Long-term survival after neoadjuvant therapy for triple-negative breast cancer under different treatment regimens: a systematic review and network meta-analysis.

BACKGROUND: Triple-negative breast cancer (TNBC) is a life-threatening subtype of breast cancer with limited treatment options. Therefore, this network meta-analysis (NMA) aimed to evaluate and compare the effect of various neoadjuvant chemotherapy (NCT) options on the long-term survival of patients with TNBC. METHODS: PubMed, Embase, Medline, Cochrane Library, Web of Science, and major international conference databases were systematically searched for randomized controlled trials (RCTs) on the efficacy of various NCT options in patients with TNBC. Searches were performed from January 2000 to June 2023. Study heterogeneity was assessed using the I2 statistic. Hazard ratios (HRs) and 95% confidence intervals (CIs) were used to evaluate disease-free survival (DFS) and overall survival (OS). Odds ratios (ORs) and 95% CIs were used to evaluate the pathologic complete response (pCR). The primary outcome was DFS. RESULTS: We conducted an NMA of 21 RCTs involving 8873 patients with TNBC. Our study defined the combination of anthracyclines and taxanes as the preferred treatment option. On this basis, the addition of any of the following new drugs is considered a new treatment option: bevacizumab (B), platinum (P), poly-ADP-ribose polymerase inhibitors (PARPi), and immune checkpoint inhibitor (ICI). Based on the surface under the cumulative ranking curve (SUCRA) values, the top three SUCRA area values of DFS were taxanes, anthracycline, and cyclophosphamide (TAC; 89.23%); CT (84.53%); and B (81.06%). The top three SUCRA area values of OS were CT (83.70%), TAC (62.02%), and B-containing regimens (60.06%). The top three SUCRA area values of pCR were B + P-containing regimens (82.7%), ICI + P-containing regimens (80.2%), and ICI-containing regimens (61.8%). CONCLUSIONS: This NMA showed that standard chemotherapy is a good choice with respect to long-term survival. Moreover, B associated with P-containing regimens is likely to be the optimal treatment option for neoadjuvant TNBC in terms of pCR.

Rituximab-combined anthracycline-free chemotherapy in newly diagnosed paediatric and adolescent patients with non-high-risk aggressive mature B cell lymphoma: protocol for a single-arm, open-label, multicentre, phase II study (the Japan Children's Cancer Group Multicentre Trial, JPLSG B-NHL-20).

INTRODUCTION: Children and adolescents with mature B cell non-Hodgkin lymphoma (B-NHL) are treated with short-intensive chemotherapy. The burden of short-term and long-term toxicity is highly relative to its high cure rate in good-risk patients. Although the addition of rituximab to standard lymphome Malin B (LMB) chemotherapy markedly prolongs event-free survival and overall survival in high-risk patients, the benefit of rituximab in good-risk patients remains to be elucidated. This clinical trial will examine whether the addition of rituximab eliminates anthracyclines in good-risk patients without compromising treatment outcomes. METHODS AND ANALYSIS: We will perform a single-arm, open-label, multicentre phase II study. Low-risk (stage I - completely resected, stage II abdominal) and intermediate-risk (stages I and II - incompletely resected; stage II - resected, other than abdominal; stage III with LDH <2× upper limit of normal) patients with newly diagnosed B-NHL are eligible. Low-risk patients receive two courses of R-COM1P (rituximab, cyclophosphamide, vincristine, methotrexate, prednisolone and intrathecal methotrexate with hydrocortisone), and intermediate-risk patients receive COP (cyclophosphamide, vincristine, prednisolone and intrathecal methotrexate with hydrocortisone) followed by two courses each of R-COM3P and R-CYM (rituximab, cytarabine, methotrexate and intrathecal methotrexate with hydrocortisone). The primary endpoint is a 3-year event-free survival rate in paediatric patients (<18 years) with intermediate-risk disease. 100 patients (10 low-risk and 90 intermediate-risk) will enrol within a 4-year enrolment period and the follow-up period will be 3 years. 108 institutions are participating as of 1 January 2024 (64 university hospitals, 29 general hospitals, 12 children's hospitals and three cancer centres). ETHICS AND DISSEMINATION: This research was approved by the Certified Review Board at NHO Nagoya Medical Center (Nagoya, Japan) on 21 September 2021. Written informed consent is obtained from all patients and/or their guardians. The results of this study will be disseminated through peer-reviewed publications and conference presentations. STUDY REGISTRATION: Japan Registry of Clinical Trials, jRCTs041210104.

Assessment of the Impact of Carvedilol Administered Together with Dexrazoxan and Doxorubicin on Liver Structure and Function, Iron Metabolism, and Myocardial Redox System in Rats.

Late cardiotoxicity is a formidable challenge in anthracycline-based anticancer treatments. Previous research hypothesized that co-administration of carvedilol (CVD) and dexrazoxane (DEX) might provide superior protection against doxorubicin (DOX)-induced cardiotoxicity compared to DEX alone. However, the anticipated benefits were not substantiated by the findings. This study focuses on investigating the impact of CVD on myocardial redox system parameters in rats treated with DOX + DEX, examining its influence on overall toxicity and iron metabolism. Additionally, considering the previously observed DOX-induced ascites, a seldom-discussed condition, the study explores the potential involvement of the liver in ascites development. Compounds were administered weekly for ten weeks, with a specific emphasis on comparing parameter changes between DOX + DEX + CVD and DOX + DEX groups. Evaluation included alterations in body weight, feed and water consumption, and analysis of NADPH2, NADP+, NADPH2/NADP+, lipid peroxidation, oxidized DNA, and mRNA for superoxide dismutase 2 and catalase expressions in cardiac muscle. The iron management panel included markers for iron, transferrin, and ferritin. Liver abnormalities were assessed through histological examinations, aspartate transaminase, alanine transaminase, and serum albumin level measurements. During weeks 11 and 21, reduced NADPH2 levels were observed in almost all examined groups. Co-administration of DEX and CVD negatively affected transferrin levels in DOX-treated rats but did not influence body weight changes. Ascites predominantly resulted from cardiac muscle dysfunction rather than liver-related effects. The study's findings, exploring the impact of DEX and CVD on DOX-induced cardiotoxicity, indicate a lack of scientific justification for advocating the combined use of these drugs at histological, biochemical, and molecular levels.

Patient-reported outcomes and symptom clusters pattern of chemotherapy-induced toxicity in patients with early breast cancer.

OBJECTIVE: This study aims to characterize patient-reported chemotherapy-induced toxicity in patients with breast cancer, determine its association with treatment regimens and patient characteristics, identify toxicity symptom clusters within a specific chemotherapy timeframe and analyze the correlation between symptom clusters within and between the timeframe to understand the changes and influences across chemotherapy. METHODS: Forty-six patient-reported toxicities during neoadjuvant/adjuvant chemotherapy for breast cancer were evaluated using adapted CTCAE version 4.0. Chi-Square/Fisher's Exact test was performed to analyze the difference in the incidence of toxicity symptoms by chemotherapy regimens. Poisson regression performed to assess factors associated with patient's total chemotherapy toxicity. Exploratory factor analysis (EFA) conducted to identify symptom clusters at T1 (first half) and T2 (second half of planned cycle). Factor scores were generated and Spearman correlation performed to explore the factor scores correlation between symptom clusters. RESULTS: A total of 142 patients with stage I-III breast cancer were included. The incidence of several toxicities differed significantly among three chemotherapy regimens. Subjects age ≥51 years are associated with lower number of reported toxicity (IRR/incidence rate ratio = 0.94, 95% confidence interval/CI 0.88 to 0.99, p = 0.042). Receiving more chemotherapy cycles are associated with higher number of reported toxicity (IRR = 1.06, 95% CI 1.03 to 1.10, p<0.001). Two symptom clusters identified at T1 (psychoneurological-pain/PNP-T1 and gastrointestinal-psychological/GIP-T1 cluster) and three at T2 (psychoneurological-pain/PNP-T2, epithelial/EPI-T2, and gastrointestinal cluster/GI-T2), with moderate-strong positive correlation between PNP-T1 and GIP-T2 (p<0.001), PNP-T1 and PNP-T2 (p<0.001), and GIP-T1 and PNP-T2 (p<0.001). CONCLUSIONS: This study investigated 46 patient-reported toxicities prospectively during adjuvant/neoadjuvant chemotherapy for early breast cancer. Anthracycline-taxane combination regimen had higher proportions of toxicity incidence. Subject's age and number of chemotherapy cycles significantly associated with total number of toxicity symptoms. Two symptom clusters at T1 and three at T2 were identified, with significant correlation between symptom clusters within and between chemotherapy timeframe.

A Spontaneous Assembling Lipopeptide Nanoconjugate Transporting the Anthracycline Drug N-Benzyladriamycin-14-valerate for Personalized Therapy of Ewing Sarcoma.

To meet the current need for a tumor-selective, targeted therapy regimen associated with reduced toxicity, our laboratory has developed a spontaneously assembled nanostructure that resembles high-density lipoproteins (HDLs). These myristoyl-5A (MYR-5A) nanotransporters are designed to safely transport lipophilic pharmaceuticals, including a novel anthracycline drug (N-benzyladriamycin-14-valerate (AD198)). This formulation has been found to enhance the therapeutic efficacy and reduced toxicity of drugs in preclinical studies of 2D and 3D models of Ewing sarcoma (EWS) and cardiomyocytes. Our findings indicate that the MYR-5A/AD198 nanocomplex delivers its payload selectively to cancer cells via the scavenger receptor type B1 (SR-B1), thus providing a solid proof of concept for the development of an improved and highly effective, potentially personalized therapy for EWS while protecting against treatment-associated cardiotoxicity.

Role of HDL cholesterol in anthracycline-induced subclinical cardiotoxicity: a prospective observational study in patients with diffuse large B-cell lymphoma treated with R-CHOP.

OBJECTIVES: Anthracycline-induced cardiotoxicity is a debilitating cardiac dysfunction for which there are no effective treatments, making early prevention of anthracycline-induced subclinical cardiotoxicity (AISC) crucial. High-density lipoprotein cholesterol (HDL-C) plays a role in cardioprotection, but its impact on AISC remains unclear. Our study aims to elucidate the protective capacity of HDL-C in AISC in patients with diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP (cyclophosphamide, vincristine, doxorubicin, prednisone and rituximab). DESIGN: Prospective observational study. SETTING: Conducted in China from September 2020 to September 2022. PARTICIPANTS: 70 chemotherapy-naïve patients newly diagnosed with DLBCL who were scheduled to receive the standard dose of R-CHOP; 60 participants included in a case-control study (DOI: 10.1186/s12885-022-10085-6). PRIMARY OUTCOME MEASURES: Serum biomarkers, 2D speckle tracking echocardiography and conventional echocardiography were measured at baseline, at the end of the third and sixth cycles of R-CHOP and 6 and 12 months after chemotherapy. RESULTS: 24 patients experienced AISC, while 10 did not. 36 patients were lost to follow-up and death. Cox regression analysis showed that higher levels of HDL-C were associated with a significantly lower risk of AISC (unadjusted HR=0.24, 95% CI 0.09 to 0.67, p=0.006; adjusted HR=0.27, 95% CI 0.09 to 0.79, p=0.017). Patients without AISC had a more stable and higher HDL-C level during the follow-up period. HDL-C levels significantly decreased from the end of the third cycle of chemotherapy to the end of the sixth cycle of chemotherapy in all patients (p=0.034), and particularly in the AISC group (p=0.003). The highest level of HDL-C was significantly higher in patients without AISC than in those with AISC (1.52±0.49 vs 1.22±0.29, p=0.034). CONCLUSIONS: Our study suggests that higher HDL-C levels may associate with lower AISC risk in patients with DLBCL treated with R-CHOP. HDL-C could be a cardioprotective target, but further research is needed to confirm its benefits and limitations. STUDY REGISTRATION NUMBER: Study registration number: ChiCTR2100054721.

Neoadjuvant Chemotherapy in High-Grade Myxoid Liposarcoma: Results of the Expanded Cohort of a Randomized Trial From Italian (ISG), Spanish (GEIS), French (FSG), and Polish Sarcoma Groups (PSG).

PURPOSE: A randomized trial was conducted to compare neoadjuvant standard (S) anthracycline + ifosfamide (AI) regimen with histology-tailored (HT) regimen in selected localized high-risk soft tissue sarcoma (STS). The results of the trial demonstrated the superiority of S in all STS histologies except for high-grade myxoid liposarcoma (HG-MLPS) where S and HT appeared to be equivalent. To further evaluate the noninferiority of HT compared with S, the HG-MLPS cohort was expanded. PATIENTS AND METHODS: Patients had localized high-grade (cellular component >5%; size ≥5 cm; deeply seated) MLPS of extremities or trunk wall. The primary end point was disease-free survival (DFS). The secondary end point was overall survival (OS). The trial used a noninferiority Bayesian design, wherein HT would be considered not inferior to S if the posterior probability of the true hazard ratio (HR) being >1.25 was <5%. RESULTS: From May 2011 to June 2020, 101 patients with HG-MLPS were randomly assigned, 45 to the HT arm and 56 to the S arm. The median follow-up was 66 months (IQR, 37-89). Median size was 107 mm (IQR, 84-143), 106 mm (IQR, 75-135) in the HT arm and 108 mm (IQR, 86-150) in the S arm. At 60 months, the DFS and OS probabilities were 0.86 and 0.73 (HR, 0.60 [95% CI, 0.24 to 1.46]; log-rank P = .26 for DFS) and 0.88 and 0.90 (HR, 1.20 [95% CI, 0.37 to 3.93]; log-rank P = .77 for OS) in the HT and S arms, respectively. The posterior probability of HR being >1.25 for DFS met the Bayesian monitoring cutoff of <5% (4.93%). This result confirmed the noninferiority of trabectedin to AI suggested in the original study cohort. CONCLUSION: Trabectedin may be an alternative to standard AI in HG-MLPS of the extremities or trunk when neoadjuvant treatment is a consideration.

Cardiovascular sequelae of trastuzumab and anthracycline in long-term survivors of breast cancer.

OBJECTIVES: Long-term follow-up of patients treated with trastuzumab largely focuses on those with reduced left ventricular ejection fraction (LVEF) on treatment completion. This study sought to evaluate the prevalence of cardiovascular risk factors, overt cardiovascular disease and cardiac imaging abnormalities using cardiac magnetic resonance (CMR), in participants with normal LVEF on completion of trastuzumab±anthracycline therapy at least 5 years previously. METHODS: Participants with human epidermal growth factor receptor 2-positive breast cancer treated with trastuzumab±anthracycline ≥5 years previously were identified from a clinical database. All participants had normal LVEF prior to, and on completion of, treatment. Participants underwent clinical cardiovascular evaluation, ECG, cardiac biomarker evaluation and CMR. Left ventricular systolic dysfunction (LVSD) was defined as LVEF <50%. RESULTS: Forty participants were recruited between 15 March 2021 and 19 July 2022. Median time since completion of trastuzumab was 7.8 years (range 5.9-10.8 years) and 90% received prior anthracycline. 25% of participants had LVSD; median LVEF was 55.2% (Q1-Q3, 51.3-61.2). 30% of participants had N-terminal pro-B-type natriuretic peptide >125 pg/mL and 8% had high-sensitivity cardiac troponin T >14 ng/L. 33% of participants had a new finding of hypertension. 58% had total cholesterol >5.0 mmol/L, 43% had triglycerides >1.7 mmol/L and 5% had a new diagnosis of diabetes. CONCLUSIONS: The presence of asymptomatic LVSD, abnormal cardiac biomarkers and cardiac risk factors in participants treated with trastuzumab and anthracycline at least 5 years previously is common, even in those with normal LVEF on completion of treatment. Our findings reinforce the relevance of comprehensive evaluation of cardiovascular risk factors following completion of cancer therapy, in addition to LVEF assessment.

Utilization of cardiac tests in anthracycline-treated cancer survivors differs between young adults and children: A claims-based analysis.

BACKGROUND: The Children's Oncology Group Guidelines recommend a cardiacechocardiogram, or comparable functional imaging, following therapy completion in survivors of childhood/adolescent cancers exposed to anthracyclines. METHODS: Using the 2009-2019 Merative™ MarketScan® Commercial Database, we examined real-world utilization of cardiac testing among 1609 anthracycline-treated survivors of childhood/adolescent cancers. RESULTS: The cumulative incidence of receiving an initial cardiac test by 5.25 years from the index date (six months after end-of-therapy) was 62.3% (95% CI = 57.5%-66.7%), with median time to initial test being 2.7 years (95% CI = 2.5%-3.1%). Young adults (18-28 years) were less likely than children (≤17 years) to receive cardiac testing (hazard ratio [HR] = 0.42, 95% CI = 0.3%-0.49%). More likely to receive cardiac testing were survivors receiving hematopoietic stem cell transplantation versus chemotherapy only (HR = 2.23, 95% CI = 1.63%-3.03%), and survivors with bone or soft tissue versus hematologic cancer (HR = 1.64, 95% CI = 1.30%-2.07%). CONCLUSIONS: Nearly 40% of anthracycline-treated survivors of childhood/adolescent cancers had not received cardiac testing within 5.25 years post-index date, with young adults least likely to receive a test.

Molecular assessment of drug-phospholipid interactions consequent to cancer treatment: a study of anthracycline-induced cardiotoxicity.

Cardiotoxicity limits the use of anthracyclines as potent chemotherapeutics. We employ classical molecular dynamics to explore anthracycline interactions with a realistic myocardial membrane and compare to an ideal membrane widely used in literature. The interaction of these two membranes with four anthracyclines; doxorubicin, epirubicin, daunorubicin, and idarubicin are studied. Careful analysis was conducted on three forms of each drug; pristine, primary metabolite, and cationic salt. By examining the molecular residence time near the membrane's surface, the average number of molecule/membrane hydrogen bonds, the immobilization of the molecules near the membrane, and the location of those molecules relative to the mid-plane of the membrane we found out that salt forms exhibit the highest cardiotoxic probability, followed by the metabolites and pristine forms. Additionally, all forms have more affinity to the upper layer of the realistic myocardial membrane. Meanwhile, an ideal membrane consisting of a single type of phospholipids is not capable of capturing the specific interactions of each drug form. These findings confirm that cardiotoxic mechanisms are membrane-layer and drug-form dependent.

"Moderate" adjuvant chemotherapy-induced leukopenia is beneficial for survival of patients with early breast cancer: a retrospective study.

BACKGROUND: The association between chemotherapy-induced leukopenia (CIL) and survival for patients with early breast cancer (EBC) is not known. We investigated the relationship between different grades of CIL and survival in patients with EBC receiving adjuvant chemotherapy. METHODS: A total of 442 patients with EBC receiving a regimen containing an anthracycline (A) and taxane (T) were included into our analysis. Survival analyses were undertaken using Kaplan-Meier curves. The P-value was calculated using the log rank test. Subgroup analysis was conducted to investigate the correlation of CIL grade and survival based on the clinicopathological characteristics of patients. Afterwards, univariate and multivariate analyses screened out independent prognostic factors to construct a prognostic model, the robustness of which was verified. RESULTS: Patients with EBC who experienced grade 2-4 ("moderate" and "severe") CIL were associated with longer overall survival (OS) than those with grade 0-1 (mild) CIL (P = 0.021). Compared with patients with mild CIL, OS was longer in patients with severe CIL (P = 0.029). Patients who suffered from moderate CIL tended to have longer OS than those with mild CIL (P = 0.082). Nevertheless, there was no distinguishable difference in OS between moderate- or severe-CIL groups. Subgroup analysis revealed that patients with moderate CIL had longer OS than those with mild CIL among patients who were premenstrual, or with human epidermal growth factor receptor 2-positive (HER2+), > 3 lymph nodes with metastases, a tumor diameter > 5 cm. A prognostic model based on menstrual status, N stage, and CIL grade showed satisfactory robustness. CONCLUSION: The grade of CIL was strongly associated with the prognosis among patients with EBC who received a regimen containing both anthracyclines and taxanes. Patients with a "moderate" CIL grade tended to have better survival outcomes.

[Particularities of arterial stiffness dynamics on the background of breast cancer chemotherapy].

BACKGROUND: Modern breast cancer chemotherapy regimens (BC) consider individual patient parameters and ranges of cardiotoxic doses. However, clinicians often record clinical and laboratory-instrumental signs of cardio- and vasculotoxicity in patients, which emphasizes the high importance of searching for markers of early toxic response. AIM: To study the characteristics of the response of arterial stiffness on the background of anthracycline-containing chemotherapy to determine potential markers of vasculotoxicity in BC patients. MATERIALS AND METHODS: 20 women with a BC were included. The patients received 4 cycles of chemotherapy in the doxorubicin + cyclophosphane (AC) regimen with an interval of 2-3 weeks, then they were injected with paclitaxel weekly for 12 injections, or docetaxel once every 3 weeks. All patients underwent TTE, arterial stiffness determination by the "gold standard" method and using volumetric sphygmography before the start of treatment, after the completion of the anthracycline component and after the end of taxanes. RESULTS: The average age of the patients was 45.5±5.31 years. After completing the course of anthracyclines, there was a significant increase in heart rate (from 65.6±9.3 to 73.3±10.1 beats/min.), a decrease in SBP (from 122.6±9.9 to 116.5±12.3 mmHg) and DBP (from 78.9±8.5 to 76.2±8.6 mmHg), a decrease in carotid femoral pulse wave velocity (cfPWV) (from 9.32±1.41 to 7.85±1.57 m/s), CAVI index on the left (from 6.78±0.81 to 6.5±0.88), the velocity of the cardio-ankle pulse wave on the right and left (from 6.7±0.6 to 6.5±0.7 m/s; from 7.0±0.6 to 6.3±0.8 m/sc, respectively). After the completion of the taxane, there was a tendency to increase these indicators, however, they remained significantly lower compared to the values before the start of treatment. CONCLUSION: A comparative analysis of arterial stiffness indicators at different stages of chemotherapy showed a more pronounced reaction of cfPWV, CAVI, cardio-ankle pulse wave to the administration of anthracyclines, which presumably may be associated with concomitant hemodynamic restructuring.

Inhibition of Galectin-9 sensitizes tumors to anthracycline treatment via inducing antitumor immunity.

Anthracyclines are a class of conventionally and routinely used first-line chemotherapy drugs for cancer treatment. In addition to the direct cytotoxic effects, increasing evidence indicates that the efficacy of the drugs also depends on immunomodulatory effects with unknown mechanisms. Galectin-9 (Gal-9), a member of the ß-galactoside-binding protein family, has been demonstrated to induce T-cell death and promote immunosuppression in the tumor microenvironment. Here, we asked whether anthracycline-mediated immunomodulatory activity might be related to Gal-9. We found that combining doxorubicin with anti-Gal-9 therapy significantly inhibited tumor growth and prolonged overall survival in immune-competent syngeneic mouse models. Moreover, Gal-9 expression was increased in response to doxorubicin in various human and murine cancer cell lines. Mechanistically, doxorubicin induced tumoral Gal-9 by activating the STING/interferon ß pathway. Clinically, Gal-9 and p-STING levels were elevated in the tumor tissues of breast cancer patients treated with anthracyclines. Our study demonstrates Gal-9 upregulation in response to anthracyclines as a novel mechanism mediating immune escape and suggests targeting Gal-9 in combination with anthracyclines as a promising therapeutic strategy for cancer treatment.

Ex vivo drug response profiling for response and outcome prediction in hematologic malignancies: the prospective non-interventional SMARTrial.

Ex vivo drug response profiling is a powerful tool to study genotype-drug response associations and is being explored as a tool set for precision medicine in cancer. Here we conducted a prospective non-interventional trial to investigate feasibility of ex vivo drug response profiling for treatment guidance in hematologic malignancies (SMARTrial, NCT03488641 ). The primary endpoint to provide drug response profiling reports within 7 d was met in 91% of all study participants (N = 80). Secondary endpoint analysis revealed that ex vivo resistance to chemotherapeutic drugs predicted chemotherapy treatment failure in vivo. We confirmed the predictive value of ex vivo response to chemotherapy in a validation cohort of 95 individuals with acute myeloid leukemia treated with daunorubicin and cytarabine. Ex vivo drug response profiles improved ELN-22 risk stratification in individuals with adverse risk. We conclude that ex vivo drug response profiling is clinically feasible and has the potential to predict chemotherapy response in individuals with hematologic malignancies beyond clinically established genetic markers.

Role and efficacy of capecitabine in the anthracycline-free regimen in breast cancer patients: a systematic review and meta-analysis.

PURPOSE: Capecitabine has extensive utilization in the treatment of diverse solid tumors, and its efficacy has been substantiated. Its oral administration and minimal toxicity in clinical practice render it advantageous. Nevertheless, uncertainty remains regarding whether capecitabine can substitute anthracycline drugs in chemotherapy regimens to achieve a lower risk of anthracycline-induced degradation. Consequently, we conducted a meta-analysis of randomized controlled trials (RCTs) to assess the potential of capecitabine as a replacement for anthracycline drugs in chemotherapy regimens for breast cancer. METHODS: We systematically searched PubMed, Embase, Web of Science, and the Cochrane Controlled Trials Register (CENTRAL) to retrieve eligible studies published before July 18, 2023. Two independent reviewers extracted relevant data from the included studies using a pre-established data extraction form. The primary endpoints of interest encompassed overall survival (OS) and progression-free survival (PFS) for postoperative adjuvant therapy, as well as pathological complete response (PCR) following neoadjuvant therapy. Adverse events were considered as secondary outcomes. The statistical analysis was performed using Revman 5.4.1. RESULTS: A total of six studies involving 2348 breast cancer patients were deemed eligible according to the selection criteria. The pooled meta-analysis revealed that there were no statistically significant differences observed in the primary outcomes of overall survival (OS) (HR 1.06, 95% CI 0.88-1.28) and progression-free survival (PFS) (HR 1.10, 95% CI 0.90-1.34) across the four postoperative adjuvant chemotherapy trials, as well as in the two neoadjuvant chemotherapy trials with respect to the primary outcome of pathological complete response (PCR) (OR 1.65, 95% CI 0.93-2.95) when comparing regimens containing anthracycline drugs to those without. In terms of adverse events, the probability of experiencing diarrhea (OR 3.94, P = 0.004) and hand-foot syndrome (OR 10.89, P = 0.004) was significantly higher in the capecitabine group, attributable to the drug characteristics. Conversely, the likelihood of developing neutropenia (OR 0.50, P = 0.03) was higher in the anthracycline group. CONCLUSIONS: According to the current evidence, there was no statistically significant difference in the primary outcomes when capecitabine was substituted for anthracycline drugs. Thus, capecitabine can be regarded as a feasible alternative in the subset of patients who necessitate the exclusion of anthracyclines.

Clinical trial protocol for PanDox: a phase I study of targeted chemotherapy delivery to non-resectable primary pancreatic tumours using thermosensitive liposomal doxorubicin (ThermoDox®) and focused ultrasound.

BACKGROUND: The dense stroma of pancreatic ductal adenocarcinomas is a major barrier to drug delivery. To increase the local drug diffusion gradient, high doses of chemotherapeutic agent doxorubicin can be released from thermally-sensitive liposomes (ThermoDox®) using ultrasound-mediated hyperthermia at the tumour target. PanDox is designed as a Phase 1 single centre study to investigate enhancing drug delivery to adult patients with non-operable pancreatic ductal adenocarcinomas. The study compares a single cycle of either conventional doxorubicin alone or ThermoDox® with focused ultrasound-induced hyperthermia for targeted drug release. METHODS: Adults with non-resectable pancreatic ductal adenocarcinoma are allocated to receive a single cycle of either doxorubicin alone (Arm A) or ThermoDox® with focused ultrasound-induced hyperthermia (Arm B), based on patient- and tumour-specific safety conditions. Participants in Arm B will undergo a general anaesthetic and pre-heating of the tumour by extra-corporal focused ultrasound (FUS). Rather than employing invasive thermometry, ultrasound parameters are derived from a patient-specific treatment planning model to reach the 41 °C target temperature for drug release. ThermoDox® is then concurrently infused with further ultrasound exposure. Tumour biopsies at the targeted site from all patients are analysed post-treatment using high performance liquid chromatography to quantify doxorubicin delivered to the tumour. The primary endpoint is defined as a statistically significant enhancement in concentration of total intra-tumoural doxorubicin, comparing samples from patients receiving liposomal drug with FUS to free drug alone. Participants are followed for 21 days post-treatment to assess secondary endpoints, including radiological assessment to measure changes in tumour activity by Positron Emission Tomography Response Criteria in Solid Tumours (PERCIST) criteria, adverse events and patient-reported symptoms. DISCUSSION: This early phase study builds on previous work targeting tumours in the liver to investigate whether enhancement of chemotherapy delivery using ultrasound-mediated hyperthermia can be translated to the stroma-dense environment of pancreatic ductal adenocarcinoma. If successful, it could herald a new approach towards managing these difficult-to-treat tumours. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04852367 . Registered 21st April 2022. EudraCT number: 2019-003950-10 (Registered 2019) Iras Project ID: 272253 (Registered 2019) Ethics Number: 20/EE/0284.

Topoisomerase IIα immunoexpression in feline mammary carcinomas: A correlation with Ki67 immunoexpression and the mitotic count.

The aim of the study was to compare the immunohistochemical expression of topoisomerase IIα protein (Topo IIα) with Ki67 expression and mitotic count in feline mammary carcinomas (FMCs). Topo IIα is considered as a proliferation indicator as well as a molecular target of anthracycline chemotherapy. The studied material included 70 FMCs from female cats treated with mastectomy. Primary mouse monoclonal antibodies directed against Topo IIα and Ki67 were used in immunohistochemical reactions. The number of mitotic figures was counted at 400× magnification in a field of 2.37 mm2. Immunohistochemical reaction for Topo IIα occurred in cell nuclei. The Topo IIα index ranged from 6.12% to 54.60% and was positively correlated with the values of the Ki67 index (r = 0.7193) and the mitotic count (r = 0. 2858). This indicates the potential possibility of use of the immunohistochemical expression of Topo IIα to assess the rate of proliferation in FMCs. The wide range of expression of Topo IIα in individual tumorus found in the conducted studies allows us to hypothesize that its assessment could be used as a predictive marker in chemotherapy of FMCs with the use of anthracyclines. However, this requires confirmation in clinical trials.