Search

Background: Patients with HER2-positive cancers often face a poor prognosis, and treatment regimens containing anti-HER2 have become the first-line treatment options for breast and gastric cancers. However, these approaches are faced with significant challenges in terms of drug resistance. Hence, it is crucial to explore precise treatment strategies aimed at improving survival outcomes. Advancements in treatment: Over the past few years, there has been rapid advancement in the realm of tumor therapy, particularly with the swift progress of immune checkpoint inhibitors, including PD-1/PD-L1 inhibitors. They exert anti-tumor effects by disrupting immune-suppressive factors within the tumor microenvironment. However, monotherapy with PD-1/PD-L1 inhibitors has several limitations. Consequently, numerous studies have explored combinatorial immunotherapeutic strategies and demonstrated highly promising avenues of development. Objective: This article aims to review the clinical trials investigating PD-1/PD-L1 inhibitor combination therapy for HER2-positive tumors. Additionally, it provides a summary of ongoing trials evaluating the efficacy and safety of these combined treatments, with the intention of furnishing valuable insights for the clinical management of HER2-positive cancer. Conclusion: Combinatorial immunotherapeutic strategies involving PD-1/PD-L1 inhibitors hold considerable promise in the treatment of HER2-positive tumors. Continued research efforts and clinical trials are warranted to elucidate optimal treatment regimens that maximize therapeutic benefits while minimizing adverse effects. [ABSTRACT FROM AUTHOR]

Purpose: The aim of the present study was to develop a population pharmacokinetic model for methotrexate (MTX) during high-dose treatment (HDMTX) in pediatric patients with acute lymphoblastic leukemia (ALL) and non-Hodgkin's lymphoma (NHL) and to describe the influence of variability factors. Methods: The study included 50 patients of both sexes (aged 1–18 years) who received 3 or 5 g/m2 of HDMTX. A nonlinear mixed effect modeling approach was applied for data analysis. Parameter estimation was performed by first-order conditional estimation method with interaction (FOCEI), whereas stepwise covariate modeling was used to assess variability factors. Results: The final model is a two-compartment model that incorporates the effect of body surface area and the influence of hemoglobin and serum creatinine on MTX clearance (CL). Population pharmacokinetic values for a typical subject were estimated at 5.75 L/h/m2 for clearance (CL), 21.3 L/m2 for volume of the central compartment (V1), 8.2 L/m2 for volume of the peripheral compartment (V2), and 0.087 L/h/m2 for intercompartmental clearance (Q). According to the final model, MTX CL decreases with increasing serum creatinine, whereas a positive effect was captured for hemoglobin. A difference of almost 32% in MTX CL was observed among patients' hemoglobin values reported in the study. Conclusion: The developed population pharmacokinetic model can contribute to the therapy optimization during HDMTX in pediatric patients with ALL and NHL. In addition to renal function and body weight, it describes the influence of hemoglobin on CL, allowing better understanding of its contribution to the disposition of HDMTX. [ABSTRACT FROM AUTHOR]

Background: Dabrafenib and trametinib represent targeted therapy options under investigation for treatment of gliomas harboring BRAF V600 mutations. We systematically reviewed the literature and conducted meta-analyses to assess the efficacy and safety of these agents. Methods: PubMed, Embase, and Scopus were searched from inception to September 2023 for studies examining dabrafenib and/or trametinib for gliomas. Outcomes included response rates (ORR, CR, PR), progression rates (PD), 6- and 12-month PFS, adverse events, and dosing modifications. Meta-analyses were conducted using random effect models. Results: Nine studies met the inclusion criteria. Meta-analysis demonstrated overall response rates (ORR) of 50% (95% confidence interval (CI): 35–65%) for low-grade gliomas (LGG) and 40% (95% CI: 29–51%) for high-grade gliomas (HGG). Pooled ORR was 45% (95% CI: 36–54%) for both glioma grades. The complete response rate was 13% (95% CI: 05–27%) for HGG and 5% (95% CI: 1–10%) for both LGG and HGG. Six-month progression-free survival (PFS) rates reached 87% in LGG and 67% in HGG and a pooled 6-month PFS 78% (95% CI: 58–98%), declining at 12 months to 67% and 44%, respectively, with a pooled 12-month PFS 56% (95% CI: 34–79%). Grade 1–4 adverse events occurred in 100% of LGG and 63% of HGG patients. Conclusions: Dabrafenib and trametinib demonstrate promising anti-tumor efficacy in gliomas, particularly low-grade tumors, achieving durable disease stabilization in many patients. However, toxicity significantly limited tolerability. Additional research should further examine efficacy and refine safe administration protocols across glioma subtypes. [ABSTRACT FROM AUTHOR]

Simple Summary: Melanoma patients with high neutrophil counts often show impaired clinical response and poor prognosis, indicating that neutrophils can support melanoma progression. The precise mechanism responsible for this correlation, especially in the context of targeted therapy, still requires clarification. We show that peripheral blood neutrophils of patients with advanced melanoma are characterized by lower CD16 surface expression compared to healthy donors, which has been reported to be associated with tumor promotion. We provide evidence that melanoma cells under dual-targeted therapy can be protected in vitro by neutrophils from both patients and healthy donors. In addition, this protective effect is dependent on cell–cell contact, as well as on culture conditions, and is observed under nonadherence. Unraveling the mechanism, the interference with the protease activity of neutrophils reduced protection. Understanding the complex interaction of neutrophils and melanoma cells might aid in discovering methods to prevent the tumor-promoting effects by neutrophils in patients. Elevated levels of peripheral blood and tumor tissue neutrophils are associated with poorer clinical response and therapy resistance in melanoma. The underlying mechanism and the role of neutrophils in targeted therapy is still not fully understood. Serum samples of patients with advanced melanoma were collected and neutrophil-associated serum markers were measured and correlated with response to targeted therapy. Blood neutrophils from healthy donors and patients with advanced melanoma were isolated, and their phenotypes, as well as their in vitro functions, were compared. In vitro functional tests were conducted through nonadherent cocultures with melanoma cells. Protection of melanoma cell lines by neutrophils was assessed under MAPK inhibition. Blood neutrophils from advanced melanoma patients exhibited lower CD16 expression compared to healthy donors. In vitro, both healthy-donor- and patient-derived neutrophils prevented melanoma cell apoptosis upon dual MAPK inhibition. The effect depended on cell–cell contact and melanoma cell susceptibility to treatment. Interference with protease activity of neutrophils prevented melanoma cell protection during treatment in cocultures. The negative correlation between neutrophils and melanoma outcomes seems to be linked to a protumoral function of neutrophils. In vitro, neutrophils exert a direct protective effect on melanoma cells during dual MAPK inhibition. This study further hints at a crucial role of neutrophil-related protease activity in protection. [ABSTRACT FROM AUTHOR]

Simple Summary: In this study, we investigated the effectiveness of the targeted cancer medication CDK4/6 inhibitors, in patients with breast cancer. These medicaments have been used for nearly a decade, but how well they work can vary greatly from one patient to another. By examining the experiences of 86 patients over a period from November 2016 to May 2020, we aimed to understand what factors might predict better or worse outcomes for patients. We discovered that certain characteristics, like the level of the progesterone receptor in the tumor and whether the cancer had spread to multiple locations or the liver, played a significant role in how long patients benefited from treatment without progression. The study also found that management characteristics during treatment could significantly affect patient outcomes. These insights are crucial for developing personalized management strategies that could lead to better outcomes for people with breast cancer. Background: The quest to comprehend the real-world efficacy of CDK4/6 inhibitors (CDKis) in breast cancer continues, as patient responses vary significantly. Methods: This single-center retrospective study evaluated CDKi use outside the trial condition from November 2016 to May 2020. Progression-free survival (PFS), time-to-treatment failure (TTF), short-term and prolonged treatment benefit (≥4 and ≥10 months), as well as prognostic and predictive markers were assessed with Kaplan–Meier and multivariate regression analyses. Results: Out of 86 identified patients, 58 (67.4%) had treatment failure of which 40 (46.5%) were due to progression. Median PFS and TTF were 12 and 8.5 months, respectively. A total of 57 (66.3%) and 42 (48.8%) patients experienced short-term and prolonged treatment benefit. Independent, significant predictors for PFS were progesterone receptor expression (HR: 0.88), multiple metastatic sites (HR: 2.56), and hepatic metastasis (HR: 2.01). Significant predictors for TTF were PR expression (HR: 0.86), multiple sites (HR: 3.29), adverse events (HR: 2.35), and diabetes (HR: 2.88). Aside from tumor biology and adverse events, treatment modifications like pausing and switching of CDKi were predictive for short-term (OR: 6.73) and prolonged (OR: 14.27) therapeutic benefit, respectively. Conclusions: These findings emphasize the importance of tailored treatment strategies, highlighting the role of PR expression, metastatic burden, and therapeutic adjustments in optimizing patient outcomes in real-world breast cancer management. [ABSTRACT FROM AUTHOR]

Simple Summary: Although women 70 years of age and older represent a large percentage of newly diagnosed breast cancer cases, older individuals are drastically underrepresented in clinical trials. Most women diagnosed with breast cancer at 70 years of age and older present with hormone receptor-positive (HR+) breast cancer. Cyclin-dependent kinase (CDK) 4/6 inhibitor-based therapy has become the standard of care for metastatic HR+ breast cancer. This study reports that metastatic breast cancer patients ≥70 years of age receiving CDK4/6 inhibitor-based treatment, particularly when combined with an aromatase inhibitor, experience prolonged progression-free survival but display no such prolongation in overall survival and report more frequent adverse effects to treatment. The reported findings can aid in the development of optimized treatments based on age and help older patients weigh treatment options. The largest portion of breast cancer patients diagnosed after 70 years of age present with hormone receptor-positive (HR+) breast cancer subtypes. Cyclin-dependent kinase (CDK) 4/6 inhibitor treatment, in conjunction with endocrine therapy, has become standard-of-care for metastatic HR+ breast cancer. In total, 320 patients with metastatic breast cancer receiving CDK4/6 inhibitor combined with fulvestrant or an aromatase inhibitor were enrolled in an ongoing observational study or were included in an IRB-approved retrospective study. All patients receiving CDK4/6 inhibitor-based therapy that were ≥70 years of age (n = 111) displayed prolonged progression-free survival (27.6 months) as compared to patients <70 years of age (n = 209, 21.1 months, HR = 1.38, p < 0.05). Specifically, patients receiving a CDK4/6 inhibitor with an aromatase inhibitor who were ≥70 years of age (n = 79) displayed exceptionally prolonged progression-free survival (46.0 months) as compared to patients receiving the same treatment who were <70 years of age (n = 161, 21.8 months, HR = 1.71, p < 0.01). However, patients ≥70 years of age also experienced more frequent adverse responses to CDK4/6 inhibitor-based treatment leading to dose reduction, hold, or discontinuation than the younger cohort (69% and 53%, respectively). Treatment strategies that may decrease toxicity without affecting efficacy (such as dose titration) are worth further exploration. [ABSTRACT FROM AUTHOR]

Simple Summary: Human epidermal receptor (HER) 2-positive advanced gastric cancer (AGC) is one of the major subtypes of gastric cancer, accounting for ~20% of all cases. After the success of a ToGA trial, the development of treatment for HER2-positive AGC had been at a standstill for a long time. Recently, trastuzumab deruxtecan in later-line therapy and the combination therapy of chemotherapy plus trastuzumab with immune checkpoint inhibitor has demonstrated significant survival benefit in first-line treatment. Currently, several clinical trials of new types of anti-HER2 agents are ongoing. Human epidermal receptor (HER) 2-positive advanced gastric cancer is one of the major subtypes of gastric cancer, accounting for ~20% of all cases. Although combination therapy with trastuzumab and chemotherapy provides meaningful survival benefit, clinical trials targeting HER2 have failed to demonstrate clinical benefits in first- or subsequent-line treatment. Trastuzumab deruxtecan, an antibody–drug conjugate, has shown positive results even in later-line treatment and has become new standard treatment. In first-line therapy, combination therapy with pembrolizumab and trastuzumab plus chemotherapy demonstrated a dramatic response rate. Therefore, the FDA rapidly approved it without waiting for the results of survival time. The emergence of combination therapy including immunotherapy with HER2-targeting agents and the development of HER2 targeting agents with or without immunotherapy have been advancing for treating HER2-positive gastric cancer. In this review, we will discuss the current status of treatment development and future perspectives for HER2-positive gastric cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Neuroblastoma (NB) presents with two patterns of disease: with or without metastasis. Both types of disease presentation include tumors with high-risk (HR) features. The management of HR-NB includes chemotherapy, surgery, radiotherapy, and anti-GD2 immunotherapy. Anti-GD2 monoclonal antibodies (mAbs) have significantly improved the outcome of HR-NB patients but they are mostly effective against disease affecting the bone and/or bone marrow (known as the osteomedullary compartment), and less so against soft tissue disease. The question arises as to whether anti-GD2 immunotherapy might benefit HR-NB patients with disease compounded by only soft tissue. In this retrospective review, we found that achieving first complete remission with chemotherapy, surgery, and radiotherapy does not prevent the risk of relapse. However, adding anti-GD2 mAbs once the patient has achieved complete remission significantly decreases the chances of relapse by 80%. Our study provides further support to indicate anti-GD2 mAbs in all cases with HR-NB. Neuroblastoma presents with two patterns of disease: locoregional or systemic. The poor prognostic risk factors of locoregional neuroblastoma (LR-NB) include age, MYCN or MDM2-CDK4 amplification, 11q, histology, diploidy with ALK or TERT mutations, and ATRX aberrations. Anti-GD2 immunotherapy has significantly improved the outcome of high-risk (HR) NB and is mostly effective against osteomedullary minimal residual disease (MRD), but less so against soft tissue disease. The question is whether adding anti-GD2 monoclonal antibodies (mAbs) benefits patients with HR-NB compounded by only soft tissue. We reviewed 31 patients treated at SJD for HR-NB with no osteomedullary involvement at diagnosis. All tumors had molecular genetic features of HR-NB. The outcome after first-line treatment showed 25 (80.6%) patients achieving CR. Thirteen patients remain in continued CR, median follow-up 3.9 years. We analyzed whether adding anti-GD2 immunotherapy to first-line treatment had any prognostic significance. The EFS analysis using Cox models showed a HR of 0.20, p = 0.0054, and an 80% decrease in the risk of relapse in patients treated with anti-GD2 immunotherapy in the first line. Neither EFS nor OS were significantly different by CR status after first-line treatment. In conclusion, adding treatment with anti-GD2 mAbs at the stage of MRD helps prevent relapse that unequivocally portends poor survival. [ABSTRACT FROM AUTHOR]

Simple Summary: In solid tumors, oxygen concentration varies between different regions. Generally, while oxygen supply is sufficient in the vicinity of blood vessels, the concentration of oxygen gradually drops as the distance from the blood vessel increases. In the regions with low oxygen content (hypoxic regions), cancer cells acquire various malignant properties, like invasiveness, altered metabolism, and therapy resistance, leading to recurrence and poor clinical outcomes of patients. Hypoxia-inducible factor (HIF) is a major regulator of hypoxia responses. Herein, we summarized how tumor hypoxia activates different mechanisms, in both HIF-dependent and HIF-independent manners, and contributes to the acquisition of chemotherapy resistance. We also discussed the involvement of epigenetic regulation in hypoxia-induced chemoresistance, with a specific example of ATAD2 protein degradation inducing drug resistance under hypoxia. Finally, we briefly reviewed some current clinical trials that target HIF and tumor hypoxia for cancer treatment or therapy sensitization. In hypoxic regions of malignant solid tumors, cancer cells acquire resistance to conventional therapies, such as chemotherapy and radiotherapy, causing poor prognosis in patients with cancer. It is widely recognized that some of the key genes behind this are hypoxia-inducible transcription factors, e.g., hypoxia-inducible factor 1 (HIF-1). Since HIF-1 activity is suppressed by two representative 2-oxoglutarate-dependent dioxygenases (2-OGDDs), PHDs (prolyl-4-hydroxylases), and FIH-1 (factor inhibiting hypoxia-inducible factor 1), the inactivation of 2-OGDD has been associated with cancer therapy resistance by the activation of HIF-1. Recent studies have also revealed the importance of hypoxia-responsive mechanisms independent of HIF-1 and its isoforms (collectively, HIFs). In this article, we collate the accumulated knowledge of HIF-1-dependent and independent mechanisms responsible for resistance of hypoxic cancer cells to anticancer drugs and briefly discuss the interplay between hypoxia responses, like EMT and UPR, and chemoresistance. In addition, we introduce a novel HIF-independent mechanism, which is epigenetically mediated by an acetylated histone reader protein, ATAD2, which we recently clarified. [ABSTRACT FROM AUTHOR]

Simple Summary: The combination of atezolizumab and bevacizumab is a standard treatment for unresectable hepatocellular carcinoma. This study investigated the relationship between the gut microbiome and treatment efficacy. Fecal samples from 37 patients with hepatocellular carcinoma treated with this combination were analyzed. Patients were divided into responders (n = 28) and non-responders (n = 9). While overall microbiome diversity was similar, certain bacteria, such as Bacteroides stercoris and Parabacteroides merdae were more abundant in responders. Patients lacking these bacteria had worse prognoses. This suggests that differences in gut microbiota play a role in the effectiveness of atezolizumab and bevacizumab therapy. The combination of atezolizumab and bevacizumab has become the first-line treatment for patients with unresectable hepatocellular carcinoma (HCC). However, no studies have reported on specific intestinal microbiota associated with the efficacy of atezolizumab and bevacizumab. In this study, we analyzed fecal samples collected before treatment to investigate the relationship between the intestinal microbiome and the efficacy of atezolizumab and bevacizumab. A total of 37 patients with advanced HCC who were treated with atezolizumab and bevacizumab were enrolled. Fecal samples were collected from the patients, and they were divided into responder (n = 28) and non-responder (n = 9) groups. We compared the intestinal microbiota of the two groups and analyzed the intestinal bacteria associated with prognosis using QIIME2. The alpha and beta diversities were not significantly different between both groups, and the proportion of microbiota was similar. The relative abundance of Bacteroides stercoris and Parabacteroides merdae was higher in the responder group than in the non-responder group. When the prognosis was analyzed by the presence or absence of those bacteria, patients without both had a significantly poorer prognosis. Differences in intestinal microbiome are involved in the therapeutic effect of atezolizumab and bevacizumab. [ABSTRACT FROM AUTHOR]

Simple Summary: Use of cancer biomarkers for tumor aggressiveness is an unmet clinical need. Differentiation of high-risk versus low-risk tumors may guide physicians to select appropriate treatment strategies tailored to the risk level of individual patients. This study aimed to evaluate the value of an optical redox imaging technique for differentiating a human melanoma mouse xenograft model with a high risk of metastasis from a low-risk mouse model. Several imaging indices were found to be significantly different between the two models. The high-risk model was found to be in a more oxidized status and to have a higher intratumor redox heterogeneity. These findings may inform further research development of the optical redox imaging approach into translatable cancer biomarkers in the future. To develop imaging biomarkers for tumors aggressiveness, our previous optical redox imaging (ORI) studies of the reduced nicotinamide adenine dinucleotide (NADH) and oxidized flavoproteins (Fp, containing flavin adenine dinucleotide, i.e., FAD) in tumor xenografts of human melanoma associated the high optical redox ratio (ORR = Fp/(Fp + NADH)) and its heterogeneity to the high invasive/metastatic potential, without having reported quantitative results for NADH and Fp. Here, we implemented a calibration procedure to facilitate imaging the nominal concentrations of tissue NADH and Fp in the mouse xenografts of two human melanoma lines, an indolent less metastatic A375P and a more metastatic C8161. Images of the redox indices (NADH, Fp, ORR) revealed the existence of more oxidized areas (OAs) and more reduced areas (RAs) within individual tumors. ORR was found to be higher and NADH lower in C8161 compared to that of A375P xenografts, both globally for the whole tumors and locally in OAs. The ORR in the OA can differentiate xenografts with a higher statistical significance than the global averaged ORR. H&E staining of the tumors indicated that the redox differences we identified were more likely due to intrinsically different cell metabolism, rather than variations in cell density. [ABSTRACT FROM AUTHOR]

Simple Summary: Sacituzumab govitecan is an antibody–drug conjugate that has been approved for the treatment of metastatic triple-negative breast cancer and, recently, also for metastatic hormone receptor-positive HER2-negative breast cancer. Although patients with metastatic breast cancer frequently need palliative radiotherapy, none of the published prospective trials studied the combination of radiotherapy and Sacituzumab govitecan. We conducted a multi-center retrospective cohort study to assess the efficacy and safety of Sacituzumab govitecan and palliative radiotherapy. We did not find signs of increased toxicity, and response rates were favorable despite extensive prior treatment. More research is necessary to determine the optimal integration of novel systemic agents and radiotherapy in the palliative setting. Sacituzumab govitecan (SG) is a new treatment option for patients with metastatic triple-negative and hormone receptor-positive, HER2-negative breast cancer. This antibody–drug conjugate is currently approved as monotherapy. Palliative radiotherapy is frequently used to treat symptomatic metastases locally. Concurrent use of SG and irradiation was excluded in clinical trials of SG, and there are currently limited published data. We report here a systematic review, as well as a retrospective multi-center study of 17 patients with triple-negative breast cancer who received concurrent SG and radiotherapy. In these patients, concurrent use was found to be efficient, safe and well tolerated. There were no apparent differences in moderate or severe acute toxicity according to the timing of SG administration. [ABSTRACT FROM AUTHOR]

Background. Janus-activated kinase 2 (JAK2) plays a pivotal role in numerous essential biological processes, including proliferation, apoptosis, and metastasis in human cells. Prior studies have indicated that inhibiting JAK2 could be a promising strategy to mitigate cell proliferation and induce apoptosis in tumor cells. Objectives. This study aimed to estimate the binding affinity of 79 herbal compounds, comprising 46 flavonoids, 21 anthraquinones, and 12 cinnamic acids, to the ATP-binding cleft of JAK2 to identify potential herbal inhibitors of JAK2. Methods. The binding affinities between ligands and JAK2 were calculated utilizing AutoDock 4.0 software in conjunction with the Cygwin environment. Cross-validation was conducted using the Schrödinger tool. Molecular dynamics simulations were employed to evaluate the stability of docked poses for the most significant JAK2 inhibitors. Furthermore, the Discovery Studio Visualizer tool was utilized to elucidate interactions between the top-ranked JAK2 inhibitors and residues within the JAK2 ATP-binding site. Results. Twelve flavonoids, two anthraquinones, and three cinnamic acids demonstrated substantial binding affinities to the protein kinase domain of the receptor, with a criterion of Δ G binding < −10 kcal/mol. Among the studied flavonoids, anthraquinones, and cinnamic acid derivatives, orientin, chlorogenic acid, and pulmatin emerged as the most potent JAK2 inhibitors, exhibiting Δ G binding scores of −14.49, −11.87, and −10.76 kcal/mol, respectively. Furthermore, the docked poses of orientin, pulmatin, and chlorogenic acid remained stable throughout 60 ns computer simulations. The average root mean square deviation values calculated for JAK2 when complexed with orientin, chlorogenic acid, and pulmatin were 2.04 Å, 2.06 Å, and 1.95 Å, respectively. Conclusion. This study underscores the robust inhibitory potential of orientin, pulmatin, and chlorogenic acid against JAK2. The findings hold promise for the development of novel and effective drugs for cancer treatment. [ABSTRACT FROM AUTHOR]

Background: Pemetrexed (PEM) is the primary chemotherapy for non‐small cell lung cancer (NSCLC), showing potential for long‐term disease stability in certain cases. However, studies examining disease control with PEM therapy are lacking. This study aimed to pinpoint clinical traits in patients with NSCLC responding well to PEM therapy, predict factors influencing disease control, and suggest optimal treatment approaches. Methods: A retrospective analysis of patients with NSCLC treated with PEM was performed to compare patients who achieved disease control after treatment with those who did not. Results: Of 73 patients, 56 (76.7%) achieved disease control with PEM therapy. In the disease control group, a significantly higher proportion of patients exhibited good performance status (PS) and received PEM doses without reduction after the second cycle. Multivariate analysis identified bevacizumab (Bev) noncompliance, PEM dose reduction, and thyroid transcription factor‐1 (TTF‐1) negativity as significant independent risk factors for disease progression during PEM therapy. Additionally, overall survival was significantly longer in the disease control group (p < 0.001). Conclusions: Our findings indicated that maintaining the dose of PEM after the second treatment cycle in patients with NSCLC, along with concurrent use of Bev and the presence of TTF‐1 positivity, could enhance disease control rates and extend survival. [ABSTRACT FROM AUTHOR]

The article provides information on Toripalimab-tpzi, a programmed death receptor-1 (PD-1)-blocking antibody, an antineoplastic agent. Toripalimab-tpzi is used in combination with cisplatin and gemcitabine for first-lien treatment of adults with metastatic or recurrent locally advanced nasopharyngeal carcinoma (NPC). Also mentioned are its dosage and administration, drug interactions, and advice to patients.

We present a patient with lung adenocarcinoma showing high PD‐L1 expression and BRAF V600E mutation, who achieved a remarkable long‐term response to the combination therapy of dabrafenib and trametinib (DT treatment) after disease progression on immunotherapy. This case may provide an opportunity for clinicians to consider the order of administration of immunotherapy and molecular targeted therapy for BRAF V600E‐positive lung cancer. [ABSTRACT FROM AUTHOR]

Little is known about the outcome for HIV-associated Hodgkin lymphoma (HIV-HL) as this is less common than HIV-negative lymphoma. Therefore, we performed a multi-center study to analyze the clinical characteristics and outcomes of HIV-HL patients in China. Nineteen cases of HIV-HL were diagnosed and treated at three center and including the sixth people's hospital of Zhengzhou, Peking union medical college hospital, and Chongqing university cancer hospital, between December 2013 and June 2022. Data on the clinical features, laboratory results, response, and prognosis were collected and analyzed. The median age at diagnosis was 43(22–74) years. All patients were infected with HIV through sexual transmission, with ten cases transmitted through man having sex with man (MSM) and nine cases transmitted through heterosexual transmission. Seven patients were diagnosed with lymphoma and found to be infected with HIV. Four cases were in stage III, and fifteen cases were in stage IV. After a median follow up of 46.8(4.0-112.9) months, 17 cases were alive after ABVD regimen chemotherapy combined with combination antiretroviral therapy (cART). The 5-year progression-free survival (PFS) and overall survival (OS) rate were 83.9% and 89.5%,respectively. HIV-HL exhibits an invasive process in clinical practice, and cART combined with ABVD regimen chemotherapy can achieve long-term survival for patients. [ABSTRACT FROM AUTHOR]

Simple Summary: This is a comprehensive overview of the approved chimeric antigen receptor T-cell products (CAR T-cells), their specific indications, treatment-related side effects, and scientific challenges. CAR T-cells have been introduced to modern hematology over the last years and have changed treatment outcomes in heavily pretreated patients with B-cell and plasma cell malignancies. To date, six commercially available CAR T-cell products have been approved by the U.S. Food and Drug Administration (FDA) and by the European Medicines Agency (EMA). These advanced therapeutic medicinal products induce strong treatment effects but can also cause adverse events that can potentially be life-threatening. Therefore, a thorough understanding of CAR T-cell function and characteristics is essential for safety and efficacy. This review provides a comprehensive overview of the clinical applications of CAR T-cells, focusing on the approved products and emphasizing their benefits but also indicating limitations and challenges. Chimeric antigen receptor (CAR) T-cell therapy has become a powerful treatment option in B-cell and plasma cell malignancies, and many patients have benefited from its use. To date, six CAR T-cell products have been approved by the FDA and EMA, and many more are being developed and investigated in clinical trials. The whole field of adoptive cell transfer has experienced an unbelievable development process, and we are now at the edge of a new era of immune therapies that will have its impact beyond hematologic malignancies. Areas of interest are, e.g., solid oncology, autoimmune diseases, infectious diseases, and others. Although much has been achieved so far, there is still a huge effort needed to overcome significant challenges and difficulties. We are witnessing a rapid expansion of knowledge, induced by new biomedical technologies and CAR designs. The era of CAR T-cell therapy has just begun, and new products will widen the therapeutic landscape in the future. This review provides a comprehensive overview of the clinical applications of CAR T-cells, focusing on the approved products and emphasizing their benefits but also indicating limitations and challenges. [ABSTRACT FROM AUTHOR]

Simple Summary: Skin cancer is the most common cancer type worldwide, and melanoma is its most aggressive and deadly form. In the past few decades, targeted therapy and immunotherapy have drastically increased survival chances for melanoma patients. However, not all patients respond to these therapies, and the majority of patients experience tumor relapse after initial response to the treatment. Continuous efforts are required to not only develop new therapeutic agents to treat this deadly disease but also to understand the underlying mechanisms leading to resistance of the tumors to treatment. In this review, we summarize data on available therapeutics for the treatment of melanoma and current knowledge on the mechanisms of resistance to melanoma therapies. Melanoma is the most aggressive and deadly form of skin cancer due to its high propensity to metastasize to distant organs. Significant progress has been made in the last few decades in melanoma therapeutics, most notably in targeted therapy and immunotherapy. These approaches have greatly improved treatment response outcomes; however, they remain limited in their abilities to hinder disease progression due, in part, to the onset of acquired resistance. In parallel, intrinsic resistance to therapy remains an issue to be resolved. In this review, we summarize currently available therapeutic options for melanoma treatment and focus on possible mechanisms that drive therapeutic resistance. A better understanding of therapy resistance will provide improved rational strategies to overcome these obstacles. [ABSTRACT FROM AUTHOR]

Simple Summary: Sarcomas are a group of rare heterogeneous neoplasms of mesenchymal origin. Despite attendant difficulties in study of such disease states, there has been at least one US Federal Drug Administration (FDA) treatment approval for sarcomas in 8 of the last 11 years since 2013. The relative costs, as well as trends in the marketplace, for medications approved for sarcoma have heretofore been unexplored. Given the expansion of medical treatments for sarcoma subtypes in the past decade, it is vital to assess the current status of the landscape to better comprehend achieved successes, challenges, and future directions. Herein, we provide an overview of some of the trends in FDA approvals as well as their associated costs and correlations with incidence as well as outcomes. Sarcomas represent a diverse set of both malignant and benign subtypes consisting of often rare and ultra-rare conditions. Over the course of the last decade, there have been numerous FDA approvals for agents treating various sarcoma subtypes. Given this burgeoning landscape of sarcoma treatments, we seek to review current FDA-approved agents with respect to their rates of incidence, approval rates, and financial costs. We gathered clinical trial data by searching FDA approval announcements from 2013 to 2023. We determined the 30 day and one year cost of therapy for patients of FDA-approved sarcoma treatments in the aforementioned timeframe. From 2013 to 2023, 14 medications have been FDA-approved for sarcoma subtypes. The 30-day dosing prices for these medications range from $11,162.86 to $46,926.00. Since 2013, the rates of approval for sarcoma medications have been higher than in prior decades. Nonetheless, there remains the potential for significant financial toxicity for patients living with sarcoma. [ABSTRACT FROM AUTHOR]

Simple Summary: In the present framework of constraints on healthcare budgets, an assessment of costs of antineoplastic drugs is a crucial step in contributing to the sustainability of public-payer systems. This study evaluated the characteristics of cancer clinical trials and potential drug cost avoidance in a large population of adult cancer patients with solid tumors enrolled in clinical trials over a 10-year period (2010–2019). These trials were conducted at the Medical Oncology Department of Vall d'Hebron University Hospital in Barcelona (Spain), one of the largest tertiary care centers in the country. Based on the data of 2930 clinical trials with 10,488 participants, it was found that the total cost of antineoplastic drugs supplied by sponsors in the clinical trials setting was EUR 107,306,084, with a potential cost savings of EUR 92,662,609. Participation in sponsored clinical trials in which drugs are provided free of charge yields considerable cost savings, with benefits in clinical strategies to reduce drug expenditures. The objective of this single-center retrospective study was to describe the clinical characteristics of adult patients with solid tumors enrolled in cancer clinical trials over a 10-year period (2010–2019) and to assess drug cost avoidance (DCA) associated with sponsors' contributions. The sponsors' contribution to pharmaceutical expenditure was calculated according to the actual price (for each year) of pharmaceutical specialties that the Vall d'Hebron University Hospital (HUVH) would have had to bear in the absence of sponsorship. A total of 2930 clinical trials were conducted with 10,488 participants. There were 140 trials in 2010 and 459 in 2019 (228% increase). Clinical trials of high complexity phase I and basket trials accounted for 34.3% of all trials. There has been a large variation in the pattern of clinical research over the study period, whereas, in 2010, targeted therapy accounted for 79.4% of expenditure and cytotoxic drugs for 20.6%; in 2019, immunotherapy accounted for 68.4%, targeted therapy for 24.4%, and cytotoxic drugs for only 7.1%. A total of four hundred twenty-one different antineoplastic agents were used, the variability of which increased from forty-seven agents in 2010, with only seven of them accounting for 92.8% of the overall pharmaceutical expenditure) to three hundred seventeen different antineoplastic agents in 2019, with thirty-three of them accounting for 90.6% of the overall expenditure. The overall expenditure on antineoplastic drugs in clinical care patients not included in clinical trials was EUR 120,396,096. The total cost of antineoplastic drugs supplied by sponsors in a clinical trial setting was EUR 107,306,084, with a potential DCA of EUR 92,662,609. Overall, clinical trials provide not only the best context for the progress of clinical research and healthcare but also create opportunities for reducing cancer care costs. [ABSTRACT FROM AUTHOR]

Simple Summary: The metabolism of cancer cells and the tumor microenvironment are of increasing interest as part of ongoing efforts to develop potential adjuvant therapies to be used along with conventional chemotherapy and radiation. In this report, the antitumor properties of two compounds that affect glucose metabolism, dichloroacetate and quercetin, are examined. Both DCA and quercetin, a naturally occurring plant flavonoid found in fruits and vegetables, demonstrate inhibitory effects on the growth of head and neck cancer both in cell culture and in a preclinical mouse model of head and neck cancer. These two compounds have synergistic antitumor effects when combined, both in vitro and in vivo. The drug combination inhibited tumor growth and induced cell death with the maintenance of an unfavorable tumor microenvironment. The altered tumor microenvironment appears to enhance immune-mediated clearance of tumors. Thus, this study supports additional preclinical research to further explore the antitumor effects of DCA and quercetin. Elevated glucose uptake and production of lactate are common features of cancer cells. Among many tumor-promoting effects, lactate inhibits immune responses and is positively correlated with radioresistance. Dichloroacetate (DCA) is an inhibitor of pyruvate dehydrogenase kinase that decreases lactate production. Quercetin is a flavonoid compound found in fruits and vegetables that inhibits glucose uptake and lactate export. We investigated the potential role and mechanisms of DCA, quercetin, and their combination, in the treatment of HPV-positive head and neck squamous cell carcinoma, an antigenic cancer subtype in need of efficacious adjuvant therapies. C57Bl/6-derived mouse oropharyngeal epithelial cells, a previously developed mouse model that was retrovirally transduced with HPV type-16 E6/E7 and activated Ras, were used to assess these compounds. Both DCA and quercetin inhibited colony formation and reduced cell viability, which were associated with mTOR inhibition and increased apoptosis through enhanced ROS production. DCA and quercetin reduced tumor growth and enhanced survival in immune-competent mice, correlating with decreased proliferation as well as decreased acidification of the tumor microenvironment and reduction of Foxp (+) Treg lymphocytes. Collectively, these data support the possible clinical application of DCA and quercetin as adjuvant therapies for head and neck cancer patients. [ABSTRACT FROM AUTHOR]

Simple Summary: In this randomized phase II trial, which included 117 older patients with metastatic colorectal cancer receiving LV5FU2 regimen with or without aflibercept, the primary endpoint was 6-month progression-free survival (PFS). The clinical hypotheses expected a PFS rate at 6 months of over 40% (60% expected). It was 54.7% in both arms (90% CI 42.5–66.5 in both). Given the 6-month PFS, the study can be considered positive. However, the toxicity of aflibercept in this elderly population was high (grade ≥ 3 toxicity in 82% of patients versus 58.2% with LV5FU2 alone), and continuation of the trial into phase III is not envisaged. Fluropyrimidine monotherapy is an option for some patients with inoperable metastatic colorectal cancer. Unlike bevacizumab, the addition of aflibercept, an antibody acting as an anti-angiogenic agent, has never been evaluated in this context. The aim of the study was to determine whether aflibercept could increase the efficacy of fluoropyrimidine monotherapy without increasing toxicity. This multicenter phase II non-comparative trial evaluated the addition of aflibercept to infusional 5-fluorouracil/folinic acid (LV5FU2 regimen) as first-line treatment in patients unfit to receive doublet cytotoxic chemotherapy. The primary endpoint was 6-month progression-free survival (PFS). The clinical hypotheses expected a PFS rate at 6 months of over 40% (60% expected). A total of 117 patients, with a median age of 81 years, were included: 59 in arm A (LV5FU2-aflibercept) and 58 in arm B (LV5FU2 alone). Six-month PFS was 54.7% in both arms (90% CI 42.5–66.5 in both). Median overall survival was 21.8 months (arm A) and 25.1 months (arm B). Overall toxicity was more common in arm A: grade ≥ 3 toxicity in 82% versus 58.2%. Given the 6-month PFS, the study can be considered positive. However, the toxicity of aflibercept in this population was high, and continuation of the trial into phase III is not envisaged. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer (BC) ranks as among the top two commonly diagnosed cancers in women worldwide. Triple-negative breast cancer (TNBC) is recognized globally as the most lethal subtype of BC, with patients often building resistance to conventional chemotherapy treatments. This study assesses the relationship between taxane-based chemotherapy resistance in BC and the oncoprotein epithelial membrane protein 2 (EMP2), with an emphasis on the aggressive TNBC group. Analyses of preclinical models and human tissue samples reveal that EMP2 may not only be used to predict patient response to taxanes but also serve as a therapeutic target for resistant disease. Our findings demonstrate a correlation between elevated EMP2 expression post-chemotherapy and reduced survival outcomes and reveal that targeting EMP2 in conjunction with chemotherapy yields a synergistic reduction in TNBC tumor volume. Thus, results shed light on a novel biomarker for guiding the personalized, targeted treatment of intractable and recurrent TNBC. Breast cancer (BC) remains among the most commonly diagnosed cancers in women worldwide. Triple-negative BC (TNBC) is a subset of BC characterized by aggressive behavior, a high risk of distant recurrence, and poor overall survival rates. Chemotherapy is the backbone for treatment in patients with TNBC, but outcomes remain poor compared to other BC subtypes, in part due to the lack of recognized functional targets. In this study, the expression of the tetraspan protein epithelial membrane protein 2 (EMP2) was explored as a predictor of TNBC response to standard chemotherapy. We demonstrate that EMP2 functions as a prognostic biomarker for patients treated with taxane-based chemotherapy, with high expression at both transcriptomic and protein levels following treatment correlating with poor overall survival. Moreover, we show that targeting EMP2 in combination with docetaxel reduces tumor load in syngeneic and xenograft models of TNBC. These results provide support for the prognostic and therapeutic potential of this tetraspan protein, suggesting that anti-EMP2 therapy may be beneficial for the treatment of select chemotherapy-resistant TNBC tumors. [ABSTRACT FROM AUTHOR]

Simple Summary: The prevalence of second neoplasms among patients with hairy cell leukemia (HCL) treated with cladribine is not negligible. Immunosuppression, high rate of cure, and aging may have a role in the pathogenesis of second cancers after HCL. We aimed to compare the risk of cancer between patients with HCL treated with cladribine and the general population. Concern has emerged about the prevalence of second cancers among patients with hairy cell leukemia (HCL) treated with purine analogs. We investigated 513 patients with HCL treated with cladribine over the last 30 years at 18 Italian centers and calculated their standardized incidence ratios (SIRs). We identified 24 patients with a second cancer diagnosed at a median time from treatment with cladribine of 59.9 months (range: 9.2–169.7 months). All patients with solid neoplasms presented with a limited-stage disease, except four cases of locally advanced cancer; multiple myeloma patients had a smoldering disease, while lymphoma patients had stage Ie and stage IV diseases. Response to therapy was complete in 19 cases; 1 patient is still receiving treatment for a relapsing bladder disease, while 2 patients progressed during treatment and died. These two patients died from unrelated causes: one from infection and one due to surgery complications. The median OS from HCL was 98.5 months (range: 38.4–409.2 months), while the median OS from second cancer was 27.6 months (range: 1–117.8 months). The SIR was 0.86 (95% CI: 0.54–1.30) for males and 1.13 (95% CI: 0.36–2.73) for females: no statistically significant differences were highlighted. We were not able to demonstrate an excess of second cancer or a significant association with the specific studied neoplasm. [ABSTRACT FROM AUTHOR]

Simple Summary: Drugs that target Aurora A kinase as a treatment for cancer can lead to activation of the PI3K/AKT/mTOR pathway and ultimately resistance to treatment. We evaluated the preliminary efficacy of the addition of an inhibitor of this pathway (TORC1/2 inhibitor sapanisertib) to Aurora A kinase inhibitor alisertib in patients with advanced solid cancers, including a group with pancreatic adenocarcinoma. Select patients experienced prolonged stabilization of their cancers when treated with this combination therapy, including two with pancreatic cancer. To explore potential differences in response to this therapy, changes in the tumor tissues and immune system were evaluated, as were changes in imaging that can evaluate tumor activity. The genetic make-up of the tumor as well as spread of cancer to the liver may contribute in this setting. Background: This study further evaluated the safety and efficacy of the combination of alisertib and sapanisertib in an expansion cohort of patients, including a subset of patients with refractory pancreatic adenocarcinoma, with further evaluation of the pharmacodynamic characteristics of combination therapy. Methods: Twenty patients with refractory solid tumors and 11 patients with pancreatic adenocarcinoma were treated at the recommended phase 2 dose of alisertib and sapanisertib. Adverse events and disease response were assessed. Patients in the expansion cohort were treated with a 7-day lead-in of either alisertib or sapanisertib prior to combination therapy, with tumor tissue biopsy and serial functional imaging performed for correlative analysis. Results: Toxicity across treatment groups was overall similar to prior studies. One partial response to treatment was observed in a patient with ER positive breast cancer, and a patient with pancreatic cancer experienced prolonged stable disease. In an additional cohort of pancreatic cancer patients, treatment response was modest. Correlative analysis revealed variability in markers of apoptosis and immune cell infiltrate according to lead-in therapy and response. Conclusions: Dual targeting of Aurora A kinase and mTOR resulted in marginal clinical benefit in a population of patients with refractory solid tumors, including pancreatic adenocarcinoma, though individual patients experienced significant response to therapy. Correlatives indicate apoptotic response and tumor immune cell infiltrate may affect clinical outcomes. [ABSTRACT FROM AUTHOR]

Background: Endocrine therapy (ET) adherence leads to increased survival in breast cancer (BC). How follow-up should be done to maximize adherence is not known. Objectives: To assess adherence to ET, factors favouring adherence to ET and effects on survival in a population-based cohort of BC patients in western Sweden. Design: This is a retrospective study. Methods: We included 358 patients operated for oestrogen receptor-positive BC and recommended 5 years of ET, in Region Halland, Sweden, year 2015 to 2016. Demographical, clinical and pathological data and use of ET were retrieved from the electronic medical records. Patients were considered adherent if taking ET for 5 years or during the full extent of the follow-up, until termination of ET due to BC relapse or death and where renewals of prescriptions of ET covered ⩾80% of the ordinated dose. Two follow-up routines were employed, ie, routine A where patients were contacted annually by nurses and a more passive follow-up routine B where patients were only contacted by nurses at 2 years and 5 years following start of ET. Results: Medication persistence for 4 years and more was good and similar between patients initiating aromatase inhibitor (AI) and tamoxifen (75.7% and 72.0%, respectively, P =.43). More patients initiating AIs changed ET due to side effects compared with patients initiating tamoxifen (24.3% vs 9.9%, respectively, P <.0001). Endocrine therapy adherence was better for follow-up routine B than for follow-up routine A (hazard ratio [HR] = 2.71 [1.44-5.09], P =.0027). Conclusions: Adherence to ET in BC is high in Western Sweden. Less regular nurse-initiated contacts between BC patients and nursesled surprisingly to a better adherence than a more regular nurse-initiated contact. Plain Language Summary: Follow-up routines are important for adherence to anti-hormonal therapy after breast cancer surgery In this study conducted in western Sweden, researchers looked at how well breast cancer (BC) patients followed their prescribed endocrine therapy (ET) for 5 years, which is crucial for their survival. They studied 358 patients diagnosed with oestrogen receptor-positive BC between 2015 and 2016. The study compared two follow-up routines: one where patients were contacted annually by nurses (routine A) and another where patients were contacted only at 2 years and 5 years after starting ET (routine B). Surprisingly, patients in routine B, with less frequent nurse contacts, were more likely to adhere with their ET compared with those in routine A. The study also found that patients taking aromatase inhibitors (AIs) were more likely to switch their ET due to side effects compared with those taking tamoxifen, but overall, adherence rates were similar between the 2 groups. In summary, the study showed that BC patients in western Sweden generally followed their prescribed ET well. In addition, having less frequent nurse-initiated contacts surprisingly improved patient adherence with their treatment. [ABSTRACT FROM AUTHOR]

Women around the world are most frequently afflicted with breast cancer, and it is one of the most frequent causes of cancer death in females. Breast cancer is usually classified according to biomarker status, triple‐negative breast cancer (TNBC) represents a distinct subtype characterized by immunohistochemical findings that denote negativity for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (Her-2) on cancer tissue. It is more common in younger women than in other subtypes. As an invasive breast cancer subtype with a unique drug-resistant phenotype and metastatic burden, it has limited treatment options, and patients have a poor prognosis with high rates of local, distant recurrence and mortality, and there is still a lack of standardized treatment protocols for TNBC. In this review, we delve into the current treatment strategies for TNBC and explore the potential for new approaches and targets in the future. This trial is registered with NCT03997123. [ABSTRACT FROM AUTHOR]

Cervical cancer significantly impacts women's health due to its high mortality rate and increasing prevalence among younger individuals, thereby posing a severe threat. Echinatin is the primary active component of licorice in traditional Chinese medicine. However, studies on its use in cervical cancer treatment are limited. In our study, 198 targets of Echinatin were identified by some databases. Among these, 40 core targets related to cervical cancer were selected. Enrichment analyses revealed that Echinatin operated through genes associated with cell cycle, apoptosis, senescence, and various cancer-related signaling pathways. Differential expression of intersecting targets was verified in the GEO database, and molecular docking also indicated a strong binding capacity between active compounds and identified targets. Moreover, the results of western blot provided further evidence at the protein level. Echinatin hindered the proliferation, migration, and invasion of HeLa and SiHa cells while increasing their apoptosis. This study predicted the potential targets and beneficial effects of Echinatin in cervical cancer treatment, which provides a new avenue for further research into the molecular mechanisms underlying the role of Echinatin in cervical cancer treatment. [ABSTRACT FROM AUTHOR]

Introduction: Cancer is the second most prevalent cause of mortality in the world, despite the availability of several medications for cancer treatment. Therefore, the cancer research community emphasized on computational techniques to speed up the discovery of novel anticancer drugs. Methods: In the current study, QSAR-based virtual screening was performed on the Zinc15 compound library (271 derivatives of methotrexate (MTX) and phototrexate (PTX)) to predict their inhibitory activity against dihydrofolate reductase (DHFR), a potential anticancer drug target. The deep learning-based ADMET parameters were employed to generate a 2D QSAR model using the multiple linear regression (MPL) methods with Leave-one-out cross-validated (LOO-CV) Q2 and correlation coefficient R2 values as high as 0.77 and 0.81, respectively. Results: From the QSAR model and virtual screening analysis, the top hits (09,27, 41,68,74,85,99,180) exhibited pIC50 ranging from 5.85 to 7.20 with a minimum binding score of -11.6 to -11.0 kcal/mol and were subjected to further investigation. The ADMET attributes using the message-passing neural network (MPNN) model demonstrated the potential of selected hits as an oral medication based on lipophilic profile Log P (0.19-2.69) and bioavailability (76.30% to 78.46%). The clinical toxicity score was 31.24% to 35.30%, with the least toxicity score (8.30%) observed with compound 180. The DFT calculations were carried out to determine the stability, physicochemical parameters and chemical reactivity of selected compounds. The docking results were further validated by 100 ns molecular dynamic simulation analysis. Conclusion: The promising lead compounds found endorsed compared to standard reference drugs MTX and PTX that are best for anticancer activity and can lead to novel therapies after experimental validations. Furthermore, it is suggested to unveil the inhibitory potential of identified hits via in-vitro and in-vivo approaches. [ABSTRACT FROM AUTHOR]

OBJECTIVE This study assessed the efficacy of chemotherapeutic agents used in combination with bevacizumab in patients with metastatic ovarian cancer who could not receive platinum. METHODS The study is a retrospective observational study. Kaplan-Meier and Cox regression methods were used for statistical analysis. RESULTS The most common metastatic sites among the 60 patients were the peritoneum (91.7%), liver (51.7%), and lung (20%). As a single agent combined with bevacizumab, 29 (48.3%) patients received paclitaxel, 16 (26.7%) received liposomal doxorubicin, and 15 (25%) received gemcitabine. The median progression- free survival was 7.5 months (95% CI, 3.4-11.4), and the median overall survival was 14.4 months (95% CI, 9.3-19.4). Among the factors that affected overall survival, the number of metastasis sites (p=0.01) was statistically significant. The type of chemotherapy used with bevacizumab (p=0.55), age (p=0.057), liver metastasis (p=0.28), lung metastasis (p=0.19), bone metastasis (p=0.13), and brain metastasis (p=0.12) were not statistically significant. CONCLUSION Single-agent chemotherapy drugs used with bevacizumab demonstrated similar efficacy against ovarian cancer. Patients' performance scores, previous treatment regimens, and side effect profiles should be considered before administering any specific chemotherapy agent in combination with bevacizumab. [ABSTRACT FROM AUTHOR]

As cancer continues to rise globally, there is growing interest in discovering novel methods for prevention and treatment. Due to the limitations of traditional cancer therapies, there has been a growing emphasis on investigating herbal remedies and exploring their potential synergistic effects when combined with chemotherapy drugs. Cinnamaldehyde, derived from cinnamon, has gained significant attention for its potential role in cancer prevention and treatment. Extensive research has demonstrated that cinnamaldehyde exhibits promising anticancer properties by modulating various cellular processes involved in tumor growth and progression. However, challenges and unanswered questions remain regarding the precise mechanisms for its effective use as an anticancer agent. This article aims to explore the multifaceted effects of cinnamaldehyde on cancer cells and shed light on these existing issues. Cinnamaldehyde has diverse anti-cancer mechanisms, including inducing apoptosis by activating caspases and damaging mitochondrial function, inhibiting tumor angiogenesis, anti-proliferation, anti-inflammatory and antioxidant. In addition, cinnamaldehyde also acts as a reactive oxygen species scavenger, reducing oxidative stress and preventing DNA damage and genomic instability. This article emphasizes the promising therapeutic potential of cinnamaldehyde in cancer treatment and underscores the need for future research to unlock novel mechanisms and strategies for combating cancer. By providing valuable insights into the role and mechanism of cinnamaldehyde in cancer, this comprehensive understanding paves the way for its potential as a novel therapeutic agent. Overall, cinnamaldehyde holds great promise as an anticancer agent, and its comprehensive exploration in this article highlights its potential as a valuable addition to cancer treatment options. [ABSTRACT FROM AUTHOR]

Follicular lymphoma (FL) is the most common subtype of indolent non-Hodgkin lymphoma in Western countries. While FL is generally incurable, standard initial therapies are associated with high response rates and durable remissions for most patients. In addition, novel targeted agents and immunotherapies are changing the treatment algorithm for patients with relapsed or refractory disease. This review discusses the initial staging, prognosis, and treatment options for newly diagnosed and relapsed/refractory FL. Initial treatment options for FL include active surveillance, radiotherapy, rituximab monotherapy, and chemoimmunotherapy. Staging with positron emission tomography/ computed tomography and bone marrow biopsy is crucial for identifying early-stage patients. Most patients with FL will receive chemoimmunotherapy as the initial treatment with options including rituximab or obinutuzumab plus cyclophosphamide, vincristine, and prednisone; cyclophosphamide, doxorubicin, vincristine, and prednisone; bendamustine; or lenalidomide. No significant differences in overall survival have been observed in randomized studies comparing these regimens. Maintenance therapy with rituximab or obinutuzumab in responders to initial chemoimmunotherapy improves progression-free survival. For relapsed/refractory FL, treatment options include chemoimmunotherapy, lenalidomide-based regimens, tazemetostat, chimeric antigen receptor (CAR)-T cell therapy (axicabtagene ciloleucel and tisagenlecleucel), and CD3/ CD20 bispecific antibodies (BsAbs). Given the encouraging outcomes obtained with CAR-T cell therapy and BsAbs, multiple trials are testing these highly active agents in earlier lines of therapy and among high-risk patients with early relapse after frontline chemoimmunotherapy. Additional studies and follow-up are needed to understand how these novel agents may further change treatment algorithms for FL. [ABSTRACT FROM AUTHOR]

Objectives: The transforming growth factor‐Beta (TGF‐ß) pathway may be involved in the radioresistance of head and neck squamous cell carcinoma (HNSCC). This study analyzed TGF‐ß receptor 1 (TGFBR1) expression in HNSCC patients and evaluated the antineoplastic and radiosensitizing effects of vactosertib, a novel TGFBR1 inhibitor, in vitro. Materials and Methods: TGFBR1 expression was examined in HNSCC patients at the mRNA level in silico and the protein level by immunohistochemistry, including surgical specimens of primary tumors, matched lymph node metastasis, and recurrent disease. Furthermore, a novel small molecule TGFBR1 inhibitor was evaluated in HNSCC cell lines. Finally, an indirect coculture model using patient‐derived cancer‐associated fibroblasts was applied to mimic the tumor microenvironment. Results: Patients with high TGFBR1 mRNA levels showed significantly worse overall survival in silico (OS, p = 0.024). At the protein level, an association between TGFBR1+ tumor and OS was observed for the subgroup with TGFBR1‐stroma (p = 0.001). Those results prevailed in multivariable analysis. Inhibition of TGFBR1 showed antineoplastic effects in vitro. In combination with radiation, vactosertib showed synergistic effects. Conclusion: Our results indicate a high risk of death in tumorTGFBR1+|stromaTGFBR1‐ expressing patients. In vitro data suggest a potential radiosensitizing effect of TGFBR1 inhibition by vactosertib. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme (GBM), is a frequent class of malignant brain tumors. Epigenetic therapy, especially with synergistic combinations is highly paid attention for aggressive solid tumors like GBM. Here, RSM optimization has been used to increase the efficient arrest of U87 and U251 cell lines due to synergistic effects. Cell lines were treated with SAHA, 5-Azacytidine, GSK-126, and PTC-209 individually and then RSM was used to find most effective combinations. Results showed that optimized combinations significantly reduce cell survival and induce cell cycle arrest and apoptosis in both cell lines. Expression of cyclin B1 and cyclin D1 were decreased while caspase3 increased expression. [ABSTRACT FROM AUTHOR]

Although the field of oncology pharmacotherapy has progressed rapidly with the introduction of novel targeted therapies, there are many unintended side effects that require knowledge of laboratory monitoring for appropriate management. The purpose of this article is to summarize the importance of appropriately interpreting laboratory test results, understanding the implications of blood chemistries, and using resources available for monitoring the parameters of novel oncologic therapies. AT A GLANCE * Novel targeted drugs used in cancer treatment can have off-target effects that may affect many organ systems, depending on the drug. * Off-target effects create less predictable side effect profiles compared with cytotoxic chemotherapy. * Nurses can manage treatment side effects through monitoring of laboratory results. [ABSTRACT FROM AUTHOR]

Objective: To determine the awareness and knowledge levels of osteoporosis in postmenopausal breast cancer survivors (PBCS) who have completed adjuvant chemoradiotherapy, are under hormonal therapy, or are being monitored, and to examine potentially related factors. Materials and Methods: Between March 2022 and December 2022, 73 breast cancer patients with clinically and biochemically proven menopause were included in the study. The demographic characteristics and clinical findings of the patients were recorded. The participants' osteoporosis knowledge level (OKL) regarding osteoporosis was evaluated with the osteoporosis knowledge test and their osteoporosis awareness level (OAL) was evaluated with the osteoporosis awareness test. P values <0.05 were considered statistically significant. Results: The mean age of the patients was 59.8±9.4 years (minimum-maximum: 32-75). Their OKL's were categorized as follows: 9.6% poor, 58.9% moderate and 31.5% good. Nutrition knowledge level (NKL) was distributed as follows: 9.6% poor, 37.3% moderate and 52.1% good. Exercise knowledge level (EKL) was distributed as follows: 13.7% poor, 31.5% moderate and 54.8% good. As the patient's age increased, it was observed that OAL, OKL, NKL and EKL decreased. A statistically significant correlation was found between higher education level and higher OAL (r=0.246, p=0.036). There was a significant inverse correlation between menopausal duration and OKL (r=-0,280, p=0.017). There was no significant difference in OAL, OKL, NKL and EKL between patients who received hormone therapy and those who did not. Conclusion: Our study, which assessed the awareness level of osteoporosis for the first time in PBCS, indicates the need for further research on the development of patient education programs for osteoporosis prevention and the improvement of methodological approaches specific to measuring awareness and knowledge levels in cancer patients. [ABSTRACT FROM AUTHOR]

* Context.--Unlike B-cell acute lymphoblastic leukemia/lymphoma (ALL/LBL), there have been few therapeutic advances in T-cell ALL (T-ALL)/LBL, an aggressive ALL/LBL subtype. Objective.--To perform a focused tissue array study to elucidate tumor markers of therapeutic potential in T-ALL/LBL. Design.--Using immunohistochemistry, we evaluated expression of leukemic antigens of interest, specifically CCchemokine receptor 4 (CCR4), among others, on available remnant diagnostic material, including tumor tissue slides obtained from formalin-fixed, paraffin-embedded preserved tissues. Results.--Our analysis identified, for the first time, expression of CCR4 in T-ALL/LBL in 11 of 27 cases (40.7%) and confirmed common expression of BCL2, CD38, and CD47, as reported previously. We also identified the expression of CD123 in 4 of 26 cases (15.4%), whereas BCL6 and PDL1 were expressed in a small number of T-ALL/LBL cases. The potential novel target CCR4 was significantly more common in the Pre/Pro-T immunophenotypic subtype, 6 of 9 (66.7%, P = .01). No additional differences in clinical and epidemiologic variables were noted among positive or negative CCR4 cases. Conclusions.--These findings support preclinical and clinical testing of therapies targeting CCR4, CD47, BCL2, CD38, and CD123 in T-ALL/LBL, and may help guide the development of targeted clinical trials in T-ALL/LBL, a rare disease in urgent need of novel therapies. [ABSTRACT FROM AUTHOR]

SMARCA4-deficient undifferentiated thoracic tumors are a rare phenomenon. A 40-year-old male was newly diagnosed with SMARCA4-deficient undifferentiated non-small cell lung cancer. He had a history of heavy smoking and job-related exposure to metal dust and melted nickel. CT imaging showed numerous right-sided pleural masses and soft tissue plaques, but no metastases. CT-guided biopsy of a pleural mass confirmed the diagnosis. He was prescribed six cycles of carboplatin paclitaxel, and follow-up imaging showed largely stable disease. Treatment was changed to nivolumab due to shortness of breath, and he received one cycle of nivolumab without considerable side effects. Unfortunately, during the second cycle of his nivolumab, the patient presented with new weakness. Imaging showed spinal cord metastasis and he underwent a laminectomy; he was subsequently followed up as an outpatient. The objective of this publication was to explore SMARCA4-deficient undifferentiated thoracic tumors, other related SMARCA4-deficient tumors, and their overall pattern of presentation. The genetic aberrations of this case are compared to recent publications that also discuss genetic aberrations commonly occurring with this disease process, with an ultimate goal of hastening detection and adding to the library of treatment results. [ABSTRACT FROM AUTHOR]

Blood cell biomarkers, such as the neutrophil-lymphocyte ratio (NLR) and the platelet-lymphocyte ratio (PLR), have been recently used as prognostic markers in tumors. In this study, we investigated the association between NLR and PLR with sociodemographic, clinical, anthropometric, and quality of life factors of hospitalized women with non-metastatic breast cancer. A cross-sectional observational study was conducted at a reference center for oncological treatment in Southeast Brazil. Female participants aged over 18 years, with a histopathological diagnosis of stage I, II or III breast cancer, in any phase of antineoplastic treatment, were included. Our study revealed a high risk for participants, with high mean values of NLR and PLR, indicating low antitumor activity and worse prognosis. The binary logistic regression model showed that there was a significant association of the NLR marker and marital status (OR = 3.1; 95%CI = 1.06-8.57; p = 0.03) and, in relation to PLR, a trend was shown for a higher chance in women of black ethnicity to have increased PLR compared to white women (OR = 4.13; 95%CI = 0.96-17.70; p = 0.05). However, the inflammatory markers (NLR and PLR) did not show any significant association with nutritional factors. NLR and PLR are inflammatory biomarkers that can be easily obtained and measured in clinical practice. [ABSTRACT FROM AUTHOR]

The antibiofilm, antibacterial, antioxidant, and anticancer activities of the methanolic extract of Padina pavonica L. were determined. Results deduced that the algal extract had a high biofilm formation inhibitory action done via crystal violet (CV) assay, to 88–99%. The results showed a strong antibacterial against the identified bacteria species. Staphylococcus aureus, Enterococcus faecalis, Pseudomonas aeruginosa, Klebsiella pneumonia, Bacillus subtilis, and the extract had moderate antibacterial activity against Escherichia coli, Pseudomonas fluorescens and Streptococcus agalactiae. The algal extract has a concentration-dependent DPPH radical scavenging activity (84.59%, with IC50 = 170.31 µg/ml). The inhibitory percent of P. pavonica methanolic extract in vitro antiproliferative activity was 1.79–98.25% with IC50 = 15.14 µg/ml against lung carcinoma. Phenols, terpenes, amino acids, alkaloids, flavones, alcohols, and fatty acids were among the metabolites whose biological actions were evaluated. In conclusion, for the first time, P. pavonica methanolic extract exhibited effective antibiofilm, antibacterial, antioxidant, and anticancer activities. [ABSTRACT FROM AUTHOR]

Introduction: To introduce a drug to the market, it's not mandatory for it to be more effective and safer than the current treatment for the same condition. Consequently, head-to-head studies between the two best treatments for the same condition are not required, and this could result in a lack of information for patients, clinicians, and decision-makers. This study aims to evaluate the presence of head-to-head studies among the drugs used for the treatment of non-small cell lung cancer (NSCLC). Methods: Taking into account the National Comprehensive Cancer Network (NCCN) guidelines updated to 2022, which list all available treatments for each NSCLC subtype, the search engine Pubmed and the platform clinicaltrials.gov were consulted to find all completed and ongoing head-to-head studies among various treatments for NSCLC. Results: Among the anti-EGFR (epidermal growth factor receptor) drugs, 7 studies were found, with 6 completed and 5 registrational for drug commercialisation. No completed study to date has compared osimertinib and afatinib. For anti-ALK (anaplastic lymphoma kinase) drugs, 7 studies were found, with 5 completed. Alectinib, brigatinib, and lorlatinib have no completed comparison studies, but all were compared with crizotinib. Among various immunotherapy-based regimens, 5 studies were found, with only 1 completed. Therapeutic regimens based on pembrolizumab, atezolizumab, or the combination of nivolumab/ipilimumab have not been compared in studies published to date. Conclusion: There are few head-to-head studies comparing treatments for NSCLC; there are no such studies between the latest generation of drugs. Consequently, ambiguous areas exist due to the lack of comparative studies among the available evidence, preventing the clinician's choice of the most effective treatment and risking the patient receiving suboptimal therapy. Simultaneously, the price of the drug cannot be determined correctly, relying only on indirect evaluations from different trials. To dispel this uncertainty, it would be desirable to initiate a process that brings together the demands derived from clinical practice and clinical research to provide clinicians and patients with the best possible evidence. [ABSTRACT FROM AUTHOR]

The World Health Organization (WHO) published its first Essential Medicines List (EML) in 1977, and it is updated biennially. One might reasonably think drugs on the EML are there because they are critical to effective, evidence-based patient care and intervention. One might not reasonably guess, however, that a particular drug's supply chain vulnerabilities that make it a shortage risk would contribute to a drug's listing on the EML. This commentary on a case first describes why the WHO makes the EML and suggests reasons why it might be important to consider a drug's shortage risk when revising and updating it. This commentary also suggests how distinguishing "essential" drugs from "vulnerable" drugs could bolster supply chain resiliency and mitigate drug shortages' disruptions to patient care. [ABSTRACT FROM AUTHOR]

Simple Summary: Glycolysis and oxidative phosphorylation play important roles in the progression and growth of cancers. The development of natural products and their semisynthetic derivatives for cancer treatment is a longstanding focus of our research interests. We developed compounds known as diaminobutoxy-substituted isoflavonoids (DBIs) that effectively stimulated Adenosine 5′ Monophosphate-activated Protein Kinase (AMPK) and suppressed the growth of colorectal cancer cells by specifically targeting mitochondrial complex I. We now report a new DBI analog, namely, DBI-2, with promising properties for cancer treatment. The combination of DBI-2 and BAY-876, a glucose transporter 1 inhibitor, exhibited synergistic effects on colorectal cancer cells. Furthermore, the therapeutic effectiveness of DBI-2 in colorectal cancer cell xenograft mouse models was enhanced by implementing a ketogenic diet, an outcome that indicated this drug/diet combination is a potentially promising combination strategy for cancer therapy. Cancer cells undergo a significant level of "metabolic reprogramming" or "remodeling" to ensure an adequate supply of ATP and "building blocks" for cell survival and to facilitate accelerated proliferation. Cancer cells preferentially use glycolysis for ATP production (the Warburg effect); however, cancer cells, including colorectal cancer (CRC) cells, also depend on oxidative phosphorylation (OXPHOS) for ATP production, a finding that suggests that both glycolysis and OXPHOS play significant roles in facilitating cancer progression and proliferation. Our prior studies identified a semisynthetic isoflavonoid, DBI-1, that served as an AMPK activator targeting mitochondrial complex I. Furthermore, DBI-1 and a glucose transporter 1 (GLUT1) inhibitor, BAY-876, synergistically inhibited CRC cell growth in vitro and in vivo. We now report a study of the structure–activity relationships (SARs) in the isoflavonoid family in which we identified a new DBI-1 analog, namely, DBI-2, with promising properties. Here, we aimed to explore the antitumor mechanisms of DBIs and to develop new combination strategies by targeting both glycolysis and OXPHOS. We identified DBI-2 as a novel AMPK activator using an AMPK phosphorylation assay as a readout. DBI-2 inhibited mitochondrial complex I in the Seahorse assays. We performed proliferation and Western blotting assays and conducted studies of apoptosis, necrosis, and autophagy to corroborate the synergistic effects of DBI-2 and BAY-876 on CRC cells in vitro. We hypothesized that restricting the carbohydrate uptake with a KD would mimic the effects of GLUT1 inhibitors, and we found that a ketogenic diet significantly enhanced the therapeutic efficacy of DBI-2 in CRC xenograft mouse models, an outcome that suggested a potentially new approach for combination cancer therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Aggressive angiomyxoma is a mesenchymal tumor with localized aggressiveness, affecting the connective tissue of the perineum or the lower pelvis. Prevalence in the population is unknown due to its rarity, making management and counseling difficult. The management of angiomyxoma includes multiple types of treatment, such as radical surgery with tumor-free margins, but the probability of local recurrence is high, despite extensive excision with unscathed mar-gins. Considering the low mitotic activity of angiomyxoma, there is not always a rationale for adjuvant radiotherapy and chemotherapy. Given its exceptionally low incidence, optimal management of the disease remains a subject of on-going debate, and a unanimous consensus on treatment strategies has yet to be reached. Aggressive angiomyxoma (AAM) is a rare, locally aggressive, myxoid mesenchymal neoplasm primarily found in the pelvic and perineal regions of young adult females. It is a slow growing and locally infiltrating tumor. Preoperative diagnosis is difficult due to the rarity of these tumors and absence of characteristic signs and symptoms. The primary management is tumor excision. Incomplete excision is common because of the infiltrating nature of the neoplasm and absence of a definite capsule. Other non- surgical modalities have been employed, such as radiotherapy, embolization, GnRH analogues or other anti-estrogenic agents. Local relapses occur in 30–40% of the cases, and often appear many years (sometimes decades) after the first excision. Occasional distant metastasis has also been reported. A limited number of cases have been reported in the literature, mostly in the form of small case series or isolated case reports. Therefore, the aim of this paper by a team of experts from the MITO rare tumors group is to review clinical findings, pathologic characteristics and outcome of patients affected by this rare condition in order to be able to offer up-to-date guidance on the management of these cases. [ABSTRACT FROM AUTHOR]

Simple Summary: Bladder cancer is a common disease in urological patients. The approach to treatment depends on the severity of the tumor; in this article, we focus on tumors that do not invade the muscle layer of the bladder. Those tumors are resected during an endoscopic procedure (TURBT), but often reoccur. Treating bladder cancer with drugs instead of surgical removal of the bladder (radical cystectomy) is paramount for patients quality of life and overall well-being. The aim of this paper is to review methods of conservative treatment of tumors unresponsive to the typical treatment of choice (BCG instillations). Bladder cancer is the 10th most popular cancer in the world, and non-muscle-invasive bladder cancer (NMIBC) is diagnosed in ~80% of all cases. Treatments for NMIBC include transurethral resection of the bladder tumor (TURBT) and intravesical instillations of Bacillus Calmette-Guérin (BCG). Treatment of BCG-unresponsive tumors is scarce and usually leads to Radical Cystectomy. In this paper, we review recent advancements in conservative treatment of BCG-unresponsive tumors. The main focus of the paper is FDA-approved medications: Pembrolizumab and Nadofaragene Firadenovec (Adstiladrin). Other, less researched therapeutic possibilities are also included, namely: N-803 immunotherapy, TAR-200 and TAR-210 intravesical delivery systems and combined Cabazitaxel, Gemcitabine and Cisplatin chemotherapy. Conservative treatment and delaying radical cystectomy would greatly benefit patients' quality of life; it is undoubtedly the future of BCG-unresponsive NMIBC. [ABSTRACT FROM AUTHOR]

Simple Summary: Head and neck cancer is the seventh most common cancer and most cases of head and neck cancer are squamous cell carcinoma (SCC). Recently, immune checkpoint inhibitors (ICPIs) such as anti-programmed cell death-1 (PD-1) have been developed. The aim of our study was to evaluate the antitumor effect of adenoviral vector carrying B7-1 (AdB7) in a murine SCC model in order to further explore the potential of the B7-1 gene in immunotherapy for head and neck cancers. Results indicated that tumor size was significantly reduced in the mice treated with both AdB7 and anti-mouse PD-1 antibody. Additionally, treatment resulted in significantly increased cell densities of total immune cells and Ki-67+ CD8+ T cells and decreased the number of regulatory T cells. Our findings indicate that adenovirus-mediated B7-1 gene expression may enhance the antitumor effect of antiPD1 against SCC. Background: The goal of this study was to evaluate the antitumor immune effects of B7-1 gene expression in addition to immune checkpoint inhibitor against squamous cell carcinoma. Methods: A murine SCC cell line, KLN205, was infected with adenoviral vector carrying B7-1 (AdB7). Infected cells were injected subcutaneously in the flanks of DBA/2 mice. Three weeks after implantation, anti-mouse PD-1 antibody (antiPD1) was intraperitonially administrated twice a week for a total of six times. Results: CD80 was significantly overexpressed in the AdB7-infected tumors. IFN-gamma in the T cells in the spleen was significantly increased and tumor size was significantly reduced in the mice treated with both AdB7 and antiPD1. Targeted tumors treated with both AdB7 and antiPD1 exhibited significantly increased cell densities of total immune cells as well as Ki-67+ CD8+ T cells and decreased regulatory T cells. Conclusions: These results suggest that the B7-1 gene transfer may enhance the antitumor effect of anti-PD1 antibody against SCC. [ABSTRACT FROM AUTHOR]

Simple Summary: The dramatic improvement in the prognosis of patients with advanced epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) became possible thanks to the advent of EGFR-tyrosine kinase inhibitors (EGFR-TKIs). In a subgroup of EGFR mutations, known as uncommon (ucEGFRmuts) and rare, NSCLC-mutated patients show, most of the time, lower EGFR-TKIs sensitivity than most common mutations, making this a great clinical point of discussion. Here, we summarized recent data about EGFR exon 20 insertion-positive NSCLC patients and Phase 3 trials ongoing, with a specific focus on the PAPILLON study. Uncommon (ucEGFRmuts) and rare epidermal growth factor receptor (EGFR) mutations account for 10–15% of diagnosed cases and consist of a heterogeneous group represented by several clusters within exons 18–21 (e.g., exon 18 point mutations, exon 21 L861X, exon 20 S768I), as well as exon 20 insertions (Ex20ins). Their incidence is under molecular and clinical investigation following recent findings that reported an increase of sensitivity and specificity of next-generation sequencing (NGS) methods. Consequently, their detection allows for the selection of emerging treatment options to significantly improve patients' outcomes in these particular subgroups of EGFR-mutated advanced non-small cell lung cancer (NSCLC). Specifically, this commentary is focused on the notable progress of the Phase 3 PAPILLON study that showed primary efficacy results from amivantamab, a bispecific antibody with specific binding and affinity to extracellular domains of EGFR and MET, plus chemotherapy in the first-line setting for EGFR exon 20 insertion–mutated advanced or metastatic NSCLC patients, as compared with chemotherapy alone, thus becoming the new standard of care in this group of patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Nabpaclitaxel plus gemcitabine is the standard of care treatment for advanced pancreatic ductal adenocarcinoma (PDAC), the third leading cause of cancer-related deaths worldwide. This therapy reported improved overall survival in metastatic PDAC. Despite the efficacy of available treatments, the poor outcome for patients with PDAC necessitates the need for novel therapies. In a preclinical study, a neutralizing monoclonal antibody specific to human platelet-derived growth factor receptor alpha (PDGFRα) has proven its efficacy in advanced PDAC. Further, a PDGFRα monoclonal antibody, olaratumab, in combination with chemotherapy demonstrated clinical benefit in patients with soft tissue sarcoma. In light of the above findings, the current trial evaluates the efficacy and safety of olaratumab and nabpaclitaxel plus gemcitabine combination therapy in treatment-naïve patients with metastatic PDAC. However, the combination therapy failed to improve survival outcomes compared with chemotherapy alone. Nevertheless, the safety profile of olaratumab was consistent with the previous studies. The efficacy and safety of olaratumab plus nabpaclitaxel and gemcitabine in treatment-naïve participants with metastatic pancreatic ductal adenocarcinoma was evaluated. An initial phase 1b dose-escalation trial was conducted to determine the olaratumab dose for the phase 2 trial, a randomized, double-blind, placebo-controlled trial to compare overall survival (OS) in the olaratumab arm vs. placebo arms. In phase 1b, 22 participants received olaratumab at doses of 15 and 20 mg/kg with a fixed dose of nabpaclitaxel and gemcitabine. In phase 2, 159 participants were randomized to receive olaratumab 20 mg/kg in cycle 1 followed by 15 mg/kg in the subsequent cycles (n = 81) or the placebo (n = 78) on days 1, 8, and 15 of a 28-day cycle, plus nabpaclitaxel and gemcitabine. The primary objective of the trial was not met, with a median OS of 9.1 vs. 10.8 months (hazard ratio [HR] = 1.05; 95% confidence interval [CI]: 0.728, 1.527; p = 0.79) and the median progression-free survival (PFS) was 5.5 vs. 6.4 months (HR = 1.19; 95% CI: 0.806, 1.764; p = 0.38), in the olaratumab vs. placebo arms, respectively. The most common treatment-emergent adverse event of any grade across both arms was fatigue. Olaratumab plus chemotherapy failed to improve the OS or PFS in participants with metastatic PDAC. There were no new safety signals. [ABSTRACT FROM AUTHOR]