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Simple Summary: Basal Cell Carcinoma is the most prevalent cancer in the white population, with a 30% lifetime risk for individuals with fair skin. The main treatment goal is to completely remove the tumor while preserving function and appearance. Surgery is usually the preferred method due to its high success rates and the ability to verify that the entire tumor has been excised. However, topical and intralesional immunotherapy, although traditionally secondary to surgery, have demonstrated effectiveness and good cosmetic outcomes. These non-surgical treatments are valuable alternatives for patients who cannot undergo surgery. The objectives of this review are to summarize the current state of topical and intralesional immunotherapy treatments for BCC and to evaluate their potential as effective alternatives for certain patient populations. Basal Cell Carcinoma (BCC) is the most common type of cancer among the white population. Individuals with fair skin have an average lifetime risk of around 30% for developing BCC, and there is a noticeable upward trend in its incidence rate. The principal treatment objectives for BCC involve achieving the total excision of the tumor while maximizing the preservation of function and cosmesis. Surgery is considered the treatment of choice for BCC for two main reasons: it allows for the highest cure rates and facilitates histological control of resection margins. However, in the subgroup of patients with low-risk recurrence or medical contraindications for surgery, new non-surgical treatment alternatives can provide an excellent oncological and cosmetic outcome. An evident and justified instance of these local therapies occurred during the COVID-19 pandemic, a period when surgical interventions carried out in hospital settings were not a viable option. [ABSTRACT FROM AUTHOR]

Simple Summary: Diffuse large B-cell lymphoma (DLBCL) is an aggressive blood cancer and the most common non-Hodgkin lymphoma. DLBCL has a 40% relapse rate with current therapies, warranting investigations into potential vulnerabilities leading to new treatment avenues. Many DLBCLs increase the levels of a protein called BCL2 that blocks lymphoma cell death and contributes to treatment resistance and relapse. A drug was developed to target BCL2 (venetoclax/ABT-199) to induce DLBCL cell death. However, it was ineffective as a single agent, revealing that DLBCL relies on more than BCL2 for survival. Our study of intrinsic venetoclax resistance and developed venetoclax resistance in DLBCL identifies new targetable vulnerabilities in DLBCL by exposing dependencies on critical cellular processes. Our findings have the potential to lead to new treatments for DLBCL and possibly other B-cell lymphomas. Clinical trials with single-agent venetoclax/ABT-199 (anti-apoptotic BCL2 inhibitor) revealed that diffuse large B-cell lymphoma (DLBCL) is not solely dependent on BCL2 for survival. Gaining insight into pathways/proteins that increase venetoclax sensitivity or unique vulnerabilities in venetoclax-resistant DLBCL would provide new potential treatment avenues. Therefore, we generated acquired venetoclax-resistant DLBCL cells and evaluated these together with intrinsically venetoclax-resistant and -sensitive DLBCL lines. We identified resistance mechanisms, including alterations in BCL2 family members that differed between intrinsic and acquired venetoclax resistance and increased dependencies on specific pathways. Although combination treatments with BCL2 family member inhibitors may overcome venetoclax resistance, RNA-sequencing and drug/compound screens revealed that venetoclax-resistant DLBCL cells, including those with TP53 mutation, had a preferential dependency on oxidative phosphorylation. Mitochondrial electron transport chain complex I inhibition induced venetoclax-resistant, but not venetoclax-sensitive, DLBCL cell death. Inhibition of IDH2 (mitochondrial redox regulator) synergistically overcame venetoclax resistance. Additionally, both acquired and intrinsic venetoclax-resistant DLBCL cells were similarly sensitive to inhibitors of transcription, B-cell receptor signaling, and class I histone deacetylases. These approaches were also effective in DLBCL, follicular, and marginal zone lymphoma patient samples. Our results reveal there are multiple ways to circumvent or overcome the diverse venetoclax resistance mechanisms in DLBCL and other B-cell lymphomas and identify critical targetable pathways for future clinical investigations. [ABSTRACT FROM AUTHOR]

Simple Summary: The use of pre-emptive and prophylactic tyrosine kinase inhibitors (TKIs) after allogeneic hematopoietic stem cell transplantation (Allo-SCT) remains highly heterogeneous and very little is known about the use of third generation TKIs in this context. In this paper, we analyze the feasibility of maintenance with ponatinib administered after Allo-SCT to prevent cytologic relapse in a population of 48 patients with Philadelphia-positive acute lymphoblastic leukemia undergoing transplant while in complete cytologic remission. Although with the caution of the retrospective data, our analysis supports the feasibility of a ponatinib maintenance strategy after Allo-SCT, resulting in a low rate of discontinuation due to toxicity and a high probability of survival and relapse-free survival, particularly in the prophylactic group. In the majority of cases where a daily dose of 45 mg was started a dose reduction to 30–15 mg/day was required, which may be the appropriate dose to balance efficacy and tolerability. The administration of TKIs after Allo-SCT in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) remains controversial, and the TKI approach (prophylactic, pre-emptive or salvage) is still heterogeneous in transplant centers. In this context, very little is known about the feasibility and safety of third-generation TKIs. In this paper, we analyze the efficacy and safety of ponatinib (PONA) administered after Allo-SCT to prevent cytologic relapse of Ph + ALL. This is a multicenter observational study including 48 patients (pts) with Ph + ALL (median age 49 years) who received PONA after Allo-SCT while in complete cytological remission (cCR); 26 (54%) had positive minimal residual disease (MRD pos) before Allo-SCT. PONA was administered after Allo-SCT prophylactically (starting with MRD neg) in 26 pts or pre-emptively (starting with MRD pos post-SCT and without hematological relapse) in 22 pts. Patients treated prophylactically with PONA started treatment earlier, at a median of 4.3 months (range 1.5–6) after Allo-SCT, than those treated pre-emptively, who started PONA at a median of 7.4 months (range 2–63) after Allo-SCT (p = 0.01). The median starting dose of PONA was 30 mg/day (range 15–45). A dose reduction was required in 10/48 (21%) of cases, but a permanent discontinuation of PONA, due to toxicity, was required in only 5/48 pts (10.5%). No deaths due to PONA-related adverse events (AEs) were reported. The median follow-up time after Allo-SCT was 34 months (range 7.7–118). At the last follow-up, the median duration of PONA therapy was 22 months (range 2–100). The 5-year OS and RFS after Allo-SCT were 92% and 71%, respectively. The 5-year RFS after Allo-SCT of pts who received PONA prophylaxis was 95%, and it was 57% for those who received PONA pre-emptively (log-rank p = 0.02). In conclusion, this multicenter analysis of 48 patients with Ph + ALL undergoing Allo-SCT while in CcR, although with the caution of the retrospective data, supports the feasibility of PONA maintenance strategy after Allo-SCT with a low rate of discontinuations (10.5%) due to PONA-related AE. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer of the penis is a relatively uncommon cancer that nevertheless can be life threatening when it is at an advanced stage. We summarized the published laboratory results that might lead to new and better treatment approaches, including those that harness the immune system. We identified several opportunities for drug development and corresponding clinical trials that are or will soon be testing these ideas in patients. In conclusion, we outline how these ongoing efforts will hopefully improve outcomes for patients with advanced penile cancer. Discovery of effective systemic therapies for patients with advanced penile cancer has been slow to occur. Comprehensive genomic profiling from several studies shed light on the molecular oncogenesis of penile squamous cell carcinoma (PSCC) and differences between HPV-related and unrelated tumors. While these two subsets of PSCC appear distinct in their biology, there are not yet specific treatment strategies recommended on that basis. Cell surface proteins have been identified that may potentially serve as drug targets for monoclonal antibodies or small molecule inhibitors. Here, we review some of the new biological insights regarding PSCC that could lead to improved therapies, as well as the related clinical trials recently completed or in progress. We conclude that antibody-drug conjugates are especially promising, as are the combinations of immune checkpoint inhibitors with other types of drugs. [ABSTRACT FROM AUTHOR]

Simple Summary: Hepatocellular carcinoma (HCC) is a common cancer and a leading cause of cancer-related deaths worldwide. However, HCC can be effectively treated in selected cases, with liver transplantation representing one of the limited options for potential cure. Unfortunately, many patients are ineligible for liver transplantation either due to an advanced tumor at initial diagnosis or due to disease progression while awaiting liver transplantation. Our review discusses the role of systemic therapies as a bridging treatment to liver transplantation, thereby enabling more HCC patients to undergo potentially curative liver transplantation. Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths. Classically, liver transplantation (LT) can be curative for HCC tumors within the Milan criteria. Bridging strategies to reduce the dropouts from LT waiting lists and/or to downstage patients who are beyond the Milan criteria are widely utilized. We conducted a literature-based review to evaluate the role of systemic therapies as a bridging treatment to liver transplantation (LT) in HCC patients. Tyrosine kinase inhibitors (TKIs) can be used as a systemic bridging therapy to LT in patients with contraindications for locoregional liver-directed therapies. Immune checkpoint inhibitor (ICI) treatment can be utilized either as a monotherapy or as a combination therapy with bevacizumab or TKIs prior to LT. Acute rejection after liver transplantation is a concern in the context of ICI treatment. Thus, a safe ICI washout period before LT and cautious post-LT immunosuppression strategies are required to reduce post-LT rejections and to optimize clinical outcomes. Nevertheless, prospective clinical trials are needed to establish definitive conclusions about the utility of systemic therapy as a bridging modality prior to LT in HCC patients. [ABSTRACT FROM AUTHOR]

Simple Summary: The recent growing interest in intermittent fasting (IF) is attributed to its preclinical benefits in various aspects of cancer management. Novel agents, namely, venetoclax and Bruton tyrosine kinase inhibitors (BTKIs), are widely used in the frontline setting of chronic lymphocytic leukemia (CLL). However, tumor lysis syndrome (TLS) and gastrointestinal bleeding (GIB) are particularly concerning for patients. This narrative review aimed to pioneer the exploration of the potential implications of IF for CLL patients receiving novel agents, focusing on GIB and TLS risks. In fluid-restricted IF, there is a higher risk of TLS with venetoclax due to dehydration, while in fluid-liberal IF, its absorption can be reduced. Moreover, during fasting conditions, the levels of gastric acid increase along with the risk of GIB in patients receiving BTKis. In the context of IF in CLL, further research is warranted to establish the safety of IF in CLL patients on novel agents. Intermittent fasting (IF) has recently gained popularity due to its emerging benefits in reducing weight and improving metabolic health. Concurrently, novel agents (NAs) like venetoclax and Bruton tyrosine kinase inhibitors (BTKIs) have revolutionized the treatment of chronic lymphocytic leukemia (CLL). Unfortunately, it is unclear whether the associated risks of tumor lysis syndrome (TLS) and gastrointestinal bleeding (GIB) are increased in IF practitioners receiving NAs. This review explored the literature available on the permissibility of IF in CLL patients undergoing treatment with first-line NAs (FLNAs). Literature was scoped to identify IF patterns and the available data on TLS and GIB risks associated with food and fluid intake in CLL patients receiving FLNAs. Although current evidence is insufficient to recommend IF in this population, it may be possible for patients on venetoclax to conservatively practice fluid-liberal IF, provided that adequate hydration and the consistent administration of food are achieved. In contrast, considering the significant risk of TLS and the pharmacokinetics of venetoclax, patients should be discouraged from practicing fluid-restricted IF, especially during the ramp-up phase. Moreover, patients on BTKIs ought to refrain from IF due to the possible risk of GIB until further data are available. Further research is needed to provide conclusive recommendations. [ABSTRACT FROM AUTHOR]

Simple Summary: Hepatocellular carcinoma is the sixth most common cancer globally and is considered one of the deadliest health issues worldwide. The rapid emergence of HCC as a global health crisis has undergone a revolutionary change in treatment strategies. Food and Drug Administration-approved drugs such as tyrosine kinase inhibitors, immune checkpoint inhibitors, and angiogenic inhibitors, as monotherapy and in combination therapies have shown significant advancement to enhance patient outcomes across HCC stages. The effect of these treatments on cellular signaling pathways and immune responses offers promising potential for prolonged survival rates. Hepatocellular carcinoma (HCC) is the deadliest emergent health issue around the globe. The stronger oncogenic effect, proteins, and weakened immune response are precisely linked with a significant prospect of developing HCC. Several conventional systemic therapies, antiangiogenic therapy, and immunotherapy techniques have significantly improved the outcomes for early-, intermediate-, and advanced-stage HCC patients, giving new hope for effective HCC management and prolonged survival rates. Innovative therapeutic approaches beyond conventional treatments have altered the landscape of managing HCC, particularly focusing on targeted therapies and immunotherapies. The advancement in HCC treatment suggested by the Food and Drug Administration is multidimensional treatment options, including multikinase inhibitors (sorafenib, lenvatinib, regorafenib, ramucirumab, and cabozantinib) and immune checkpoint inhibitors (atezolizumab, pembrolizumab, durvalumab, tremelimumab, ipilimumab, and nivolumab), in monotherapy and in combination therapy to increase life expectancy of HCC patients. This review highlights the efficacy of multikinase inhibitors and immune checkpoint inhibitors in monotherapy and combination therapy through the analysis of phase II, and III clinical trials, targeting the key molecular pathways involved in cellular signaling and immune response for the prospective treatment of advanced and unresectable HCC and discusses the upcoming combinations of immune checkpoint inhibitors-tyrosine kinase inhibitors and immune checkpoint inhibitors-vascular endothelial growth factor inhibitors. Finally, the hidden challenges with pharmacological therapy for HCC, feasible solutions for the future, and implications of possible presumptions to develop drugs for HCC treatment are reported. [ABSTRACT FROM AUTHOR]

Simple Summary: The demand for multitarget-directed anticancer agents has been steadily increasing, as cancer remains a leading cause of death worldwide. Dyrk and Clk kinases play crucial roles in cancer cell division and survival. Our study presents novel Dyrk1/Dyrk1B/Clk1 inhibitors, developed by modifying our previous class of Clk1 inhibitors. These potent new inhibitors successfully halted the division of cancer cells without impacting normal cells. Additionally, we examined the effect of these compounds on the cell cycle to identify the specific phase affected. Finally, our compounds demonstrated the ability to activate pathways that induce cell death in cancer cells. Numerous studies have reported that Dyrk1A, Dyrk1B, and Clk1 are overexpressed in multiple cancers, suggesting a role in malignant disease. Here, we introduce a novel class of group-selective kinase inhibitors targeting Dyrk1A, Dyrk1B, and Clk1. This was achieved by modifying our earlier selective Clk1 inhibitors, which were based on the 5-methoxybenzothiophene-2-carboxamide scaffold. By incorporating a 5-hydroxy group, we increased the potential for additional hydrogen bond interactions that broadened the inhibitory effect to include Dyrk1A and Dyrk1B kinases. Within this series, compounds 12 and 17 emerged as the most potent multi-kinase inhibitors against Dyrk1A, Dyrk1B, and Clk1. Furthermore, when assessed against the most closely related kinases also implicated in cancer, the frontrunner compounds revealed additional inhibitory activity against Haspin and Clk2. Compounds 12 and 17 displayed high potency across various cancer cell lines with minimal effect on non-tumor cells. By examining the effect of these inhibitors on cell cycle distribution, compound 17 retained cells in the G2/M phase and induced apoptosis. Compounds 12 and 17 could also increase levels of cleaved caspase-3 and Bax, while decreasing the expression of the antiapoptotic Bcl-2 protein. These findings support the further study and development of these compounds as novel anticancer therapeutics. [ABSTRACT FROM AUTHOR]

Simple Summary: Scientists are studying proteins like kinesin spindle protein and Aurora B, crucial for cell division and potential targets in cancer treatment. Drugs aimed at these proteins show promise in lab tests for killing cancer cells, but in clinical trials alone, they are not always effective, possibly due to varied cancer cell responses. To enhance their efficacy, researchers are exploring combinations with other cell-killing drugs. Our study focused on Navitoclax, an inducer of cancer cell death, tested alongside Ispinesib and Barasertib, targeting kinesin spindle protein and Aurora B, respectively. Together, these drugs induced significant cancer cell death, mainly through apoptosis. Moreover, imaging techniques revealing their combined effects suggest that combining these drugs could be a potent cancer treatment strategy, warranting further investigation in clinical trials. Many proteins regulating mitosis have emerged as targets for cancer therapy, including the kinesin spindle protein (KSP) and Aurora kinase B (AurB). KSP is crucial for proper spindle pole separation during mitosis, while AurB plays roles in chromosome segregation and cytokinesis. Agents targeting KSP and AurB selectively affect dividing cells and have shown significant activity in vitro. However, these drugs, despite advancing to clinical trials, often yield unsatisfactory outcomes as monotherapy, likely due to variable responses driven by cyclin B degradation and apoptosis signal accumulation networks. Accumulated data suggest that combining emerging antimitotics with various cytostatic drugs can enhance tumor-killing effects compared to monotherapy. Here, we investigated the impact of inhibiting anti-apoptotic signals with the BH3-mimetic Navitoclax in oral cancer cells treated with the selective KSP inhibitor, Ispinesib, or AurB inhibitor, Barasertib, aiming to potentiate cell death. The combination of BH3-mimetics with both KSP and AurB inhibitors synergistically induced substantial cell death, primarily through apoptosis. A mechanistic analysis underlying this synergistic activity, undertaken by live-cell imaging, is presented. Our data underscore the importance of combining BH3-mimetics with antimitotics in clinical trials to maximize their effectiveness. [ABSTRACT FROM AUTHOR]

Simple Summary: Among the different types of breast cancers, triple-negative breast cancer (TNBC) has a poor prognosis and is the most difficult type to treat by monotherapy due to the absence of common targeting receptors. In our review, we focused on the current advanced combination therapies, which include immunotherapy and chemotherapy, immunotherapy and gene therapy, and nanotechnology-based combination therapies for TNBC treatment. Additionally, we discussed the therapeutic outcomes of in vivo studies and clinical trials of the combination therapies. Triple-negative breast cancer (TNBC), lacking specific receptors found in other breast cancer subtypes, poses significant treatment challenges due to limited therapeutic options. Therefore, it is necessary to develop novel treatment approaches for TNBC. In the last few decades, many attempts have been reported for alternative tools for TNBC treatment: immunotherapy, radiotherapy, targeted therapy, combination therapy, and nanotechnology-based therapy. Among them, combination therapy and nanotechnology-based therapy show the most promise for TNBC treatment. This review outlines recent advancements in these areas, highlighting the efficacy of combination therapy (immunotherapy paired with chemotherapy, targeted therapy, or radiotherapy) in both preclinical and clinical stages and nanotechnology-based therapies utilizing various nanoparticles loaded with anticancer agents, nucleic acids, immunotherapeutics, or CRISPRs in preclinical stages for TNBC treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: The treatment of chronic lymphocytic leukemia is constantly evolving. Within the past few years, the treatment algorithm of patients with CLL has been radically transformed by the introduction of BTK and BCL2 inhibitors. This change has raised the need to optimize their use to ensure the greatest possible efficacy by personalizing therapies as much as possible. This review aims to clarify how to tailor the sequence of different treatments in CLL, and illustrate what resources are currently available to patients previously treated with the different molecules. As treatments with BTK inhibitors and BCL2 inhibitors have replaced the use of chemoimmunotherapy in CLL in both first-line and relapsed patients, it becomes critical to rationalize their use and exploit the full potential of each drug. Despite their proven, robust, and manifest efficacy, BTKis and BCL2is fail to provide long-term disease control in some categories of patients, and to date this is an unmet clinical need that is critical to recognize and address. Ongoing clinical trials are evaluating new treatment algorithms and new molecules to progressively thin this population. In this review for each category of patients we explicate the different possible patterns of treatment sequencing based on currently available evidence, starting from the frontline to currently ongoing trials, in order to optimize therapies as much as possible. [ABSTRACT FROM AUTHOR]

Simple Summary: Targeted agents, such as Bruton's Tyrosine Kinase inhibitors and BCL-2 inhibitors, have transformed the treatment landscape for Chronic Lymphocytic Leukemia (CLL). While these therapies offer a more precise approach compared to traditional chemotherapy, they also bring a spectrum of adverse events that can impact patient health and treatment efficacy. This review aims to provide a comprehensive overview of the management strategies for these AEs, encompassing cardiac complications, Tumor Lysis Syndrome, bleeding risks, and other organ-specific challenges. Our goal is to equip healthcare professionals with the knowledge to effectively manage these adverse events, enhancing patient safety and optimizing therapeutic outcomes. The insights from this review will contribute to better clinical decision-making and patient care in CLL treatment, highlighting the significance of personalized management in the era of targeted therapy. The treatment landscape for CLL has undergone a profound transformation with the advent of targeted agents (TAs) like Bruton's Tyrosine Kinase inhibitors (BTKis) and BCL-2 inhibitors (BCL-2is). These agents target crucial cellular pathways in CLL, offering superior efficacy over traditional chemo-immunotherapy, which has led to improved progression-free and overall survival rates. This advancement promises enhanced disease control and potentially normal life expectancy for many patients. However, the journey is not without challenges, as these TAs are associated with a range of adverse events (AEs) that can impact treatment efficacy and patient quality of life. This review focuses on detailing the various AEs related to TA management in CLL, evaluating their frequency and clinical impact. The aim is to present a comprehensive guide to the effective management of these AEs, ensuring optimal tolerability and efficacy of TAs. By reviewing the existing literature and consolidating findings, we provide insights into AE management, which is crucial for maximizing patient outcomes in CLL therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: The VELOUR randomized phase III trial established aflibercept (an anti-angiogenic targeting VEGF-A, VEGF-B, and placenta growth factor) combined with FOLFIRI as an effective treatment in patients with metastatic colorectal cancer (mCRC) failing a prior oxaliplatin-based regimen. This real-world study mandated by Polish Health Authorities aimed at assessing the benefits/risks of aflibercept plus FOLFIRI prescribed to Polish patients with mCRC according to reimbursement criteria. The activity of aflibercept plus FOLFIRI in such patients was confirmed, and no new safety signal was reported. Background: This was an observational study prospectively evaluating the effectiveness and safety of aflibercept/FOLFIRI administered in second-line mCRC per the reimbursement criteria in Poland. Methods: Consecutive mCRC patients who progressed with first-line oxaliplatin-based chemotherapy received aflibercept (4 mg/kg IV) followed by FOLFIRI every 2 weeks until progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS); overall survival (OS) and safety were the secondary endpoints. Results: A total of 93 patients were treated at 17 Polish sites. A median of 10 cycles was administered. Over a median treatment duration of 5.3 months, median PFS and median OS were 8.4 months [95% CI, 6.9–9.9] and 27.0 months [95% CI, 23.9–30.1], respectively. There was no significant impact of primary tumor location, metastatic site, or KRAS status on PFS and OS. Main grade ≥ 3 adverse events were neutropenia (16%), hypertension (8%), diarrhea (4%), and stomatitis (4%). Conclusions: The benefits/risks of Aflibercept plus FOLFIRI administered per the Polish reimbursement criteria in second-line treatment of mCRC after failure of a prior oxaliplatin-based regimen is confirmed. [ABSTRACT FROM AUTHOR]

Simple Summary: The hallmark of NF2 is bilateral vestibular schwannomas, which progressively enlarge, leading to sensorineural hearing loss, tinnitus, facial weakness, and pain that translates to social impairment and clinical depression. To better understand disease progression and characterize treatment response, we developed a panel of five tests suitable for the mouse vestibular schwannoma model and investigated how tumor growth and treatment affect gait, coordination, and motor function. These methods, paired with hearing tests, enable a comprehensive evaluation of tumor-induced neurological deficits and facilitate the assessment of the effectiveness of novel therapeutics to improve NF2 treatments. NF2-related Schwannomatosis (NF2-SWN) is a disease that needs new solutions. The hallmark of NF2-SWN, a dominantly inherited neoplasia syndrome, is bilateral vestibular schwannomas (VSs), which progressively enlarge, leading to sensorineural hearing loss, tinnitus, facial weakness, and pain that translates to social impairment and clinical depression. Standard treatments for growing VSs include surgery and radiation therapy (RT); however, both carry the risk of further nerve damage that can result in deafness and facial palsy. The resultant suffering and debility, in combination with the paucity of therapeutic options, make the effective treatment of NF2-SWN a major unmet medical need. A better understanding of these mechanisms is essential to developing novel therapeutic targets to control tumor growth and improve patients' quality of life. Previously, we developed the first orthotopic cerebellopontine angle mouse model of VSs, which faithfully mimics tumor-induced hearing loss. In this model, we observed that mice exhibit symptoms of ataxia and vestibular dysfunction. Therefore, we further developed a panel of five tests suitable for the mouse VS model and investigated how tumor growth and treatment affect gait, coordination, and motor function. Using this panel of ataxia tests, we demonstrated that both ataxia and motor function deteriorated concomitantly with tumor progression. We further demonstrated that (i) treatment with anti-VEGF resulted in tumor size reduction, mitigated ataxia, and improved rotarod performance; (ii) treatment with crizotinib stabilized tumor growth and led to improvements in both ataxia and rotarod performance; and (iii) treatment with losartan did not impact tumor growth nor ameliorate ataxia or motor function. Our studies demonstrated that these methods, paired with hearing tests, enable a comprehensive evaluation of tumor-induced neurological deficits and facilitate the assessment of the effectiveness of novel therapeutics to improve NF2 treatments. [ABSTRACT FROM AUTHOR]

Simple Summary: The evaluation of therapeutic approaches over a decade at a tertiary cancer center in Germany was undertaken due to the frequent and critical discussions surrounding the selection of chemotherapy regimens and the incorporation of prophylactic cranial irradiation (PCI) in the management of limited disease small cell lung cancer (LD-SCLC). We found significant differences in progression-free survival (PFS) and overall survival (OS) between patients treated with carboplatin and etoposide (CP) and those treated with cisplatin and etoposide (EP), with EP showing better outcomes. Concomitant chemotherapy was also associated with improved PFS and OS. Notably, PCI was found to significantly improve OS and showed a trend towards improved PFS. Female patients had better OS, and the type of chemotherapy and PCI remained independent predictors of survival. This research provides valuable insights into treatment patterns, outcomes, and survival predictors for LD-SCLC, emphasizing the importance of personalized treatment approaches and the potential benefits of PCI. However, the study's retrospective nature and sample-size limitations should be considered, highlighting the need for further prospective studies in this field. In this study, we investigated the outcomes and factors influencing treatment efficacy in 93 patients with limited disease small cell lung cancer (LD-SCLC), with a median age of 64 years. We focused on the impact of chemotherapy regimens, prophylactic cranial irradiation (PCI), and patient-related variables. The median follow-up for OS was 17.3 months. We observed a statistically significant difference in PFS between LD-SCLC patients treated with cisplatin and etoposide (EP) and those treated with carboplatin and etoposide (CP) (PFS: EP 13.63 months vs. CP 6.54 months, p < 0.01). Patients treated with EP had better overall survival (OS) than CP-treated patients (OS: EP 26.9 months vs. CP 16.16 months, p < 0.01). Concomitant chemotherapy was associated with improved PFS (p = 0.003) and OS (p = 0.002). Patients receiving PCI showed superior OS (p = 0.05) and a trend towards improved PFS (p = 0.057). Female gender was associated with better OS (p = 0.025). Most patients had an ECOG performance status of 0 (71%). This real-world study underscores the importance of multidisciplinary LD-SCLC management, emphasizing the roles of chemotherapy, radiotherapy, and PCI. These findings inform personalized treatment strategies and emphasize the need for prospective trials to validate these results and optimize LD-SCLC treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Discussed here is a review of the changing landscape in the treatment of mantle cell lymphoma (MCL) regarding the emergence and use of targeted therapy. Targeted therapy is the use of small molecules designed to interrupt specific mechanisms within the cancer cell to exert anti-tumor efficacy. Targeting such mechanisms relies upon our understanding of what makes a cancer cell malignant. MCL is a difficult-to-treat lymphoid cancer that relies heavily upon constitutive intracellular signaling, promoting its growth and survival. The mainstay of MCL treatment has been to treat it with cytotoxic chemotherapy; however, targeted therapies have allowed for improved treatment outcomes and continue to change the way we manage this disease. This review aims to describe what targeted therapies are being utilized in MCL treatment and their mechanisms of action, safety, and efficacy, as well as future directions for their use in MCL treatment. Mantle cell lymphoma (MCL) is a rare, heterogeneous B-cell non-Hodgkin's lymphoma. The standard front-line treatment utilizes chemotherapy, often followed by consolidation with an autologous hematopoietic cell transplant; however, in most patients, the lymphoma will recur and require subsequent treatments. Additionally, mantle cell lymphoma primarily affects older patients and is frequently chemotherapy-resistant, which has further fostered the necessity for new, chemotherapy-free treatment options. In the past decade, targeted therapies in mantle cell lymphoma have been practice-changing as the treatment paradigm shifts further away from relying primarily on cytotoxic agents. Here, we will review the pathophysiology of mantle cell lymphoma and discuss the emergence of targeted, chemotherapy-free treatments aimed at disrupting the abnormal biology driving its lymphomagenesis. Treatments targeting the constitutive activation of NF-kB, Bruton's Tyrosine Kinase signaling, and anti-apoptosis will be the primary focus as we discuss their clinical data and toxicities. Our review will also focus primarily on the emergence and use of targeted therapies in the relapsed/refractory setting but will also discuss the emergence of their use in front-line therapy and in combination with other agents. [ABSTRACT FROM AUTHOR]

Simple Summary: Treosulfan and melphalan (TreoMel)-based high-dose chemotherapy (HDCT) has been successfully used as a conditioning regimen in acute myeloid leukemia (AML) patients undergoing autologous stem cell transplantation (ASCT). However, despite intensive first-line induction treatment and upfront consolidation with HDCT and ASCT, AML relapse rates are still high, and further efforts are needed to improve patient outcomes. In this study, we investigated how increased doses of melphalan impact the safety of HDCT with TreoMel and patient outcomes. A total of 51 AML patients were included in the analysis: 31 (60.8%) received standard-dose treosulfan combined with melphalan 140 mg/m2 (TreoMel 140) and 20 (39.2%) received melphalan 200 mg/m2 (TreoMel 200). There were no statistically significant differences in relapse (0.45 vs. 0.30, p = 0.381) and mortality rates (0.42 vs. 0.15, p = 0.064) between the melphalan 140 mg/m2 and 200 mg/m2 cohorts, nor for PFS (HR: 0.81, 95% CI: 0.29–2.28, p = 0.70) or OS (HR: 0.70, 95% CI: 0.19–2.57, p = 0.59) for the TreoMel 140 vs. TreoMel 200 cohorts. The side effect profile was comparable between both patient groups. Our results show that a higher melphalan dose is well tolerated. No significant differences for patient outcomes could be observed, possibly due to the relatively small patient cohort and short follow-up. Longer follow-up and prospective randomized studies would be required to confirm the safety profile and clinical benefit. (1) Background: Treosulfan and melphalan (TreoMel)-based high-dose chemotherapy (HDCT) has shown promising safety and efficacy as a conditioning regimen for acute myeloid leukemia (AML) patients undergoing autologous stem cell transplantation (ASCT). However, despite intensive first-line induction treatment and upfront consolidation with HDCT and ASCT, AML relapse rates are still high, and further efforts are needed to improve patient outcomes. The aim of this study was to compare two melphalan dose schedules in regard to the safety of TreoMel HDCT and patient outcomes. (2) Methods: We retrospectively analyzed the safety and efficacy of two melphalan dose schedules combined with standard-dose treosulfan in AML patients undergoing HDCT and ASCT at the University Hospital of Bern, Switzerland, between August 2019 and August 2023. Patients received treosulfan 42 g/m2 combined with either melphalan 140 mg/m2 (TreoMel 140) or melphalan 200 mg/m2 (TreoMel 200). Co-primary endpoints were progression-free survival (PFS), overall survival (OS), as well as safety profile. (3) Results: We included a total of 51 AML patients: 31 (60.8%) received TreoMel 140 and 20 (39.2%) TreoMel 200. The patients' basal characteristics were comparable between both cohorts. No significant differences in the duration of hospitalization or the adverse event profile were identified. There were no statistically significant differences in relapse (0.45 vs. 0.30, p = 0.381) and mortality rates (0.42 vs. 0.15, p = 0.064) between the melphalan 140 mg/m2 and 200 mg/m2 cohorts, nor for PFS (HR: 0.81, 95% CI: 0.29–2.28, p = 0.70) or OS (HR: 0.70, 95% CI: 0.19–2.57, p = 0.59) for the TreoMel 140 vs. TreoMel 200 cohort. (4) Conclusions: A higher dose of melphalan (TreoMel 200) was well tolerated overall. No statistically significant differences for patient outcomes could be observed, possibly due to the relatively small patient cohort and the short follow-up. A longer follow-up and prospective randomized studies would be required to confirm the safety profile and clinical benefit. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic cancer is predicted to be the second-highest cause of cancer mortality in the US by 2040. It is driven by various mutations including KRAS, TP53, SMAD4, and CDKN2A. Roughly 1 in 10 patients with pancreatic cancer have wildtype KRAS (KRASWT). We studied 27 patients with KRASWT to better understand their molecular characteristics and potential for precision medicine. Our findings revealed that KRASWT PDAC is enriched with potentially treatable genetic alterations, including those affecting the MAPK pathway, DNA repair pathway, and kinase fusion genes. One of our KRASWT PDAC patients was found to have a specific, targetable TFG-MET mutation and they responded well to treatment with a cMET inhibitor. This suggests that KRASWT PDAC has unique genetic characteristics that could be targeted with specific treatments tailored to each patient, highlighting the importance of comprehensive genetic profiling in KRASWT PDAC. Purpose: To investigate the molecular characteristics of and potential for precision medicine in KRAS wildtype pancreatic ductal adenocarcinoma (PDAC). Patients and Methods: We investigated 27 patients with KRASWT PDAC at our institution. Clinical data were obtained via chart review. Tumor specimens for each subject were interrogated for somatic single nucleotide variants, insertion and deletions, and copy number variants by DNA sequencing. Gene fusions were detected from RNA-seq. A patient-derived organoid (PDO) was developed from a patient with a MET translocation and expanded ex vivo to predict therapeutic sensitivity prior to enrollment in a phase 2 clinical trial. Results: Transcriptomic analysis showed our cohort may be stratified by the relative gene expression of the KRAS signaling cascade. The PDO derived from our patient harboring a TFG-MET rearrangement was found to have in vitro sensitivity to the multi-tyrosine kinase inhibitor crizotinib. The patient was enrolled in the phase 2 SPARTA clinical trial and received monotherapy with vebrelitinib, a c-MET inhibitor, and achieved a partial and durable response. Conclusions: KRASWT PDAC is molecularly distinct from KRASMUT and enriched with potentially actionable genetic variants. In our study, transcriptomic profiling revealed that the KRAS signaling cascade may play a key role in KRASWT PDAC. Our report of a KRASWT PDAC patient with TFG-MET rearrangement who responded to a cMET inhibitor further supports the pursuit of precision oncology in this sub-population. Identification of targetable mutations, perhaps through approaches like RNA-seq, can help enable precision-driven approaches to select optimal treatment based on tumor characteristics. [ABSTRACT FROM AUTHOR]

Simple Summary: Low-grade serous ovarian cancer is a rare type of ovarian cancer that usually has an indolent growth and affects younger women. It has markers that suggest it might respond to hormone therapy, but unfortunately, this treatment does not work well for many patients because the cancer becomes resistant to it. We do not fully understand why this happens. In breast cancer, similar resistance mechanisms are studied, so we are exploring if we can apply what we learn there to improve treatment for this type of ovarian cancer. This review looks at why hormone therapy might stop working in ovarian cancer and explores new ways to make it more effective. The goal is to find better treatment options for patients with advanced low-grade serous ovarian cancer, who currently do not have many choices for treatment. Low-grade serous ovarian cancer (LGSOC) is a rare ovarian malignancy primarily affecting younger women and is characterized by an indolent growth pattern. It exhibits indolent growth and high estrogen/progesterone receptor expression, suggesting potential responsiveness to endocrine therapy. However, treatment efficacy remains limited due to the development of endocrine resistance. The mechanisms of resistance, whether primary or acquired, are still largely unknown and present a significant hurdle in achieving favorable treatment outcomes with endocrine therapy in these patients. In estrogen receptor-positive breast cancer, mechanisms of endocrine resistance have been largely explored and novel treatment strategies to overcome resistance have emerged. Considering the shared estrogen receptor positivity in LGSOC and breast cancer, we wanted to explore whether there are any parallel mechanisms of resistance and whether we can extend endocrine breast cancer treatments to LGSOC. This review aims to highlight the underlying molecular mechanisms possibly driving endocrine resistance in ovarian cancer, while also exploring the available therapeutic opportunities to overcome this resistance. By unraveling the potential pathways involved and examining emerging strategies, this review explores valuable insights for advancing treatment options and improving patient outcomes in LGSOC, which has limited therapeutic options available. [ABSTRACT FROM AUTHOR]

Simple Summary: The mainstay of treatment for non-muscle invasive bladder cancer is transurethral resection of the tumor followed by intravesical treatment for intermediate- or high-risk disease. Duration and type of intravesical treatment depend on specific characteristics of the tumor and the patient's disease course. Patients with non-muscle invasive bladder cancer are closely monitored with frequent surveillance cystoscopies following treatment. This type of cancer has a low progression rate; however, it has a high rate of recurrence with the current recommended treatments. Therefore, patients often find themselves having to undergo multiple resections and rounds of intravesical treatment throughout their lifetime. This is not only burdensome for patients but also costly for the healthcare system. Given the high recurrence with the standard treatment options, it is important to continue investigating novel therapies. The goal of this review article is to outline the most recent therapies available or in clinical trials for the treatment of non-muscle invasive bladder cancer. The landscape of treatment for non-muscle invasive bladder cancer is rapidly changing. A complete and careful transurethral resection is the mainstay of initial treatment and is followed by intravesical therapy in intermediate or high-risk cases. The standard of care is intravesical BCG. Many alternative or additive approaches to this are being explored. We divided this review into three relevant spaces to consider these novel treatment approaches: (1) low-risk disease, for which intravesical therapy is not usually considered, (2) BCG-naïve disease (i.e., considering alternatives to the standard therapy), and (3) BCG-unresponsive disease. We performed a review of published literature and summarized ongoing trials in the United States. Novel approaches that we explored include surgical techniques for resection, alterations in dwell time for intravesical therapy, delivery method and schedule of intravesical therapies, new intravesical therapy agents, and systemic therapies (especially immunotherapy). These are thoroughly outlined throughout this review article, and the numerous modalities being studied demonstrate significant promise for the future treatment of the expanding space of NMIBC. [ABSTRACT FROM AUTHOR]

Simple Summary: Classical Hodgkin Lymphoma is a blood cancer, accounting for 0.5% of all new cancer diagnoses. Despite high cure chances, approximately 20% of patients are refractory to frontline treatment or relapse thereafter. Treatment strategies for relapsed/refractory patients have progressively lower chances of inducing a persistent complete remission. Therefore, great efforts are being made to further improve rates of response of frontline therapy, as well as to explore the efficacy of new compounds and different drug combinations. The present review aims to summarize these efforts, offering an overview of recent advances and future perspectives in the field. Classical Hodgkin Lymphoma (cHL) is a highly curable disease, but around 20% of patients experience progression or relapse after standard frontline chemotherapy regimens. Salvage regimens followed by autologous stem cell transplants represent the historical treatment approach for these cases. In the last decade, with the increasing understanding of cHL biology and tumor microenvironment role in disease course, novel molecules have been introduced in clinical practice, improving outcomes in the relapsed/refractory setting. The anti-CD30 antibody-drug conjugated brentuximab vedotin and PD-1/PD-L1 checkpoint inhibitors represent nowadays curative options for chemorefractory patients, and randomized trials recently demonstrated their efficacy in frontline immune-chemo-combined modalities. Several drugs able to modulate the patients' T-lymphocytes and NK cell activity are under development, as well as many anti-CD30 chimeric antigen receptor T-cell products. Multiple tumor aberrant epigenetic mechanisms are being investigated as targets for antineoplastic compounds such as histone deacetylase inhibitors and hypomethylating agents. Moreover, JAK2 inhibition combined with anti-PD1 blockade revealed a potential complementary therapeutic pathway in cHL. In this review, we will summarize recent findings on cHL biology and novel treatment options clinically available, as well as promising future perspectives in the field. [ABSTRACT FROM AUTHOR]

Simple Summary: Molecular directed therapy for hepatocellular carcinoma (HCC) involves targeting specific signaling pathways that normally promote cancer cell growth and survival. Accordingly, a blockage of these pathways leads to tumor shrinkage and improves the patient outcome. Recent advancements in molecular directed therapies have focused on tyrosine kinase and angiogenesis inhibition, thus targeting pathways involved in the molecular pathogenesis of HCC. Especially the vascular endothelial growth factor (VEGF) signaling pathway is one of the most prominent pathways involved in HCC progression. The combination of inhibiting VEGF signaling and immune-directed therapy or double immunocheckpoint inhibition are the mainstay of contemporary treatment strategies and promising agents for future combination treatment regimens. However, the effectiveness of these therapies may vary among patients, highlighting the need to identify the specific molecular alterations for tailored therapeutic approaches. Additionally, in modern systemic therapy of patients with HCC, the underlying pathology of the liver has always been encountered to identify population subgroups in terms of pathophysiology and underlying liver function to predict response to different therapeutic regimens. We conducted a comprehensive review of the current literature of published data and clinical trials (MEDLINE), as well as published congress contributions and active recruiting clinical trials on targeted therapies in hepatocellular carcinoma. Combinations of different agents and medical therapy along with radiological interventions were analyzed for the setting of advanced HCC. Those settings were also analyzed in combination with adjuvant situations after resection or radiological treatments. We summarized the current knowledge for each therapeutic setting and combination that currently is or has been under clinical evaluation. We further discuss the results in the background of current treatment guidelines. In addition, we review the pathophysiological mechanisms and pathways for each of these investigated targets and drugs to further elucidate the molecular background and underlying mechanisms of action. Established and recommended targeted treatment options that already exist for patients are considered for systemic treatment: atezolizumab/bevacizumab, durvalumab/tremelimumab, sorafenib, lenvatinib, cabozantinib, regorafenib, and ramucirumab. Combination treatment for systemic treatment and local ablative treatment or transarterial chemoembolization and adjuvant and neoadjuvant treatment strategies are under clinical investigation. [ABSTRACT FROM AUTHOR]

Simple Summary: Selecting and developing effective therapies for distinct epithelial ovarian cancer subtypes necessitates tumor models that accurately recapitulate the individual characteristics and microenvironmental interactions. Patient-derived tumor models offer a promising approach by preserving the tumor's integrity, providing a platform for personalized treatment strategies. Zebrafish embryos could be a useful tool for quickly testing potential treatments in parallel. In this research article, we aimed to evaluate the model using a real-world case study and compare results with existing in vitro and in vivo models. A patient-derived cell line from a low-grade serous ovarian cancer with a KRAS mutation was engrafted in zebrafish embryos. Xenografts were assigned to a five-day treatment with trametinib and/or luminespib, targeting two complementary pathways that have previously shown efficacy in other cancer models of this cell line. The zebrafish model offers several options to analyze the response of the tumor to drug exposure. Here, we evaluated both cell growth and cell death, which showed a significant positive tumor response upon treatment that was amplified further by combining the drugs. Ovarian cancer (OC) is an umbrella term for cancerous malignancies affecting the ovaries, yet treatment options for all subtypes are predominantly derived from high-grade serous ovarian cancer, the largest subgroup. The concept of "functional precision medicine" involves gaining personalized insights on therapy choice, based on direct exposure of patient tissues to drugs. This especially holds promise for rare subtypes like low-grade serous ovarian cancer (LGSOC). This study aims to establish an in vivo model for LGSOC using zebrafish embryos, comparing treatment responses previously observed in mouse PDX models, cell lines and 3D tumor models. To address this goal, a well-characterized patient-derived LGSOC cell line with the KRAS mutation c.35 G>T (p.(Gly12Val)) was used. Fluorescently labeled tumor cells were injected into the perivitelline space of 2 days' post-fertilization zebrafish embryos. At 1 day post-injection, xenografts were assessed for tumor size, followed by random allocation into treatment groups with trametinib, luminespib and trametinib + luminespib. Subsequently, xenografts were euthanized and analyzed for apoptosis and proliferation by confocal microscopy. Tumor cells formed compact tumor masses (n = 84) in vivo, with clear Ki67 staining, indicating proliferation. Zebrafish xenografts exhibited sensitivity to trametinib and luminespib, individually or combined, within a two-week period, establishing them as a rapid and complementary tool to existing in vitro and in vivo models for evaluating targeted therapies in LGSOC. [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]

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]

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]

Simple Summary: Multiple myeloma (MM) is an incurable disease affecting predominantly elderly people (>65 years of age). Despite improvement in the 10-year survival rate for MM patients due to the advent of medications, including immunomodulatory drugs (IMiDs) (such as pomalidomide and lenalidomide) and proteasome inhibitors, coupled with autologous stem cell transplant, more effective and safe therapies are still needed. Bromodomain-containing protein 9 (BRD9) has been shown to be important for the survival of MM cells. We discovered that drugs that block the function of BRD9 increase the effectiveness of IMiDs and can override resistance to these medications. Our findings suggest that the combined use of IMiDs and drugs that target BRD9 could potentially improve clinical outcomes for MM patients. Progress in the treatment of multiple myeloma (MM) has resulted in improvement in the survival rate. However, there is still a need for more efficacious and tolerated therapies. We and others have shown that bromodomain-containing protein 9 (BRD9), a member of the non-canonical SWI/SNF chromatin remodeling complex, plays a role in MM cell survival, and targeting BRD9 selectively blocks MM cell proliferation and synergizes with IMiDs. We found that synergy in vitro is associated with the downregulation of MYC and Ikaros proteins, including IKZF3, and overexpression of IKZF3 or MYC could partially reverse synergy. RNA-seq analysis revealed synergy to be associated with the suppression of pathways associated with MYC and E2F target genes and pathways, including cell cycle, cell division, and DNA replication. Stimulated pathways included cell adhesion and immune and inflammatory response. Importantly, combining IMiD treatment and BRD9 targeting, which leads to the downregulation of MYC protein and upregulation of CRBN protein, was able to override IMiD resistance of cells exposed to iberdomide in long-term culture. Taken together, our results support the notion that combination therapy based on agents targeting BRD9 and IKZF3, two established dependencies in MM, represents a promising novel therapeutic strategy for MM and IMiD-resistant disease. [ABSTRACT FROM AUTHOR]

Simple Summary: Modern ovarian cancer treatment has not substantially improved outcomes, and superior therapeutic strategies are needed. The aim of this study was to evaluate the efficacy of artesunate and navitoclax drug combination in ovarian cancer. We determined the combination of these two drugs was extraordinarily effective in multiple models of ovarian cancer, in vitro, inhibiting cancer cell proliferation more than expected based on single-agent activities. Unfortunately, we were unable to validate these findings using a mouse model of metastatic ovarian cancer. These data provide valuable information regarding the potential utility and challenges associated with the artesunate/navitoclax drug combination for ovarian cancer therapy. Artesunate belongs to a class of medications derived from the sweet wormwood plant (Artemisia annua) known as artemisinins. Artesunate has traditionally been used as a frontline treatment for severe malaria but has also demonstrated antineoplastic activity against various malignancies, including ovarian cancer. Data suggest that artesunate exacerbates cellular oxidative stress, triggering apoptosis. In the current study, we investigated the ability of navitoclax, an inhibitor of the antiapoptotic Bcl-2 protein family, to enhance artesunate efficacy in ovarian cancer cells. Artesunate and navitoclax both demonstrated antiproliferative effects on 2D and 3D ovarian cancer cell models as single agents. Upon combination of navitoclax with artesunate, antineoplastic drug synergy was also observed in each of the 2D cell lines and ovarian tumor organoid models tested. Further investigation of this drug combination using intraperitoneal CAOV3 xenograft models in BALB/scid mice showed that the artesunate/navitoclax doublet was superior to single-agent artesunate and vehicle control treatment. However, it did not outperform single-agent navitoclax. With optimization, this drug combination could provide a new therapeutic option for ovarian cancer and warrants further preclinical investigation. [ABSTRACT FROM AUTHOR]

Simple Summary: This study investigates the combined therapeutic potential of revumenib and tamibarotene in acute myeloid leukemia (AML) with histone-lysine-N-methyltransferase 2A rearrangement (KMT2Ar) or mutated Nucleophosmin gene (NPM1c). Menin inhibition is considered a promising treatment for such AML cases, but resistance mutations pose challenges. Elevated retinoic acid receptor alpha (RARA) expression levels indicate favorable outcomes with tamibarotene, known for restoring differentiation or inducing apoptosis. The combination of revumenib and tamibarotene demonstrated highly synergistic effects in MV4:11 cells, marked by apoptosis induction while MOLM13 and OCI-AML3 cells showed increased differentiation markers. Patient-derived AML cells exhibited in parts corresponding effects, suggesting a potential strategy for relapsed/refractory AML patients with specific molecular characteristics. Inhibition of menin in acute myeloid leukemia (AML) harboring histone-lysine-N-methyltransferase 2A rearrangement (KMT2Ar) or the mutated Nucleophosmin gene (NPM1c) is considered a novel and effective treatment approach in these patients. However, rapid acquisition of resistance mutations can impair treatment success. In patients with elevated retinoic acid receptor alpha (RARA) expression levels, promising effects are demonstrated by the next-generation RARalpha agonist tamibarotene, which restores differentiation or induces apoptosis. In this study, the combination of revumenib and tamibarotene was investigated in various KMT2Ar or NPM1c AML cell lines and patient-derived blasts, focusing on the potential synergistic induction of differentiation or apoptosis. Both effects were analyzed by flow cytometry and validated by Western blot analysis. Synergy calculations were performed using viability assays. Regulation of the relevant key mediators for the MLL complex were quantified by RT-qPCR. In MV4:11 cells characterized by the highest relative mRNA levels of RARA, highly synergistic induction of apoptosis is demonstrated upon combination treatment. Induction of apoptosis by combined treatment of MV4:11 cells is accompanied by pronounced induction of the pro-apoptotic protein BAX and a synergistic reduction in CDK6 mRNA levels. In MOLM13 and OCI-AML3 cells, an increase in differentiation markers like PU.1 or a decreased ratio of phosphorylated to total CEBPA is demonstrated. In parts, corresponding effects were observed in patient-derived AML cells carrying either KMT2Ar or NPM1c. The impact of revumenib on KMT2Ar or NPM1c AML cells was significantly enhanced when combined with tamibarotene, demonstrating synergistic differentiation or apoptosis initiation. These findings propose promising strategies for relapsed/refractory AML patients with defined molecular characteristics. [ABSTRACT FROM AUTHOR]