one of the known susceptibility genes can be detected. Therefore, about 3/4 of all PPGL patients can be assigned to one of the three molecular clusters that have been identified in the last years with difference in the underlying pathogenetic mechanisms, biochemical phenotype, metastatic potential, and prognosis. While surgery represents the mainstay of treatment for localized PPGLs, several therapeutic options are available in advanced and/or metastatic setting. However, only few of them hinge upon prospective data and a cluster-oriented approach has not yet been established. In order to render management even more personalized and improve the prognosis of this molecularly complex disease, it is undoubtable that genetic testing for germline mutations as well as genome profiling for somatic mutations, where available, must be improved and become standard practice. This review summarizes the current evidence regarding diagnosis and treatment of PPGLs, supporting the need of a more cluster-specific approach in clinical practice.

Langerhans cell histiocytosis (LCH) is a rare disease that has a variable clinical presentation and unpredictable behavior. Until recently, therapeutic options were limited. Insights into the role of mitogen-activated protein kinase (MAPK) signaling have allowed the increased use of targeted treatments. Before the advent of drugs that interfere with this pathway, investigations concerning the tyrosine kinase inhibitor imatinib opened the way to a rationale-based therapeutic approach to the disease. Imatinib block the binding site of ATP in the BCR/ABL protein and is also a platelet-derived growth factor receptor (PDGFR) and a KIT (CD117) kinase inhibitor. A case of refractory LCH with brain involvement was reported to be successfully treated with imatinib. Thereafter, we further explored the role of this tyrosine kinase inhibitor. The present study is composed of an immunohistochemical evaluation of PDGFRβ expression and a clinical evaluation of imatinib in a series of LCH patients. In the first part, a series of 10 samples obtained from LCH patients was examined and a strong immunohistochemistry expression of PDGFRβ was found in 40% of the cases. In the clinical part of the study, five patients were enrolled. Long-lasting disease control was obtained. These results may suggest a potential role for this drug in the current age.

Opinion Statement Sarcomas are rare neoplasms, whose complex management is a consequence of their heterogeneity. Due to their variegate histology and characteristics, prospective trials are challenging to design. Thus, diagnostic and therapeutic guidelines are often based on limited evidence available, and only few and dated systemic treatment regimens are included in our current practice. For all these reasons, we believe that implementing therapeutic options, including local approach, is mandatory to guarantee the best management possible to patients. We explored evidence about locoregional treatments, assuming they could represent a fundamental part of an integrated oncological approach. The goal is to maximize local control of oligometastatic or oligoprogressive diseases, saving systemic treatment options for later stages, as well as to avoid demolitive surgery in patients affected by locally advanced sarcomas. Although several retrospective and prospective series have been conducted, evidence available is still poor in our opinion. Research should focus on evaluating predictive factors and individualized follow up strategies to identify ideal patients’ features and more sensitive histological subtypes.

Background: thymic basaloid carcinoma (BTC) is an extremely rare tumor, and very little data are available on BTC’s biology, clinical behavior, drug sensitivity, and patient outcomes. Methods: We performed a retrospective observational study on patients diagnosed with BTC in 11 referral centers of TYME. All BTC diagnoses were reviewed by the referring pathologist. Results: Twenty-eight patients were identified. A total of 22/28 patients were included. Eighteen patients had TNM stage I–III disease, and all underwent surgery; three patients received preoperative chemotherapy, and 10 patients received adjuvant radiotherapy. With a median follow-up of 46 (1–133) months, median overall survival (mOS) and median relapse-free survival were not reached. At 48 months, OS was 77% (95%CI 43–92), and DFS was 63% (95%CI 30–83). The median OS of the 4 patients diagnosed with metastatic disease was 7 months. Six patients received first-line systemic treatment for metastatic disease, and all showed tumor responses. Anti-tumor activity was also observed with an anti-VEGFR TKI and a multi-TKI inhibitor combined with an anti-PD1 antibody. Next-generation sequencing performed in three tumor samples did not identify actionable alterations or microsatellite instability. Conclusions: BTC is an extremely rare tumor that usually presents as a localized disease. Patients diagnosed with stage I–III disease can achieve long-term DFS, and efforts should be made to perform radical surgical resection combined with perioperative treatment whenever appropriate. Patients with advanced disease progression have a poor prognosis despite a high response rate to systemic treatments.

Some commonly available patient or disease characteristics may be associated with progression-free survival (PFS) and overall survival (OS) in EGFR-mutant non-small cell lung cancer (NSCLC) patients receiving EGFR-TKIs (epidermal growth factor receptor - tyrosine kinase inhibitors). We performed a systematic review and meta-analysis of randomized control trials (RCTs) to explore differences in outcomes associated with EGFR-TKIs among subgroups of EGFR-mutant NSCLC patients. Pooled HRs for progression or death (PFS-HRs) and pooled HRs for death (OS-HRs) were compared among sub-groups defined according to baseline clinical and demographic variables as well as type of EGFR mutation. In the entire assessable population of 4465 EGFR-mutant NSCLC patients, significant interactions with PFS were found for gender (males vs. females; pooled ratio of the PFS-HRs = 1.2; 95% CI 1.12–1.56), smoking history (smokers vs. non-smokers; pooled ratio of the PFS-HRs = 1.26; 95% CI 1.05–1.51), and type of EGFR mutation (patients with exon 21 L858R mutation vs. exon 19 deletion; pooled ratio of the PFS-HRs = 1.39; 95% CI 1.18–1.63). Male patients, smokers and patients with EGFR exon 21 L858R mutation may derive less benefit from EGFR-TKIs compared to female patients, non-smokers and patients with EGFR exon 19 deletion.

We propose a new methodology for long-term biopotential recording based on an MEMS multisensor integrated platform featuring a commercial electrostatic charge-transfer sensor. This family of sensors was originally intended for presence tracking in the automotive industry, so the existing setup was engineered for the acquisition of electrocardiograms, electroencephalograms, electrooculograms, and electromyography, designing a dedicated front-end and writing proper firmware for the specific application. Systematic tests on controls and nocturnal acquisitions from patients in a domestic environment will be discussed in detail. The excellent results indicate that this technology can provide a low-power, unexplored solution to biopotential acquisition. The technological breakthrough is in that it enables adding this type of functionality to existing MEMS boards at near-zero additional power consumption. For these reasons, it opens up additional possibilities for wearable sensors and strengthens the role of MEMS technology in medical wearables for the long-term synchronous acquisition of a wide range of signals.