Treatment Of Invasive Cancer Research Articles

Less Invasive Primary Treatment for Colorectal Cancer After Implementation of National Screening: A Nationwide Cohort Study.

The effect of organized colorectal cancer (CRC) screening on type of primary treatment remains sparsely investigated. This study evaluated the difference in primary treatment strategy between patients diagnosed with screen-detected (SD-CRC) and non-screen-detected colorectal cancer (NSD-CRC) in a national CRC screening program. This was a retrospective national register-based cohort study. Data on patients aged between 50 and 75years and diagnosed with SD-CRC or NSD-CRC were retrieved from the national colorectal cancer screening database and the Danish Colorectal Cancer Group database. Outcomes related to surgical invasiveness were compared between the two cohorts. Differences were expressed as relative risks using log-binomial generalized linear regression models. UICC stage IV specific outcomes were analyzed using the same method. All analyses were adjusted for sex, age, type of cancer (colonic/rectal), and Charlson comorbidity index. The study included 4707 patients with SD-CRC and 7328 with NSD-CRC. Therapeutic flexible endoscopy (SD-CRC: n = 636 vs. NSD-CRC: n = 334, RR: 2.50, P < 0.001), (robotic-assisted) laparoscopic resection ((n = 616 vs. n = 773, RR: 1.27, P < 0.001), n = 2759 vs. n = 3471, RR: 1.11, P < 0.001), and radical resection (n = 3890 vs. n = 4834, RR: 1.02, P = 0.002) were significantly more frequent in the SD-CRC group. The rates of emergency priority (n = 32 vs. n = 562, RR: 0.09, P < 0.001), open surgery (n = 391 vs. n = 1410, RR: 0.53, P < 0.001), supplementary organ resection (n = 259 vs. n = 860, RR: 0.56, P < 0.001), and stoma formation (n = 526 vs. n = 1040, RR: 0.89, P = 0.007) were significantly lower in the SD-CRC group. The rate of patients undergoing surgery with UICC stage IV disease was significantly higher in the SD-CRC group (SD-CRC: n = 262, NSD-CRC: n = 994, RR: 1.43, P < 0.001). SD-CRC remained associated with less invasive primary surgical treatment following adjustment for potential healthy user bias. UICC stage IV disease may be less advanced in patients with SD-CRC.

Editorial Comment to Recent advancements in the diagnosis and treatment of non-muscle invasive bladder cancer: Evidence update of surgical concept, risk stratification, and BCG-treated disease.

Editorial Comment to Recent advancements in the diagnosis and treatment of non-muscle invasive bladder cancer: Evidence update of surgical concept, risk stratification, and BCG-treated disease.

Acquired haemophilia as a complicating factor in treatment of non-muscle invasive bladder cancer: A case report

In recent years, because of the growing desire to improve the noninvasiveness and safety of tumor treatments, sonodynamic therapy has gradually become a popular research topic. However, due to the complexity of the therapeutic process, the relevant mechanisms have not yet been fully elucidated. One of the widely accepted possibilities involves the effect of reactive oxygen species. In this review, the mechanism of reactive oxygen species production by sonodynamic therapy (SDT) and ways to enhance the sonodynamic production of reactive oxygen species are reviewed. Then, the clinical application and limitations of SDT are discussed. In conclusion, current research on sonodynamic therapy should focus on the development of sonosensitizers that efficiently produce active oxygen, exhibit biological safety, and promote the clinical transformation of sonodynamic therapy.

Microwave-activated Cu-doped zirconium metal-organic framework for a highly effective combination of microwave dynamic and thermal therapy

Percutaneous microwave ablation (PMA) is a thermoablative method used as a minimally invasive treatment for liver cancer. However, the application of PMA is limited by its insufficient ROS generation efficiency and thermal effects. Herein, a new microwave-activated Cu-doped zirconium metal-organic framework (MOF) (CuZr MOF) used for enhanced PMA has a significantly improved microwave sensitizing effect. Owing to the strong inelastic collisions between ions confined in numerous micropores, CuZr MOF has strong microwave sensitivity and high thermal conversion efficiency, which can significantly improve microwave thermal therapy (MTT). Moreover, because of the existence of Cu2+ ions, a further benefit of CuZr MOF is their Fenton-like activity, in particular, microwaves used as an excitation source for microwave dynamic therapy (MDT) can improve the Fenton-like reaction to maximize the synergistic effectiveness of cancer therapy. Importantly, CuZr MOF can inhibit the production of heat shock proteins (HSPs) by producing abundant ROS to enhance tumor destruction. Mechanistically, we found that CuZr MOF + MW treatment modulates ferroptosis-mediated tumor cell death by targeting the HMOX1/GPX4 axis. In summary, this study develops a novel CuZr MOF microwave sensitizer with great potential for synergistic treatment of liver cancer by MTT and MDT.

Radical Cystectomy in the Treatment of Invasive Bladder Cancer: Long-Term Results in 1,054 Patients.

To evaluate our long-term experience with patients treated uniformly with radical cystectomy and pelvic lymph node dissection for invasive bladder cancer and to describe the association of the primary bladder tumor stage and regional lymph node status with clinical outcomes. All patients undergoing radical cystectomy with bilateral pelvic iliac lymphadenectomy, with the intent to cure, for transitional-cell carcinoma of the bladder between July 1971 and December 1997, with or without adjuvant radiation or chemotherapy, were evaluated. The clinical course, pathologic characteristics, and long-term clinical outcomes were evaluated in this group of patients. A total of 1,054 patients (843 men [80%] and 211 women) with a median age of 66 years (range, 22 to 93 years) were uniformly treated. Median follow-up was 10.2 years (range, 0 to 28 years). There were 27 (2.5%) perioperative deaths, with a total of 292 (28%) early complications. Overall recurrence-free survival at 5 and 10 years for the entire cohort was 68% and 66%, respectively. The 5- and 10-year recurrence-free survival for patients with organ-confined, lymph node-negative tumors was 92% and 86% for P0 disease, 91% and 89% for Pis, 79% and 74% for Pa, and 83% and 78% for P1 tumors, respectively. Patients with muscle invasive (P2 and P3a), lymph node-negative tumors had 89% and 87% and 78% and 76% 5- and 10-year recurrence-free survival, respectively. Patients with nonorgan-confined (P3b, P4), lymph node-negative tumors demonstrated a significantly higher probability of recurrence compared with those with organ-confined bladder cancers (P < .001). The 5- and 10-year recurrence-free survival for P3b tumors was 62% and 61%, and for P4 tumors was 50% and 45% , respectively. A total of 246 patients (24%) had lymph node tumor involvement. The 5- and 10-year recurrence-free survival for these patients was 35%, and 34%, respectively, which was significantly lower than for patients without lymph node involvement (P < .001). Patients could also be stratified by the number of lymph nodes involved and by the extent of the primary bladder tumor (p stage). Patients with fewer than five positive lymph nodes, and whose p stage was organ-confined had significantly improved survival rates. Bladder cancer recurred in 311 patients (30%) . The median time to recurrence among those patients in whom the cancer recurred was 12 months (range, 0.04 to 11.1 years). In 234 patients (22%) there was a distant recurrence, and in 77 patients (7%) there was a local (pelvic) recurrence. These data from a large group of patients support the aggressive surgical management of invasive bladder cancer. Excellent long-term survival can be achieved with a low incidence of pelvic recurrence.

Intraoperative Radiation Therapy as a Safe Alternative to Whole Breast Radiation for Treatment of Minimally Invasive Breast Cancers: A Retrospective Cohort Study.

Intraoperative radiation therapy (IORT) in select populations is a viable alternative to whole breast radiation therapy (WBRT) in the treatment of biopsy-proven localized invasive and non-invasive breast cancer. We aim to assess recurrence and complication rates following IORT in lumpectomy patients at a community hospital in Baltimore City. An IRB-approved retrospective cohort study was conducted on consecutive cases of lumpectomy with IORT from 2013 through 2020 by a single surgeon. Patient demographics, tumor and operative characteristics, and complications were retrieved from electronic medical records. Primary outcomes were postoperative complications and local recurrence rates. The final cohort included 117 patients with mean follow-up time of 2.60 + 1.78years. Mean age was 69.84 + 8.77years. Thirty-three (28.21%) of patients developed a seroma. Odds of seroma formation were mildly significant for skin spacing [OR: 1.18, 95% CI: (1.02-1.37)] and balloon fill volume [1.04 (1.00-1.08)], but not for age, BMI, diabetes, former or current smoking status, history of WBRT, tumor size, or balloon size. Three (2.6%) patients had local recurrence. Odds of local recurrence were mildly significant for increased tumor size [1.14 (1.04-1.24)] and not significant for any other covariates. IORT exposure did not confer higher rates of complications and the local recurrence rate mirrored that of the general population undergoing lumpectomy and WBRT. This study demonstrates the need for equitable treatment options based on individual needs: IORT is a safe alternative to WBRT in certain subpopulations, especially those with physical, social, or personal limitations preventing participation in a 3- to 7-week time commitment of WBRT.

Recent advancements in the diagnosis and treatment of non-muscle invasive bladder cancer: Evidence update of surgical concept, risk stratification, and BCG-treated disease.

In the management of non-muscle invasive bladder cancer (NMIBC), disease progression and long-term control are determined by the intensity of delivered treatment and surveillance and the cancer cells' biological nature. This requires risk stratification-based postoperative management, such as intravesical instillation of chemotherapy drugs, Bacillus Calmette-Guérin (BCG), and radical cystectomy. Advancements in mechanical engineering, molecular biology, and surgical skills have evolved the clinical management of NMIBC. In this review, we describe the updated evidence and perspectives regarding the following aspects: (1) advancements in surgical concepts, techniques, and devices for transurethral resection of the bladder tumor; (2) advancements in risk stratification tools for NMIBC; and (3) advancements in treatment strategies for BCG-treated NMIBC. Repeat transurethral resection, en-bloc transurethral resection, and enhanced tumor visualization, including photodynamic diagnosis and narrow-band imaging, help reduce residual cancer cells, provide accurate diagnosis and staging, and sensitive detection, which are the first essential steps for cancer cure. Risk stratification should always be updated and improved because the treatment strategy changes over time. The BCG-treated disease concept has recently diversified to include BCG failure, resistance, refractory, unresponsiveness, exposure, and intolerance. A BCG-unresponsive disease is an extremely aggressive subset unlikely to respond to a rechallenge with BCG. Numerous ongoing clinical trials aim to develop a future bladder-sparing approach for very high-risk BCG-naïve NMIBC and BCG-unresponsive NMIBC. The key to improving the quality of patient care lies in the continuous efforts to overcome the clinical limitations of bedside management.

Next generation drugs in urothelial cancer: adenoviruses in the treatment of BCG-unresponsive nonmuscle invasive bladder cancer

Next generation drugs in urothelial cancer: adenoviruses in the treatment of BCG-unresponsive nonmuscle invasive bladder cancer

Diminished Short-Term Efficacy of Reduced-Dose Induction BCG in the Treatment of Non-Muscle Invasive Bladder Cancer.

The ongoing Bacillus Calmette-Guérin (BCG) shortage has created challenges for the treatment of non-muscle invasive bladder cancer (NMIBCa). Our objective was to evaluate the efficacy of reduced-dose induction BCG (RD-iBCG) compared to full-dose induction BCG (FD-iBCG) regarding recurrence rates. We hypothesized that patients receiving RD-iBCG may recur at a higher rate compared to those who received FD-iBCG therapy. A retrospective review of all patients with NMIBCa treated with intravesical therapy at our institution between 2015-2020 was conducted. Inclusion criteria consisted of having a diagnosis of AUA intermediate or high-risk NMIBCa with an indication for a six-week induction course of FD or RD-BCG with at least 1 year of documented follow up. The data were censored at one year. Propensity score matching for age, sex, tumor pathology, and initial vs. recurrent disease was performed. The primary endpoint was bladder cancer recurrence, reported as recurrence-free survival. A total of 254 patients were reviewed for this study. Our final cohort was 139 patients after exclusion. Thirty-nine percent of patients had HGT1 disease. 38.6% of patients receiving RD-BCG developed a recurrence of bladder cancer within a one-year follow-up as compared to 33.7% of patients receiving FD therapy. After propensity matching, this value remained statistically significant (p = 0.03). In conclusion, RD-iBCG for NMIBCa is associated with a significantly greater risk of recurrence than full-dose induction therapy, suggesting that RD-iBCG may not be equivalent or non-inferior to full-dose administration in the short term.

An affordable automated LED array system for optimizing photodynamic therapy protocols

Photodynamic therapy (PDT) is a promising minimally invasive alternative cancer treatment that, due to fluorescent properties of the drug (photosensitizer), can be used as a theragnostic agent. The efficacy of this treatment largely relies on the successful activation of the photosensitizer with appropriate light. While certain studies demonstrate comparable outcomes between LED and laser activation, there remains a lack of consensus regarding the differential effects of pulsed versus continuous light. In response to the limited availability of commercially versatile equipment capable of fully controlling pulsed light, we have developed an LED array system for optimizing PDT protocols. The designed equipment is versatile, has an intuitive user-friendly interface, and adapts to sterile conditions required for in-vitro studies. It also enables precise control of light irradiation, allowing to freely modify power, pulse width, frequency, exposure time and wavelength. In this study, the developed LED array system was employed to optimize PDT protocols for breast cancer theragnostic, using Fotoenticine as photosensitizer. The obtained results highlight the importance of appropriate irradiation equipment in PDT lighting protocol optimization. In this sense, significant improvements in therapeutic efficacy were observed when using 10 Hz frequency and 10 or 20% duty cycles. This resulted in a remarkable transition from a non-cytotoxic dose in continuous mode to a fully cytotoxic condition, leading to a >95% enhancement in the therapeutic effect.

Three-Dimensional Breast Cancer Model to Investigate CCL5/CCR1 Expression Mediated by Direct Contact between Breast Cancer Cells and Adipose-Derived Stromal Cells or Adipocytes.

The tumor microenvironment (TME) in breast cancer is determined by the complex crosstalk of cancer cells with adipose tissue-inherent cells such as adipose-derived stromal cells (ASCs) and adipocytes resulting from the local invasion of tumor cells in the mammary fat pad. This leads to heterotypic cellular contacts between these cell types. To adequately mimic the specific cell-to-cell interaction in an in vivo-like 3D environment, we developed a direct co-culture spheroid model using ASCs or differentiated adipocytes in combination with MDA-MB-231 or MCF-7 breast carcinoma cells. Co-spheroids were generated in a well-defined and reproducible manner in a high-throughput process. We compared the expression of the tumor-promoting chemokine CCL5 and its cognate receptors in these co-spheroids to indirect and direct standard 2D co-cultures. A marked up-regulation of CCL5 and in particular the receptor CCR1 with strict dependence on cell-cell contacts and culture dimensionality was evident. Furthermore, the impact of direct contacts between ASCs and tumor cells and the involvement of CCR1 in promoting tumor cell migration were demonstrated. Overall, these results show the importance of direct 3D co-culture models to better represent the complex tumor-stroma interaction in a tissue-like context. The unveiling of tumor-specific markers that are up-regulated upon direct cell-cell contact with neighboring stromal cells, as demonstrated in the 3D co-culture spheroids, may represent a promising strategy to find new targets for the diagnosis and treatment of invasive breast cancer.

Sorafenib-Loaded PLGA Carriers for Enhanced Drug Delivery and Cellular Uptake in Liver Cancer Cells.

Currently, conventional treatments of hepatocellular carcinoma (HCC) are not selective enough for tumor tissue and lead to multidrug resistance and drug toxicity. Although sorafenib (SOR) is the standard first-line systemic therapy approved for the clinical treatment of HCC, its poor aqueous solubility and rapid clearance result in low absorption efficiency and severely limit its use for local treatment. Herein, we present the synthesis of biodegradable polymeric Poly (D, L-Lactide-co-glycolide) (PLGA) particles loaded with SOR (PS) by emulsion-solvent evaporation process. The particles are carefully characterized focusing on particle size, surface charge, morphology, drug loading content, encapsulation efficiency, in vitro stability, drug release behaviour and tested on HepG2 cells. Additionally, PLGA particles have been coupled on side emitting optical fibers (seOF) integrated in a microfluidic device for light-triggered local release. PS have a size of 248 nm, tunable surface charge and a uniform and spherical shape without aggregation. PS shows encapsulation efficiency of 89.7% and the highest drug loading (8.9%) between the SOR-loaded PLGA formulations. Treating HepG2 cells with PS containing SOR at 7.5 µM their viability is dampened to 40%, 30% and 17% after 48, 129 and 168 hours of incubation, respectively. The high PS stability, their sustained release profile and the rapid cellular uptake corroborate the enhanced cytotoxicity effect on HepG2. With the prospect of developing biomedical tools to control the spatial and temporal release of drugs, we successfully demonstrated the potentiality of seOF for light-triggered local release of the carriers. Our prototypical system paves the way to new devices integrating microfluidics, optical fibers, and advanced carriers capable to deliver minimally invasive locoregional cancer treatments.

Novel nomograms for predicting survival for immediate breast reconstruction patients diagnosed with invasive breast cancer-a single-center 15-year experience.

Immediate breast reconstruction is widely accepted following oncologic mastectomy. This study aimed to build a novel nomogram predicting the survival outcome for Chinese patients undergoing immediate reconstruction following mastectomy for invasive breast cancer. A retrospective review of all patients undergoing immediate reconstruction following treatment for invasive breast cancer was performed from May 2001 to March 2016. Eligible patients were assigned to a training set or a validation set. Univariate and multivariate Cox proportional hazard regression models were used to select associate variables. Two nomograms were developed based on the training cohort for breast cancer-specific survival (BCSS) and disease-free survival (DFS). Internal and external validations were performed, and the C-index and calibration plots were generated to evaluate the performance (discrimination and accuracy) of the models. The 10-year estimated BCSS and DFS were 90.80% (95% CI: 87.30%-94.40%) and 78.40% (95% CI: 72.50%-84.70%), respectively, in the training cohort. In the validation cohort, they were and 85.60% (95% CI, 75.90%-96.50%) and 84.10% (95% CI, 77.80%-90.90%), respectively. Ten independent factors were used to build a nomogram for prediction of 1-, 5- and 10-year BCSS, while nine were used for DFS. The C-index was 0.841 for BCSS and 0.737 for DFS in internal validation, and the C-index was 0.782 for BCSS and 0.700 for DFS in external validation. The calibration curve for both BCSS and DFS demonstrated acceptable agreement between the predicted and actual observation in the training and the validation cohorts. The nomograms provided valuable visualization of factors predicting BCSS and DFS in invasive breast cancer patients with immediate breast reconstruction. The nomograms may have tremendous potential in guiding individualized decision-making for physicians and patients in choosing the optimized treatment methods.

The Impact of an Enrolment in Clinical Trial on Tolerance and Pathological Response for Patients Treated by Neoadjuvant MVAC Against an Invasive Bladder Cancer. A Retrospective Comparative Study

IntroductionMVAC (Methotrexate, Vinblastine, Adriamycin, and Cisplatin) neoadjuvant chemotherapy a standard treatment for invasive bladder cancer is associated with mainly haematological toxicities. Randomized clinical trials remain a gold standard for treatment outcomes and efficacy assessment. Patients enrolled in clinical trials are selected and tend to benefit from a stricter follow-up unlike everyday clinical practice patients. Conversely, real-life observational studies better define the effectiveness of treatments in clinical routine practice. The aim of this study is to analyse the impact of clinical trial monitoring on MVAC-related toxicities. Material and MethodsPatients with an infiltrative localized bladder cancer treated by MVAC neoadjuvant chemotherapy between 2013 and 2019 were enrolled, and divided into 2 groups: patients included in a clinical trial namely “VESPER study” during their treatment and patients treated in clinical routine practice. ResultsOut of 59 patients were enrolled in this retrospective study, 13 patients were included in a clinical trial. Clinical characteristics were similar between the 2 groups. Comorbidities were more frequent in the nonclinical trial group (NCTG). Completed 6 cures treatment proportion was higher in the clinical trial group (CTG) (69.2% vs. 50%). Yet, in this group, patients had more doses reduction (38.5% vs. 19.6%). The proportion of complete pathologic response was higher in patients enrolled in clinical trial (53.8% vs. 39.1%). Statistically, the expected stricter monitoring due to clinical trial enrolment had no impact on the complete pathologic response and clinically relevant toxicities. DiscussionWhen compared to conventional clinical practice, clinical trial enrolment induced no significant difference on the pathologic complete response or toxicity rate. Further large prospective studies are needed to confirm these data.

Microwave-Assisted Chemical Ablation (MA-CA): A Novel Microwave-Assisted Tissue Ablation Procedure—Preliminary Assessment of Efficiency

Microwave (MW) ablation is becoming a routine technology in the interventional radiology field. A new approach combining MW ablation and chemical ablation is developed in this paper. The rationale for the development of this Microwave-Assisted Chemical Ablation (MA-CA) technology was to improve the utility of thermal ablation as a minimally invasive treatment for cancer. The experimental conditions for ex vivo bovine liver samples were: A—100 W (120 s) with no addition of ethanol; B—100 W (30 s), wait (60 s) (no power), and 100 W (90 s) with no addition of ethanol; C—100 W (30 s), wait (60 s), 100 W (30 s), and 100 W (60 s) with the addition of 5 mL ethanol; and D—100 W (30 s), wait (60 s), 100 W (30 s), 0 W (30 s) with the addition of 2.5 mL ethanol, and 100 W (60 s) with the addition of 5 mL ethanol (12,000 Joules Total). The results showed that with the use of ethanol, the ablation zone was enlarged and revealed improved sphericity. This novel combination has greater advantages than either technology individually. The objective is to increase the precision and efficiency of MW ablation and to broaden the range of tissues and pathologies that can be treated using this new approach, and to validate the benefits that arise from combining the advantages of MW and chemical ablation in a relevant setting.

Electromotive Drug Administration Chemotherapy with Mitomycin C Versus Bacillus Calmette-Guerin for the Treatment of Non-Muscle Invasive Bladder Cancer.

Devices that increase the penetrance of intravesical chemotherapeutics are emerging as alternatives to classical Bacillus Calmette Guérin (BCG) treatment. To compare the efficacy of mitomycin C applied with the electromotive drug delivery device (MMC-EMDA) versus BCG in patients with intermediate and high-risk non-muscle-invasive bladder cancer (NMIBC) without carcinoma in situ (CIS). Prospective non-randomized study in which 47 patients received MMC-EMDA (40 mg of MMC diluted in 50 mg of distilled water at 20 mA for 30 min. Regimen of 6 weekly and then 6 monthly instillations) and 48 patients received BCG (50 mg of OncoCITE® diluted in 50 ml of normal saline for 60 min. Regimen of 6 weekly instillations and then 3 weekly instillations at months 3, 6 and 12). The primary endpoint was the recurrence-free rate (RFR) at 24 months. Secondary endpoints were time to recurrence and progression-free rate (PFR) at 24 months follow-up. Baseline patient assessment and mean follow-up time were similar in both groups (MMC-EMDA group: 26.4 months; BCG group: 28.4 months (p = 0.44)). The RFR at 24 months was 80.9% for the MMC-EMDA group and 77.1% for the BCG group (p = 0.969). The mean time to recurrence was 12.5 months in the MMC-EMDA group and 14 months in the BCG group (p = 0.681). At 24 months, PFR was 97.9% in the MMC-EMDA group and 93.8% in the BCG group (p = 0.419). No differences were found between MMC-EMDA and BCG treatments in patients with high-risk and intermediate-risk NMIBC without CIS.

Preclinical development of RAG1-40-31L: A novel small activating RNA-lipid conjugate targeting tumor suppressor gene p21 for treatment of non-muscle invasive bladder cancer.

e16620 Background: Loss-of-function of tumor suppressor genes are the dominant driving force in tumorigenesis. Restoration in function and/or expression of these genes holds tremendous therapeutic potential in cancer treatment. Bladder cancer is the 9th leading cause of cancer-related deaths in the United States in which ~75% of all newly diagnosed cases are non-muscle invasive bladder cancer (NMIBC). Standard-of-care includes intravesical installation of Bacillus Calmette-Guerin following tumor resection with an expected failure rate of ~50% within 6 months for patients with high-grade tumors. RNA activation (RNAa) is a mechanism in which short RNA duplexes termed small activating RNA (saRNA) induce gene transcription by targeting non-coding regulatory sequence ( i.e., promoters) embedded in chromatin. Thus, saRNA-induced overexpression of p21WAF1/CIP1 (p21) – a tumor suppressor of several anti-growth pathways – may hold therapeutic potential in bladder cancer. Through conjugation of a novel lipid ( i.e., C5X5), we have created a p21-targeting saRNA drug candidate referred to as RAG01-40-31L for delivery to bladder cancer cells in vivo. The aim of this work was to characterize the intravesical administration of RAG01-40-31L on p21 induction and its anti-tumor potential in NMBIC models. Methods: In vitro expression analyses were performed to investigate p21 induction via saRNA in KU7 and T24 bladder cancer cell lines by RT-qPCR and immunoblot analysis. Cell cycle analysis and tumorigenicity assays examined impact of RAG1-40-31L on cancer cell growth. Orthotopic human bladder tumors were established in female BALB/c nude mice using the recombinant cell line KU7 engineered to overexpress luciferase reporter. Tumor growth was monitored in live animals via luciferase bioluminescence using an in vivo imaging system. Plasma and tissue were harvested for drug exposure and expression analytics. Results: In vitro analyses indicated RAG1-40-31L activated p21 expression by approximately 6-fold and inhibited bladder cancer cell growth ( i.e., cell cycle arrest, apoptosis, and senescence) in a dose-dependent manner with low nanomolar potency. Intravesical administration of RAG1-40-31L (3 times per week for 2 weeks) inhibited growth of orthotopic tumors by 65% in mouse bladder models. Single-dose pharmacokinetics demonstrated a half-life (t1/2) of ~114 h with minimal systemic exposure (~0.05% of that of bladder tissue). Conclusions: These data constitute a preclinical proof-of-concept for saRNA as a novel p21-targeting modality in the treatment of cancer. The C5X5 lipid conjugate appears to be a viable approach to enhance oligonucleotide delivery and activity in bladder cancer. Preclinical safety assessment studies to enable clinical trials of RAG01-40-31L are currently underway.

EE383 Cost-Utility and Value of Information Analysis of Novel Treatments for BCG-Unresponsive Non-Muscle Invasive Bladder Cancer

Nadofaragene firadenovec (awaiting regulatory approval) and pembrolizumab are bladder-sparing alternatives for treating Bacillus Calmette–Guérin (BCG)-unresponsive, high-risk non-muscle invasive bladder cancer (NMIBC). Cost-utility and value of information (VOI) analyses of these treatments, compared with a hypothetical treatment comparator based on approved and investigational therapies, were conducted from a United States health system perspective.

Clinical-pathological characterization of patients with HER2 negative breast cancer submitted to adjuvant docetaxel/cyclophosphamide (TC), TC4 versus TC6.

e12530 Background: The optimal number of cycles of adjuvant docetaxel and cyclophosphamide (TC) in patients with HER2 negative breast cancer is unknown. The serious long-term adverse events associated with anthracyclines led researchers to question the risk-benefit ratio of anthracycline-based regimens, especially in those without axillary lymph node involvement, leading to an increasing trend to omit anthracyclines in adjuvant treatment. Therefore, we do not know for sure which clinical-pathological characteristics would favor the use of TC4 versus TC6. Objective: To evaluate the clinical-pathological characteristics of patients who received adjuvant treatment for invasive breast cancer, her2 negative, stage I-III with TC4 or TC6 in a Brazilian service. Methods: This is a retrospective observational cohort study of patients diagnosed with invasive breast cancer, her2 negative, stage I-III, who received adjuvant treatment with TC4 or TC6, between January 2010 and December 2022 at AC Camargo Cancer Center, São Paulo, Brazil. Results: We analyzed 186 patients, 98% female, 52.3% pre-menopausal, 68.7% had at least one comorbidity, 10% mutation in the BRCA1/2 gene, 5% had a previous history of DCis or IDC. 62.2% underwent breast-conserving surgery and 80% underwent sentinel lymph node (SL). Regarding the pathological characteristics of the tumor 82.9% invasive ductal carcinoma (IDC), 42.7% histological grade (HG) III, 90% were hormone receptor positive (HR+) and only 10% triple negative (TN), staging 66% pT1, 71% pN0, being grouped into 63.7% stage I, 34.6% stage II; 1.7% stage III. Only 9% underwent oncotype, 5% of them had some contraindication to anthracycline. Regarding treatment groups 72.4% received TC4 versus 27.6% TC6. There were no treatment-related deaths. Regarding the TC4 / TC6 groups (%) and clinical-pathological characteristics: pre-menopausal 60.5 / 49% ( p= 0.225), comorbidity 3 / 6% ( p= 0.400), contraindication to anthracycline 4.7 / 6% ( p= 0.714). Conservative surgery 61.5 / 64% ( p= 0.894), SL 81 / 78% ( p= 0.504), GH III 39.8 / 50% (p = 0.334), pT2 staging 26.4 / 40 % (p = 0.087), pN1 11.7/ 22% (p = 0.050), stage I 65.9/58%, II 33.3 / 38%, III 0.8 /4 % (p = 0.212). RH- 8.7 / 14% (p = 0.444). Did not complete treatment 3.2 / 12% (p = 0.033), toxicities G3/4 9.7 / 12.5% (p = 0.791), FN G3/4 3.8 / 4% (p = 1.00) and neuropathies 8.9 / 28.6% (p = 0.002). Late toxicities 5.7 / 18.4% (p = 0.018). Extended hormone therapy 35/ 50% (p = 0.142). Systemic recurrences 12.5% / 2% (p = 0.566). Conclusions: TC6 was more indicated in patients with GH III, pT2 and/or pN1, stage II and III, RH-, therefore patients who received TC6 had a lower chance of completing the treatment, as well as greater toxicities, mainly late peripheral neuropathy, and more indications of extended hormone therapy, however those who performed the TC6 had less chance of systemic recurrences.

Safety and efficacy of robotic-assisted versus laparoscopic distal gastrectomy after neoadjuvant chemotherapy for advanced gastric cancer.

Robot-assisted distal gastrectomy (RADG) has been used in the minimally invasive surgical treatment of gastric cancer, but the research on advanced gastric cancer (AGC) after neoadjuvant chemotherapy (NAC) has not been reported. This study aimed to analyze the outcomes of RADG versus laparoscopic distal gastrectomy (LDG) after NAC for AGC. This was a retrospective propensity score-matched analysis from February 2020 and March 2022. Patients who underwent RADG or LDG for AGC (cT3-4a/N +) following NAC were enrolled and a propensity score-matched analysis was performed in a 1:1 manner. The patients were divided into RADG group and LDG group. The clinicopathological characteristics and short-term outcomes were observed. After propensity score matching, 67 patients each in the RADG and LDG groups. RADG was associated with a lower intraoperative blood loss (35.6 vs. 118.8ml, P = 0.014) and more retrieved lymph nodes (LNs) (50.7 vs. 39.5, P < 0.001), more extraperigastric (18.3 vs. 10.4, P < 0.001), and suprapancreatic LNs (16.33 vs. 13.70, P = 0.042). The RADG group showed lower VAS scores at postoperative 24h (2.2 vs 3.3, P = 0.034), earlier ambulation (1.3 vs. 2.6, P = 0.011), aerofluxus time (2.2 vs. 3.6, P = 0.025), and shorter postoperative hospital stay (8.3 vs. 9.8, P = 0.004). There were no significant differences in the operative time (216.7 vs.194.7min, P = 0.204) and postoperative complications between the two groups. RADG may be a potential therapeutic option for patients with AGC after NAC considering its advantages in perioperative period compared with LDG.