Therapeutic drug monitoring (TDM) is used to optimize drug therapy by ensuring efficacy or preventing toxicity. For a limited number of cytotoxic antineoplastic drugs, for aminoglycoside antibiotics, and for vancomycin the use of TDM is common practice. In this article, we summarize recent advances and indications for the TDM of antineoplastic agents in children, focusing on protein kinase inhibitors and the cytotoxic drug fludarabine. We also summarize recent recommendations for antimicrobial TDM of beta-lactam antibiotics and vancomycin.

Cancer is one of the leading causes of death worldwide. Recent advances in precision oncology have enabled many specific cancer patient populations to respond well and achieve longer survival with small-molecule kinase inhibitors, which have become a new therapeutic strategy for tumors. Since 2001, the Food and Drug Administration has approved 108 and 63 new anticancer drugs for treating solid tumors and hematological malignancies, respectively, 89 of which belong to the large group of small-molecule kinase inhibitors (SMKIs). Compared to conventional chemotherapeutic agents such as cyclophosphamide, doxorubicin, and 5-FU, SMKIs offer better efficacy with fewer toxic side effects. Nevertheless, with the development of more novel SMKIs and their wider clinical application to a larger population of cancer patients, variable degrees of cardiotoxic adverse events have emerged for some SMKIs during cancer therapy. This review comprehensively summarizes the most updated progress in the cardiotoxicity of SMKIs in cancer therapy and discusses the new findings and mechanisms, which will provide emerging strategies for the prevention of cardiotoxicity caused by small molecule targeted drugs and the design of the next generation of low cardiotoxicity targeted drugs.

Patients with hard-to-treat or rare cancers and those not responding to standard-of-care (SoC) treatment have unmet needs. Limited access to novel drugs is an increasing additional challenge. In 2003, the Danish government adopted a Health Act to ensure that treatment of patients with life-threatening disease could be reevaluated by independent experts. The Danish Health Authority (DHA) set up an Expert Advisory Panel to provide advice on possibilities for further treatment of patients, including treatment not approved nationally. A few years later, clinical units were established that could offer unestablished treatment to patients by referral from the Panel. The treatment was first reimbursed by the Government and later by regional authorities.

We present the structure, workflow, and impact of the Health Act for 21 years for patients with cancer. Annual reports from the DHA were the primary data source.

11 034 cases from 9603 cancer patients were evaluated by the Panel from 2003 to 2023, representing a median of 372 unique cases yearly. In 53%, the Panel advised on further treatment in Denmark, and of these, 56% were recommended nationally nonapproved treatment, 21% SoC treatment or workup, and 19% clinical trial participation. In 4.5% of cases, advice was given on treatment abroad. A significant decline in admissions to the Panel from a peak of 1167 patients in 2008 to 3-400 yearly from 2012 to 2017 followed the conversion of nonapproved treatments to SoC practice. A shift in drug reimbursement, independent of Panel advise, reduced the clinical impact and explained the further decline observed in admissions lately to only 51 patients in 2023.

This unique national scheme provided early access to treatment for patients with no further SoC options and facilitated the introduction of new cancer treatments, initiation of clinical trials, and establishment of trial units in the country. The scheme may be adapted to other countries with a public healthcare system. Results of the current report indicate that impact is dependent on delivering clinical units and reimbursement associated with the recommended treatment.

The fragility index (FI) has been applied as a supplement to the noncomprehensive P-values to assess the robustness of randomized controlled trials (RCTs). The objective of this study is to evaluate the statistical robustness of RCTs of advanced/metastatic renal cell cancer (a/mRCC) using the FI.

RCTs related to a/mRCC published in the 4 highest-impact general medical journals and the 25 highest-impact urological journals between January 1, 2000, and December 31, 2023, were identified from PubMed database. The FI was calculated by using Fisher's exact test. Spearman's correlation analysis was conducted to assess potential correlates regarding FI.

16 eligible RCTs were screened with a median total sample size of 654.5 (IQR, 461-847) and a median patients lost to follow-up of 14 (IQR, 3-23). The median FI was 12.5 (IQR, 8.5-27), suggesting that a switch in outcomes in only 13 patients would have reversed the significance of the trials. The number of patients lost to follow-up exceeded or equaled to the FI in 7 (44%) RCTs. P-values were negatively associated with the FI, while the number of patients lost to follow-up and patients enrolled were not statistically significant.

Not all RCTs associated with a/mRCC are as statistically robust as previously considered and should therefore be construed carefully. We suggest that additional reporting of FI in urological RCTs as a supplement to the P-value to assist readers in concluding reliably by considering the fragility of the outcomes.

The tumor microenvironment (TME) plays a pivotal role in cancer progression and metastasis, with vascular endothelial growth factor (VEGF) signaling serving as a key regulator of tumor angiogenesis and immune evasion. VEGF induces abnormal blood vessel formation, promoting tumor growth, immune suppression, and metastasis through epithelialmesenchymal transition (EMT). As a result, VEGF signaling has become a critical therapeutic target in cancer treatment. This review examines the molecular mechanisms driving VEGF-mediated tumor growth and angiogenesis, with a focus on the interaction between tumor and endothelial cells and the dual role of VEGF in fostering vascularization and immune suppression. Current anti-VEGF therapies, including monoclonal antibodies (e.g., bevacizumab) and tyrosine kinase inhibitors (TKIs), have demonstrated efficacy and have received FDA approval for various cancers; however, therapeutic resistance remains a significant challenge. Strategies to overcome resistance, such as novel VEGF inhibitors, vascular normalization approaches, and combination therapies with immune checkpoint inhibitors, have been explored. Additionally, future directions emphasize the need for personalized approaches to improve treatment efficacy and reduce metastasis. A comprehensive understanding of VEGF signaling in the TME may pave the way for more effective cancer therapies.

Although hypertension is a common side effect of tyrosine kinase inhibitor (TKI) treatment for renal cell carcinoma (RCC), there is limited evidence regarding its occurrence and related risk factors. Preliminary studies suggest that proton pump inhibitors (PPIs) may mitigate the risk of TKI-induced hypertension; however, their clinical effectiveness remains unclear.

In this study, we examined the prevalence of TKI-induced hypertension and the patterns of antihypertensive prescriptions among patients with RCC in Japan. Additionally, we investigated factors associated with TKI-induced hypertension to assess the potential impact of PPIs.

Data from patients diagnosed with RCC who were prescribed TKIs between April 2008 and July 2021 were retrospectively gathered from a Japanese administrative database. TKI-induced hypertension was detected following the diagnosis of hypertension and subsequently the prescription of an antihypertensive agent during TKI therapy. The prescription details for antihypertensive agents were organized in a tabular format. Cox proportional hazards regression analysis was conducted to examine factors contributing to TKI-induced hypertension. Among the 225 patients analyzed, 36.4% experienced hypertension, and calcium channel blockers were the most prescribed antihypertensive agents. Pre-existing hypertension was identified as a risk factor for TKI-induced hypertension, while the concurrent use of PPIs did not show a tendency to reduce the risk of TKI-induced hypertension.

These findings indicate the importance of blood pressure management in patients with elevated baseline blood pressure.

Despite that incorporating antiangiogenic in combination with immune-checkpoint inhibitors as the standard first-line treatment for advanced clear cell renal cell cancer (ccRCC) yields promising outcomes, these regimens often lead to significant toxicity. However, a subgroup of patients has shown responsiveness to VEGFR tyrosine-kinase inhibitors (TKIs) in monotherapy, leading to the question of whether employing combination therapies can significantly enhance overall survival in all patients over monotherapy. Thus, we aim to identify gene expression signatures that can predict TKI response within subpopulations that might benefit from single-agent therapies, to minimize unnecessary exposure to combination therapies and their associated toxicities, as well as to discover new potential therapeutic targets to improve ccRCC treatment. Based on prior data, the androgen receptor (AR) might meet both conditions.

We evaluated the association between AR expression, assessed through NanoString® technology-derived mRNA counts, and the clinical outcomes of 98 ccRCC patients treated with first-line antiangiogenics and determined its association with other genes implicated in ccRCC tumorigenesis.

Higher AR-expression correlates significantly with better prognosis and survival based on the MSKCC risk score, and longer PFS. Furthermore, we have identified a gene set signature associated with AR-overexpression and several genes involved in angiogenesis and transcriptional targets of the hypoxia-inducible factor, a cornerstone of ccRCC.

AR-overexpression and its association with other genes could favor a transcriptomic signature set to aid in identifying patients suitable for TKI in monotherapy, rather than aggressive combinations, enhancing thus, precision and personalized therapeutic decisions.

Post-marketing surveillance focusing on hepatic function disorder was requested owing to its higher incidence in the pembrolizumab plus axitinib group than in the sunitinib group in KEYNOTE-426. We aimed to evaluate the prevalence and risk factors of adverse events (AEs) of hepatic function disorder in patients with unresectable/metastatic renal cell carcinoma (RCC) treated with pembrolizumab plus axitinib in real-world clinical practice in Japan.

Patients were observed for 9 months after starting treatment with pembrolizumab plus axitinib.

In total, 193 patients were included in the safety analysis set (median age, 70 years). Most patients did not have a history of hepatic function disorder before starting treatment (96.4%, 186/193). The median treatment period was 27.1 weeks. At the 9-month data cut-off, 62.2% (120/193) of patients discontinued treatment, the most common reason being any AE in 31.1% (60/193). The incidence of AEs of hepatic function disorder was 30.1% (58/193) for any grade and 15.0% (29/193) for grade ≥ 3. Most AEs of hepatic function disorder occurred within 3 months from starting treatment. AEs of hepatic function disorder were the reason for discontinuation of pembrolizumab in 9.3% (18/193) of patients; axitinib, 7.3% (14/193); and both pembrolizumab and axitinib, 5.2% (10/193). No background factors were identified as being associated with the occurrence of AEs of hepatic function disorder.

There were no new safety signals for AEs of hepatic function disorder, and the incidence was consistent with that reported in KEYNOTE-426, in Japanese patients with radically unresectable/metastatic RCC treated with pembrolizumab plus axitinib.

Angiogenesis, a crucial process in tumor growth and metastasis, necessitates targeted therapeutic intervention. This review reviews the latest knowledge of anti-angiogenesis targets in tumors, with emphasis on the molecular mechanisms and signaling pathways that regulate this process. We emphasize the tumor microenvironment's role in angiogenesis, examine endothelial cell metabolic changes, and evaluated potential therapeutic strategies targeting the tumor vascular system. At the same time, we analyzed the signaling pathway and molecular mechanism of tumor angiogenesis in detail. In addition, this paper also looks at the development trend of tumor anti-angiogenesis drugs, including their future development direction and challenges, aiming to provide prospective insight into the development of this field. Despite their potential, anti-angiogenic therapies encounter challenges like drug resistance and side effects, necessitating ongoing research to enhance cancer treatment strategies and the efficacy of these therapies.

Bicyclol, a drug stemmed from the traditional Chinese medicine Schisandra chinensis, has been widely utilized in clinical practice due to its efficacy and safety to manage hepatopathy. Its diverse biological properties-including antiviral, anti-inflammatory, antifibrotic, immunomodulatory, antioxidative, antisteatotic, and antitumor effects-underscore its significant medicinal effects in versatile hepatic disorders, incorporating viral hepatitis, non-alcoholic fatty liver disease, hepatocellular carcinoma, acute hepatic failure, hepatic fibrosis as well as drug-induced liver injury. Furthermore, ongoing researches into the molecular mechanisms, biological activities and mode of actions concerning bicyclol have uncovered its potential therapeutic implications in other multiple diseases/conditions. Studies have indicated promising efficacy pertaining to bicyclol to treat idiopathic pulmonary fibrosis, acute lung injury, cerebral ischemia/reperfusion injury, renal dysfunction, renal cell carcinoma, and cardiovascular diseases. Accordingly, this narrative review article summarizes the current understanding of diverse biological activities and underpinning mechanisms of bicyclol across a range of diseases, as well as its pharmacokinetics, toxicity profile and shed light on future perspectives.

The management of metastatic renal cell carcinoma (mRCC) has advanced with recent therapies, yet optimizing treatment remains challenging due to disease heterogeneity and the growing number of options. Integrating systemic and local treatments requires a multidisciplinary approach to improve outcomes.

This review summarizes recent developments in treatment for mRCC. Upfront immuno-oncology (IO)-based combinations have improved survival, though concerns about overtreatment and toxicity persist. While the role of cytoreductive nephrectomy (CN) has declined to some extent, it may still benefit well-selected patients. Metastasis-directed therapies, including metastasectomy and stereotactic radiotherapy, provide prognostic value, particularly for oligometastatic lesions or brain metastases. Comprehensive genomic profiling (CGP) holds promise for personalized treatment but is currently limited by the lack of actionable mutations and predictive biomarkers.

A personalized, multimodal approach is essential for optimizing mRCC management. Careful patient selection is key to balancing the benefits of treatment with the risks of toxicity. While CN and metastasis-directed therapies remain useful in select cases, advancing individualized care requires the development of validated biomarkers and broader application of CGP.

Unlike one-snap data collection methods that only identify high-risk patients, machine learning models using time-series data can predict adverse events and aid in the timely management of cancer.

This study aimed to develop and validate machine learning models for sunitinib- and sorafenib-associated thyroid dysfunction using a time-series data collection approach.

Time series data of patients first prescribed sunitinib or sorafenib were collected from a deidentified clinical research database. Logistic regression, random forest, adaptive Boosting, Light Gradient-Boosting Machine, and Gradient Boosting Decision Tree were used to develop the models. Prediction performances were compared using the accuracy, precision, recall, F1-score, area under the receiver operating characteristic curve, and area under the precision-recall curve. The optimal threshold for the best-performing model was selected based on the maximum F1-score. SHapley Additive exPlanations analysis was conducted to assess feature importance and contributions at both the cohort and patient levels.

The training cohort included 609 patients, while the temporal validation cohort had 198 patients. The Gradient Boosting Decision Tree model without resampling outperformed other models, with area under the precision-recall curve of 0.600, area under the receiver operating characteristic curve of 0.876, and F1-score of 0.583 after adjusting the threshold. The SHapley Additive exPlanations analysis identified higher cholesterol levels, longer summed days of medication use, and clear cell adenocarcinoma histology as the most important features. The final model was further integrated into a web-based application.

This model can serve as an explainable adverse drug reaction surveillance system for predicting sunitinib- and sorafenib-associated thyroid dysfunction.

Kidney cancer is a commonly diagnosed cancer in adults, and clear cell renal cell carcinoma (ccRCC) is the most common histological subtype. Immune checkpoint inhibitors have revolutionized care for patients with ccRCC, either as adjuvant therapy or combined with other agents in advanced disease. However, biomarkers to predict therapeutic benefits are lacking. Here, we explore biomarkers that predict therapeutic response in other tumor types and discuss the reasons for their ineffectiveness in ccRCC. We also review emerging predictive and prognostic biomarkers to prioritize in ccRCC, including gene expression signatures.

Vascular endothelial growth factor receptor (VEGFR-2) inhibitors are critical in cancer therapy due to their role in suppressing tumor angiogenesis. Herein, we report a new series of thiadiazole-based derivatives as potential VEGFR-2 inhibitors with promising anticancer activity.

The synthesized compounds were evaluated for anti-proliferative activity against human cancer cell lines (HCT-116, MCF-7, and HepG-2), and WI-38 as normal cells. Sorafenib was used as a reference drug. VEGFR-2 inhibitory activity was determined, followed by cell cycle analysis, apoptosis assays, Q-RT-PCR analysis, and wound-healing assays. In silico molecular docking was conducted to explore binding interactions.

Among the tested compounds, 13b exhibited potent anti-proliferative activity (IC50: 3.98-11.81 µM) and strong VEGFR-2 inhibition (IC50: 41.51 nM), surpassing sorafenib (IC50: 53.32 nM). Cell cycle analysis revealed that 13b induced G2/M phase arrest in MCF-7 cells. Apoptosis levels increased from 2% to 52%, accompanied by a > 12-fold rise in the Bax/Bcl-2 ratio and activation of caspase-8/9. Additionally, 13b significantly suppressed MCF-7 cell migration, with only 5.28% wound closure. In silico studies confirmed its strong VEGFR-2 binding interactions.

Thiadiazole-based derivatives, particularly compound 13b, exhibit potent VEGFR-2 inhibition, anti-proliferative effects, apoptosis induction, and anti-migratory activity, supporting their potential as promising anticancer agents.

Advancements in immunotherapy and angiogenesis-targeted therapies have transformed the upfront treatment of renal cell carcinoma (RCC). However, long-term prognoses for patients with unresectable and metastatic disease often remain limited, with the majority experiencing progression after exposure to front-line therapy. In most cases of relapsed or refractory (R/R) disease after prior exposure to an immune checkpoint inhibitor (ICI), there is no role for ICI-rechallenge. Therefore, treatment of R/R RCC relies on the appropriate selection of therapies targeting growth pathways dependent on vascular endothelial growth factor (VEGF) or hypoxia-inducible factor (HIF).

This review article summarizes the current landscape of targeted therapies for use in second-line or later-line settings for the treatment of clear cell and non-clear cell RCC. Novel therapeutic strategies currently in development are also discussed.

The treatment of R/R RCC primarily consists of inhibition of VEGF, HIF, and mTOR pathways, and the selection of a specific agent depends on the histologic subtype of the tumor, the prior lines of therapy chosen, and patient co-morbidities. Future tumor-based and circulating biomarker research might one day enable the identification of transcriptional signatures that could predict a response to immune, angiogenesis, or HIF-based therapies.

Hand-foot skin reaction (HFSR) is a common adverse effect of vascular endothelial growth factor receptor (VEGFR) inhibitors that significantly impacts patients' quality of life. Prevention and management of HFSR require individualized approaches, but risk factors remain unclear. This study aimed to develop artificial intelligence (AI) models to predict grade ≥ 2 HFSR using clinical data and foot sole images from 93 instances of VEGFR inhibitor administration in 76 patients. Image-based, clinical information-based, and ensemble AI models achieved areas under the curve of 0.550, 0.693, and 0.699, respectively. At a high-specificity cutoff, the ensemble AI had a positive predictive value of 0.824, suggesting potential clinical utility for identifying high-risk patients. Feature importance analysis revealed heavier weight, good performance status, lack of prior VEGFR inhibitor exposure, and baseline skin toxicity as risk factors. These findings represent the first AI-based HFSR prediction models and provide insights for preventive interventions, but further accuracy improvements are needed.

Dramatic advances in biological discoveries, since the 1990s, have continued to reshape the treatment paradigm of metastatic renal cell carcinoma (RCC). Von Hippel Lindau (VHL) gene alterations are associated with pro-angiogenic activity and are central to the pathogenesis of clear cell RCC (ccRCC), the most predominant histologic subtype of RCC. Antiangiogenic strategies revolving around this VHL/HIF/VEGF axis have been shown to improve survival in metastatic ccRCC. The discovery of immune checkpoints and agents that target their inhibition introduced a new treatment paradigm for patients with RCC. While initially approved as monotherapy, studies investigating immune checkpoint inhibitor combinations have led to their approval as the new standard of care, providing durable responses and unprecedented improvements in clinical outcome. Despite these advances, the projected 14 390 deaths in 2024 from RCC underscore the need to continue efforts in expanding and optimizing treatment options for patients with metastatic RCC. This article reviews key findings that have transformed the way we understand and treat metastatic RCC, in addition to highlighting novel treatment strategies that are currently under development.

Betulinic acid isolated from Platanus orientalis bark was modified in one-pot reaction to furnish 12 ureidic derivatives. The synthesized derivatives were tested against an array of cancer cell lines, colon HCT-116, breast MCF-7, pancreatic MIA PaCa-2, and prostate PC-3 cancer cell lines. Among the synthesized compounds, BA1 exhibited potent anti-cancer activity with IC50 of 0.84 and 3.87 µM against HCT-116 and PC-3 using doxorubicin as standard. Our study demonstrates the anti-proliferative and anti-metastatic role of BA1, thus inducing apoptosis in prostrate and colorectal cell lines.

Renal cell carcinoma (RCC) is a common kidney disease associated with high mortality. Sorafenib is a protein kinase inhibitor that targets multiple kinases and is used for treating different cancers, including RCC. However, sorafenib resistance in patients with RCC hampers its use. Therefore, elucidating the molecular mechanisms underlying sorafenib resistance in RCC and developing novel therapeutic strategies to overcome drug resistance are vital. In this study, we found that the expression level of the long noncoding RNA (lncRNA) E2F1 messenger RNA stabilizing factor (EMS) was significantly higher in sorafenib-resistant RCC tissues and cell lines than in sorafenib-sensitive RCC tissues and cell lines. lncRNA EMS knockdown improved the sensitivity of sorafenib-resistant RCC cells to sorafenib treatment, as evidenced by decreased cell proliferation and increased apoptosis. Additionally, lncRNA EMS silencing combined with sorafenib treatment markedly inhibited RCC tumor development in vivo. Moreover, it was systematically shown that lncRNA EMS sponged miR-363-3p, whose expression was decreased in sorafenib-resistant RCC. Notably, miR-363-3p negatively regulated the expression of dual-specificity phosphatase 10 (DUSP10) by targeting its 3'-UTR. Furthermore, miR-363-3p overexpression restored sorafenib sensitivity, whereas upregulated DUSP10 expression promoted sorafenib resistance in sorafenib-resistant cell lines. In conclusion, the lncRNA EMS/miR-363-3p/DUSP10 axis regulates sorafenib resistance in RCC, and these molecules are promising biomarkers and therapeutic targets for patients with sorafenib-resistant RCC.

Management of advanced non-clear cell renal cell carcinoma (nccRCC) is challenging due to disease rarity and heterogeneity. The combination of multi-targeted tyrosine kinase inhibitor (TKI) with immune checkpoint inhibitor (ICI) has emerged as an effective treatment strategy, but well-designed, phase III randomized clinical trials are needed to demonstrate superiority over current treatment options. Zanzalintinib is a novel, multi-targeted TKI that has demonstrated promising preclinical anti-tumor activity in combination with ICIs. STELLAR-304 is a phase III trial evaluating first-line zanzalintinib plus nivolumab versus sunitinib in advanced nccRCC. Primary endpoints are progression-free survival and objective response rate. Secondary endpoint is overall survival. To our knowledge, STELLAR-304 is the first phase III study assessing a TKI-ICI combination in nccRCC patients across multiple subtypes.Clinical Trial Registration: This trial is registered at ClinicalTrials.gov (identifier: NCT05678673).

Cervical cancer remains one of the leading causes of cancer-related deaths among women globally, and there is still a need to research molecular targets that can be used for prognosis assessment and personalized molecular therapies. Here, we investigate the role of potential molecular target ribosomal L22-like 1 (RPL22L1) on cervical cancer, identify its potential mechanisms, and explore its related applications in prognosis and molecular therapies.

Multiple cervical cancer cohorts online, tissue microarrays and clinical tissue specimens were analyzed for the association between RPL22L1 expression and patient outcomes. Functional and molecular biology studies of cell and mice models were used to clarify the effects and potential mechanisms of RPL22L1 on cervical cancer.

RPL22L1 is highly expressed in both cervical adenocarcinoma and squamous cell carcinoma, and its expression is significantly associated with histology grade, clinical stage, recurrence, vascular space involvement, tumor sizes and poor prognosis. In vitro and in vivo experiment revealed that RPL22L1 overexpression significantly promoted cervical cancer cell proliferation, migration, invasion, tumorigenicity and Sorafenib resistance, which were attenuated by RPL22L1 knockdown. Mechanistically, RPL22L1 competitively binds to ERK phosphatase DUSP6, leading to excessive activation of ERK. The combined application of ERK inhibitors can effectively inhibit RPL22L1 overexpressing cervical cancer cells both in vivo and in vitro.

RPL22L1 promotes malignant biological behavior of cervical cancer cells by competitively binding with DUSP6, thereby activating the ERK pathway. The combined use of Sorafenib and an ERK inhibitor is a potentially effective molecular targeted therapy for RPL22L1-high cervical cancer.

Neovascularization is an important process in brain tumor development, invasion and metastasis. Several research studies have indicated that the VEGF signaling target has potential for reducing angiogenesis in brain tumors. However, targeting VEGF signaling has not met the expected efficacy, despite initial enthusiasm. This is partly because tumors cleverly use alternative growth factor pathways, other than VEGF signaling, to restore angiogenesis. Multi-target inhibitors have been developed to inhibit several receptor kinases that play a role in the development of angiogenesis. By simultaneously affecting various receptor kinases, these treatments can potentially obstruct various angiogenic pathways that are involved in brain cancer advancement, often offering a more holistic strategy than treatments focusing on just one kinase. Since 2009, the FDA has approved a number of multi-kinase inhibitors that target angiogenic growth factor receptors (e.g., VEGFR, PDGFR, FGFR, RET, c-KIT, MET, AXL and others) for treatment of malignant diseases, including brain cancer. Here, we present some recent results from the literature regarding the preclinical and clinical effects of these inhibitors on brain tumors.

The combination of sorafenib with transarterial chemoembolization (TACE) is being investigated for its potential to improve outcomes in advanced hepatocellular carcinoma (HCC).

To evaluate the efficacy of this combined treatment strategy in enhancing overall survival (OS) and progression-free survival (PFS) compared to monotherapies.

A systematic review was conducted following the PRISMA guidelines. A comprehensive search was performed across PubMed, EMBASE, Web of Science, and the Cochrane Library up to May 8, 2024. Studies were included if they compared sorafenib plus TACE to sorafenib alone or TACE alone in adults with advanced HCC. Primary outcomes were OS, PFS, response rates, and safety profiles. Data extraction and quality assessment were independently performed by two reviewers. Heterogeneity was assessed using the I² statistic, and a random-effects model was applied for pooling data. Sensitivity analysis and publication bias assessment were also conducted.

A total of twelve studies involving 1174 patients met the inclusion criteria. Significant heterogeneity was observed for both OS (I² = 72.6%, P < 0.001) and PFS (I² = 83.7%, P < 0.001). The combined treatment of sorafenib with TACE significantly improved OS [hazard ratio (HR) = 0.60, 95% confidence interval (CI): 0.44-0.76] and PFS (HR = 0.54, 95%CI: 0.38-0.69). Sensitivity analysis confirmed the robustness of these findings. Funnel plots and Egger's test indicated no significant publication bias.

Sorafenib combined with TACE significantly enhances both OS and PFS in patients with advanced HCC compared to monotherapy. This combination therapy represents a promising approach to improving clinical outcomes in advanced liver cancer.

China has historically relied on importing new drugs to fulfill domestic clinical needs. However, stringent requirements for local clinical trials for these imported drugs has often delayed their market approval, restricting timely access for patients. To address this issue, China has implemented regulatory flexibility in certain contexts, allowing for expedited approval processes when appropriate. This study aimed to evaluate the characteristics of novel cancer drugs qualifying for flexible approval in China from 2012 to 2021, focusing on pivotal trials features, clinical benefits, safety profiles, and unmet medical needs.

This cohort study identified all newly imported cancer drugs and their indications approved by the China's National Medical Products Administration (NMPA) from 2012 to 2021. Indications meeting standard requirements were categorized as regular approvals, while those supported by limited clinical data from Chinese patients were classified as flexible approvals. Development strategies, pivotal trials characteristics, and clinical outcomes were extracted from publicly available review documents and drug labels. Unmet medical needs were assessed based on two dimensions: the availability of standard-of-care treatments and the novelty of medicines. We compared the pivotal trial characteristics, efficacy end points, safety (serious adverse events) and the extent of unmet clinical needs, between flexible and regular approvals using Chi-square tests. A random-effects meta-regression was conducted to examine the association between flexible status and hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS).

Among 59 novel cancer drugs approved for importation to China between 2012 and 2021, 56 products with 92 indications were included in this analysis, based on the availability of their review documents. Of these, 48 indications (52%) qualified for flexible approvals, while 44 indications (48%) received regular approvals. The median number of Chinese patients involved in the datasets for flexible approvals was significantly lower than for regular approvals (27 [IQR, 0-62] vs. 165 [IQR, 99-245], p < 0.001). Flexible approvals were more frequently supported by early-phase (18/61 vs. 1/60, p < 0.001) and single-arm (22/61 vs. 1/60, p < 0.001) pivotal trials, with response rates frequently used as the primary endpoint (24/61 vs. 1/60, p < 0.001). Meta-regression analysis revealed that flexible approvals were associated with improved OS (HR 0.61 vs. 0.72, p < 0.01), and a weaker association for PFS (HR 0.39 vs. 0.51, p = 0.03). The rate of serious adverse events was slightly higher, but not significantly, in the flexible approval group than the regular approval group (43% vs. 35%, p = 0.06). Flexible approvals were more likely to be indicated for diseases with no available existing drugs (31/48 vs. 10/44, p < 0.001) and for first-in-class drugs (21/48 vs. 9/44, p = 0.03).

China's regulatory flexibility in approving imported cancer drugs has enabled access to therapies with limited domestic clinical data. These decisions are largely associated with the potential for greater clinical benefits and the need to address unmet medical needs. The approach offers valuable insights into regulatory considerations for global regulatory practices. By adopting similar regulatory flexibility, other nations could enhance drug accessibility and promote more adaptive regulatory practices.

This work was funded by National Natural Science Foundation of China (72374119, 82102886) Beijing Natural Science Foundation (7242114) and Beijing Nova Program.

Genitourinary cancers affect over 480,000 patients in the United States annually. While promising therapeutic modalities continue to emerge, notably immune checkpoint inhibitors, molecular targeted therapies, antibody-drug conjugates, and radioligand therapies, these treatments are associated with a spectrum of adverse side-effects, including ophthalmologic toxicities. In this review, we cover the most commonly used antineoplastic agents for the kidneys, bladder, urinary tracts, prostate, testis, and penis, detailing mechanism, indication, and recent trials supporting their use. For each category of antineoplastic therapy, we describe the epidemiology, management, and clinical presentation, of common ophthalmologic toxicities stemming from these agents. This review serves to augment awareness and recognition of possible ophthalmologic manifestations resulting from the use of antineoplastic agents in genitourinary malignancy. Early identification of these side effects can hasten ophthalmology referral and ultimately improve visual outcomes in patients experiencing medication-induced ocular toxicities.

Cancer due to its heterogeneous nature and large prevalence has tremendous socioeconomic impacts on populations across the world. Therefore, it is crucial to discover effective panels of biomarkers for diagnosing cancer at an early stage. Cancer leads to alterations in cell growth and differentiation at the molecular level, some of which are very unique. Therefore, comprehending these alterations can aid in a better understanding of the disease pathology and identification of the biomolecules that can serve as effective biomarkers for cancer diagnosis. Metabolites, among other biomolecules of interest, play a key role in the pathophysiology of cancer whose levels are significantly altered while 'reprogramming the energy metabolism', a cellular condition favored in cancer cells which is one of the hallmarks of cancer. Metabolomics, an emerging omics technology has tremendous potential to contribute towards the goal of investigating cancer metabolites or the metabolic alterations during the development of cancer. Diverse metabolites can be screened in a variety of biofluids, and tumor tissues sampled from cancer patients against healthy controls to capture the altered metabolism. In this review, we provide an overview of different metabolomics approaches employed in cancer research and the potential of metabolites as biomarkers for cancer diagnosis. In addition, we discuss the challenges associated with metabolomics-driven cancer research and gaze upon the prospects of this emerging field.

In Norway, 5-year survival rates of patients with renal cell carcinoma (RCC) are increasing. The objective of this study was to describe the survival of real-world patients with metastatic RCC (mRCC) across Norway and to identify associated factors. The results may provide additional information on the benefits of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) in clinical practice.

We performed a longitudinal, retrospective, non-interventional cohort study using data from four national registries. The study included adults diagnosed with mRCC between 1 January 1995 and 31 December 2018. Primary endpoint was to evaluate overall survival (OS) in all included patients. Secondary endpoints included further analysis of treatment patterns and possible impact on OS. Secondary endpoint analysis was performed in patients diagnosed with mRCC between 1 January 2008 and 31 December 2018, as complete data on systemic therapies were available from 2008 and onwards.

In total, 4078 patients were diagnosed with mRCC in the period from 1995 to 2018. The median OS since initial mRCC diagnosis was 1.17 years. OS appeared to improve over time, 5-year OS was 10% in patients diagnosed in the period 1995-2001 compared to 25% in 2012-2015. The secondary analysis included 2338 patients. Fifty-five percent (55%) of the patients received systemic treatment. No differences were observed in the number of treatment lines administered over time or in the number of lines of treatment administered according to tumor histology. Among 343 patients who received ≥3 treatment lines, we observed longer OS in patients who received an ICI as a part of their treatment, with a median OS of 4.51 compared to 2.31 years.

Provision of information into registries is mandatory in Norway. This retrospective, registry-based study provides real-world evidence on patient outcomes and treatments of the Norwegian patients with mRCC in the period from 1995 to 2018.

A series of novel molecules with pyrazolopyrimidine-4-amine core were designed and synthesized as potential cytotoxic agents over Renal Cell Carcinoma cells (UO-31). Results of cytotoxic activity against UO-31 cells showed that pyrazolopyrimidines 19 and 31 were found to be more cytotoxic than sorafenib (SOR). The cytotoxic activity of these compounds appeared to correlate with their ability to inhibit p38α MAPK which are 2.53- and 2.27- folds more potent than SOR. Moreover, results of the cell cycle analysis as well as the results of annexin-V on the (UO-31) cells showed that pyrazolopyrimidines 19 and 31 had a pro-apoptotic activity higher than SOR by 1.42- and 1.20- folds, respectively. Furthermore, compounds 19 and 31 were found to be effective in arresting the cell cycle throughout the accumulation of the cells at G2/M phase. Finally, the tested compounds decreased the TNF concentration as well as increased the expression of tumor suppressor gene p53, Bax/BCL-2 ratio and caspase 3/7.

RAF kinases, particularly the BRAF isoform, play a crucial role in the MAPK/ERK signaling pathway, regulating key cellular processes such as proliferation, differentiation, and survival. Dysregulation of this pathway often caused by mutations in the BRAF gene or alterations in upstream regulators like Ras and receptor tyrosine kinases contributes significantly to cancer development. Mutations, such as BRAF-V600E, are present in a variety of malignancies, with the highest prevalence in melanoma. Targeted therapies against RAF kinases have achieved substantial success, especially in BRAF-V600E-mutant melanomas, where inhibitors like vemurafenib and dabrafenib have demonstrated remarkable efficacy, leading to improved patient outcomes. These inhibitors have also shown clinical benefits in cancers such as thyroid and colorectal carcinoma, although to a lesser extent. Despite these successes, therapeutic resistance remains a major hurdle. Resistance mechanisms, including RAF dimerization, feedback reactivation of the MAPK pathway, and paradoxical activation of ERK signaling, often lead to diminished efficacy over time, resulting in disease progression or even secondary malignancies. In response, current research is focusing on novel therapeutic strategies, including combination therapies that target multiple components of the pathway simultaneously, such as MEK inhibitors used in tandem with RAF inhibitors. Additionally, next-generation RAF inhibitors are being developed to address resistance and enhance therapeutic specificity. This review discusses the clinical advancements in RAF-targeted therapies, with a focus on ongoing efforts to overcome therapeutic resistance and enhance outcomes for cancer patients. It also underscores the persistent challenges in effectively targeting RAF kinase in oncology.

Despite the seriousness of lung adverse events (AEs) associated with sorafenib, comprehensive data are limited. This study was conducted to examine the disproportionality, times to onset, incidence rates, and outcomes of sorafenib-associated lung AEs, using the Japanese Adverse Drug Event Report database.

Data for the period between April 2004 and May 2023 were analyzed. Data on lung AEs were extracted, and the relative disproportionality of AEs was estimated using reporting odds ratios (RORs).

A total of 2,230,863 reports were analyzed, and 8,374 reports of AEs associated with sorafenib, including 381 lung AEs, were identified. Signals were detected for two lung AEs: metastases to the lung and tracheal hemorrhage. Fatal outcomes were observed for both AEs. Histograms of the median times to onset of the two detected lung AE signals showed that AEs occurred from 49 to 275 days after sorafenib administration. Weibull distributions showed that the incidences of these AEs occurred constantly throughout the exposure period (random failure type).

This study focused on lung AEs associated with sorafenib, highlighting serious outcomes such as lung metastases and tracheal hemorrhage. Continuous monitoring for these AEs is crucial from treatment initiation through the entire therapy course.

Due to its intricate molecular and structural characteristics, vascular endothelial growth factor receptor 2 (VEGFR-2) is essential for the development of new blood vessels in various pathological processes and conditions, especially in cancers. VEGFR-2 inhibitors have demonstrated significant anticancer effects by blocking many signaling pathways linked to tumor growth, metastasis, and angiogenesis. Several small compounds, including the well-tolerated sunitinib and sorafenib, have been approved as VEGFR-2 inhibitors. However, the widespread side effects linked to these VEGFR-2 inhibitors-hypertension, epistaxis, proteinuria, and upper respiratory infection-motivate researchers to search for new VEGFR-2 inhibitors with better pharmacokinetic profiles. The key molecular interactions required for the interaction of the small molecules with the protein target to produce the desired pharmacological effects are identified using computer-aided drug design (CADD) methods such as pharmacophore and QSAR modeling, structure-based virtual screening, molecular docking, molecular dynamics (MD) simulation coupled with MM/PB(GB)SA, and other computational strategies. This review discusses the applications of these methods for VEGFR-2 inhibitor design. Future VEGFR-2 inhibitor designs may be influenced by this review, which focuses on the current trends of using multiple screening layers to design better inhibitors.

Thioredoxin Reductase (TrxR) functions to recycle thioredoxin (Trx) during hydroperoxide metabolism mediated by peroxiredoxins and is currently being targeted using the FDA-approved anti-rheumatic drug, auranofin (AF), to selectively sensitize cancer cells to therapy. AF treatment decreased TrxR activity and clonogenic survival in small cell lung cancer (SCLC) cell lines (DMS273 and DMS53) as well as the H727 atypical lung carcinoid cell line. AF treatment also significantly sensitized DMS273 and H727 cell lines in vitro to sorafenib, an FDA-approved multi-kinase inhibitor that depleted intracellular glutathione (GSH). The pharmacokinetic, pharmacodynamic, and safety profile of AF was examined in nude mice with DMS273 xenografts administered AF intraperitoneally at 2 mg/kg or 4 mg/kg (IP) once (QD) or twice daily (BID) for 1-5 d. Plasma levels of AF were 10-20 μM (determined by mass spectrometry of gold), and the optimal inhibition of TrxR activity was obtained at 4 mg/kg once daily, with no effect on glutathione peroxidase 1 activity. This AF treatment extended for 14 d, inhibited TrxR (>75%), and resulted in a significant prolongation of median overall survival from 19 to 23 d (p = .04, N = 30 controls, 28 AF). In this experiment, there were no observed changes in animal bodyweight, complete blood counts (CBCs), bone marrow toxicity, blood urea nitrogen, or creatinine. These results support the hypothesis that AF effectively inhibits TrxR both in vitro and in vivo in SCLC, sensitizes NETs and SCLC to sorafenib, and could be repurposed as an adjuvant therapy with targeted agents that induce disruptions in thiol metabolism.

The primary objective of this study was to closely monitor and identify adverse events (AEs) associated with Sorafenib, a pharmacological therapeutic agent used to treat hepatocellular carcinoma, renal cell carcinoma, and thyroid cancer. The ultimate goal was to optimize patient safety and provide evidence-based guidance for the appropriate use of this drug.

Reports from the FDA Adverse Event Reporting System (FAERS) database were comprehensively collected and analyzed, covering the first quarter of 2004 to the first quarter of 2024. Disproportionality analysis was performed using robust algorithms for effective data mining to quantify the signals associated with Sorafenib-related AEs.

In total, we identifued 18,624 patients (82,857 AEs in the Sorafenib population) from the collected reports and examined, the occurrence of Sorafenib-induced AEs in 26 organ systems. The study results revealed the presence of the expected AEs, including Diarrhoea, Palmar-plantar erythrodysaesthesia syndrome, Hepatocellular carcinoma, Fatigue, and Rash, which was consistent with the information provided in the drug insert. In addition, unexpected significant AEs, such as Gait inability, Palmoplantar keratoderma and Hyperkeratosis were observed at the preferred term (PT) level. These findings suggest the potential occurrence of adverse reactions not currently documented in drug descriptions.

This study successfully detected new and unforeseen signals associated with Sorafenib-related AEs related to Sorafenib administration, providing important insights into the complex correlations between AEs and Sorafenib use. The results of this study emphasize the critical importance of continuous and vigilant surveillance for the timely identification and effective management of AEs to improve the overall patient safety and wellbeing in the context of Sorafenib therapy.

Renal cell carcinoma (RCC) is one of the most diagnosed urological malignancies with high mortality and increasing incidence. What's more, the sunitinib resistance undoubtedly increased the difficulties in RCC therapy. Circular RNAs (circRNAs) are a newly found type of non-coding RNAs with a special circular structure, and are found to participate in the occurrence development, chemoresistance, and prognosis of cancers. Ferroptosis regulates disease progression mainly via polyunsaturated fatty acid metabolism and glutamine catabolic pathways. The mechanism of circRNAs contributed to sunitinib resistance through ferroptosis has not been elucidated clearly.

In our research, we identified a novel circRNA Hsa_circ_0072732 from circRNA datasets (GSE108735 and GSE100186). RNase R and Actinomycin D assays were used to detect the loop structure and stability of circRNAs. qRT-PCR and western blot were used for the detection of RNA and protein levels. CCK8 assays were used to detect proliferation and cell viability. Lipid peroxidation (MDA), and reactive oxygen species (ROS) were detected by indicted kits. Dual-luciferase reporter and RNA pull-down assays were used to detect the RNA interactions.

Our results showed that Hsa_circ_0072732 was highly expressed in RCC cells. Further investigations showed that the silence of Hsa_circ_0072732 could increase RCC sensitivity to sunitinib. Hsa_circ_0072732 contributed to sunitinib chemoresistance by impairing ferroptosis. Hsa_circ_0072732 exerts its function mainly by acting as sponges for miR-548b-3p and regulating the expression SLC7A11. Our research suggests that ferroptosis is involved in sunitinib resistance, and targeting ferroptosis is a promising way for RCC treatment.

Our research suggests Hsa_circ_0072732 enhanced renal cell carcinoma sunitinib resistance by inhibiting ferroptosis through miR-548b-3p/SLC7A11.

Drug-induced cardiotoxicity (DICT) poses a significant challenge in the prognosis of cancer patients, particularly with the use of antineoplastic agents like anthracyclines and targeted therapies such as trastuzumab. This review delves into the intricate interplay between drugs and proteins within cardiac cells, focusing on the role of proteostasis as a therapeutic target for mitigating cardiotoxicity. We explore the in vivo modeling of proteostasis, highlighting the complex intracellular environment and the emerging techniques for monitoring proteostasis. Additionally, we discuss how cardiotoxic drugs disrupt protein homeostasis through direct chemical denaturation, endoplasmic reticulum stress, unfolded protein response, chaperone dysfunction, impairment of the proteasome system, and dysregulation of autophagy. Finally, we provide insights into the applications of cardioprotective drugs targeting proteostasis to prevent cardiotoxicity and the adoption of structural proteomics to evaluate potential cardiotoxicity. By gaining a deeper understanding of the role of proteostasis underlying DICT, we can pave the way for the development of targeted therapeutic strategies to safeguard cardiac function while maximizing the therapeutic potential of antineoplastic drugs.

Variants in the RAS family (HRAS, NRAS and KRAS) are among the most common mutations found in cancer. About 19% patients with cancer harbor RAS mutations, which are typically associated with poor clinical outcomes. Over the past four decades, KRAS has long been considered an undruggable target due to the absence of suitable small-molecule binding sites within its mutant isoforms. However, recent advancements in drug design have made RAS-targeting therapies viable, particularly with the approval of direct KRASG12C inhibitors, such as sotorasib and adagrasib, for treating non-small cell lung cancer (NSCLC) with KRASG12C mutations. Other KRAS-mutant inhibitors targeting KRASG12D are currently being developed for use in the clinic, particularly for treating highly refractory malignancies like pancreatic cancer. Herein, we provide an overview of RAS signaling, further detailing the roles of the RAS signaling pathway in carcinogenesis. This includes a summary of RAS mutations in human cancers and an emphasis on therapeutic approaches, as well as de novo, acquired, and adaptive resistance in various malignancies.

Molecular targeted tyrosine kinase inhibitors (TKIs) have produced unprecedented treatment response in cancer therapy for patients harboring specific oncogenic mutations. While the TKIs are mostly well tolerated, they were reported to increase serum levels of creatine kinase (CK) and cause muscle metabolism-related toxicity. CK is an essential enzyme involved in cellular energy metabolism and muscle function. Elevated serum CK levels can arise from both physiological and pathological factors, as well as triggered by specific drug classes. The incidence of serum CK elevation induced by a few approved TKIs (brigatinib, binimetinib, cobimetinib-vemurafenib combination [Food and Drug Administration, United States]; aumolertinib, and sunvozertinib [only approved by National Medical Products Administration, China]) were over 35%. CK elevation-related symptoms include myopathy, myositis, inclusion body myositis (IBM), cardiotoxicity, rhabdomyolysis, rash, and acneiform dermatitis. High-level or severe symptomatic CK elevation may necessitate dose reduction and indirectly dampen TKI efficacy. This review presents an updated summary about the prevalence rate and recent research about mechanisms leading to TKI-induced serum CK elevation in cancer patients. The utility of monitoring serum CK levels for predicting TKI-induced adverse effects and their management will also be discussed.

The distinct pathological and molecular features of kidney cancer in adaptation to oxygen homeostasis render this malignancy an attractive model for investigating hypoxia signalling and potentially developing potent targeted therapies. Hypoxia signalling has a pivotal role in kidney cancer, particularly within the most prevalent subtype, known as renal cell carcinoma (RCC). Hypoxia promotes various crucial pathological processes, such as hypoxia-inducible factor (HIF) activation, angiogenesis, proliferation, metabolic reprogramming and drug resistance, all of which contribute to kidney cancer development, growth or metastasis formation. A substantial portion of kidney cancers, in particular clear cell RCC (ccRCC), are characterized by a loss of function of Von Hippel-Lindau tumour suppressor (VHL), leading to the accumulation of HIF proteins, especially HIF2α, a crucial driver of ccRCC. Thus, therapeutic strategies targeting pVHL-HIF signalling have been explored in ccRCC, culminating in the successful development of HIF2α-specific antagonists such as belzutifan (PT2977), an FDA-approved drug to treat VHL-associated diseases including advanced-stage ccRCC. An increased understanding of hypoxia signalling in kidney cancer came from the discovery of novel VHL protein (pVHL) targets, and mechanisms of synthetic lethality with VHL mutations. These breakthroughs can pave the way for the development of innovative and potent combination therapies in kidney cancer.

The present study investigated the prognosis of patients who received palliative radiotherapy (RT) for bone metastases (BMs) from renal cell cancer (RCC), and assessed the prognostic factors specific to BMs from RCC. A total of 109 patients with RCC and BMs who underwent RT for the first time were included in the study. Prognostic factors were evaluated using multivariate analysis and a scoring system based on regression coefficients was devised. The median follow-up time was 9 months, and the 0.5-year overall survival (OS) rate was 73.0%. In the multivariate analysis, the significant prognostic factors were higher performance status (≥2), no control of the primary site, disseminated metastasis, lymph node metastasis and multiple BMs. A score of 1 point was assigned to each risk factor. The median OS times were 19.0 and 5.0 months in patients with a total score of ≤1 (n=49) and >1 (n=60), respectively (P<0.01). In conclusion, a comprehensive prognostic assessment using these factors may be useful for predicting the prognoses of patients with BMs from RCC. In addition, this scoring system may be useful in selecting the optimal RT dose.