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Antibody-drug conjugates (ADCs), combining the cytotoxicity of the drug payload with the specificity of monoclonal antibodies, are one of the rapidly evolving classes of anti-cancer agents. These agents have been successfully incorporated into the treatment paradigm of many malignancies, including non-small cell lung cancer (NSCLC). The NSCLC is the most prevalent subtype of lung cancer, having a considerable burden on the cancer-related mortality and morbidity rates globally. Several ADC molecules are currently approved by the Food and Drug Administration (FDA) to be used in patients with NSCLC. However, the successful management of NSCLC patients using these agents was met with several challenges, including the development of resistance and toxicities. These shortcomings resulted in the exploration of novel therapeutic targets that can be targeted by the ADCs. This review aims to explore the recently identified ADC targets along with their oncologic mechanisms. The ADC molecules targeting these biomarkers are further discussed along with the evidence from clinical trials. [ABSTRACT FROM AUTHOR]

Antibody–drug conjugates (ADCs) are anticancer agents with the capacity to selectively deliver their payloads to cancer cells. Antibody–drug conjugates consist of a monoclonal antibody backbone connected by a linker to cytotoxic payloads. Antibody–drug conjugate effect occurs either by directly targeting cancer cells via membrane antigen or through "bystander effect." Antibody–drug conjugates have demonstrated efficacy against various types of tumors, including breast cancer. Ado-trastuzumab emtansine is presently the only approved ADC for the treatment of breast cancer in the early setting, while several ADCs are now approved for metastatic breast cancer. Due to the transformative impact that several ADCs have reported in the setting of advanced breast cancer, researchers are now testing more of such compounds in the early setting, to portend benefits to patients through highly potent anticancer drugs. Ongoing trials hold the potential to transform treatment protocols for early breast cancer in the near future. These trials are aiming at evaluating different treatment modulation approaches, as informed by breast cancer risk of recurrence, including toward treatment de-escalation. Efforts are provided in ongoing clinical trials to identify the patients who will benefit most, to pursue paradigms of precision medicine with the novel ADCs. This review focuses on the potential role of ADCs in early breast cancer, providing an overview of the latest progress in their development and how they are implemented in ongoing clinical trials. [ABSTRACT FROM AUTHOR]

The concurrent incidence of lung cancer and tuberculosis is expected to escalate due to the projected growth in the older population. Combination therapy with osimertinib and antituberculosis drugs has not been well‐established. We report a case of successful treatment involving the concomitant administration of osimertinib and antituberculosis drugs in an older patient, an 89‐year‐old female, diagnosed with epidermal growth factor receptor (EGFR)‐mutant lung cancer and pulmonary tuberculosis. Accumulating evidence is warranted to develop an optimal treatment strategy for patients with lung cancer and tuberculosis. [ABSTRACT FROM AUTHOR]

Background: Berberine (BBR), an isoquinoline alkaloid from Coptidis rhizoma, has been found to have powerful activities against various human malignancies, including breast cancer. However, the underlying antitumor mechanisms of BBR in breast cancer remain poorly understood. Methods: Breast cancer cells were cultured and treated with different doses (0, 20, 40, and 60 μM) of BBR for 48 h. Cell viability, proliferation, apoptosis, invasion, and migration were assessed using 3‐(4, 5‐dimethyl‐2‐thiazolyl)‐2, 5‐diphenyl‐2H‐tetrazolium bromide (MTT), 5‐ethynyl‐2′‐deoxyuridine (EdU), flow cytometry, transwell, and wound healing assays. Fibroblast growth factor 7 (FGF7), methyltransferase‐like 3 (METTL3), and insulin‐like growth factor‐2 mRNA‐binding protein 3 (IGF2BP3) mRNA levels and protein levels were measured using real‐time quantitative polymerase chain reaction (RT‐qPCR) and western blot. Interaction between METTL3 and FGF7 m6A was assessed using methylated RNA immunoprecipitation (MeRIP)‐qPCR and RNA immunoprecipitation (RIP) assay. Binding ability between IGF2BP3 and FGF7 mRNA was analyzed using RIP assay. Results: BBR treatment hindered breast cancer cell proliferation, invasion, migration, and induced apoptosis. FGF7 expression was upregulated in breast cancer tissues, while its level was reduced in BBR‐treated tumor cells. FGF7 upregulation relieved the repression of BBR on breast cancer cell malignant behaviors. In mechanism, METTL3 stabilized FGF7 mRNA through the m6A‐IGF2BP3‐dependent mechanism and naturally improved FGF7 expression. BBR treatment inhibited breast cancer growth in vivo. Conclusion: BBR treatment blocked breast cancer cell growth and metastasis partly by regulating METTL3‐mediated m6A modification of FGF7 mRNA, providing a promising therapeutic target for breast cancer treatment. [ABSTRACT FROM AUTHOR]

Approximately 10% to 15% of breast cancer cases in young women are diagnosed in patients harbouring germline (g) pathogenic or likely pathogenic variants (PVs) in the BReast CAncer 1 (BRCA1) or BReast CAncer 2 (BRCA2) genes. Preclinical and clinical studies showed a potential negative effect of germline BRCA 1/2 (g BRCA1/2) PVs on ovarian reserve and reproductive potential, even before starting anticancer therapies. The aim of this article is to summarize the current literature on the fertility potential of young g BRCA1/2 PVs carriers with breast cancer and the risk of gonadotoxicity associated with anticancer treatments. Moreover, we describe the available evidence on the efficacy of fertility preservation techniques in young g BRCA1/2 PVs carriers and the safety data on having a pregnancy after breast cancer treatment. [ABSTRACT FROM AUTHOR]

Topological indices (TIs) have rich applications in various biological contexts, particularly in therapeutic strategies for cancer. Predicting the performance of compounds in the treatment of cancer is one such application, wherein TIs offer insights into the molecular structures and related properties of compounds. By examining, various compounds exhibit different degree-based TIs, analysts can pinpoint the treatments that are most efficient for specific types of cancer. This paper specifically delves into the topological indices (TIs) implementations in forecasting the biological and physical attributes of innovative compounds utilized in addressing cancer through therapeutic interventions. The analysis being conducted to derivatives of sulfonamides, namely, 4-[(2,4-dichlorophenylsulfonamido) methyl]cyclohexanecarboxylic acid (1), ethyl 4-[(naphthalene-2-sulfonamido) methyl]cyclohexanecarboxylate (2), ethyl 4-[(2,5-dichlorophenylsulfonamido) methyl]cyclohexanecarboxylate (3), 4-[(naphthalene-2-sulfonamido) methyl]cyclohexane-1-carboxylic acid (4) and (2S)-3-methyl-2-(naphthalene-1-sulfonamido)-butanoic acid (5), is performed by utilizing edge partitioning for the computation of degree-based graph descriptors. Subsequently, a linear regression-based model is established to forecast characteristics, like, melting point and formula weight in a quantitative structure-property relationship. The outcomes emphasize the effectiveness or capability of topological indices as a valuable asset for inventing and creating of compounds within the realm of cancer therapy. [ABSTRACT FROM AUTHOR]

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]

Introduction: It is well known that patients with objective response to pembrolizumab have a durable duration of response, leading to favorable survival outcomes. We investigated the possibility of predicting the objective response with concise indicators obtained from daily clinical practice. Methods: In our multi-institutional cohort, 220 platinum-refractory metastatic urothelial carcinoma (mUC) patients treated with pembrolizumab for at least 6 weeks with complete information of objective response were investigated. Results: The median follow-up was 7.3 months, and 119 patients deceased during the follow-up. A multivariate logistic regression analysis exhibited two independent variables predicting the objective response, including the neutrophil-lymphocyte ratio (NLR) change at 6 weeks of treatment and liver metastasis. We proposed a risk group using these two indicators. Patients with no predictive indicators/one of those were assigned to favorable (42%)/intermittent (47%) risk groups. Patients with both indicators were assigned to poor risk (11%). Notably, the objective response rate was well delineated in 41%, 25%, and 0% for favorable-, intermediate-, and poor-risk groups, respectively (p < 0.001). Distinct overall survival (OS) between the risk groups was also confirmed with the median OS of 14.1, 11.7, and 4.2 months in favorable-, intermediate-, and poor-risk groups, respectively. Conclusions: At the 6 weeks of the pembrolizumab treatment, our risk model predicts the objective response rate precisely. Notably, those classified as "poor risk" – marked by liver metastasis and an increased NLR – should be considered for alternative therapy with a different mode of action, highlighting a critical decision point in treatment optimization. [ABSTRACT FROM AUTHOR]

Introduction: The multicenter randomized phase III KHBO1401 study (gemcitabine+cisplatin+S-1 [GCS] vs. GC in biliary tract cancers [BTC]) demonstrated that GCS not only prolonged patient survival but also achieved a high response rate and that it should be good for neoadjuvant therapy. Therefore, to explore the possibilities of neoadjuvant therapy, we investigated the tumor shrinkage pattern. Methods: Among the total of 246 patients enrolled in the KHBO1401, the tumor shrinkage pattern and survival were investigated in patients with measurable BTC (n = 183, 74%; GCS, n = 91; GC, n = 92). Results: The tumor shrinkage pattern could be divided into 4 categories based on the response at 100 days after enrollment: categories A (<–30% in size), B (−30–0%), C (0% to +20%), and D (>+20%). The GCS arm included more category A and B cases (61 [67%] vs. 33 [36%], p < 0.0001). Each category predicted the best response and overall survival (p < 0.0001). Category A showed sustained tumor response compared with category B; in GCS, the time to maximum tumor response was 165 ± 76 days in category A and 139 ± 78 in category B. Categories C and D did not achieve tumor shrinkage. The maximum tumor shrinkage size in category A was −53% in the GCS arm and −65% in the GC arm (p = 0.0892). Twenty percent of patients in the GCS showed tumor regrowth 154 ± 143 days later. Conclusion: GCS provided faster and greater tumor shrinkage with better survival in comparison to GC, although 20% of patients showed regrowth after 6 cycles. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is often diagnosed in advanced stages. Following sorafenib, lenvatinib (LENV) has been approved as a first‐line treatment option for unresectable HCC. In the past few years, at least 9 large‐scale cohort studies have examined the efficacy and safety of LENV compared to atezolizumab plus bevacizumab (ATE/BEV) in unresectable HCC, but there is currently no direct meta‐analysis conducted for a comprehensive consolidation. To provide the most updated meta‐analysis of the clinical efficacy and safety of ATE/BEV versus LENV for patients with unresectable HCC. Our studies comparing the efficacy and safety of ATE/BEV and LENV in unresectable HCC were systematically searched in PubMed, Embase, and Web of Science from inception to February 2023. Outcomes measured were overall survival (OS), progression‐free survival (PFS), mortality, complete response (CR), partial response (PR), objective response rate (ORR), disease control rate (DCR), progressive disease (PD), stable disease (SD), and adverse events (AEs). Seven eligible studies involving 4428 patients (1569 in the ATE/BEV group and 2859 in the LENV group) were included in the narrative synthesis. All baseline characteristics were similar between the 2 groups except for Child‐Pugh class B. Ultimately, our meta‐analysis showed that the LENV group had longer OS and PFS than the ATE/BEV group. Moreover, patients on LENV were more likely to achieve SD, whereas those on ATE/BEV were more likely to achieve PR. [ABSTRACT FROM AUTHOR]

Abnormal activation of the Wnt/β-catenin signaling pathway is a driving force behind the progression of gastric cancer. Atovaquone, known as an antimalarial drug, has emerged as a potential candidate for anti-cancer therapy. This study investigated atovaquone's effects on gastric cancer and its underlying mechanisms. Using gastric cancer cell lines, we found that atovaquone, at concentrations relevant to clinical use, significantly reduced their viability. Notably, atovaquone exhibited a lower effectiveness in reducing the viability of normal gastric cells compared to gastric cancer cells. We further demonstrated that atovaquone inhibited gastric cancer growth and colony formation. Mechanism studies revealed that atovaquone inhibited mitochondrial respiration and induced oxidative stress. Experiments using ρ0 cells, deficient in mitochondrial respiration, indicated a slightly weaker effect of atovaquone on inducing apoptosis compared to wildtype cells. Atovaquone increased phosphorylated β-catenin at Ser45 and Ser33/37/Thr41, elevated Axin, and reduced β-catenin. The inhibitory effects of atovaquone on β-catenin were reversed upon depletion of CK1α. Furthermore, the combination of atovaquone with paclitaxel suppressed gastric cancer growth and improved overall survival in mice. Given that atovaquone is already approved for clinical use, these findings suggest its potential as a valuable addition to the drug arsenal available for treating gastric cancer. [ABSTRACT FROM AUTHOR]

Kinase is an enzyme that helps in the phosphorylation of the targeted molecules and can affect their ability to react with other molecules. So, kinase influences metabolic reactions like cell signaling, secretory processes, transport of molecules, etc. The increased activity of certain kinases may cause various types of cancer, i.e. leukemia, glioblastoma, and neuroblastomas. So, the growth of particular cancer cells can be prevented by the inhibition of the kinase responsible for those cancers. Natural products are the key resources for the development of new drugs where approximately 60% of anti-tumor drugs are being developed with the same including specific kinase dwellers. This study comprised molecular interactions of various molecules (obtained from natural sources) as kinase inhibitors for the treatment of cancer. It is expected that by analyzing the skeleton behavior, the process of action, and the body-related activity of these organic products, new cancer-avoiding molecules can be developed. [ABSTRACT FROM AUTHOR]

Introduction: Platinum-based chemotherapy is the mainstay of first-line therapy for advanced-stage non-small cell lung cancer (NSCLC). Although carboplatin-induced hypersensitivity reactions (HSRs) commonly occur following multiple cycles of therapy, they are rarely observed during the first cycle of the treatment. Case report: Here, we report the case of a 70-year-old man with advanced-stage NSCLC who developed HSR possibly caused by carboplatin during the first cycle of induction with platinum-doublet chemotherapy plus pembrolizumab. The patient presented with bronchial obstruction due to a centrally located tumor. No driver mutations were detected, and the programmed death-ligand 1 expression ranged from 1% to 24%. Consequently, the patient was treated with pembrolizumab combined with carboplatin and paclitaxel. However, immediately after the start of carboplatin, the blood pressure and oxygen levels of the patient dropped and he began exhibiting an altered level of consciousness. These findings indicated carboplatin-induced anaphylaxis. Hypotension and oxygen desaturation improved following carboplatin discontinuation and normal saline administration. Management and outcome: The basophil activation test for both carboplatin and cisplatin was negative. Thus, the risk of anaphylaxis owing to both drugs was ruled out, and carboplatin was believed to have induced grade 3 HSR. Subsequently, carboplatin-based chemotherapy was switched to cisplatin-based chemotherapy. HSR was not observed during the four treatment cycles with pembrolizumab, cisplatin, and pemetrexed, and best response was partial response. Discussion: Cisplatin-based chemotherapy could be used as an alternate treatment in patients with NSCLC who develop severe carboplatin-induced HSR. [ABSTRACT FROM AUTHOR]

Objective: Patients with cancer often use complementary and alternative medication (CAM). This research aims to study the current attitude of healthcare professionals toward the use of CAM to improve current care. Methods: A questionnaire on both the current practice and opinions about CAM use was sent to healthcare professionals in Amsterdam UMC, who work for the department of hematology or oncology. Oncologists, hematologists, residents, (specialized) nurses, dieticians, (hospital)pharmacists, and pharmacy technicians were asked to participate in this study. Results: Among eligible healthcare professionals, 77 responded to the questionnaire (34%). Overall, 87% of healthcare professionals indicate it is important to be aware of their patient's CAM use, and all find the potential of drug–herb interactions important. However, more than half of the healthcare professionals inquire about the patient's CAM use infrequently. In addition, only 15% of the healthcare professionals stated they had sufficient knowledge of CAM to advise patients on their use of CAM. Conclusions: Healthcare professionals are aware of the potential risks of CAM use in combination with anti-cancer treatment. However, CAM use is not yet discussed with every patient. This may be due to healthcare professionals' lack of knowledge about CAM. [ABSTRACT FROM AUTHOR]

Background: There have been reports on the impact of concurrent drugs on the outcome of immunotherapy for non‐small cell lung carcinoma (NSCLC). However, the effect of some drugs, such as antibiotics and nonsteroidal anti‐inflammatory drugs (NSAIDs), has not been clarified in patients with NSCLC. In the present study, we aimed to assess the association between concurrent drugs and the outcomes of immune checkpoint inhibitors (ICIs) alone or in combination with chemotherapy for patients with advanced NSCLC. Methods: We retrospectively assessed patients with advanced NSCLC who underwent ICI treatment between September 2017 and December 2021 at Kobe University Hospital. We evaluated the data regarding the use of antibiotics within 30 days before ICI initiation, as well as the use of proton pump inhibitors (PPIs) and NSAIDs during ICI initiation. Results: A total of 127 patients were assessed, among whom 28 (22.0%) patients received antibiotics, 39 (30.7%) PPIs, and 36 (28.3%) NSAIDs. No significant differences were observed between the patients with and without antibiotic use. However, patients using NSAIDs had significantly worse objective response rates (ORR) and progression‐free survival (PFS) with ICI alone or in combination with chemotherapy compared to those who did not (ORR, 47.2% vs. 67.0%; p = 0.045. PFS, 6.3 months vs. 10.8 months; p = 0.02). Patients using PPIs demonstrated a worse ORR of ICI in combination with chemotherapy compared to those who did not (ORR, 45.2% vs. 72.6%; p = 0.013). Conclusions: The unnecessary use of NSAIDs along with immunotherapy should be discouraged. [ABSTRACT FROM AUTHOR]

Background: For advanced non‐small cell lung cancer (NSCLC), combination therapies including a PD‐1 inhibitor plus chemotherapy or a PD‐1 inhibitor, CTLA‐4 inhibitor, and chemotherapy are standard first‐line options. However, data directly comparing these regimens are lacking. This study compared the efficacy of pembrolizumab plus chemotherapy (CP) against nivolumab plus ipilimumab and chemotherapy (CNI) in a real‐world setting. Methods: In this multicenter retrospective study, we compared the efficacy and safety of CP and CNI as first‐line therapies in 182 patients with stage IIIB–IV NSCLC. Primary outcomes were overall survival (OS) and progression‐free survival (PFS), while secondary outcomes included the response rate (RR) and safety profiles. Kaplan–Meier survival curves and Cox proportional hazards models were utilized for data analysis, adjusting for confounding factors such as age, gender, and PD‐L1 expression. Results: In this study, 160 patients received CP, while 22 received CNI. The CP group was associated with significantly better PFS than the CNI group (median 11.7 vs. 6.6 months, HR 0.56, p = 0.03). This PFS advantage persisted after propensity score matching to adjust for imbalances. No significant OS differences were observed. Grade 3–4 adverse events occurred comparably, but immune‐related adverse events were numerically more frequent in the CNI group. Conclusions: In real‐world practice, CP demonstrated superior PFS compared with CNI. These findings can inform treatment selection in advanced NSCLC. [ABSTRACT FROM AUTHOR]

Background: Patients with oropharyngeal squamous cell carcinoma (OPSCC) treated with radiation-based therapy suffer from short- and long-term toxicities that affect quality of life (QOL). Transoral robotic surgery (TORS) has an established role in the management of early OPSCC but adjuvant treatment is often indicated postoperatively due to the high incidence of nodal metastasis associated with advanced human papillomavirus (HPV)-related OPSCC. To overcome the need for adjuvant radiation therapy (RT), neoadjuvant chemotherapy followed by TORS and neck dissection (ND) is proposed. This study aimed to assess if QOL in HPV-associated OPSCC receiving neoadjuvant chemotherapy followed by TORS and ND returns to baseline within 12 months of completing treatment. Methods: A 12 month longitudinal study was carried out at McGill University Health Centre in Montreal, Canada, among a convenience sample of patients with American Joint Committee on Cancer Seventh Edition stage III and IVa HPV-related OPSCC who were treated with neoadjuvant chemotherapy followed by TORS and ND. QOL data were obtained pretreatment and at 1, 3, 6, and 12 months following treatment completion using the European Organisation for Research and Treatment of Cancer Core and Head and Neck extension modules. Paired t tests and mixed models for repeated measures analysis were used to assess changes in QOL from baseline to 12 months postoperatively and over time, respectively. Results: Nineteen of 23 patients (median age 58 years) who received the study treatment fulfilled the eligibility criteria. OPSCC subsites were palatine tonsil (n = 12) and base of tongue (n = 7). All 19 patients were treated per protocol and none required adjuvant RT as per pathology review and protocol requirements at a postoperative multidisciplinary team tumor board discussion. No significant differences were found when comparing 12 month QOL follow-up scores to pretreatment scores in measures that would likely be affected by RT [eg, swallowing (P =.7), social eating (P =.8), xerostomia (P =.9)]. Conclusion: In HPV-related OPSCC, neoadjuvant chemotherapy followed by TORS and ND as definitive treatment is associated with excellent QOL outcomes. Postoperative QOL scores returned to baseline by 3 months and were maintained for all measures, indicating a return to normal function. [ABSTRACT FROM AUTHOR]

Purpose Health-system pharmacists play a crucial role in monitoring the pharmaceutical pipeline to manage formularies, allocate resources, and optimize clinical programs for new therapies. This article aims to support pharmacists by providing periodic updates on new and anticipated novel drug approvals. Summary Selected drug approvals anticipated in the 12-month period covering the first quarter of 2024 through the fourth quarter of 2024 are reviewed. The analysis emphasizes drugs expected to have significant clinical and financial impact in hospitals and clinics, as selected from 59 novel drugs awaiting US Food and Drug Administration approval. This year's pipeline includes recently added drugs with various indications including oncology, infectious diseases, genetic disorders, and rare diseases. New cellular and gene therapies are rapidly evolving and being studied for several rare diseases and cancers. Conclusion More oncology agents, including gene therapies, oral agents, and monoclonal antibodies, are in the pipeline this year. Additional diseases targeted by new novel drugs, including cellular and gene therapies, are hemophilia, nonalcoholic steatohepatitis, Alzheimer's disease, and rare diseases such as galactosemia and epidermolysis bullosa. [ABSTRACT FROM AUTHOR]

Introduction: Restrictive eligibility criteria in cancer drug trials result in low enrollment rates and limited population diversity. Relaxed eligibility criteria (REC) based on solid evidence is becoming necessary for stakeholders worldwide. However, the absence of high‐quality, favorable evidence remains a major challenge. This study presents a protocol to quantitatively evaluate the impact of relaxing eligibility criteria in common non‐small cell lung cancer (NSCLC) protocols in China, on the risk–benefit profile. This involves a detailed explanation of the rationale, framework, and design of REC. Methods: To evaluate our REC in NSCLC drug trials, we will first construct a structured, cross‐dimensional real‐world NSCLC database using deep learning methods. We will then establish randomized virtual cohorts and perform benefit–risk assessment using Monte Carlo simulation and propensity matching. Shapley value will be utilized to quantitatively measure the effect of the change of each eligibility criterion on patient volume, clinical efficacy and safety. Discussion: This study is one of the few that focuses on the problem of overly stringent eligibility criteria cancer drug clinical trials, providing quantitative evaluation of the effect of relaxing each NSCLC eligibility criterion. This study will not only provide scientific evidence for the rational design of population inclusion in lung cancer clinical trials, but also establish a data governance system, as well as a REC evaluation framework that can be generalized to other cancer studies. [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]

Topical ruxolitinib 1.5% cream (Opzelura®), a Janus kinase (JAK) inhibitor, is the first treatment to be approved in several countries for use in patients aged ≥ 12 years with non-segmental vitiligo. In the identical phase III TRuE-V1 and TRuE-V2 trials, significantly more ruxolitinib cream recipients were able to achieve statistically significant and clinically meaningful facial and total body repigmentation, as well as reductions in vitiligo noticeability, compared with vehicle recipients. Efficacy was sustained in longer-term analyses to week 104 of treatment. Ruxolitinib 1.5% cream was generally tolerable in these trials; the most common treatment-related adverse events were acne, pruritus and exfoliation, all at the application site. As with orally administered JAK inhibitors, topical ruxolitinib carries boxed warnings in the USA for serious infections, mortality, malignancy, major adverse cardiovascular events (MACE) and thrombosis, although the incidences were low with topical application. Thus, topical ruxolitinib 1.5% cream is an effective and generally tolerable treatment option for patients aged ≥ 12 years with non-segmental vitiligo. Plain Language Summary: Non-segmental vitiligo is a chronic autoimmune disease where the skin throughout the body loses its pigmentation, and is usually managed with topical therapies, light therapy or surgery. Topical ruxolitinib 1.5% cream (Opzelura®) is the first treatment approved in several countries for patients aged ≥ 12 years with non-segmental vitiligo. It inhibits Janus kinase (JAK) proteins, reducing the destruction of skin pigment-producing cells. In two clinical trials, significantly more ruxolitinib cream recipients achieved significant and meaningful skin repigmentation compared with patients who received a non-medicated cream; these results were sustained to week 104 of treatment. Ruxolitinib 1.5% cream was generally tolerable; the most common treatment-related adverse events were acne, itchiness and exfoliation, all at the application site. Topical ruxolitinib has special warnings in the USA for major adverse cardiovascular events (MACE), blood clots, serious infections, death and cancer (associated with the use of oral JAK inhibitors), although incidence rates for these adverse events were low in the clinical trials. Topical ruxolitinib 1.5% cream is an effective and generally tolerable treatment option for patients aged ≥ 12 years with non-segmental vitiligo. [ABSTRACT FROM AUTHOR]

Introduction: Evorpacept is a CD47-blocking agent currently being developed for the treatment of various cancers. Interference by evorpacept in pretransfusion compatibility testing has been reported at limited plasma concentrations. Although various mitigation strategies have been proposed, none are practical. This in vitro study assessed evorpacept-induced interference at extended concentrations and investigated the capability of a novel mitigation agent, Evo-NR. Methods: Antibody screening tests were performed on evorpacept-spiked plasma with (anti-E and anti-Jka) or without alloantibodies at evorpacept concentrations up to 2,000 μg/mL using manual gel cards and automated analyzers. Evorpacept-coated red blood cells (RBCs) (rr [ce/ce], Fy[a+b−], S−s+) were tested by direct antiglobulin testing (DAT) and antigen typing using anti-Fyb and anti-S reagents at indirect antiglobulin testing (IAT) phase. Evo-NR was used to resolve the interference in plasma and RBC samples. Flow cytometry was used to assess the mitigation effects. Results: Evorpacept-spiked plasma showed panreactive interference in antibody screening tests using manual gel cards (2+ to 3+) and automated analyzers (4+). A carryover effect was also observed in the automated analyzers. The use of a 3- to 6-fold molar excess of Evo-NR effectively resolved the interference in the plasma and enabled accurate alloantibody identification. Although the reduction in evorpacept binding to RBCs was identified via flow cytometry, Evo-NR was incapable of resolving the serologic interference observed in DAT and antigen typing at IAT phase. Discussion: Evorpacept showed constant panreactivity and a carryover effect at high concentrations. Evo-NR successfully resolved the interference in the plasma samples and could be considered a practical and efficient mitigation solution. Implementation of Evo-NR has the potential to support RBC transfusion for patients undergoing evorpacept treatment. [ABSTRACT FROM AUTHOR]

Coactivator-associated arginine methyltransferase 1 (CARM1) is significant as a key member of the PRMT family, crucial for regulating arginine methylation, and its association with colorectal cancer underscores its potential as a therapeutic target. Consequently, CARM1 inhibitors have emerged as potential therapeutic agents in cancer treatment and valuable chemical tools for cancer research. Despite steady progress in CARM1 inhibitor research, challenges persist in discovering effective, isoform-selective, cell-permeable, and in vivo-active CARM1 inhibitors for colorectal cancer. This review summarizes the research progress on CARM1 and its relationship with colorectal cancer, aiming to provide a theoretical basis for the radiotherapy of colorectal cancer. [ABSTRACT FROM AUTHOR]

Background: Malignant glomus tumors (MGTs) are rare malignancies, which grow rapidly and are aggressive. Surgical resection has been regarded as the standard management, but treatment options for those unresectable tumors are limited, resulting in a high recurrence rate and poor prognosis. Case Description: An 85-year-old man presented with gross hematuria and was diagnosed with MGTs of bladder. The patient achieved long-term local control after multimodal therapy comprising radiotherapy, iodine-125 seeds brachytherapy, transcatheter arterial chemoembolization, and antiangiogenic targeted therapy. Conclusion: MGTs occurring in the bladder are clinically rare and refractory. The case presented here highlights the importance of multidisciplinary diagnosis and treatment, providing evidence that radiotherapy and antiangiogenic therapy may play an important role in unresectable bladder MGT. [ABSTRACT FROM AUTHOR]

Aims: This study sets out to identify dysregulated plexins and investigate their roles in KIRC through an integrated bioinformatics approach. Methods: RNA-sequencing data and clinicopathological information of KIRC, extracted from The Cancer Genome Atlas (TCGA) database, were used to perform comprehensive bioinformatics analysis. Results: Almost all plexin gene family members were dysregulated in KIRC. Univariate and multivariate Cox regression analyses revealed that PLXNA1/B3 were independent prognostic factors of overall survival in patients with KIRC. Mechanically, PLXNA1/B3 may promote ccRCC progression through several cancer-related signaling pathways, tumor immunity, and angiogenesis. Drug sensitivity analysis suggested that vemurafenib was the potential drug for PLXNA1/B3. Conclusion: Herein, we found that PLXNA1/B3 were independent prognostic factors, making them attractive new targets for KIRC treatment. [ABSTRACT FROM AUTHOR]

Introduction: Alpelisib is approved in combination with endocrine therapy (ET) to treat patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) progressive metastatic breast cancer (MBC). The SOLAR-1 trial demonstrated the efficacy of this oral agent and showed that, while alpelisib improves outcomes compared to placebo, it is also associated with clinically relevant adverse events (AEs). There is a pressing need for improved knowledge on the effectiveness and tolerability of this agent in real-world patient populations. Methods: We conducted a retrospective cohort study of patients with HR+, HER2− MBC treated with alpelisib and ET. We assessed the safety, tolerability, and effectiveness of alpelisib in a real-world population. Deidentified patient-, tumor-, and outcome-related data, including AEs, were collected and summarized. Kaplan-Meier methods were applied for survival analyses, and stratified analyses of interest were conducted. A p value <0.05 was considered statistically significant. Results: A total of 76 women treated with alpelisib + ET were included in our cohort. Most had been previously treated with cyclin-dependent kinase (CDK) 4/6 inhibitors and chemotherapy for MBC. The estimated median progression-free survival was 5.2 months (95% CI, 4.1–8.0). The median overall survival was longer among patients without prior everolimus therapy (hazard ratio, 4.28 [95% CI, 1.64–11.16]; p = 0.0012), and no significant outcome differences were observed between patients treated with different starting doses of alpelisib. Approximately 31.6% of patients permanently discontinued alpelisib due to AEs, and 32.9% had at least one dose reduction. The most common grade 3/4 AEs were hyperglycemia (21%), fatigue (13.2%), and diarrhea (10.5%). Conclusions: For progressive HR+, HER2− MBC, alpelisib + ET showed effectiveness in a real-world patient population that was comparable to published clinical trial data, regardless of starting dose. However, the effectiveness of alpelisib following previous everolimus exposure may be limited and, hence, should be a consideration to decide sequencing of therapy in these patients. Patients treated with alpelisib are at risk for clinically relevant AEs and require close monitoring. [ABSTRACT FROM AUTHOR]

Introduction: Neuroendocrine carcinoma (NEC) is characterized by a poor prognosis and is generally treated with platinum and etoposide combination therapy as first-line chemotherapy. However, it remains uncertain whether carboplatin and etoposide combination therapy (CE) and cisplatin and etoposide combination therapy (PE) have comparable treatment efficacy. In this retrospective analysis, we compared the efficacy and safety of CE and PE in patients with NEC. Methods: We retrospectively reviewed the patient's clinical record from 2005 to 2022 at the Department of Medical Oncology, Tohoku University Hospital. Patients who received either CE or PE were included in the study. Statistical analyses were performed using JMP Pro 16.0 (SAS Institute Inc., Cary, NC, USA). Results: A total of 104 patients were enrolled, with 73 patients assigned to the CE group and 31 patients assigned to the PE group. Statistically, the response rate, progression-free survival time and overall survival time were 42.6%, 5.1 months (95% CI: 3.5–6.3) and 13.6 months (95% CI: 8.9–17.4), respectively, in the CE groups and 44.4%, 5.6 months (95% CI: 3.1–7.0) and 12.5 months (95% CI: 11.2–14.6), respectively, in the PE groups. There was no significant difference in treatment efficacy between the CE and the PE groups. However, the number of patients with elevated creatinine (3.35 mg/dL and 3.88 mg/dL in 2 patients, respectively) was significantly higher in the PE group than in the CE group. Conclusion: The efficacy of CE and PE in patients with NEC is comparable. However, the incidence of renal dysfunction was found to be significantly higher in the PE group than in the CE group. [ABSTRACT FROM AUTHOR]

Background: Since the success of the PACIFIC trial, durvalumab has become the clear standard of care for many patients with stage III non-small cell lung cancer (NSCLC) after concurrent chemoradiotherapy (CRT). However, the duration of immune consolidation and the efficacy and safety of different immune agents remain unclear. We conducted a systematic review of relevant studies. Methods: We searched all the relevant studies in PubMed, Embase, and Cochrane Library databases. We also reviewed abstracts of relevant conferences to prevent omissions. The meta-analysis was performed using Stata version 16.0. Results: CRT combined with immunotherapy can improve progression-free survival (PFS) (hazard rate [HR]: 0.60, 95% confidence interval [CI, 0.55–0.60) and overall survival (OS) (HR: 0.59, 95% CI, 0.53–0.66) compared with no immunotherapy. The pooled 24-month PFS and 24-month OS rates were 48.1% (95% CI, 43.5–52.7%) and 71.3% (95% CI, 67.3–75.2%), respectively. Subgroup analysis showed that 24-month OS rates were 60.7% (95% CI, 51.0–70.3%) and 77.4% (95% CI, 73.2–81.7%) at 1 year and 2 years of immune consolidation, respectively. The pooled 1-year completion rate for immune consolidation was 35.6% (95% CI, 31.3–39.8%). The pooled rate of pneumonitis for all grades was 41.7% (95% CI, 31.9–51.9%). The pooled rate of pneumonitis ≥ grade 3 was 6.7% (95% CI, 5.0–8.5%). The incidence of pneumonitis ≥ grade 3 after 1 year of immunotherapy is 4.8% (95% CI, 3.1–6.5%). The incidence of pneumonitis ≥ grade 3 after 2 years of immunotherapy is 5.1% (95% CI, 2.9–7.3%). Conclusions: Prolonging the duration of immunotherapy consolidation increases survival benefits in patients with stage III NSCLC without causing higher side effects. Older patients, due to high incidence of pneumonia and low immunotherapy completion rate, have less survival benefit. [ABSTRACT FROM AUTHOR]

Background: Neoadjuvant chemoimmunotherapy (NCIT) for locally advanced esophageal squamous cell carcinoma (ESCC) is supported by increasing data, but the sample size is limited, and the findings are not completely consistent. We conducted a real‐world study and a meta‐analysis to evaluate the efficacy and safety of NCIT in locally advanced ESCC. Methods: We retrospectively assessed the outcomes of patients with locally advanced ESCC who completed NICT and subsequent esophagectomy at our hospital between January 2019 and December 2022, including pathological complete response (pCR) rate, major pathological response (MPR) rate, 1‐, 2‐, and 3‐year overall survival (OS) rates, disease control rate (DCR), objective response rate (ORR), 1‐year recurrence rate, R0 resection rate and adverse events. Moreover, a meta‐analysis of 27 published literatures was also conducted for comparison. Results: In the analysis, 128 patients were studied, with 25% achieving pCR, 46.1% MPR, and 99.2% R0 resection. The 1‐, 2‐, and 3‐year OS rates were 91.41% (95% CI: 85.15%–95.63%), 75.00% (95% CI: 66.58%–82.23%) and 64.84% (95% CI: 55.91%–73.07%).ORR and DCR were 31.2% (95% CI: 23.31–39.99) and 64.1% (95% CI: 55.15%–72.38%), and the 1‐year recurrence rate was 26.7% (95% CI: 22.5%–38.1%). Treatment‐related events occurred in 96.1% but were acceptable. In a meta‐analysis of 27 studies with 1734 patients, pooled rates for pCR, MPR, ORR, DCR, and R0 resection were 29%, 52%, 71%, 97%, and 98%, respectively, with a 1‐year recurrence rate of 12%. Conclusion: NCIT is safe and provides potential survival benefits for patients with locally advanced ESCC. However, randomized phase 3 trial data is still needed. [ABSTRACT FROM AUTHOR]