Reduce Tumor Recurrence Research Articles

Long non‐coding RNA‐regulated alternative splicing modulates key cancer pathway in lung adenocarcinoma

Long non‐coding RNA‐regulated alternative splicing modulates key cancer pathway in lung adenocarcinoma

Prognostic analysis of inflammatory response-related genes and biomarkers in patients with urothelial carcinoma of ureter.

Ureteral urothelial carcinoma is a common urinary system tumor, accounting for 40% to 60% of all ureteral diseases. This study attempted to analyze the prognosis of patients with urothelial carcinoma, judging ureteral urothelial carcinoma by genes and biomarkers of inflammatory response. In this paper, co-expression network analysis and gene-based image fusion evaluation methods were proposed to obtain the prognosis results of patients with ureteral urothelial carcinoma. The experimental results showed that the levels of PLR and NLR increased, and the levels of HGB and HCT decreased; high PLR and high NLR levels, low HGB and low HCT levels were all risk factors affecting bladder urothelial carcinoma, and their ratios (OR) were 1.023, 1.611, 0.961, 0.859, 1.015, 1.072, 0.979, and 0.951, respectively. However, high PLR and high NLR levels were independent risk factors for bladder urothelial carcinoma, and their OR values were 1.497 and 1.071, respectively. Through biomarker diagnosis, the area under the curve, sensitivity, specificity and Youden index of hsa-mir-17, hsa-mir-93, hsa-mir-429 and hsa-mir-20a all exceeded 0.9, indicating that this is a potential diagnostic indicators. All in all, during the treatment of ureteral cancer, in order to reduce tumor recurrence, systemic therapy should be combined with ureteral cancer. In addition, this study also analyzed the prognosis of chemotherapy patients, and the results showed that immunotherapy may increase the risk of tumor cell reperfusion during chemotherapy.

Combination of GD2-directed bispecific trifunctional antibody therapy with Pd-1 immune checkpoint blockade induces anti-neuroblastoma immunity in a syngeneic mouse model.

Despite advances in treating high-risk neuroblastoma, 50-60% of patients still suffer relapse, necessitating new treatment options. Bispecific trifunctional antibodies (trAbs) are a promising new class of immunotherapy. TrAbs are heterodimeric IgG-like molecules that bind CD3 and a tumor-associated antigen simultaneously, whereby inducing a TCR-independent anti-cancer T cell response. Moreover, via their functional Fc region they recruit and activate cells of the innate immune system like antigen-presenting cells potentially enhancing induction of adaptive tumor-specific immune responses. We used the SUREK trAb, which is bispecific for GD2 and murine Cd3. Tumor-blind trAb and the monoclonal ch14.18 antibody were used as controls. A co-culture model of murine dendritic cells (DCs), T cells and a neuroblastoma cell line was established to evaluate the cytotoxic effect and the T cell effector function in vitro. Expression of immune checkpoint molecules on tumor-infiltrating T cells and the induction of an anti-neuroblastoma immune response using a combination of whole cell vaccination and trAb therapy was investigated in a syngeneic immunocompetent neuroblastoma mouse model (NXS2 in A/J background). Finally, vaccinated mice were assessed for the presence of neuroblastoma-directed antibodies. We show that SUREK trAb-mediated effective killing of NXS2 cells in vitro was strictly dependent on the combined presence of DCs and T cells. Using a syngeneic neuroblastoma mouse model, we showed that vaccination with irradiated tumor cells combined with SUREK trAb treatment significantly prolonged survival of tumor challenged mice and partially prevent tumor outgrowth compared to tumor vaccination alone. Treatment led to upregulation of programmed cell death protein 1 (Pd-1) on tumor infiltrating T cells and combination with anti-Pd-1 checkpoint inhibition enhanced the NXS2-directed humoral immune response. Here, we provide first preclinical evidence that a tumor vaccination combined with SUREK trAb therapy induces an endogenous anti-neuroblastoma immune response reducing tumor recurrence. Furthermore, a combination with anti-Pd-1 immune checkpoint blockade might even further improve this promising immunotherapeutic concept in order to prevent relapse in high-risk neuroblastoma patients.

Multidisciplinary treatment for locally advanced gastric cancer: A systematic review and network meta-analysis.

This study aimed to evaluate the efficacy of multidisciplinary treatment for patients with locally advanced gastric cancer (LAGC) who underwent radical gastrectomy. Randomised controlled trials (RCTs) comparing the effectiveness of surgery alone, adjuvant chemotherapy (CT), adjuvant radiotherapy (RT), adjuvant chemoradiotherapy (CRT), neoadjuvant CT, neoadjuvant RT, neoadjuvant CRT, perioperative CT and hyperthermic intraperitoneal chemotherapy (HIPEC) for LAGC were searched. Overall survival (OS), disease-free survival (DFS), recurrence and metastasis, long-term mortality, adverse events (grade ≥3), operative complications and R0 resection rate were used as outcome indicators for meta-analysis. Forty-five RCTs with 10077 participants were finally analysed. Adjuvant CT had higher OS (hazard ratio [HR] = 0.74, 95% credible interval [CI] = 0.66-0.82) and DFS (HR = 0.67, 95% CI = 0.60-0.74) than surgery-alone group. Perioperative CT (odds ratio [OR] = 2.56, 95% CI = 1.19-5.50) and adjuvant CT (OR = 0.48, 95% CI = 0.27-0.86) both had more recurrence and metastasis than HIPEC + adjuvant CT, while adjuvant CRT tended to have less recurrence and metastasis than adjuvant CT (OR = 1.76, 95% CI = 1.29-2.42) and even adjuvant RT (OR = 1.83, 95% CI = 0.98-3.40). Moreover, the incidence of mortality in HIPEC + adjuvant CT was lower than that in adjuvant RT (OR = 0.28, 95% CI = 0.11-0.72), adjuvant CT (OR = 0.45, 95% CI = 0.23-0.86) and perioperative CT (OR = 2.39, 95% CI = 1.05-5.41). Analysis of adverse events (grade ≥3) showed no statistically significant difference between any two adjuvant therapy groups. A combination of HIPEC with adjuvant CT seems to be the most effective adjuvant therapy, which contributes to reducing tumour recurrence, metastasis and mortality - without increasing surgical complications and adverse events related to toxicity. Compared with CT or RT alone, CRT can reduce recurrence, metastasis and mortality but increase adverse events. Moreover, neoadjuvant therapy can effectively improve the radical resection rate, but neoadjuvant CT tends to increase surgical complications.

Pseudocapsule and pseudocapsule-based extracapsular resection in pituitary neuroendocrine tumors.

Since Costello etal. proposed the concept of pseudocapsule of pituitary neuroendocrine tumors (PitNETs) in 1936, many studies have been published on its occurrence, development process, histopathology, and morphology. Pseudocapsule has been proposed as the anatomical interface between PitNETs and normal pituitary gland, therefore the so-called pseudocapsule-based extracapsular resection (ER) technique was developed as an extracapsular surgery method for PitNETs,which differs from the conventional intracapsular resection (IR). In recent years, ER has also been widely used in patients of different tumor types, sizes, and age groups, because the pseudocapsule can be identified more clearly under the endoscopy. Endoscopic transsphenoidal resection for PitNETs has become the preferred surgical method. We reviewed relevant literatures in the past 10 years, showing that ER could achieve better rate of gross total resection (GTR) and biochemical remission, and reduce tumor recurrence than IR, without increasing postoperative complications. Therefore, the pseudocapsule and ER should be valued by neurosurgeons and actively promoted clinically.

BCG downregulates PD1 and PD-L1 expression in bladder cancer cells co-cultivated with peripheral blood mononuclear cells

PurposeBCG is the standard of care to treat high risk non-muscle invasive bladder cancer (NMIBC), reducing recurrence. PD-L1 is a ligand of the co-inhibitory receptor PD1 that has been shown to be expressed by tumor cells of distinct origin related to unfavorable prognosis. The development of a new class of target drugs that inhibit PD-L1 and PD1 has opened a new perspective for urothelial cancer treatment. Although there are few studies searching for the role of BCG over PD1 and PD-L1, many clinical trials are in course using the immune checkpoint inhibitors together with BCG as a new regime to treat NMIBC.Material and methodsWe analyzed the expression of PD1 and PD-L1 using qRT-PCR in RT4 bladder cancer (BCa) epithelial cells co-cultivated with peripheral blood mononuclear cells (PBMC) after treatment with BCG.ResultsThere was a significantly reduction in PD1 and PD-L1 expression by BCa epithelial cells after BCG treatment. In PBMC PD1 was significantly overexpressed.ConclusionOur results suggest that one of the mechanisms related to the success of BCG in reducing tumor recurrence in NMIBC may be related to the negative control of PD1 and PD-L1 in tumor cells.

Novel insight into the role of immunotherapy in gastrointestinal cancer (Review).

To date, great progress has been made in studying the immunology of cancer and the development of immunotherapies. Immunotherapy has become an effective clinical strategy for cancer treatment in courtesy of its unique features. It has been demonstrated to delay tumor progression, reduce tumor recurrence and metastasis, and even cure tumors through enhancing the immune response, stimulating tumor-specific immunity and breaking immune tolerance. Several different immunotherapeutic approaches and methods are in the process of being developed, including the use of cytokines, immune checkpoint inhibitors, engineered T cells (such as T-cell-receptor T cells and chimeric antigen receptor T cells) and cancer vaccines. Digestive system neoplasms pose a serious threat to human health, including esophageal cancer, gastric cancer and colorectal cancer, and immunotherapy is considered to be a promising new avenue for the treatment of digestive system neoplasms. However, certain challenges remain in terms of the broad implementation of immunotherapies due to the incompletely understood mechanisms underlying tumorigenesis. Therefore, it is crucially important to understand both the various different types of immunotherapy and the immune landscapes in digestive system neoplasms in order to reduce the side effects associated with these therapies. The present review discusses existing and newly emerging immunotherapeutic methods that may be applied in the treatment of digestive system neoplasms and how their clinical efficacy may be enhanced.

Potassium Ion Channels in Malignant Central Nervous System Cancers.

Simple SummaryMalignant central nervous system (CNS) cancers are notoriously difficult to treat, with just one-third of patients surviving five years post-diagnosis. Their location within the brain and brainstem presents several challenges to successful treatment, including surgical inaccessibility and designing effective therapies that pass the brain’s protective barrier. Furthermore, high-grade CNS cancer is also prone to recurrence, and the secondary tumours that arise are highly resistant to treatment. Potassium ion channels are a class of transmembrane proteins involved in maintaining the electrical microenvironment of cells. In cancers, these proteins are known to play a significant role in the development of cancer hallmarks like proliferation, invasion, and adaptive drug resistance. Our review explores the relationship between potassium ion channel function and the progression of malignant CNS cancers. Targeting these proteins presents a promising, novel treatment strategy, with several FDA-approved potassium ion channel-targeting drugs already in clinical use for various CNS disorders.Malignant central nervous system (CNS) cancers are among the most difficult to treat, with low rates of survival and a high likelihood of recurrence. This is primarily due to their location within the CNS, hindering adequate drug delivery and tumour access via surgery. Furthermore, CNS cancer cells are highly plastic, an adaptive property that enables them to bypass targeted treatment strategies and develop drug resistance. Potassium ion channels have long been implicated in the progression of many cancers due to their integral role in several hallmarks of the disease. Here, we will explore this relationship further, with a focus on malignant CNS cancers, including high-grade glioma (HGG). HGG is the most lethal form of primary brain tumour in adults, with the majority of patient mortality attributed to drug-resistant secondary tumours. Hence, targeting proteins that are integral to cellular plasticity could reduce tumour recurrence, improving survival. This review summarises the role of potassium ion channels in malignant CNS cancers, specifically how they contribute to proliferation, invasion, metastasis, angiogenesis, and plasticity. We will also explore how specific modulation of these proteins may provide a novel way to overcome drug resistance and improve patient outcomes.

Multiomic characterization and drug testing establish circulating tumor cells as an ex vivo tool for personalized medicine

SummaryMatching the treatment to an individual patient’s tumor state can increase therapeutic efficacy and reduce tumor recurrence. Circulating tumor cells (CTCs) derived from solid tumors are promising subjects for theragnostic analysis. To analyze how CTCs represent tumor states, we established cell lines from CTCs, primary and metastatic tumors from a mouse model and provided phenotypic and multiomic analyses of these cells. CTCs and metastatic cells, but not primary tumor cells, shared stochastic mutations and similar hypomethylation levels at transcription start sites. CTCs and metastatic tumor cells shared a hybrid epithelial/mesenchymal transcriptome state with reduced adhesive and enhanced mobilization characteristics. We tested anti-cancer drugs on tumor cells from a metastatic breast cancer patient. CTC responses mirrored the impact of drugs on metastatic rather than primary tumors. Our multiomic and clinical anti-cancer drug response results reveal that CTCs resemble metastatic tumors and establish CTCs as an ex vivo tool for personalized medicine.

Selected Articles from This Issue

MOXR0916 is an agonist antibody that targets the OX40 receptor. Ligation of OX40 provides costimulatory signals to effector T cells and functional inhibition of regulatory T cells. Here, Kim and colleagues demonstrated the safety of MOXR0916 in patients with solid tumors with no dose-limiting toxicities observed. Serial tumor biopsies demonstrated limited evidence of immune activation in a heterogeneous population. Minimal antitumor activity was observed in indication-specific expansion cohorts enrolled at the recommended dose of 300 mg every 3 weeks selected based on projected tumor OX40 receptor saturation. Therefore, clinical proof-of-concept for OX40 agonism was not demonstrated by this phase I study. Whether combination with established agents with complementary mechanisms of action, such as anti-PD-L1, or whether an alternative approach to targeting the OX40 receptor can achieve more compelling efficacy remains to be determined.Outcomes for patients with locally recurrent head and neck squamous cell carcinoma (HNSCC) remain poor. Although salvage surgery is currently the standard of care, surgery fails to achieve disease control in more than half of patients. To date, no adjuvant therapy has been shown to provide survival benefit after salvage resection. Here, Leddon and colleagues report the results of a phase II open-labeled trial of adjuvant nivolumab after salvage resection for recurrent HNSCC. They found that adjuvant nivolumab was well tolerated. Two-year disease-free survival after following adjuvant nivolumab was 71.4%, which is significantly longer than a historical control sample with similar baseline characteristics. Further study in randomized controlled trials is warranted to establish clinical efficacy.Telomere maintenance is essential for uncontrolled tumor proliferation. Most tumors maintain telomere length via reactivation of telomerase reverse transcriptase (TERT) expression. Identifying clinically translatable imaging biomarkers of TERT has the potential to enable noninvasive assessment of tumor proliferation and response to therapy. Batsios and colleagues utilized deuterium metabolic imaging following administration of deuterated pyruvate to noninvasively monitor TERT expression in tumor-bearing mice in vivo. Importantly, lactate production from deuterated pyruvate is a biomarker of early response to therapy, prior to anatomical alterations, thereby providing clinicians with a novel tool for assessment of tumor proliferation and treatment response in cancer.Perineural invasion (PNI) occurs frequently in oral squamous cell carcinoma. However, diagnostic criteria of PNI vary and its role as an independent predictor of prognosis has not been established. Schmitd and colleagues reveal that PNI is an important predictor of prognosis among patients with no lymph node metastasis. Moreover, patients with nerves closer to the tumor have poor outcomes even if diagnosed as PNI-negative using current criteria. Consistent with clinical findings, spatial transcriptomic analysis of nerves in sections of human tumors shows a gradient of gene expression that is dependent on nerve-tumor distance. Together, these findings support broadening the definition of PNI to make it more clinically relevant. Moreover, the transcriptomic data reveal an injury response to the tumor; mechanisms involved in response to stress and growth are upregulated in nerves proximal to cancer. Understanding how these mechanisms contribute to clinical outcomes is crucial for developing new treatment strategies that reduce tumor recurrence.

Abstract 5553: Anti-CD19-CD22 antibody drug conjugate to reduce tumor recurrence in B-cell hematologic cancers

Abstract With 1,279,000 new cases in 2020 and high incidence of relapse, hematologic cancers present significant opportunity for drug development. B-cell caners arise from various developmental stages of the B lymphocyte, and occur in several forms, including leukemia, lymphoma, and multiple myeloma. CD19 and CD22 are validated targets for B cell cancers, each with multiple drugs approved. However, single targeting therapies showed a poor median response likely due to loss of antigen expression upon treatment stress. CD19&CD22 dual targeting antibody drug conjugate can be a powerful killer of B-cell cancers, with more targeted patient populations due to the high expression of CD19, and good anti-tumor efficacy due to the high internalizing ability of CD22.To this end, we developed 7E11-13G9, which is a bispecific antibody designed for antibody-drug-conjugate for a larger market of B-cell hematological cancers.By the strong CD19 binding arm of 7E11 and the efficient CD22-mediated internalizing arm of 13G9, 7E11-13G9 BsAb kills more tumor cells with high potency and efficacy. In tumor cell killing assay, bispecific 7E11-13G9 showed significantly better anti-tumor efficacy than any of the benchmark antibodies, and even better than the combination of the anti-CD19 benchmark Loncastuximab with the anti-CD22 benchmark Inotuzumab. Significantly better anti-tumor effect and delayed tumor recurrence of CD19-CD22 bispecific compared with single target was demonstrated in Nalm6 acute lymphocyte leukemia model. 7E11-13G9 BsAb is stable and has good productivity in transient expression. Proof of concept study of antibody drug conjugate based on 7E11-13G9 was prepared, and showed great anti-tumor efficacy both in vitro and in vivo. Citation Format: Liang Du, Tingting Wan, Yi Jin, Jijun Yuan. Anti-CD19-CD22 antibody drug conjugate to reduce tumor recurrence in B-cell hematologic cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5553.

P-296 Neoadjuvant chemotherapy in locally advanced cardia tumor

The gastroesophageal junction (GEJ) and gastric cardia are anatomical sites with a high incidence of Adenocarcinoma. In Iran, gastric cancer is ranked as the most prevalent malignancy amongst men and third amongst women. Additionally, it has the highest mortality rate of all malignancies in Iran(WHO). Neoadjuvant chemotherapy has proven efficient in decreasing tumor size and lymph node involvement, thus facilitating the process of surgery, reducing tumor recurrence, and increasing the life span. This study investigates the tumor response to neoadjuvant chemotherapy and feasibility of surgery following it and patients' tolerance to FLOT regimen in locally advanced gastric cardia cancers. This cross-sectional study enrolled 28 patients with cardia adenocarcinoma referred to Bouali Hospital for 14 months. The inclusion criteria were locally advanced adenocarcinoma of the cardia confirmed by pathology report and endosonography (EUS), performance status(PS) < 2 (ECOG criteria), and the patient’s consent to the treatment. Patients with T3 or T4 with or without lymph node involvement and T1 or T2 with lymph node involvement were categorized as locally advanced A chemotherapy regimen (FLOT) was administered for three cycles before surgery, each lasting 48 hours and two weeks apart. Two to three weeks after the third cycle of chemotherapy, all patients were reassessed by endoscopy and EUS for tumor response to neoadjuvant chemotherapy. Among the 28 participants, 19 (67.9%) were male, and 9 (32.1%) were female. The mean age was 64.42 (SD=13.71) years. All patients in the study had T3 (71.1% ) and T4 (28.6%), while after receiving chemotherapy, only 7.2% of patients had T3 and T4 (p-value 0.005). FLOT regimen was relatively well tolerated. Serious complications that made us interrupt or postpone the treatment were not seen. Leukopenia and fever occurred 6-10 days post-chemotherapy in 11 patients. We could do surgery for 26 of our patients. One patient denied doing an operation, and the other had a problem with anesthesia. Neoadjuvant chemotherapy with FLOT regimen is relatively well tolerated in our patients with locally advanced gastric adenocarcinoma and, in most cases, decreased the cardia tumor's size and lymph node involvement.

Abstract B018: Targeting Notch4 and HIF2α signaling reduces the ability of cells to survive chemotherapy by undergoing the polyaneuploid transition

Abstract Giant cancer cells have been ignored for 200 years, but recently coupled to a role in metastasis and therapeutic resistance. Some cancer cells appear to survive environmental stress, such as chemotherapy or radiotherapy, via a polyaneuploid transition. This results in a PolyAneuploid Cancer Cell (PACC) state with up to 10-fold larger cell sizes. It is proposed that PACCs utilize a conserved evolutionarily or developmental program for polyploidization, which is commonly observed in other organisms and tissues. After a stress-induced formation, the PACC state first undergoes a period of quiescence and eventually undergoes reductive cell division to give rise to proliferative progeny. We hypothesize that PACCs play a role in tumor recurrence and therapy resistance by surviving the initial treatment and subsequently reseeding the tumor via pseudohypoxic HIF signaling. Dosing with LD50 cisplatin for 72h results in the induction of the PACC state in cancer cell lines from breast (HCC1806), renal (786-0), colon (HCT116), and lung (U1690) tumors. Cells in the PACC state had 3-fold larger nuclei after 3 days of treatment and 6-fold larger nuclei after 10 days. Transcriptomic data showed an overall decrease in gene expression across all 4 cell lines. However, there was an increased expression of HIF2 (2.7-fold), Notch4 (2-fold), Plekhs1 (2.3-fold) in PACCs relative to untreated control. Moreover, there was an increase in the expression of replication dependent histones. Overall, ATACseq indicated a reduction in open chromatin in PACCs, as measured by reduced levels of histone 4 and histone 4 modifications (H4k5ac, h4k16ac, H4R3me2). However, H3k27me3 was increased 20% and AP1 binding sites were enriched in open chromatin regions. HIF2 and AP1 cooperate to regulate gene expression and confer therapy resistance. We hypothesize that AP1 is activated in response to treatment and stabilizes HIF2 under oxygenated conditions. HIFs regulate regulators of the cell cycle to induce polyploidy and downregulate β-catenin, a known inducer of cytokinesis. Small molecule inhibition of Notch and HIF-2α reduced PACC formation by 50% and 65% respectively at day 3 and 60% and 75% at day 10. The surviving PACCs were smaller than those untreated by Notch and HIF-2α inhibitors. Large metabolic changes must be undertaken to generate and sustain the larger cellular mass accompanied by polyploidy. HIF signaling metabolically rewires cells to a glycolytic phenotype that provides a carbon source for increased de novo generation of nucleotides, lipids, and proteins. Indicative of this rewiring is that PACCs have increased expression of Hexokinase (2.5-fold), CPT1 (2.3-fold), and GP6D (2-fold). In conclusion, tumor cells that survive chemotherapy are polyaneuploid, larger, and in an altered metabolic state. This process appears driven by Notch4 and HIF-2α signaling. Combining conventional chemotherapy with Notch or HIF2α inhibitors presents an opportunity to reduce tumor recurrence by inhibiting a survival mechanism. Citation Format: Christopher P. Carroll, Emma Hammarlund, Kenneth J. Pienta, Sarah R. Amend. Targeting Notch4 and HIF2α signaling reduces the ability of cells to survive chemotherapy by undergoing the polyaneuploid transition [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr B018.

One Shoot, Two Birds: Alleviating Inflammation Caused by Ischemia/Reperfusion Injury to Reduce the Recurrence of Hepatocellular Carcinoma

Inflammation is crucial to tumorigenesis and the development of metastasis. Hepatic ischemia/reperfusion injury (IRI) is an unresolved problem in liver resection and transplantation which often establishes and remodels the inflammatory microenvironment in liver. More and more experimental and clinical evidence unmasks the role of hepatic IRI and associated inflammation in promoting the recurrence of hepatocellular carcinoma (HCC). Meanwhile, approaches aimed at alleviating hepatic IRI, such as machine perfusion, regulating the gut-liver axis, and targeting key inflammatory components, have been proved to prevent HCC recurrence. This review article highlights the underlying mechanisms and promising therapeutic strategies to reduce tumor recurrence through alleviating inflammation induced by hepatic IRI.

PARP inhibitors chemopotentiate and synergize with cisplatin to inhibit bladder cancer cell survival and tumor growth

BackgroundManagement of bladder cancer (BLCA) has not changed significantly in the past few decades, with platinum agent chemotherapy being used in most cases. Chemotherapy reduces tumor recurrence after resection, but debilitating toxicities render a large percentage of patients ineligible. Recently approved immunotherapy can improve outcomes in only a third of metastatic BLCA patients. Therefore, more options for therapy are needed. In this study, we explored the efficacy of PARP inhibitors (PARPi) as single agents or as combinations with platinum therapy.MethodsWe treated BLCA cells with PARPi (olaparib, niraparib, rucaparib, veliparib, or talazoparib) alone or as the combination of cisplatin with PARPi. We then measured their survival, proliferation, apoptosis, as well as their ability to form colonies. BLCA xenografts in male SCID mice were treated similarly, followed by the assessment of their growth, proliferation, and apoptosis.ResultsPARPi niraparib and talazoparib were effective in reducing BLCA cell survival as single agents. Combinations of Cisplatin with talazoparib and niraparib effectively reduced the survival of BLCA cells, while veliparib was not effective even at high concentrations. In vivo, the combinations of cisplatin with niraparib, rucaparib, or talazoparib reduced BLCA xenograft growth significantly.ConclusionsWe provide evidence that PARPi can be effective against BLCA as single agents or as combinatorial therapy with cisplatin.

MOF@COF nanocapsule for the enhanced microwave thermal-dynamic therapy and anti-angiogenesis of colorectal cancer

Microwave thermal therapy (MWTT) shows great prospect in cancer treatments due to its non-invasive or minimally invasive nature and deep penetration through the tissue. However, incomplete ablation and elevated expression of many pro-tumor angiogenesis after MWTT (e.g., vascular endothelial growth factor, VEGF) induced tumor recurrence still remains an obstacle, especially in some tumors prone to recurrence and metastasis, such as colorectal cancer. Herein, we propose a nanocapsule of covalent organic framework cladding metal organic framework (MOF@COF) with microwave (MW) thermal-dynamic sensitization and co-action of tumor anti-angiogenesis. The MOF of Bi-Mn-porphyrin (BM) is designed as MW sensitizer to generate cytotoxic 1O2 and heat for microwave dynamic therapy (MWDT) synergistic MWTT. The COF is covalently coated on BM for further augmenting these two sensitization properties, as well as loading hydrophobic inhibitor of Apatinib to downregulate the expression of VEGF for inhibiting tumor recurrence. Furthermore, the contained Bi and porphyrin endow system with CT and fluorescence imaging (FI) capabilities. In vivo experiments verify that this combination therapy significantly impairs the growth of colorectal cancer with no recurrent carcinoma. Therefore, our work presents an integrated strategy derived from MOF@COF for remarkably augmenting single MWTT to reduce tumor recurrence.

FimH confers mannose-targeting ability to Bacillus Calmette-Guerin for improved immunotherapy in bladder cancer

BackgroundBladder cancer is a common disease worldwide with most patients presenting with the non-muscle-invasive form (NMIBC) at initial diagnosis. Postoperational intravesical instillation of BCG is carried out for patients with...

Polyglutamate-based nanoconjugates for image-guided surgery and post-operative melanoma metastases prevention.

Rationale: Cutaneous melanoma is the most aggressive and deadliest of all skin malignancies. Complete primary tumor removal augmented by advanced imaging tools and effective post-operative treatment is critical in the prevention of tumor recurrence and future metastases formation.Methods: To meet this challenge, we designed novel polymeric imaging and therapeutic systems, implemented in a two-step theranostic approach. Both are composed of the biocompatible and biodegradable poly(α,L-glutamic acid) (PGA) nanocarrier that facilitates extravasation-dependent tumor targeting delivery. The first system is a novel, fluorescent, Turn-ON diagnostic probe evaluated for the precise excision of the primary tumor during image-guided surgery (IGS). The fluorescence activation of the probe occurs via PGA degradation by tumor-overexpressed cathepsins that leads to the separation of closely-packed, quenched FRET pair. This results in the emission of a strong fluorescence signal enabling the delineation of the tumor boundaries. Second, therapeutic step is aimed to prevent metastases formation with minimal side effects and maximal efficacy. To that end, a targeted treatment containing a BRAF (Dabrafenib - mDBF)/MEK (Selumetinib - SLM) inhibitors combined on one polymeric platform (PGA-SLM-mDBF) was evaluated for its anti-metastatic, preventive activity in combination with immune checkpoint inhibitors (ICPi) αPD1 and αCTLA4.Results: IGS in melanoma-bearing mice led to a high tumor-to-background ratio and reduced tumor recurrence in comparison with mice that underwent surgery under white light (23% versus 33%, respectively). Adjuvant therapy with PGA-SLM-mDBF combined with ICPi, was well-tolerated and resulted in prolonged survival and prevention of peritoneal and brain metastases formation in BRAF-mutated melanoma-bearing mice.Conclusions: The results reveal the great clinical potential of our PGA-based nanosystems as a tool for holistic melanoma treatment management.

CD47-targeted optical molecular imaging and near-infrared photoimmunotherapy in the detection and treatment of bladder cancer

Transurethral resection of bladder tumor (TURBT) followed by intravesical therapy remains the most effective strategy for the management of non-muscle-invasive bladder cancer worldwide. TURBT has two purposes: to remove all visible tumors and to obtain tumor specimens for histopathological analysis. However, the detection of flat and small malignant lesions under white-light cystoscopy is extremely challenging, and residual lesions are still the main reason for the high recurrence rate of bladder cancer. We hypothesized that visual enhancement of malignant lesions using targeted optical molecular imaging could potentially highlight residual tumors in the bladder during surgery, and near-infrared photoimmunotherapy (NIR-PIT) could kill exfoliated cancer cells and residual tumors. A mouse model of complete or partial bladder tumor resection was established under the guidance of optical molecular imaging mediated by indocyanine green and anti-CD47-Alexa Fluor 790, respectively. Once the tumor recurred, mouse model received repeated CD47-targeted NIR-PIT. After complete resection, there was no tumor recurrence. Furthermore, the growth rate of recurrent tumor decreased significantly after repeated NIR-PIT. Therefore, CD47-targeted optical molecular imaging can potentially assist urologists to detect and remove all tumors, and repeated NIR-PIT shows the potential to reduce tumor recurrence rates and inhibit the growth of recurrent tumor.

Thoracic fascial planes blocks in operative bed of modified radical mastectomy and their role in alleviating post-mastectomy pain: a prospective randomized study

Background: Proper pain management after modified radical mastectomy is crucial for improving postoperative outcomes, reducing tumor recurrence, enhancing anti-metastatic activity and achieving excellent patient`s satisfaction. Thoracic fascial planes (TFP) blocks are novel, and safe analgesia modalities to control postmastectomy pain. This study was designed to assess the efficacy and safety of intraoperative TFP blocks for providing postoperative analgesia after modified radical mastectomy.Methods: During the period from March 2020 to April 2021, 30 females (ages 25–67 years) were scheduled for elective MRM and selected randomly to one of two groups; group-A included 15 patients who underwent MRM and anesthetized with both general anesthesia and regional anesthesia (TFP blocks), group-B included 15 patients who underwent MRM and anesthetized with only general anesthesia.Results: The group-A had statistically significantly lower pain scores. The time of first rescue nalbuphine dose post-operatively was statistically significantly longer in group-A compared to group-B. The total 24h nalbuphine consumption and postoperative non-steroidal ketorolac requirements/48h were significantly lower in group-A compared to group-B. Satisfaction score in group-A was statistically significantly better than that in group-B.Conclusions: Intraoperative thoracic fascial planes blocks are simple, safe, and highly effective analgesic modalities after breast surgery.