Chemotherapy Research Articles

Efficacy of radiolabelled PD-L1-targeted nanobody in predicting and evaluating the combined immunotherapy and chemotherapy for resectable non-small cell lung cancer.

This study aimed to assess the predictive and evaluative value of PD-L1 targeted 68Ga-THP-APN09 PET/CT in the neoadjuvant immunotherapy combined with chemotherapy for resectable non-small cell lung cancer (NSCLC), and to explore its potential in indicating immunotherapy-related adverse effects (irAEs). Fifty patients with resectable NSCLC enrolled in this prospective study underwent baseline 68Ga-THP-APN09 PET/CT and 18F-FDG PET/CT, with follow-up 18F-FDG PET/CT conducted, additionally, 36 patients received follow-up 68Ga-THP-APN09 PET/CT. Surgery was performed following 2-4 cycles of toripalimab combined with chemotherapy if R0 resection was feasible. The major pathologic response (MPR) state of the post-operative specimen and the adverse effects following combined therapy were documented. The correlation between PD-L1 expression and baseline 68Ga-THP-APN09 PET/CT uptake was determined. The predictive and evaluative efficacies of baseline and follow-up 68Ga-THP-APN09 PET/CT, along with 18F-FDG PET/CT, in determining MPR, were compared. The SUVmax values of baseline 68Ga-THP-APN09 PET/CT were significantly higher in patients exhibiting high-positive PD-L1 expression compared to those with low-positive and negative expression (P = 0.001). And the SUVmax values of baseline 68Ga-THP-APN09 PET/CT in the response group, as determined by 18F-FDG PET/CT evaluation, were significantly higher than those in the non-response group (3.4 vs. 2.4, P < 0.001). Totally, 41 patients underwent surgery, of which 27 achieved MPR, while 14 did not. The SUVmax in baseline 68Ga-THP-APN09 PET/CT demonstrated statistical significance between the MPR and non-MPR groups, with area under the ROC curve (AUC) of 0.88 (95%CI: 0.77-0.99) in identifying MPR. However, the SUVmax in baseline 18F-FDG PET/CT failed to demonstrated significant predictive power, with AUC values of 0.68 (95%CI: 0.50-0.86, P = 0.076). While the SUVmax in follow-up 68Ga-THP-APN09 and 18F-FDG PET/CT, along with their change rate (ΔSUVmax%), demonstrated good predictive efficacy in identifying MPR, with AUC values of 0.81 (0.64-0.98), 0.91 (0.82-1.00), 0.93 (0.84-1.00), and 0.96 (0.89-1.00), respectively. Furthermore, the follow-up 68Ga-THP-APN09 PET/CT could remarkedly indicate the potential for thyroiditis. Baseline 68Ga-THP-APN09 PET/CT alone could predict efficacy and assist in patient screening for immunotherapy combined chemotherapy in resectable NSCLC, and the follow-up 68Ga-THP-APN09 PET/CT and their change rates could aid in therapy evaluation. Additionally, follow-up 68Ga-THP-APN09 PET/CT could be utilized to monitor the immunotherapy-related thyroiditis during the therapy. NCT05156515, registered 8 December 2021, https://register. gov/prs/app/action/SelectProtocol?sid=S000BMSI%26;selectaction=Edit%26;uid=U000503E%26;ts=2%26;cx=zeghuw .

Pharmacogenomics influence on MDR1-associated cancer resistance and innovative drug delivery approaches: advancing precision oncology.

Currently, there is a growing concern surrounding the treatment of cancer, a formidable disease. Pharmacogenomics and personalized medicine have emerged as significant areas of interest in cancer management. The efficacy of many cancer drugs is hindered by resistance mechanisms, particularly P-glycoprotein (P-gp) efflux, leading to reduced therapeutic outcomes. Efforts have intensified to inhibit P-gp efflux, thereby enhancing the effectiveness of resistant drugs. P-gp, a member of the ATP-binding cassette (ABC) superfamily, specifically the multidrug resistance (MDR)/transporter associated with antigen processing (TAP) sub-family B, member 1, utilizes energy derived from ATP hydrolysis to drive efflux. This review focuses on genetic polymorphisms associated with P-gp efflux and explores various novel pharmaceutical strategies to address this challenge. These strategies encompass SEDDS/SNEDDS, liposomes, immunoliposomes, solid lipid nanoparticles, lipid core nanocapsules, microemulsions, dendrimers, hydrogels, polymer-drug conjugates, and polymeric nanoparticles. The article aims to elucidate the interplay between pharmacogenomics, P-gp-mediated drug resistance in cancer, and formulation strategies to improve cancer therapy by tailoring formulations to genetically susceptible patients.

Response to neoadjuvant chemotherapy in early breast cancers is associated with epithelial-mesenchymal transition and tumor-infiltrating lymphocytes.

Epithelial-mesenchymal transition (EMT) and tumor-infiltrating lymphocytes (TILs) play a central role in early-stage breast cancer (BC) and are associated with chemoresistance, stemness, and invasion. The objective of this study was two fold: (a) by investigating the predictive value of EMT and TILs, we aimed to estimate the chance of achieving a response after neoadjuvant chemotherapy (NAC) and (b) to evaluate the potential changes of EMT and TILs in BC upon NAC. Using bulk RNA sequencing and immunofluorescence (IF) for EMT (E-cadherin and vimentin) and lymphocyte markers (CD3, CD8, FOXP3), we analyzed pre- and post-NAC tumor samples from 100 early-BC patients treated with NAC. For each BC molecular subtype, we compared the expression of EMT and TILs, at the RNA and protein level, between responding and non-responding tumors. Paired analysis of pre- and post-NAC samples was performed for patients with residual disease after NAC. RNA sequencing of pre- and post-NAC samples identified significant differences in EMT-related and inflammation-related gene expression between non-responding (RCB-II/III) and responding (RCB-0/I) tumors. Increased EMT-related marker expression was observed after NAC in cases with residual disease, in particular in the luminal subtype. Characterization of TILs in pre-NAC samples showed substantially more CD3 + CD8-FOXP3-lymphocytes in responding HER2+ tumors compared with non-responding. Paired analyses of pre- and post-NAC samples demonstrated higher levels of CD3 + CD8 + FOXP3-lymphocytes in residual luminal and triple-negative BC and higher levels of CD3 + CD8-FOXP3-lymphocytes in residual triple-negative BC compared with other subtypes of lymphocytes. We found that there is an unmet clinical need for reliable biomarkers to predict response to NAC in BC. Our results suggest that an upregulation of the EMT gene signature in diagnostic biopsies is associated with poor response to NAC in early BC, across all subtypes. Additionally, changes in EMT and in the TIL population occur in residual tumors after NAC. These findings could help to personalize future NAC and adjuvant treatment regimens.

Overcoming hypoxia-induced breast cancer drug resistance: a novel strategy using hollow gold-platinum bimetallic nanoshells

Breast cancer (BC) is a significant cause of cancer-related deaths among women worldwide. Hypoxia, a common feature of solid tumor, is associated with drug resistance and a poor prognosis in BC. In this study, we present a strategy to overcome hypoxia-induced chemotherapy tolerance in BC. Specifically, we synthesized a hollow gold (Au)-platinum (Pt) bimetallic nanoshell for the first time, which acted as a drug delivery system (DDS) for doxorubicin (DOX). The photothermal effect, induced by the surface plasmon resonance (SPR) from the Au-Pt shell under near infrared-II (NIR-II) laser irradiation, not only directly causes tumor cell death through photothermal therapy (PTT), but also significantly enhances the catalase-like activity between Pt nanoparticles and endogenous H2O2. This, subsequently, results in a heightened yield of O2, which further facilitates the release of DOX. This process alleviates tumor hypoxia and down-regulating hypoxia-inducible factor-1α (HIF-1α), multidrug resistance gene 1 (MDR1), and P-glycoprotein (P-gp), which can reverse drug resistance and achieve more effective DOX chemotherapy effects. Significantly, the increased availability of oxygen further re-polarizes immunosuppressive M2 macrophages into antitumor M1 macrophages. This study presents a novel strategy to tackle tumor proliferation and enhance tumor response to chemotherapy, offering hope for reversing in drug resistance in cancerous lesions.Graphical

Heavy medicine: the need for ethical stewardship of metal and metalloid-based medicines and technologies.

Metals and metalloids including cobalt, gadolinium, lutetium, and germanium are used in numerous medical applications spanning diverse specialities including orthopedics, radiology, oncology, and healthcare artificial intelligence. These medical advances include cobalt containing orthopedic implants, gadolinium-based contrast agents, lutetium-containing cancer drugs, and germanium-based semiconductors. While these metal and metalloid-based solutions do improve patient care, there is a heavy side to how the elements needed for these solutions are mined, extracted, and discarded. These practices often exploit and harm vulnerable populations and environments. As healthcare professionals, we should be aware of the entire mineral to medicine lifecycle. As providers and consumers of these metal and metalloid-based solutions, we must advocate for more responsible and ethical extraction and recycling practices. As researchers and educators, we must promote and support continued research and development into less resource-intense medical solutions that can both improve patient care and sustainability.

Mechanisms, Models, and Clinical Applications of Cell Membrane Electroporation

Electroporation is an essential biophysical process that involves the use of pulsed electric fields to temporarily increase the permeability of cell membranes. A comprehensive overview of the main clinical and biomedical applications of cellular electroporation is provided here with a particular focus on cancer therapy, genetics, and drug delivery. The review concentrates on the characterization of membrane stresses caused by electroporation and their impact on cell membrane structure and dynamics. It analyses the relationship between applied electric fields, cell geometry, and membrane composition with the aim of developing mathematical models to simulate cell geometries and the electroporation process. Furthermore, it identifies both the beneficial effects and potential complications of the electroporation treatment, as well as the various mathematical models that have been developed to simulate the effects of such treatments. The use of sophisticated simulation algorithms enables an in-depth investigation of the intricate relationship between electrical parameters and cellular responses, facilitating a comprehensive assessment of the efficacy and safety of the electroporation procedures.

PSTK inhibition activates cGAS-STING, precipitating ferroptotic cell death in leukemic stem cells.

Differentiation arrest and dependence on oxidative metabolism are features shared among genetically diverse acute myeloid leukemias (AML). A phenotypic CRISPR-Cas9 screen in AML identified dependence on phosphoseryl-tRNA kinase (PSTK), an atypical kinase required for the biosynthesis of all selenoproteins. In vivo, PSTK inhibition (PSTKi) impaired AML cell growth and leukemic stem cell self-renewal. Notably, timed pharmacologic PSTKi effectively targeted chemo-resistant AML in murine and patient-derived xenograft models, showing selectivity for malignant cells over normal hematopoietic cells. Mechanistically, PSTKi-induced reactive oxygen species (ROS) triggering mitochondrial DNA release into the cytosol and activated cGAS-STING. This activation in turn disrupted iron metabolism augmenting ROS generation and amplifying ferroptosis. Together, these findings reveal a self-reinforcing PSTK-cGAS-STING-ROS loop culminating in an oxidative crisis and ferroptotic cell death of leukemic stem cells. The data highlight the potential for augmenting standard cancer chemotherapies using timed metabolic intervention to eliminate chemopersisting cells and thereby impede disease relapse.

System level network data and models attack cancer drug resistance.

Drug resistance is responsible for >90% of cancer related deaths. Cancer drug resistance is a system level network phenomenon covering the entire cell. Small-scale interactomes and signalling network models of drug resistance guide directed drug development. Recently, proteome-wide human interactome and signalling network data have become available, which have been extended by drug-target interactions, drug resistance-inducing mutations, as well as by several cancer and drug resistance-related multi-omics datasets. System level signalling network models have become available examining therapy resistance, performing in silico clinical trials, and conducting large, in silico drug combination screens. Drug resistance network data and models have become interoperable and reliable. These advances paved the road for building proteome-wide drug resistance models.

The Impact of Preoperative Radiotherapy and Chemotherapy on Autologous Breast Reconstruction Outcomes—A Retrospective Single-Center Study

Background: While radiotherapy (RT) and chemotherapy (CT) significantly improve breast cancer outcomes, they may affect breast reconstruction by causing vascular damage and delayed wound healing. This retrospective study evaluates how preoperative RT, CT, or the combination of both impacts intraoperative and postoperative outcomes in immediate or delayed deep inferior epigastric perforator (DIEP) flap breast reconstructions. Methods: We conducted a single-center review of all patients undergoing autologous DIEP flap reconstruction after mastectomy between 2018 and 2024. Patients were divided into four groups: RT only, CT only, a combination of RT and CT, and a control group with no preoperative therapies. Intraoperative and postoperative outcomes were then compared among these groups, with statistical significance defined as p &lt; 0.05. Results: We included 114 patients representing 141 DIEP-flap breast reconstructions. Flap survival rate was 98.5%. In the univariate analysis, total microvascular recipient site complications were significantly higher in the RT + CT group (14.0%, p = 0.021). Donor-site complication rates differed significantly among the four groups (p = 0.025), with the highest rate observed in the RT + CT group (44.7%). In the logistic regression analysis, ischemia time was found as an independent risk factor for total recipient site complications, but not for microvascular complications (OR = 1.019, 95%-CI = 1.004–1.035, p = 0.014). Conclusions: Combined RT + CT significantly increased microsurgical complications. Ischemia time correlated with higher odds of total recipient site complications. Individualized patient management and diminished ischemia time are likely to improve flap survival.

The Current Status of Adjuvant Chemotherapy for Colorectal Cancer in Japan: A Paradigm Shift from Oral Fluoropyridine Single Therapy to the Oxaliplatin Regimen

The effectiveness of oxaliplatin (L-OHP) has been reported overseas; however, in Japan, the prognosis of colorectal cancer (CRC) patients is reported to be good, and there has been a long debate about the applicability of L-OHP combination therapy in Japan. In recent years, the results of the ACHIEVE trial have become clear, and the standard consensus in Japan establishes L-OHP combination therapy for a duration of 3 months as the adjuvant treatment for CRC.

Exploring the role of artificial intelligence in chemotherapy development, cancer diagnosis, and treatment: present achievements and future outlook

BackgroundArtificial intelligence (AI) has emerged as a transformative tool in oncology, offering promising applications in chemotherapy development, cancer diagnosis, and predicting chemotherapy response. Despite its potential, debates persist regarding the predictive accuracy of AI technologies, particularly machine learning (ML) and deep learning (DL).ObjectiveThis review aims to explore the role of AI in forecasting outcomes related to chemotherapy development, cancer diagnosis, and treatment response, synthesizing current advancements and identifying critical gaps in the field.MethodsA comprehensive literature search was conducted across PubMed, Embase, Web of Science, and Cochrane databases up to 2023. Keywords included “Artificial Intelligence (AI),” “Machine Learning (ML),” and “Deep Learning (DL)” combined with “chemotherapy development,” “cancer diagnosis,” and “cancer treatment.” Articles published within the last four years and written in English were included. The Prediction Model Risk of Bias Assessment tool was utilized to assess the risk of bias in the selected studies.ConclusionThis review underscores the substantial impact of AI, including ML and DL, on cancer diagnosis, chemotherapy innovation, and treatment response for both solid and hematological tumors. Evidence from recent studies highlights AI’s potential to reduce cancer-related mortality by optimizing diagnostic accuracy, personalizing treatment plans, and improving therapeutic outcomes. Future research should focus on addressing challenges in clinical implementation, ethical considerations, and scalability to enhance AI’s integration into oncology care.

PEGylated Nanoliposomes Encapsulated with Anticancer Drugs for Breast and Prostate Cancer Therapy: An Update

There are different types of cancer treatments, including surgery, radiotherapy, and chemotherapy. However, the complexity of cancer has resulted in treatment challenges to medicinal scientists and a socio-economic burden to the public health system globally. The pharmacological limitations associated with the current conventional anticancer drugs include lack of specificity, poor bioavailability, toxicity, drug resistance, and poor delivery mechanisms, which make cancer treatment challenging. Thus, the number of cancer cases is escalating rapidly, especially breast and prostate cancer in women and men, respectively. The application of nanoformulations is gaining momentum for treating different cancer types. However, they also exhibit challenges that must be addressed for effective cancer treatment. Nanoliposomes are nanoformulations that are widely explored for cancer treatment with interesting therapeutic outcomes. They have been functionalized with PEG to further improve their therapeutic outcomes. Hence, this review provides an update on PEGylated nanoliposomes loaded with anticancer drugs for the treatment of breast and prostate cancer, focusing on pre-clinical studies published in the last decade (2015 to 2024) to reflect the recent advancements made in the design of PEGylation nanoliposomes. Highlights of the clinically and commercially available PEGylation nanoliposomes are also presented in this review.

Targeting Frequent Efferocytosis in Tumor Microenvironment is a New Direction for Cancer Treatment

A variety of factors, such as dietary habits, the external environment, and individual genetic differences, can lead to the development of cancer. While chemotherapy and radiotherapy are commonly used for cancer treatment, drug resistance and side effects are prevalent issues. Therefore, there is an urgent need to find new treatment modalities. Studies have shown that radiotherapy and chemotherapy can lead to a significant increase in apoptotic cells (ACs) within the tumor microenvironment (TME). The process of phagocytosis helps maintain homeostasis by engulfing and removing these ACs from the organism promptly, which is referred to as efferocytosis. However, it has been observed that excessive efferocytosis can promote the formation of an immunosuppressive TME, which is detrimental to tumor therapy. Thus, inhibiting efferocytosis to enhance the formation of an immune microenvironment shows promise as a treatment direction for tumors. As researchers gradually uncover the molecular mechanisms of efferocytosis, various small‐molecule inhibitors and monoclonal antibodies are actively being assessed in clinical trials. Targeting efferocytosis is anticipated to emerge as a promising approach in tumor treatment. In this review, the intricate steps involved in efferocytosis are explored and the current drugs that targeting this process for cancer treatment are outlined.

Early Check-In Protocol: Identifying Medication Issues in Patients with Cancer at Health System Specialty Pharmacy.

Several studies have illustrated value in early patient contact following oral anticancer medication (OAM) initiation, particularly within the first 14 days of therapy, as adverse effects may lead to early discontinuation or poor adherence. Health-system specialty pharmacies (HSSPs) are optimally positioned to adopt this best practice through formalized protocols designed to identify and mitigate medication-related issues. To outline an HSSP-led early check-in protocol for patients taking OAMs and to describe the subsequent interventions conducted by the HSSP team and their acceptance rate. HSSPs enacted a protocol in January 2021 requiring oncology pharmacists - to contact patients within 14 days of OAM initiation, aiming to optimize adverse effect management, offer supportive care, address adherence, and provide education. To evaluate the impact of the early check-in protocol, we conducted a retrospective, multicenter, observational study across CPS's health system clients from January 2022 to November 2023. HSSP pharmacists created 1698 interventions for 1184 patients from the early check-in. The cancer types most frequently associated with an intervention were breast (n = 431, 25.4%), gastrointestinal (n = 245, 14.4%), and prostate (n = 206, 12.1%). The most frequent intervention categories were adverse drug reactions (ADRs) (n = 1,548, 91.2%) and adherence (n = 55, 3.2%). Overall, 95.5% of pharmacist recommendations were accepted by patients and/or providers. Implementing an early check-in protocol allows HSSP pharmacists to mitigate barriers to OAM adherence. This study emphasizes the importance of early check-in and illustrates the scope of the oncology pharmacist's role by evaluating critically meaningful interventions and quantifying pharmacist recommendations and acceptance rate.

L-glutaminase synthesis by Klebsiella pneumoniae (AS KP 23) isolated from clinical strain, and its efficacy against human hepatocellular and breast cancer cell lines.

Cancer is a major cause of morbidity and mortality worldwide. The proliferation of cancer cells depends largely on glutamine for survival and proliferation. Glutamine serves as a carbon source for the synthesis of metabolites and lipids via the TCA cycle, as well as a source of nitrogen for the synthesis of amino acids and nucleotides. Recently, the role of glutamine metabolism in cancer has been explored in many studies. Therefore, it provides a scientific relationship for targeting glutamine metabolism for cancer treatment. L-glutaminase which is a powerful anticancer medication that is widely used around the world, works by removing L-glutamine from cancerous cells. L-glutaminase has been cited as the most potent molecule that inhibits the proliferation of cancer cells, which significantly raises the possible applicability of cancer therapy and the possibility of its application as an alternative drug to chemotherapy. The first investigation into the antitumor property of L-glutaminase revealed its inhibitory effect on the growth of Gardner lymphosarcoma (6C3HED) and L-1210 leukemia cells. In the same study, glutaminase from Pseudomonas spp., in combination with azaserine enhanced the degree of tumor growth inhibition. Subsequently, L-glutaminase was administered intravenously in patients with acute lymphoblastic leukemia and acute myeloid leukemia. Recently, a purified L-glutaminase from Streptomyces sp. D214 was shown to be the most effective, with an IC50 value of 10mg/ml against the MCF-7 tumor cell line. Also, various in vitro studies have revealed that the activity of glutaminase against the proliferation of tumor cell lines using the MTT (3-(4,5- dimethylthiazol-2-yl)- 2, 5-diphenyltetrazolium bromide) cell proliferation assay. Alcaligenes faecalis KLU102 glutaminase was able to reduce the viability of HeLa cells in a dose-dependent manner, with an IC50 value of 12.5mg/ml within 24h. In this study, a bacterium extracellular from human stool samples was extracted and identified using morphological, biochemical, and molecular methods. The 16S rRNA gene was 100% identical to the sequence from Klebsiella pneumoniae and was submitted to GenBank under accession number OQ703039. Thus, this strain was named Klebsiella pneumoniae AS KP 23. Further kinetic studies on the purified enzyme were performed. In addition, the pH stability of the L-glutaminase enzyme was slightly affected over the pH range of 7.0-9.0 after 2h of pre-incubation, and the rate of thermal inactivation of the L-glutaminase enzyme increased with higher temperatures and longer preheating periods. In addition, the stability of the tested enzyme decreased with an increasing storage period at -20°C. The SDS-PAGE revealed that the L-glutaminase subunits had a molecular weight of around 97kDa. L-glutaminase was purified 1.33-fold with a final specific activity of 799.9 U/mg protein using gel filtration chromatography. The enzyme´s cytotoxic activity showed severe toxicity against the HepG-2 human hepatocellular and breast cancer cell lines. Klebsiella pneumoniae glutaminase was able to reduce the viability of HeLa cells in a dose-dependent manner, with an IC50 value of 305.78µg/ml in human hepatocellular carcinoma and an IC50 value of 400.51µg/ml in breast cancer cell lines. Klebsiella pneumoniae AS KP 23 was a genetically determined microbial species isolated from human stool samples. The production of extracellular enzymes was examined. Additionally, purified L-glutaminase inhibited the growth of normal cells and showed potent anticancer activity against numerous cancer cell lines in the study. Its broad pH and temperature range, combined with its unique and highly stable catalytic activity, make it an excellent choice for use as an effective cancer inhibitor.

Oncologic oUTcomes of neoadjuvant chemotherapy for obSTructive colon cAncer after steNt decompression (OUTSTAND trial); A study protocol of multicenter non-inferiority randomized controlled trial.

For obstructive colon cancer, many studies have been conducted on the use of self-expandable metallic stents (SEMS) as a bridge to surgery (BTS). However, there are currently no available prospective data on the impact of bridging period and there is a lack of research on the effects of neoadjuvant chemotherapy during the bridging period. Patients who undergo successful SEMS placement for obstructive left-sided colon adenocarcinoma without metastases will be eligible for this study. This study is a multicenter, non-inferiority, randomized (1:1), open-label, controlled trial. The patients assigned to the control group will undergo curative surgery within two weeks after successful SEMS placement. The patients assigned to the experimental group will undergo three cycles of neoadjuvant FOLFOX chemotherapy within two weeks after successful SEMS placement. Curative surgery will be performed within four weeks of the last administration of neoadjuvant FOLFOX. Circulating tumor DNA (ctDNA) will be collected at specific time points. The optimal time interval for SEMS placement as a BTS can significantly impact long-term oncologic outcomes. In this study, our goal is to identify the optimal time interval for SEMS placement as a BTS. Recently, there has been interest in applying neoadjuvant chemotherapy for locally advanced colon cancer. In the context of early treatment for tumor dissemination following SEMS placement, neoadjuvant chemotherapy may be beneficial for delayed surgery after SEMS placement as a BTS. The results of this trial will be an important reference for the application of neoadjuvant chemotherapy in locally advanced colon cancer. Additionally, researchers will investigate whether ctDNA can serve as a reliable indicator to guide decisions about the timing and type of subsequent treatment. Based on the results of this trial, a patient-tailored treatment strategy can be developed for obstructive colon cancer. This study is registered on ClinicalTrials.gov Identifier: NCT04889820, registered on May 17, 2021 in clinicaltrials.gov; Protocol ID: XC21MIDI0004.

A Retrospective Analysis of Pembrolizumab With or Without Chemotherapy in Advanced Non-small Cell Lung Cancer: Experience From a Tertiary Care Hospital

A Retrospective Analysis of Pembrolizumab With or Without Chemotherapy in Advanced Non-small Cell Lung Cancer: Experience From a Tertiary Care Hospital

Factors associated with longitudinal progression of the cumulative burden of morbidity and overall mortality after cisplatin-based chemotherapy for testicular cancer.

To comprehensively evaluate the longitudinal progression of cumulative burden of morbidity (CBM) in testicular cancer survivors (TCS) following standard-dose cisplatin-chemotherapy and the impact of modifiable risk factors on morbidity and early-mortality. Participants completed first-line chemotherapy ≥6 months before baseline assessments with comprehensive questionnaires and physical-examinations. Based on follow-up assessments (median: 7 years later), longitudinal progression of adverse health outcomes (AHOs) and CBM score (encompassing AHO number and severity) was examined. Baseline health behaviors and AHOs were evaluated for associations with mortality using mixed-effects parametric proportional-hazards regression to identify modifiable risk factors. Among 616 TCS longitudinally assessed, 23% experienced worsening CBM post-chemotherapy (median: 11 years [IQR = 7-15]). Declines were driven by worsening treatment-related AHOs: tinnitus (29.7%), hearing loss (24.4%), Raynaud's (22.6%), neuropathy (18.5%), and neuropathic-pain (10.7%). Baseline factors associated with worsening neuropathy included lack of aerobic physical-activity (OR = 1.98, 95%CI = 1.06-3.72) and obesity (OR = 1.85, 95%CI = 1.17-2.92). These were also related to worsening neuropathic-pain (OR = 2.82, p = .009; and OR = 2.29; p = .023). Twenty-nine deaths occurred among 1,830 five-year TCS (4.2% cumulative hazard) (median age: 48-years [range = 22-74]). Participants reporting neuropathic-pain (HR = 3.64, 95%CI = 1.45-9.10), no aerobic (HR = 6.56, 95%CI = 2.73-15.8), or no low-impact physical-activity (HR = 3.96, 95%CI = 1.40-11.2) had significantly higher mortality, as did TCS indicating fair (HR = 9.23, 95%CI = 3.08-27.8) or poor (HR = 18.5, 95%CI = 3.30-103) health. Relationships between pain and mortality were mediated through lowered physical-activity (p = .036). Clinically-actionable factors associated with early mortality identify high-risk TCS in need of closer monitoring and targeted interventions. The significant relationship between neuropathic-pain and mortality, mediated by low physical-activity, is the first to our knowledge in TCS.

Implantable Polymer Scaffolds Loaded with Paclitaxel–Cyclodextrin Complexes for Post-Breast Cancer Tissue Reconstruction

The side effects associated with the chemotherapy of triple-negative breast cancer (TNBC), such as nucleotide-binding oligomerization domain (NOD)-like receptor family (NLR), pyrin domain containing 3 (NLRP3) inflammasome activity, are responsible for the treatment failure and high mortality rates. Therefore, advanced delivery systems have been developed to improve the transport and targeted administration of anti-tumor agents at the tumor sites using tissue engineering approaches. Implantable delivery systems based on biodegradable polymers are an effective alternative due high biocompatibility, porosity, and mechanical strength. Moreover, the use of paclitaxel (PTX)-cyclodextrin complexes increases the solubility and permeability of PTX, enhancing the bioavailability and efficacy of the drug. All of these properties contribute to the efficient encapsulation and controlled release of drugs, preventing the damage of healthy tissues. In the current study, we detailed the synthesis process and evaluation of 3D scaffolds based on gelatin functionalized with methacryloyl groups (GelMA) and pectin loaded with PTX–cyclodextrin inclusion complexes on TNBC pathogenesis in vitro and in vivo. Bio-physio-chemical analysis of the proposed scaffolds revealed favorable mechanical and biological properties for the cellular component. To improve the drug solubility, a host–guest interaction was performed by the complexation of PTX with a cyclodextrin derivative prior to scaffold synthesis. The presence of PTX suppressed the growth of breast tumor cells and promoted caspase-1 activity, the release of interleukin (IL)-1β, and the production of reactive oxygen species (ROS), conditioning the expression levels of the genes and proteins associated with breast tumorigenesis and NLRP3 inflammasome. The in vivo experiments suggested the activation of pyroptosis tumor cell death, confirming the in vitro experiments. In conclusion, the bio-mechanical properties of the GelMA and pectin-based scaffolds as well as the addition of the PTX–cyclodextrin complexes allow for the targeted and efficient delivery of PTX, suppressing the viability of the breast tumor cells via pyroptosis cell death initiation.

Neoadjuvant Chemotherapy in Muscle-Invasive Bladder Cancer: A Nationwide Analysis of Eligibility, Utilization, and Outcomes

Objectives: To investigate neoadjuvant chemotherapy (NAC) eligibility, utilization, and survival outcomes for muscle-invasive bladder cancer patients undergoing radical cystectomy (RC) in a Finnish population. Materials and Methods: Data from the Finnish National Cystectomy Database (2005–2017) was combined with Finnish Cancer Registry survival data. NAC utilization rates were reported, and downstaging rates were calculated based on final pathological staging. Logistic regression analyzed NAC usage and complete response (CR) predictors. Results: Since 2011, 29% of 1157 patients received NAC. Its usage remained consistent, and the number of eligible patients not receiving NAC decreased during the study period. Among NAC patients, pathology T-category was pT0 (34%), pT1-Ta-Tis (16%), pT2 (23%), pT3 (20%), and pT4 (7%) tumors, with pN0 in 82%. In the RC + NAC group, the 5-year overall survival (OS) rates were 89% for patients with no residual disease (pT0N0), 82% for those with organ-confined residual disease (pT1, Tis, Ta, T2/N0), and 49% for patients with non-organ-confined residual disease (pT3+/N+). The corresponding cancer-specific survival (CSS) rates were 93%, 86%, and 57%, respectively. Patients with organ-confined residual disease after NAC had survival outcomes comparable to those who underwent RC alone. Higher age; odds ratio (OR) 0.93, [95% Confidence Interval (CI): 0.90–0.95] and Charlson Co-morbidity Index–score [OR 0.88 (0.79–0.98)] reduced the likelihood of receiving NAC, while a smaller center size increased the probability [OR 1.82 (1.02–3.28)]. More treatment cycles [OR 0.70, (95% CI: 0.51–0.93)] and a favorable GFR [OR 0.38 (0.16–0.88)] were associated with achieving CR. Conclusion: We report that NAC is well-utilized across Finland, with CR rates comparable to recent trials. Additionally, our survival rates are reasonable, and even with organ-confined residual disease after NAC, survival outcomes are similar to those who underwent RC alone.