Cancer Therapy Research Articles

Targeted nanomedicine for reprogramming the tumor innate immune system: From bench to bedside

Tumor-associated innate immune cells such as tumor-associated macrophages, neutrophils, dendritic cells play a crucial role in tumor progression, angiogenesis and metastasis. These cells also control the efficacy of chemotherapy and immunotherapy by inducing drug resistance and immunosuppression, leading to therapeutic failures. Therefore, targeting the tumor-associated innate immune cells has gained high attention for the development of effective cancer therapy. Nanomedicine based strategies to target these cells are highly relevant and can be used to reprogram these cells. In this review, we discuss the fundamental roles of the tumor-associated innate immune cells in the tumor microenvironment and different strategies to modulate them. Then, nanomedicine-based strategies to target different tumor innate immune cells are explained in detail. While the clinical development of the targeted nanomedicine remains a great challenge in practice, we have provided our perspectives on various factors such as pharmaceutical aspects, preclinical testing and biological aspects which are crucial to consider before translating these targeting strategies to clinics.

Recent advances in nanogels for drug delivery and biomedical applications.

Nanotechnology has shown great promise for researchers to develop efficient nanocarriers for better therapy, imaging, and sustained release of drugs. The existing treatments are accompanied by serious toxicity limitations, leading to severe side effects, multiple drug resistance, and off-target activity. In this regard, nanogels have garnered significant attention for their multi-functional role combining advanced therapeutics with imaging in a single platform. Nanogels can be functionalized to target specific tissues which can improve the efficiency of drug delivery and other challenges associated with the existing nanocarriers. Translation of nanogel technology requires more exploration towards stability and enhanced efficiency. In this review, we present the advances and challenges related to nanogels for cancer therapy, ophthalmology, neurological disorders, tuberculosis, wound healing, and anti-viral applications. A perspective on recent research trends of nanogels for translation to clinics is also discussed.

Codelivery of metformin and methotrexate with optimized chitosan nanoparticles for synergistic triple-negative breast cancer therapy in vivo.

The development of effective therapeutic strategies for triple-negative breast cancer (TNBC), an aggressive subtype with limited treatment options, remains a critical challenge. This study aimed to design and evaluate a combination therapy using chitosan nanoparticles (Cs NPs) loaded with metformin (Met) and methotrexate (MTX) as a promising approach for TNBC management. The Cs NPs exhibited an average size of 78.8 ± 25.84 nm for blank Cs NPs, 84.50 ± 22.54 nm for Met-Cs NPs, and 86.70 ± 30.90 nm for MTX-Cs NPs, with positive surface charges of 26.40 ± 1.40 mV, 28.20 ± 1.60 mV, and 14.30 ± 2.40 mV, respectively. The drug encapsulation efficiency was 88.56 ± 2.26 % for Met-Cs NPs and 97.03 ± 0.52 % for MTX-Cs NPs. The cellular uptake studies demonstrated a time-dependent increase in the accumulation of Shikonin-labeled Cs NPs in 4T1 cells. The cytotoxicity assays revealed that Met-Cs NPs and MTX-Cs NPs exhibited significantly lower IC50 values (19.85 μg/mL and 103.2 ng/mL, respectively) compared to the plain drugs at 48 h. The combination of Met-/MTX-Cs NPs showed a synergistic cytotoxic effect, inducing 50 % cell death at 15.233 μg/mL of Met and 0.166 μg/mL of MTX. In vivo studies using a 4T1 xenograft mouse model demonstrated that the combination of Met-/MTX-Cs NPs resulted in a 100 % reduction in initial tumor volume, compared to a 40 % decrease with the free drug combination. The tumor growth inhibition was 70.45 % for the Met-/MTX-Cs NPs group, significantly higher than the 33.86 % observed in the free drug combination group. The findings of this study highlight the potential of the Met-/MTX-Cs NPs combination as a novel and effective therapeutic approach for TNBC management. The enhanced therapeutic efficacy, improved safety profile, and the ability to modulate key signaling pathways make this nanoparticle-based combination therapy a promising candidate for further clinical investigation.

A biocompatible drug controlled release system based on β-cyclodextrin crosslinked magnetic lactose/ZIF-8 metal-organic frameworks for cancer treatment

Natural saccharides (Chitosan, Lactose, alginate, and β-cyclodextrin) have recently attracted much attention from researchers as drug delivery systems for cancer therapy. In this regard, for the first time, we designed a new targeted carrier based on magnetic lactose-modified ZIF-8 metal-organic frameworks crosslinked with β-cyclodextrin (M-Lactose@ZIF-8-β-CD) for the pH-responsive controlled release of anticancer drugs, hydrophilic doxorubicin (DOX), and hydrophobic curcumin (CUR) to MCF-7 breast cancer cells. The encapsulation efficiency of M-Lactose@ZIF-8-β-CD was found to be 95.16% for DOX and 65.01% for CUR. The in vitro release studies showed a pH-responsive controlled release of DOX and CUR from M-Lactose@ZIF-8-β-CD at pH 5, which confirmed the performance of the prepared carrier in the cancerous microenvironments. The release mechanism of both drugs was well described by the Korsmeyer-Peppas and Fickian diffusion. In addition, in vitro cytotoxicity, hemolysis, and antioxidant investigations clearly showed that the prepared M-Lactose@ZIF-8-β-CD carriers had good biocompatibility, high blood compatibility, and excellent antioxidant activity due to the presence of natural saccharides in carriers. Based on these findings, the M-Lactose@ZIF-8-β-CD can be applied as a promising targeted co-drug delivery carrier for cancer therapy.

Extracellular vesicles powered cancer immunotherapy: Targeted delivery of adenovirus-based cancer vaccine in humanized melanoma model.

Malignant melanoma, a rapidly spreading form of skin cancer, is becoming more prevalent worldwide. While surgery is successful in treating early-stage melanoma, patients with advanced disease have only a 20% chance of surviving beyond five years. Melanomas with mutations in the NRAS gene are characterized for a more aggressive tumor biology, poorer prognosis and shorter survival. Hence, new therapeutic strategies are needed, especially for this specific group of patients. Novel approaches, such as cancer vaccines, offer promising solutions by stimulating the anti-tumor immune response. Nevertheless, their clinical efficacy is still modest and more effective approaches are required. Herein, we propose the systemic administration of the adenovirus-based cancer vaccine complexed in extracellular vesicles (EVs) with the aim of achieving a targeted therapeutic effect. The vaccine was based on previously tested oncolytic adenovirus Ad5/3-D24-ICOSL-CD40L in combination with melanoma-specific antigens targeting NRAS mutations to enhance the anticancer effect. The antineoplastic properties of the oncolytic vaccine were evaluated in xenograft MUG Mel-2 melanoma BALB/c nude mice. Moreover, to mimic the tumor microenvironment, while investigating at the same time immune cell infiltration and drug penetration, we established a 3D co-culture model based on human NRAS mutated MUG Mel-2 spheroids and PBMCs (HLA matched), which displayed a synergistic effect when treated with the cancer vaccine compared to relative controls. Subsequently, we investigated the systemic delivery of the vaccine in EV formulations in a humanized NSG MUG Mel-2 melanoma mouse model. Our study provides a promising strategy for a tumor-targeted vaccine delivery by EVs, resulting in improved anticancer efficacy and increased infiltration of tumor-infiltrating lymphocytes. This study explores the potential of EVs for the selective delivery of cancer vaccines against malignancies, such as NRAS melanoma. Overall, this research could pave the way for applying autologous EVs as a safe and efficacious tool for targeted cancer therapy.

Potential of natural polysaccharide for ovarian cancer therapy

Potential of natural polysaccharide for ovarian cancer therapy

Deciphering the Therapeutic Applications of Nanomedicine in Ovarian Cancer Therapy: An Overview.

The majority of deadly cancers that afflict the female reproductive system occur in the ovary. Around 1,40,000 women worldwide die from ovarian cancer each year, making it the sixth most common cancer-associated deceases among females in the United States. Modern, cutting-edge treatments like chemotherapy and surgery frequently produce full remissions, but the recurrence rate is still very high. When this crippling condition is diagnosed, there are frequently few therapeutic choices available because of how quietly it manifests. Healthcare practitioners must have a fundamental grasp of the warning signs and symptoms of ovarian cancer, as well as the imaging techniques and treatment choices available, to give the patient the best care possible. The discipline of medical nanotechnology has gained a lot of momentum in recent years in resolving issues and enhancing the detection and treatment of different illnesses, including cancer. This article gives a brief summary of types, risk factors and approaches to ovarian cancer treatment. We subsequently discussed the pathophysiology of ovarian cancer with the risk factors. This review also emphasizes the various signalling pathways involved in ovarian cancer. Our comprehensive integration of recent findings in fundamental research in the nano arena reveals the strong interest in these nanomedicines in ovarian cancer treatment. However, these nanomedicines still require more research, as indicated by the comparatively small number of clinical trials ongoing. This article will provide a reference for ovarian cancer treatment.

Developing a novel P-glycoprotein inhibitor and pairing it with oral paclitaxel liposomes for enhanced cancer therapy

The mucus layer and intestine epithelium pose challenges to the bioavailability of orally administered paclitaxel (PTX). A novel P-glycoprotein inhibitor, (S)-2-decanoylamino-3-(1-naphthyl)propionyl-leucyl-valine (PgpI), was synthesized in this study. Its structure was characterized using 1H NMR, 13C NMR, ESI-MS and IR spectroscopies. The efficacy and in vivo toxicity of PgpI were comprehensively evaluated by R8-PEG@PLs&PgpI, i.e., the oral combination of PgpI and octaarginine R8-PEG-DSPE modified PTX liposomes (R8-PEG@PLs), for lung cancer treatment. The joint forms between PgpI and R8-PEG@PLs were investigated and the affinity of PgpI for intestinal P-glycoprotein remained unaffected when combined externally with R8-PEG@PLs (R8-PEG@PLs&PgpI), compared to the diminished affinity for internal combination. The primary endocytic pathway for R8-PEG@PLs&PgpI in Caco-2 cells was the lipid raft, with increased percentage of macropinocytosis compared to unmodified PTX liposomes (PLs). The established physiology-based cellular kinetic models revealed that the net internalization rate of PTX was 2.3 times higher in R8-PEG@PLs&PgpI than in PLs, correlating with in vivo 2.2 times of antitumor rate. R8-PEG@PLs&PgpI may address the deficits of PLs in human lung A549 tumor-bearing mice due to the lower drug concentration than in normal mice. The external combination of R8-PEG@PLs&PgpI, offering maximal efficacy and security of PgpI, is promising for oral PTX delivery.

Cold Atmospheric Plasma in Cancer Therapy: Molecular Insights, Novel Concepts, and Future Opportunities

Over the past 2 decades, cold atmospheric plasma (CAP) has been playing increasingly pivotal roles in cutting edge biomedical applications and has developed into an innovative field of research of growing importance. One promising new medical application of CAP is cancer treatment. Being able to richly induce both reactive oxygen and nitrogen species, CAP has been shown to effectively control events critical to cancer initiation/progression; selectively inducing Deoxyribonucleic acid (DNA) damage and apoptotic cell deaths, reducing tumor volume and vasculature, halting metastasis and conferring anti-tumor effects by taking advantage of e.g., synergies among and between chemotherapeutic drugs and nanoparticles. This paper discusses molecular and immunological mechanisms of CAP treatment as a potential tool against cancers, with a focus on the novel mechanisms by which CAP interacts with chemotherapeutic drugs and nanotechnology. We then attempt to draw parallels between what is already known about the mechanisms of CAP activity, some novel concepts and attempts of CAP synergy, and the knowledge we would need to develop CAP as a potential therapeutic strategy in oncotherapy. HIGHLIGHTS This article focused on critical review of cold atmospheric plasma’s (CAP) application in cancer therapy. CAP technology in cancer treatment has been expected to cause a medical and therapeutic implications. CAP has strong anticancer efficacy and has been reported about the cell migration and apoptosis. The major role of reactive oxygen and nitrogen species of plasma discharge is to control the core state of cancer transition. GRAPHICAL ABSTRACT

Targeting c-Met in Cancer Therapy: Unravelling Structure-Activity Relationships and Docking Insights for Enhanced Anticancer Drug Design.

The c-Met receptor, a pivotal player in oncogenesis and tumor progression, has become a compelling target for anticancer drug development. This review explores the intricate landscape of Structure-Activity Relationship [SAR] studies and molecular binding analyses performed on c-Met inhibitors. Through a comprehensive examination of various chemical scaffolds and modifications, SAR investigations have elucidated critical molecular features essential for the potent inhibition of c-Met activity. Additionally, molecular docking studies have provided invaluable insights into how c-Met inhibitors interact with their target receptor, facilitating the rational design of novel compounds with enhanced efficacy and selectivity. This review highlights key findings from recent SAR and docking studies, particularly focusing on the structural determinants that govern inhibition potency and selectivity. Furthermore, the integration of computational methodologies with experimental approaches has accelerated the discovery and optimization of c-Met inhibitors, fostering the advancement of promising candidates for clinical applications. Overall, this review underscores the pivotal role of SAR and molecular docking studies in advancing our understanding of c-Met inhibition and guiding the rational design of next-generation anticancer agents targeting this pathway.

Environment-friendly Synthesis of AgNPs from Fimbristylis miliacea Flower Extract: Characterization and its Applications as an Antioxidant Activity, Anticancerous Activity and in the Reduction of 4-Nitrophenol

Background: Silver metal is useful in a variety of fields. Different silver salts exhibit good application in the organic transformation. The use of a green methodology in AgNPs preparation has gained interest of young researchers. Plant systems are employed in the green approach of preparing AgNPs, serving as both a stabilizing and reducing agent. Silver nanoparticles (AgNPs) made from silver salts exhibit a variety of biological activities and may be useful in organic transformation. Method: AgNPs were synthesized with the use of flower extract from Fimbristylis miliacea, which acts as a stabilizing and reducing agent. Result: Fimbristylis miliacea flower extract is used as a reducing and stabilising agent for preparation of AgNPs. These synthesised AgNPs were characterised by using FTIR, XRD, FESEM/ EDS, HR-TEM, TGA, and ICP-AES. Fimbristylis milliciea flower extract was subjected to FTIR and HR-LCMS analysis in order to identify the phytoconstituents that are responsible for the reduction of AgNO3. The HR-TEM shows particle size between 8.98434+0.69669nm and 19.07464+1.4384nm. The size of AgNPs determined by using HR-TEM shows good agreement with XRD particle size. The synthesized AgNPs show excellent antioxidant properties with IC50=56.45 μg/mL. The present study confers significant cytotoxic activity against MDA-MB-231 human breast cancer cell line culture (IC50= 61.97 μg/ml). The AgNPs show a faster reduction of 4-nitrophenol. Conclusion: In conclusion, we have prepared AgNPs by using Fimbristylis miliacea flower extract. The study further concludes that green synthesis of AgNPs has many advantages as compared to chemical methods, such as cost-effectiveness, rapid, and environment-friendly methods. The results indicated that the biosynthesized AgNPs have significant cytotoxic activity against the MDA-MB-231 breast cancer cell line. Further, it indicates that biosynthesized AgNPs can be a potential alternative agent for human breast cancer therapy. The cytotoxic potential can be used for treatments and provides a new method to develop molecules for cancer therapy. The catalytic activity of AgNPs was examined by using the reduction of 4-nitrophenol. It shows that the reduction of 4-nitrophenol in 6 minutes is confirmed by using 1H NMR analysis.

Blood Cell Membrane-Coated Nanomaterials as a Versatile Biomimetic Nanoplatform for Antitumor Applications

The application of nanomaterials in tumor therapy is increasingly widespread, offering more possibilities for enhanced tumor therapy. However, the unclear biological distribution and metabolism of nanomaterials may lead to immune rejection or inflammatory reactions, posing numerous challenges to their clinical translation. The rich diversity and multifaceted functions of blood cells offer promising biological avenues for enhancing the application of nanoparticles in cancer therapy. Blood cell membranes, being made of naturally found components in the body, exhibit significant biocompatibility, which can reduce the body’s immune rejection response, extend the drug’s residence time in the bloodstream, and enhance its bioavailability. Integrating blood cell membranes with nanomaterials enhances tumor therapy by improving targeted delivery, prolonging circulation time, and evading immune responses. This review summarizes recent advancements in the application of blood cell membrane-coated nanomaterials for antitumor therapy, with a particular focus on their use in photodynamic and photothermal treatments. Additionally, it explores their potential for synergistic effects when combined with other therapeutic modalities.

Critical role of non-coding RNA-mediated ferroptosis in urologic malignancies

Urologic malignancies, characterized by their high aggressiveness and metastatic potential, pose a significant public health challenge globally. Ferroptosis, a novel mode of cell death, typically arises from intracellular iron ion overload and the accumulation of lipid peroxides. This process has been shown to play a crucial regulatory role in various pathological conditions, particularly in cancer, including urologic cancers. However, the comprehensive regulatory mechanisms underlying ferroptosis remain poorly understood, which somewhat limits its broader application in cancer therapy. Non-coding RNAs (ncRNAs), which encompass microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), are non-coding transcripts that play pivotal roles in various physiological processes, such as proliferation, differentiation, apoptosis, and cell cycle regulation, by modulating the expression of target genes. The biological functions and potential regulatory mechanisms of ncRNAs in the context of cancer-related ferroptosis have been partially elucidated. Research indicates that ncRNAs can influence the progression of urologic cancers by affecting cell proliferation, migration, and drug resistance through the regulation of ferroptosis. Consequently, this review aims to clarify the functions and mechanisms of the ncRNA-ferroptosis axis in urologic cancers and to evaluate the clinical significance of ferroptosis-related ncRNAs, thereby providing new insights into cancer biology and therapeutic strategies that may ultimately benefit a diverse range of cancer patients.

Associations between tertiary lymphoid structure density and immune checkpoint inhibitor efficacy in solid tumors: systematic review and meta-analysis

BackgroundTertiary lymphoid structures (TLS) play a crucial role in tumor immunity, yet their relationship with the efficacy of immune checkpoint inhibitors (ICI) in cancer therapy is not fully understood. This study aims to systematically evaluate how TLS density influences treatment outcomes in cancer patients receiving ICI therapy.MethodsThe PubMed, Embase, Cochrane Library, and Web of Science databases were searched for eligible studies published before January 22, 2024. Our analysis encompassed odds ratios (ORs) for response rates (RRs) and hazard ratios (HRs) for progression-free survival (PFS), each with their respective 95% confidence intervals (CIs).ResultsOur meta-analysis, including 19 clinical trials with 1,752 patients, identified a strong correlation between high TLS density and increased RR to ICIs (OR= 2.99, 95% CI: 2.14-4.18, P < 0.001). Furthermore, a higher TLS density was associated with prolonged PFS (HR=0.75, 95% CI: 0.63-0.88, P < 0.001). Specifically, in the context of non-small cell lung cancer (NSCLC), breast cancer (BC), renal cell carcinoma (RCC), esophageal cancer (EC), and urothelial carcinoma (UC), a significant relationship was observed between high TLS density and better ICI efficacy. Publication bias did not affect the integrity of our conclusions. Sensitivity analysis further reinforced the reliability of our aggregated outcomes.ConclusionOur meta-analysis underscores the predictive role of TLS density in determining the RR and PFS among cancer patients undergoing ICI therapy. These results highlight the prognostic significance of TLS, suggesting its potential as a biomarker for guiding treatment decisions, even in tumor types traditionally considered ICI-resistant. Clinicians are recommended to assess TLS density as a part of patient evaluation to optimize ICI therapy initiation.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42023439875.

Influence of Nanomedicine as a Smart Weapon on Multidrug Resistance in Cancer Therapy.

Cancer is the leading cause of death worldwide. The effectiveness of chemotherapy in cancer patients is still significantly hampered by Multidrug Resistance (MDR). Tumors exploit the MDR pathways to invade the host and limit the efficacy of chemotherapeutic drugs that are delivered as single drugs or combinations. Further, overexpression of ATP-binding Cassette transporter (ABC transporter) proteins augments the efflux of chemotherapeutic drugs and lowers their intracellular accumulation. Recent progress in the development of nanotechnology and nanocarrier-based drug delivery systems has shown a better perspective with respect to the improvement of cancer chemotherapy. Nanoparticles/nanomaterials are designed to target the immune system and tumor microenvironment of cancer cells for a variety of cancer treatments in order to improve bioavailability and reduce toxicity. This review elucidates the successful use of nanomaterials for cancer therapy and addressing the MDR and throws some light on the present obstacles impeding their translation to clinical use.

AI-Guided Cancer Therapy for Patients with Coexisting Migraines

Background: Cancer remains a leading cause of death worldwide. Progress in its effective treatment has been hampered by challenges in personalized therapy, particularly in patients with comorbid conditions. The integration of artificial intelligence (AI) into patient profiling offers a promising approach to enhancing individualized anticancer therapy. Objective: This narrative review explores the role of AI in refining anticancer therapy through personalized profiling, with a specific focus on cancer patients with comorbid migraine. Methods: A comprehensive literature search was conducted across multiple databases, including PubMed, Scopus, and Google Scholar. Studies were selected based on their relevance to AI applications in oncology and migraine management, with a focus on personalized medicine and predictive modeling. Key themes were synthesized to provide an overview of recent developments, challenges, and emerging directions. Results: AI technologies, such as machine learning (ML), deep learning (DL), and natural language processing (NLP), have become instrumental in the discovery of genetic and molecular biomarkers of cancer and migraine. These technologies also enable predictive analytics for assessing the impact of migraine on cancer therapy in comorbid cases, predicting outcomes and provide clinical decision support systems (CDSS) for real-time treatment adjustments. Conclusions: AI holds significant potential to improve the precision and effectiveness of the management and therapy of cancer patients with comorbid migraine. Nevertheless, challenges remain over data integration, clinical validation, and ethical consideration, which must be addressed to appreciate the full potential for the approach outlined herein.

From weight loss to cancer treatment: Fasting as an adjuvant anticancer therapy

The number of studies that have been conducted on the possible benefits of different types of fasting or calorie restriction on cancer therapy, including the likelihood that these treatments lessen side effects, has been limited. However, the results are nevertheless promising. Chemotherapy’s adverse effects have led to a quest for options that reduce reliance on it. The susceptibility of tumorous cells to specific metabolites and nutrient deficiency is increasingly recognized as a key characteristic of the disease. This review delves into the data on various fasting methods and calorie restriction in rodents and humans, with a focus on biological adaptations that could potentially lower cancer risk or enhance cancer treatment results. We also emphasize recent scientific developments regarding the use of prolonged fasting and fasting-mimicking diets as a possible additional treatment for patients receiving immunotherapy or other treatments. This approach shows promise in enhancing treatment effectiveness, preventing resistance, and minimizing side effects. This study proposes that combining fasting and calorie restriction with chemotherapy, immunotherapy, or other therapies might be a potential technique to improve treatment efficacy, avoid resistance, and reduce adverse effects.

Histological features of the Purkinje neurons of the Albino rat (Rattus norvegicus) following letrozole administration.

Aromatase inhibitors are increasingly being used as adjuvant therapy for hormone-responsive cancers. These drugs may reduce the endogenous estrogen production in the cerebellum. Prolonged use has been associated with symptoms such as ataxia, poorer balance performance and diminished verbal memory, suggesting impaired cerebellar function. Thus, this study sought to outline the structural basis for the cerebellar deficits observed. Twenty-seven male rats (3 baseline, 15 experimental, 9 control) aged three months were recruited with the intervention group receiving 0.5 mg/kg of letrozole daily for 50 days by oral gavage while the control group received normal saline. Their cerebella were harvested for histological processing on days 20, 35, and 50. Photomicrographs were taken and analysed using Fiji ImageJ software. The dendritic spine densities and Purkinje linear densities were coded and analyzed using IBM SPSS Statistics version 25.0. A P-value of ≤0.05 was considered significant. A temporal decline in the Purkinje linear density as well as pyknosis and cytoplasmic eosinophilia was noted in the intervention group (P=0.1). Further, the dendritic spine density of the Purkinje neurons in the intervention group was markedly reduced (P=0.01). The reduction in the linear cell density and the dendritic spine density of the Purkinje cells following letrozole administration may provide an anatomical basis for the functional cerebellar deficits seen in chronic aromatase inhibitor use.

A 3-arm randomized control trial to compare the efficacy of re-circulant hyperthermic intravesical chemotherapy versus conventional intravesical mitomycin C and BCG therapy for intermediate-risk non-muscle invasive bladder cancer.

To evaluate the efficacy and side effects of re-circulant hyperthermic intravesical chemotherapy versus conventional treatments for intermediate risk non-muscle invasive bladder cancer (NMIBC). A randomized 3-arm, parallel group trial was conducted at a single tertiary care centre. 135 patients with low-grade intermediate-risk cancer, having undergone complete resection of bladder tumor were included. Patients were assigned 1:1:1, to receive intra-vesical chemo-hyperthermia (C-HT), mitomycin-C (MMC) or BCG therapy. There was no treatment crossover. Patients were followed up with check cystoscopy every 3 months for histopathological recurrence. The three arms were comparable in terms of age, gender, tumor size, number of tumors and clinical stage or grade of tumors. Mean tumor size was 2.58 (± 0.88) cm and the mean number of tumors resected was 2.04 (± 1.02) (Range 1-5). There was no significant difference between the various groups for tumor recurrence (χ2 = 1.96, p = 0.375) or time to recurrence (13.6 vs. 10.8 vs. 9.8 months, p = 0.844)though incidence of non-healing necrotic area was higher with C-HT (22.2% vs. 11.1% and 4.8%, χ2 = 6.093, p = 0.048). Median (IQR) follow up period was 26 (12-52) months. Treatment discontinuation or drug intolerance was significantly higher in BCG arm (p = 0.03). Intravesical C-HT with MMC, conventional MMC and BCG are equally effective and comparable alternatives for intravesical therapy in low-grade intermediate-risk NMIBC. Higher incidence of non-healing resection site with C-HT and higher local symptoms with BCG are a concern.

Inavolisib-Based Therapy in PIK3CA-Mutated Advanced Breast Cancer

BackgroundInavolisib is a highly potent and selective inhibitor of the alpha isoform of the p110 catalytic subunit of the phosphatidylinositol 3-kinase complex (encoded by PIK3CA) that also promotes the degradation of mutated p110α. Inavolisib plus palbociclib–fulvestrant has shown synergistic activity in preclinical models and promising antitumor activity in early-phase trials.MethodsIn a phase 3, double-blind, randomized trial, we compared first-line inavolisib (at an oral dose of 9 mg once daily) plus palbociclib–fulvestrant (inavolisib group) with placebo plus palbociclib–fulvestrant (placebo group) in patients with PIK3CA-mutated, hormone receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative locally advanced or metastatic breast cancer who had had relapse during or within 12 months after the completion of adjuvant endocrine therapy. The primary end point was progression-free survival as assessed by the investigator.ResultsA total of 161 patients were assigned to the inavolisib group and 164 to the placebo group; the median follow-up was 21.3 months and 21.5 months, respectively. The median progression-free survival was 15.0 months (95% confidence interval [CI], 11.3 to 20.5) in the inavolisib group and 7.3 months (95% CI, 5.6 to 9.3) in the placebo group (hazard ratio for disease progression or death, 0.43; 95% CI, 0.32 to 0.59; P<0.001). An objective response occurred in 58.4% of the patients in the inavolisib group and in 25.0% of those in the placebo group. The incidence of grade 3 or 4 neutropenia was 80.2% in the inavolisib group and 78.4% in the placebo group; grade 3 or 4 hyperglycemia, 5.6% and 0%, respectively; grade 3 or 4 stomatitis or mucosal inflammation, 5.6% and 0%; and grade 3 or 4 diarrhea, 3.7% and 0%. No grade 3 or 4 rash was observed. Discontinuation of any trial agent because of adverse events occurred in 6.8% of the patients in the inavolisib group and in 0.6% of those in the placebo group.ConclusionsIn patients with PIK3CA-mutated, hormone receptor–positive, HER2-negative locally advanced or metastatic breast cancer, inavolisib plus palbociclib–fulvestrant led to significantly longer progression-free survival than placebo plus palbociclib–fulvestrant, with a greater incidence of toxic effects. The percentage of patients who discontinued any trial agent because of adverse events was low. (Funded by F. Hoffmann–La Roche; INAVO120 ClinicalTrials.gov number, NCT04191499.)