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Opinion Statement: Hepatocellular carcinoma (HCC) is a common type of tumor worldwide. The development of systemic treatment of advanced HCC has remained stagnant for a considerable period. During the last years, a series of new treatment regimens based on the combination of immunotherapeutic drugs and targeted drugs have been gradually developed, increased the objective response rate (ORR), overall survival (OS), and progression free survival (PFS) of HCC patients. Among the different combination therapy groups, atezolizumab plus bevacizumab and sintilimab plus IBI-305 seem to have unique advantages, while head-to-head comparisons are still needed. A comprehensive understanding of the developments, the ongoing clinical trials and the mechanisms of combination of immunotherapy and targeted therapy might lead to the development of new combination strategies and solving current challenges such as the molecular biomarkers, the clinical administration order of drugs and the second-line treatments after combination therapy. [ABSTRACT FROM AUTHOR]

The development and use of HER2-targeted drugs has improved the prognosis of HER2-positive cancer patients. However, in addition to improved survival rates, treatment-induced adverse events and nontumor-related deaths have increased. We sought to assess the incidence of cardiovascular adverse events when HER2-targeted drugs are combined with other drugs. We systematically searched the literature on the cardiotoxicity of anti-HER2 drugs in electronic databases, including PubMed, Web of Science, Cochrane Library, OVID and CNKI, from their inception to April 2022. The Cochrane Collaboration's tool for assessing risk of bias and the Jadad scale were used to evaluate the risk of bias and quality of the studies, respectively. For each included trial, we calculated the incidence of cardiovascular adverse effects (CAEs) and 95% confidence intervals (95% CIs) and performed a meta-analysis using a random effects model (REM). The meta-analysis was performed using R 4.2.1. We included 41 randomized clinical trials (RCTs) in the meta-analysis, consisting of 56 groups and 31,934 patients. The meta-analysis revealed the following: (1) The incidence of cardiotoxicity in groups given monoclonal antibody treatment was 14% for single therapy (95% CI: 2–34%) and 10%, 11%, and 12% for adjuvant therapy combined with combined therapy (95% CI: 6–13%), chemotherapy (95% CI: 8–13%) and endocrine therapy (95% CI: 7–18%), respectively. However, in the groups treated with the antibody‒drug conjugates (ADCs), the percentage of patients treated with the combination therapy was 1% (95% CI: 0–2%) and 5% (95% CI: 4–7%), respectively, with a significant difference (P < 0.01). The heterogeneity among the included studies was significant (I2 = 94%, p < 0.01). (2) When monoclonal antibodies were combined with chemotherapy, the incidence of cardiotoxicity under anthracycline-containing therapy (10.3%) was significantly greater than that under nonanthracycline-containing therapy (8.8%). (3) Significant differences were found between subgroups, except for the endocrine group versus some others, although this difference might result from the different inclusion criteria of the original trials. (1) When anti-HER2 drugs are administered in combination with anthracycline-containing chemotherapy, the incidence of cardiotoxicity is greater than with other drugs. (2) Safety benefits can be achieved by replacing traditional monoclonal antibodies with ADCs. The comprehensive use of these drugs necessitates collaboration between oncologists and cardiologists. [ABSTRACT FROM AUTHOR]

Objective: The study purpose was to explore the causal association between pyruvate metabolism and breast cancer (BC), as well as the molecular role of key metabolic genes, by using bioinformatics and Mendelian randomization (MR) analysis. Methods: We retrieved and examined diverse datasets from the GEO database to ascertain differentially acting genes (DAGs) in BC via differential expression analysis. Following this, we performed functional and pathway enrichment analyses to ascertain noteworthy molecular functions and metabolic pathways in BC. Employing MR analysis, we established a causal association between pyruvate metabolism and the susceptibility to BC. Additionally, utilizing the DGIdb database, we identified potential targeted medications that act on genes implicated in the pyruvate metabolic pathway and formulated a competing endogenous RNA (ceRNA) regulatory network in BC. Results: We collected the datasets GSE54002, GSE70947, and GSE22820, and identified a total of 1127 DEGs between the BC and NC groups. GO and KEGG enrichment analysis showed that the molecular functions of these DEGs mainly included mitotic nuclear division, extracellular matrix, signaling receptor activator activity, etc. Metabolic pathways were mainly concentrated in PI3K−Akt signaling pathway, Cytokine−cytokine receptor binding and Pyruvate, Tyrosine, Propanoate and Phenylalanine metabolism, etc. In addition, MR analysis demonstrated a causal relationship between pyruvate metabolism and BC risk. Finally, we constructed a regulatory network between pathway genes (ADH1B, ACSS2, ACACB, ADH1A, ALDH2, and ADH1C) and targeted drugs, as well as a ceRNA (lncRNA-miRNA-mRNA) regulatory network for BC, further revealing their interactions. Conclusions: Our research revealed a causal association between pyruvate metabolism and BC risk, found that ADH1B, ACSS2, ACACB, ADH1A, ALDH2, and ADH1C takes place an important part in the development of BC in the molecular mechanisms related to pyruvate metabolism, and identified some potential targeted small molecule drugs. [ABSTRACT FROM AUTHOR]

The current review aims to uphold all the attributes of protein-based nanostructures and their applications in therapeutics. Nanostructures have successfully revolutionized the era of novel drug delivery systems. Owing to the paramount advantages of nanoscale preparations, they have gained importance exponentially in recent years. Among the varied range of nanostructures, protein-based nanostructures have acquired a predominant orientation. Being a natural biomolecule, proteins have zero levels of toxicity, biodegradability, and biocompatibility. The present scenario states that the fourth generation of nanomedicines is being formulated which implements biomolecule nano-vectors that can exhibit the virtues of target specificity, multifunctionality, and stimuli-responsiveness. By virtue of possessing these attributes, apart from being able to partake in complex supramolecular assemblage, proteins have proven to be the best approach in the development of nanoscale structures. The review studies the supremacy of various protein-based nanoparticles over other nanostructures, their mode of preparation, efficacious delivery of a plethora of drugs, and their implementation in the field of nanomedicines along with various characterization techniques. As our insightfulness of protein-based nanoparticles expands, they grip boundless potential for revolutionizing drug delivery and renovating the treatment scenario for a widespread range of disorders. [ABSTRACT FROM AUTHOR]

Background: In the last decade, Ibrutinib has become the standard of care in the treatment of several lymphoproliferative diseases such as chronic lymphocytic leukemia (CLL) and several non-Hodgkin lymphoma. Beyond Bruton tyrosine kinase inhibition, Ibrutinib shows broad immunomodulatory effects that may promote the occurrence of infectious complications, including opportunistic infections. The infectious burden has been shown to vary by disease status, neutropenia, and prior therapy but data focusing on severe infections requiring intensive care unit (ICU) admission remain scarce. We sought to investigate features and outcomes of severe infections in a multicenter cohort of 69 patients receiving ibrutinib admitted to 10 French intensive care units (ICU) from 1 January 2015 to 31 December 2020. Results: Median time from ibrutinib initiation was 6.6 [3–18] months. Invasive fungal infections (IFI) accounted for 19% (n = 13/69) of severe infections, including 9 (69%; n = 9/13) invasive aspergillosis, 3 (23%; n = 3/13) Pneumocystis pneumonia, and 1 (8%; n = 1/13) cryptococcosis. Most common organ injury was acute respiratory failure (ARF) (71%; n = 49/69) and 41% (n = 28/69) of patients required mechanical ventilation. Twenty (29%; n = 20/69) patients died in the ICU while day-90 mortality reached 55% (n = 35/64). In comparison with survivors, decedents displayed more severe organ dysfunctions (SOFA 7 [5–11] vs. 4 [3–7], p = 0.004) and were more likely to undergo mechanical ventilation (68% vs. 31%, p = 0.010). Sixty-three ibrutinib-treated patients were matched based on age and underlying malignancy with 63 controls receiving conventional chemotherapy from an historic cohort. Despite a higher median number of prior chemotherapy lines (2 [1–2] vs. 0 [0–2]; p < 0.001) and higher rates of fungal [21% vs. 8%, p = 0.001] and viral [17% vs. 5%, p = 0.027] infections in patients receiving ibrutinib, ICU (27% vs. 38%, p = 0.254) and day-90 mortality (52% vs. 48%, p = 0.785) were similar between the two groups. Conclusion: In ibrutinib-treated patients, severe infections requiring ICU admission were associated with a dismal prognosis, mostly impacted by initial organ failures. Opportunistic agents should be systematically screened by ICU clinicians in this immunocompromised population. [ABSTRACT FROM AUTHOR]

This study is aimed at the preparation and evaluation of walnut meal-derived elastase inhibitory peptide loaded in chitosan-tripolyphosphate (CS-TPP) nanoparticles (NPs). It was shown that the maximum encapsulation efficiency of FFVPF could reach 94.58 ± 0.23%. TEM microphotographs, polydispersity index, and zeta-sizer reports indicated that FFVPF-loaded CS-TPP NPs were in nanometric range and were spherical, discrete, and uniform in size with PDI less than 0.3. FTIR analysis indicated that the peptides interacted with CS-TPP NPs through strong hydrogen bonds and electrostatic interactions. The CS-TPP FFVPF NPs showed better stability with heating treatment, pH treatment, or photochemical treatment. Moreover, the in vitro release profile of peptides was identified. The release rate of encapsulated FFVPF was released explosively to 77.22 ± 2.21% and gradually slowed down. These findings highlighted the prospect of CS-TPP NPs as an oral delivery system, and the application of peptides within food and pharmaceutical products. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide. Consequently, it is essential to identify biomarkers for treatment response and the prognosis prediction. We investigated whether ABL1 can function as a biomarker or a drug target for HCC. We assessed the ABL1 expression, genetic alterations and patients' survival from LinkedOmics, GEO, TCGA and Human Protein Atlas. We analyzed PPI, GO and KEGG pathways. GSEA was analyzed for functional comparison. The current drugs targeting ABL1 were statistically analyzed using DRUGSURV and DGIdb database. We found ABL1 is overexpressed in HCC and its higher expression reduces survival probability. Genetic changes of ABL1 are not frequent. We screened out 25 differentially expressed genes correlated with ABL1. The top functions of ABL1 are biological regulation, metabolic process, protein-containing, and protein binding. KEGG pathways showed that ABL1 and correlated with ABL1 significantly genes markedly enriched in the ErbB signaling pathway, and pathways in cancer. We counted the existing drugs targeting ABL1, which indicates that inhibiting ABL1 expression may improve the survival probability of HCC. In conclusion, ABL1 plays a crucial role in the development and progression of this cancerization and is a potential drug target. [ABSTRACT FROM AUTHOR]

Licorice chalcone A (LCA) possesses a variety of pharmacological activities amid poor solubility in water which consequently restricts its clinical application. In this study, LCA micelles (LCA-M) and LCA micelles modified with TPGS (LCA-M-T) were prepared, wherein in vitro, in vivo, and hepatoprotection potential of the formulations were evaluated. LCA-M-T and LCA-M were prepared by thin-film dispersion method and characterized by a transmission electron microscope (TEM). The encapsulation efficiency, in vitro release, and stability of LCA-M-T and LCA-M were detected by HPLC and UV, respectively. The pharmacokinetics, tissue distribution studies, and pharmacodynamics research were also carried out after oral administration. The sizes of micellar particles were 34.02 ± 0.29 nm (LCA-M) and 62.46 ± 0.51 nm (LCA-M-T) with 0.223 ± 0.021 (LCA-M) and 0.343 ± 0.006 (LCA-M-T) polydispersities, − 35.06 ± 2.27 mV (LCA-M) and − 38.58 ± 1.69 mV (LCA-M-T) zeta potentials, and 95.2 ± 0.27% (LCA-M) and 90.34 ± 0.31% (LCA-M-T) encapsulation efficiencies. The drug loadings were 8.56 ± 0.27% (LCA-M) and 8.04 ± 0.19% (LCA-M-T). The two preparations released quickly and reached over 95% in the four-dissolution media (pH = 1.2 pH = 6.8 pH = 7 pH = 7.4). The preparations of LCA showed significant elevation of cumulative release compared with the free LCA and more importantly 119% (LCA-M) and 285% (LCA-M-T) increments in the relative oral bioavailability of the drug. Preparations of LCA may act as a promising approach to improve solubility and enhance bioavailability and liver protective activity of LCA. [ABSTRACT FROM AUTHOR]

Aim: In recent decades, there has been a revolutionary decrease in cancer-related mortality and an increase in survival due to the introduction of novel targeted drugs. Nevertheless, drugs targeting human epidermal growth factor receptor 2 (HER-2), angiogenesis, and other tyrosine kinases also come with unexpected cardiac side effects, including heart failure, hypertension, arterial thrombosis, and arrhythmias, and have mechanisms that are unlike those of classic chemotherapeutic agents. In addition, it is challenging to address some problems, as the existing guidelines need to be more specific, and further large-scale clinical trials and experimental studies are required to confirm the benefit of administering cardioprotective agents to patients treated with targeted therapies. Therefore, an improved understanding of cardiotoxicity becomes increasingly important to minimize the pernicious effects and maximize the beneficial effects of targeted agents. Methods: "Cardiotoxicity", "targeted drugs", "HER2", "trastuzumab", "angiogenesis inhibitor", "VEGF inhibitor" and "tyrosine kinase inhibitors" are used as keywords for article searches. Results: In this article, we report several targeted therapies that induce cardiotoxicity and update knowledge of the clinical evidence, molecular mechanisms, and management measures. [ABSTRACT FROM AUTHOR]

Background: The recurrence rate of hepatocellular carcinoma (HCC) after partial hepatectomy is still high. How to choose the most appropriate anti-tumor drug in the early postoperative period is crucial to improve the prognosis of patients. Recently, MiniPDX has been widely used as a new and reliable preclinical research model capable of predicting the sensitivities of anti-tumor drugs.Methods: Twenty-eight patients with HCC were selected to use the MiniPDX model to screen the most sensitive anti-tumor drugs from five groups of drug regimens for preventive treatment after partial hepatectomy, and another 42 patients with HCC were selected to be treated with Sorafenib during the same period as the control group. The tumor-free survival rate and overall survival rate were analyzed and compared between these two groups. The relationship between drug sensitivity and biomarkers related to HCC was also analyzed.Results: Kaplan-Meier survival curve analysis showed that the tumor-free survival (DFS) of patients in the MiniPDX group was significantly longer than that in the control group (median DFS: 25.8 months vs. 18.2 months, P = 0.022, HR 2.19, 95% CI 1.17-4.12). The overall survival (OS) of the patients in the MiniPDX group was also longer than that in the control group (median OS: 29.4 months vs. 23.8 months, P = 0.039, HR 2.37, 95% CI 1.12-5.00). The longest follow-up period was 36 months. The relationship analyzed between the efficacy of the five drugs (Regorafenib, Regorafenib, Lenvatinib, Gemcitabine, 5-FU + Oxaliplatin) and AFP, Ki-67, VEGFR, FGFR, P53, and Nrf2 showed different correlations.Conclusion: The use of the MiniPDX model to select drugs to guide anti-tumor treatment after partial hepatectomy could effectively prolong the survival of patients with HCC. [ABSTRACT FROM AUTHOR]

Recently, Georgia State University’s Centennial Hall was the premier location for the 2017 International Conference on Triple Negative Breast Cancer (TNBC): Illuminating Actionable Biology, which was held from Sept. 18 to 20, 2017, in Atlanta, USA. The conference featured a stellar line-up of domestic and international speakers and diverse participants including TNBC survivors, luminaries in breast cancer research, medical students and fellows, clinicians, translational researchers, epidemiologists, biostatisticians, bioinformaticians, and representatives from the industry. This report distills the burning questions that spiked the event and summarizes key themes, findings, unique opportunities and future directions that emerged from this confluence of thought leaders. [ABSTRACT FROM AUTHOR]

Central nervous system (CNS) tumors are a leading cause of death in pediatric oncology. New drugs are desperately needed to improve survival. We evaluated the outcome of children and adolescents with CNS tumors participating in phase I trials within the Innovative Therapies for Children with Cancer (ITCC) consortium. Patients with solid tumors aged < 18 years at enrollment in their first dose-finding trial between 2000 and 2014 at eight ITCC centers were included retrospectively. Survival was evaluated using univariate/multivariate analyses. Overall, 114 patients were included (109 evaluable for efficacy). Median age was 10.2 years (range 1.0–17.9). Main diagnoses included: medulloblastoma/primitive neuroectodermal tumors (32.5%) and high-grade gliomas (23.7%). Complete/partial responses (CR/PR) were reported in 7.3% patients and stable disease (SD) in 23.9%. Performance status of 90–100%, school/work attendance, normal ALT/AST and CR/PR/SD correlated with better overall survival (OS) in the univariate analysis. No variables assessable at screening/enrollment were associated with OS in the multivariate analysis. Five patients (4.5%) were discontinued from study due to toxicity. No toxic deaths occurred. Median OS was 11.9 months with CR/PR, 14.5 months with SD and 3.7 months with progressive disease (p < 0.001). The enrollment of children and adolescents with CNS tumors in phase I trials is feasible, safe and offers potential benefit for the patients. Sustained disease stabilization has a promising role as a marker of anti-tumor activity in children with CNS tumors participating in phase I trials. [ABSTRACT FROM AUTHOR]

Objective: This study investigated the inhibitory effects of bevacizumab monoclonal antibodies in combination with chemotherapy in different time sequences on a human gastric cancer cell line (MGC-803). Methods: Cultured MGC-803 human gastric cancer cells were treated with bevacizumab in combination with chemotherapy treatment in different time sequences. The effects on cell growth inhibition were determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell cycle distribution and the rate of cell apoptosis were determined by propidium iodide staining followed by flow cytometry. Results: Drug administration for different time sequences significantly inhibited the growth of MGC-803 cells. Based on group comparisons ( P < 0.01), the effect of 24 h bevacizumab treatment prior to combination 5-fluorouracil and cisplatin (FP) was the strongest ( F = 241.313, 246.856, all P values <0.001). Treating MGC-803 cells with bevacizumab for 24 h before combination FP induced significant G2/M phase arrest ( F = 231.991, P < 0.001) and significantly increased gastric cancer cell apoptosis. Bevacizumab in combination with chemotherapy significantly inhibits the proliferation of MGC-803 gastric cancer cells. Conclusions: The mechanism may be related to cell cycle arrest at S phase and the induction of apoptosis in MGC-803 gastric cancer cells. [ABSTRACT FROM AUTHOR]

Background: Gastric cancer is the second most common cause of cancer-related death in the world, and its prognosis remains poor with a median overall survival of 12 months for advanced disease. Advances in the understanding of molecular genetics have led to the development of directed molecular targeted therapy in gastric cancer, leading to improve patient outcomes and quality of life. Discussion: In the treatment of human epidermal growth factor receptor 2 (HER2)-positive gastric cancer, the addition of trastuzumab significantly improves survival in the first-line setting of therapy. Ramucirumab, an antibody directed against vascular endothelial growth factor receptor 2, significantly improved progression-free and overall survival and has been approved for second-line treatment of gastric cancer. Anti-mesenchymal-epithelial transition (c-MET), mammalian target of rapamycin inhibitors, and polo-like kinase 1 inhibitors are under investigation as a novel therapeutic option for the treatment of gastric cancer. The novel therapies target the key immune checkpoint interaction between a T cell co-inhibitory receptor called programmed death 1 (PD-1) and one of its immunosuppressive ligands, PD-L1. This article reviews molecular targeted therapies in gastric cancer, in light of recent advances. [ABSTRACT FROM AUTHOR]

The identification of prognostic factors in patients with renal cell carcinoma (RCC) represents an area of increasing interest. In this retrospective study, we evaluated the prognostic role of carbonic anhydrase-IX, ezrin, and neuropilin in metastatic RCC patients. The expression of several biomarkers were measured by immunohistochemistry (IHC) in 45 patients with advanced stage RCC treated with second-line tyrosine kinase inhibitors (TKIs) targeting vascular endothelial growth factor (VEGF) after failure of interferon-alpha between January 2007 and June 2012. Kaplan-Meier curves and log-rank tests were used for analysis of progression-free survival (PFS) and overall survival (OS), and a multivariate Cox proportional hazard model was employed to identify factors with an independent effect on the survival. Age, ezrin and neuropilin-2 overexpression were found to be statistically significant factors ( P < 0.05) for PFS in the univariate analysis. Ezrin and neuropilin-2 overexpression, hemoglobin and albumin level were statistically significant factors ( P < 0.05) for OS in the univariate analysis. Multivariate analysis revealed that low expression of ezrin and neuropilin-2 was an independent prognostic factor for PFS and OS. The median PFS was 4 months for patients overexpressing neuropilin-2 versus 11 months for those with lower expression of neuropilin-2 ( p = 0.033). The median OS was longer in patients with low levels of neuropilin-2 expression (26 months) compared to patients overexpressing neuropilin-2 (13 months) ( p = 0.023). Increased expression of ezrin was associated with poor prognosis in patients treated with TKIs targeting VEGF (PFS, 3 vs 7 months; p = 0.012). High ezrin expression was associated with shorter OS ( p = 0.009). This is the first study in the literature showing that neuropilin-2 and ezrin are related with prognosis in patients with advanced RCC. [ABSTRACT FROM AUTHOR]

Background: Considerable progress has been made in our understanding of the biological basis for cancer therapy-induced mucosal barrier injury (mucositis). The last formal review of the subject by MASCC/ISOO was published in 2007; consequently, an update is timely. Methods: Panel members reviewed the biomedical literature on mucositis pathobiology published between January 2005 and December 2011. Results: Recent research has provided data on the contribution of tissue structure changes, inflammation and microbiome changes to the development of mucositis. Additional research has focused on targeted therapy-induced toxicity, toxicity clustering and the investigation of genetic polymorphisms in toxicity prediction. This review paper summarizes the recent evidence on these aspects of mucositis pathobiology. Conclusion: The ultimate goal of mucositis researchers is to identify the most appropriate targets for therapeutic interventions and to be able to predict toxicity risk and personalize interventions to genetically suitable patients. Continuing research efforts are needed to further our understanding of mucositis pathobiology and the pharmacogenomics of toxicity. [ABSTRACT FROM AUTHOR]

Copyright of Der Pathologe is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The last 20 years was characterized by great improvements in the efficacy and tolerability of anticancer therapies. Most of these changes are related to the introduction of targeted drugs, which presents a better activity on the biology of cancer and less toxicity. Nevertheless, the initial enthusiasm was cooled by the emerging evidences of cardiac side effects. The aim of this review is to describe the actual knowledge about the possible cardiotoxicity of targeted drugs. The most important need is the detection of early cardiotoxicity and the evidence of subtle myocardial dysfunction that allows to begin a protective therapy. In our review we analyzed the non invasive imaging techniques to early predict myocardial dysfunction. Echocardiography seems to be the ideal method for her availability, safety and clinical usefulness, in particular the new echocardiographic techniques like speckle tracking. [ABSTRACT FROM AUTHOR]

The paper reviews some of the transformations of cancer clinical trial protocols made necessary by the emergence of molecularly targeted agents. These changes include the creation of a new phase of clinical trials (phase 0) and the alteration of the parameters governing the other three phases. The situation remains unstable: repeated attempts to speed up the development of new drugs have not yet led to a consensus on how to best do so. The new targeted agents raise issues that go beyond the purely technical as changing protocols implicate changes in the organization of translational research. [ABSTRACT FROM AUTHOR]

Cancer chemotherapy was introduced at the same time as antibacterial chemotherapy but has not been nearly such a success. However, there is a growing optimism in oncology today due to the introduction of several more or less target-specific drugs as complements to the conventional cytotoxic drugs introduced half a century ago. The success in the treatment of chronic myelogenous leukemia by imatinib, inhibiting the bcr-abl-activated tyrosine kinase and thereby interrupting the signal transduction pathways that lead to leukemic transformation with impressive survival benefit, has paved the way for this new optimism. Another success story is the introduction of trastuzumab in breast cancers overexpressing the HER-2 receptor. In contrast, there has been little progress in other malignancies such as metastatic malignant melanoma, although very recently, clinical trials with new targeted drugs have shown increased survival. All major pharmaceutical companies now have ambitious development programs in the cancer area. However, the high costs of the novel drugs cause economic distress in the health care system in many countries leading to an intense debate on the cost-effectiveness of these drugs in relation to other health care activities. [ABSTRACT FROM AUTHOR]

Copyright of Der Onkologe is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Der Onkologe is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Oncology therapeutics have entered a new era, with the recent approval by the US Food and Drug Administration of 16 novel targeted agents. In many instances, these agents have led to breakthroughs in cancer care, such as imatinib for the treatment of chronic myeloid leukemia and bevacizumab for the treatment of colorectal, lung, and breast cancers. Toxicities of targeted agents are also novel-no longer primarily resulting in hematologic, gastrointestinal, and skin toxicities. As with all new and innovative therapies, the price tags for these agents are substantial, ranging from a mean per person annual cost of $13,000 to $100,000 in many cases. Despite the high cost of these drugs, the value of these agents has been important. In this paper, we review the concepts of value and cost effectiveness as they apply to targeted cancer agents and provide some initial insights on the economics of targeted oncology drugs. [ABSTRACT FROM AUTHOR]

Renal cell carcinomas (RCCs) of the clear cell type are associated with alteration of the von Hippel-Lindau ( VHL) tumor suppressor gene, the subsequent stabilization and overexpression of hypoxia inducible factor (HIF), which causes upregulation of transforming growth factor-alpha (TGFα), thereby generating an autocrine loop via the epidermal growth factor receptor (EGFR). So far, there is only limited information available about the differential expression of the EGFR and TGFα in clinical samples of RCCs harboring VHL alterations. In this study, we report comparative analyses of the EGFR and TGFα protein and messenger RNA (mRNA) expression in 99 RCCs of the clear cell type including 54 tumors with known VHL status and show that in comparison to their VHL wild type (wt) counterparts, TGFα and EGFR are more frequently expressed in RCCs harboring VHL alterations. Furthermore, upregulation of EGFR but not TGFα protein expression correlated to higher tumor stage. We speculate that EGFR expression is associated with the VHL status of RCCs and discuss the findings with respect to their potential impact on novel targeted therapeutic approaches to RCC. [ABSTRACT FROM AUTHOR]

Oligonucleotides specifically bind to complementary sequences of either genomic DNA or genomic RNA through hydrogen bonding of base pairs. In principle, relatively short oligomers (<20 bases) can specifically hybridize with DNA or RNA and thus be used for novel drug design strategies involving targeted interference of genetic expression at the level of transcription or translation. Conceivable chemotherapeutic applications predicated on sequence-specific hybridization ('antisense' inhibition) require oligonucleotide analogues that are resistant to in vivo degradation by enzymes such as nucleases. Nuclease-resistant analogues having modified internucleoside linkages (e.g., methylphosphonates or phosphorothioates) or modified nucleosides (e.g., 2′- 0-methylribose or α-anomers) are now readily available by means of automated synthesis, and there are various classes of pendant groups (e.g., alkylating or intercalating agents) that can be attached to increase the efficacy of these analogues. The present account reviews this area of research by classifying structures and mechanisms of action, with comments on stereochemistry. Biological studies are briefly summarized, and pharmaceutically related topics of interest are noted. [ABSTRACT FROM AUTHOR]

Purpose of Review: Modern oncology is witnessing a renaissance of its pharmacologic armamentarium. Old generation drugs, such as anthracyclines and other cytotoxic or cytostatic drugs, were plagued with a lack of specificity and with the possible occurrence of untoward effects in the cardiovascular system and other healthy tissues. The old drugs are now combined with, or replaced by, new agents that are more specific in attacking some unique moieties and vital functions of cancer cells, causing less noxious effects in healthy tissues. Regrettably, however, the new "targeted" drugs still cause varying levels of cardiac or vascular toxicity. Here, we describe the case of trastuzumab, a monoclonal antibody that dramatically improved the life expectancy of women with Erbb2-overexpressing breast tumor, while also raising concerns about a possible incidence of cardiac dysfunction. Recent Findings: The scientific community counts experts that label trastuzumab as a "cardiotoxic agent" and other experts that maintain a more benign assessment. We describe the biologic foundations and clinical evidence for such controversy. We show that trastuzumab cardiotoxicity is probably overrated, leading some experts to raise unjustified overconcerns about the cardiotoxicity of trastuzumab as a single agent or in combination with anthracyclines or other old and new drugs. We analyze the biases that caused trastuzumab cardiotoxicity to be overrated. Summary: Trastuzumab is a life-saving agent showing a moderate and clinically manageable cardiac dysfunction, and yet, it is portrayed as cardiotoxic. We take the trastuzumab lesson to reaffirm that cardio-oncologists should provide cancer patients with the best therapeutic opportunity, as is the case for trastuzumab, while also devising the necessary strategies of risk assessment and mitigation. [ABSTRACT FROM AUTHOR]