Diffusion weighted MRI and apparent diffusion coefficient as a prognostic biomarker in evaluating chemotherapy-antiangiogenic treated stage IV non-small cell lung cancer: A prospective, single-arm, open-label, clinical trial (BevMar).

PURPOSE: When treating Lung Cancer, it is necessary to identify early treatment failure to enable timely therapeutic adjustments. The Aim of this study was to investigate whether changes in tumor diffusion during treatment with chemotherapy and bevacizumab could serve as a predictor of treatment failure. MATERIAL AND METHODS: A prospective single-arm, open-label, clinical trial was conducted between September 2014 and December 2020, enrolling patients with stage IV non-small cell lung cancer (NSCLC). The patients were treated with chemotherapy-antiangiogenic combination. Diffusion weighted magnetic resonance imaging (DW-MRI) was performed at baseline, two, four, and sixteen weeks after initiating treatment. The differences in apparent diffusion coefficient (ADC) values between pre- and post-treatment MRIs were recorded as Delta values (ΔADC). We assessed whether ΔADC could serve as a prognostic biomarker for overall survival (OS), with a five year follow up. RESULTS: 18 patients were included in the final analysis. Patients with a ΔADC value ≥ -3 demonstrated a significantly longer OS with an HR of 0.12 (95 % CI; 0.03- 0.61; p = 0.003) The median OS in patients with a ΔADC value ≥ -3 was 18 months, (95 % C.I; 7-46) compared to 7 months (95 % C.I; 5-9) in those with a ΔADC value < -3. CONCLUSION: Our findings suggest that early changes in tumor ADC values, may be indicative of a longer OS. Therefore, DW-MRI could serve as an early biomarker for assessing treatment response in patients receiving chemotherapy combined with antiangiogenic therapy.

Immunotherapy combined with antiangiogenic therapy as third- or further-line therapy for stage IV non-small cell lung cancer patients with ECOG performance status 2: A retrospective study.

BACKGROUND: Patients with Eastern Cooperative Oncology Group performance status (ECOG PS) 2 probably cannot tolerate chemotherapy or other antitumor therapies. Some studies have reported that immunotherapy combined with antiangiogenic therapy is well-tolerated and shows good antitumor activity. However, the efficacy of this combination as a later-line therapy in patients with ECOG PS 2 is unclear. This study evaluated the effectiveness and safety of this combination strategy as third- or further-line therapy in stage IV non-small cell lung cancer (NSCLC) patients with ECOG PS 2. METHODS: In this retrospective study, patients treated with camrelizumab plus antiangiogenic therapy (bevacizumab, anlotinib, or recombinant human endostatin) were included. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), quality of life (QOL) assessed by ECOG PS, and safety were analyzed. RESULTS: Between January 10, 2019, and February 28, 2024, a total of 59 patients were included. The ORR was 35.6% (21/59) and the DCR was 86.4%. With a median follow-up of 10.5 months (range: 0.7-23.7), the median PFS was 5.5 months (95% confidence interval [CI]: 3.8-7.3) and the median OS was 10.5 months (95% CI: 11.2-13.6). QOL was improved (≥1 reduction in ECOG PS) in 39 patients (66.1%). The most common Grade 3-4 treatment-related adverse events were hepatic dysfunction (6 [10%]), hypertension (5 [8%]), and hypothyroidism (3 [5%]). There were no treatment-related deaths. CONCLUSIONS: Third- or further-line immunotherapy combined with antiangiogenic therapy is well-tolerated and shows good antitumor activity in stage IV NSCLC patients with ECOG PS 2. Future large-scale prospective studies are required to confirm the clinical benefits of this combination therapy.

Cardiovascular Eligibility Criteria and Adverse Event Reporting in Combined Immune Checkpoint and VEGF Inhibitor Trials.

Background: Combination therapy with immune checkpoint inhibitors (ICIs) and vascular endothelial growth factor inhibitors (VEGFIs) has improved cancer outcomes and is increasingly used. These drug classes are associated with cardiovascular toxicities when used alone, but heterogeneity in trial design and reporting may limit knowledge of toxicities in patients receiving these in combination. Objectives: The aim of this study was to assess consistency and clarity in definitions and reporting of cardiovascular eligibility criteria, baseline characteristics, and cardiovascular adverse events in ICI and VEGFI combination trials. Methods: A scoping review was conducted of phase 2 to 4 randomized controlled trials of ICI and VEGFI combination therapy for solid tumors. Trial cardiovascular eligibility criteria and baseline cardiovascular characteristic reporting in trial publications was assessed, and cardiovascular adverse event definitions and reporting criteria were also examined. Results: Seventeen trials (N = 10,313; published 2018-2022) were included. There were multiple cardiovascular exclusion criteria in 15 trials. No primary trial publication reported baseline cardiovascular characteristics. Thirteen trials excluded patients with prior heart failure, myocardial infarction, hypertension, or stroke. There was heterogeneity in defining cardiovascular conditions. "Grade 1 to 4" cardiovascular adverse events were reported when incidence was ≥5% to 25% in 15 trials. Incident hypertension was recorded in all trials, but other cardiovascular events were not consistently reported. No trial specifically noted the absence of cardiovascular events. Conclusions: In ICI and VEGFI combination trials, there is heterogeneity in cardiovascular exclusion criteria, reporting of baseline characteristics, and reporting of cardiovascular adverse events. This limits an optimal understanding of the incidence and severity of events relating to these combinations. Better standardization of these elements should be pursued. (Exclusions and Representation of Patients With Kidney Disease and Cardiovascular Disease in Drug Trials of the Novel Systemic Anti-Cancer Therapies VEGF-Signalling Pathway Inhibitors Alone or in Combination With Immune Checkpoint Inhibitors; CRD42022337942).

Research progress of exosomes in the angiogenesis of digestive system tumour.

Malignant tumours of the digestive system cover a wide range of diseases that affect the health of people to a large extent. Angiogenesis is indispensable in the development, and metastasis of tumours, mainly in two ways: occupation or formation. Vessels can provide nutrients, oxygen, and growth factors for tumours to encourage growth and metastasis, so cancer progression depends on simultaneous angiogenesis. Recently, exosomes have been proven to participate in the angiogenesis of tumours. They influence angiogenesis by binding to tyrosine kinase receptors (VEGFR)-1, VEGFR-2, and VEGFR-3 with different affinities, regulating Yap-VEGF pathway, Akt pathway or other signaling pathway. Additionally, exosomes are potential therapeutic vectors that can deliver many types of cargoes to different cells. In this review, we summarize the roles of exosomes in the angiogenesis of digestive system tumours and highlight the clinical application prospects, directly used as targers or delivery vehicles, in antiangiogenic therapy.

Radiotherapy and Anrotinib in Malignant Glomus Tumor of the Bladder: A Case Report and Literature Review.

Background: Malignant glomus tumors (MGTs) are rare malignancies, which grow rapidly and are aggressive. Surgical resection has been regarded as the standard management, but treatment options for those unresectable tumors are limited, resulting in a high recurrence rate and poor prognosis. Case Description: An 85-year-old man presented with gross hematuria and was diagnosed with MGTs of bladder. The patient achieved long-term local control after multimodal therapy comprising radiotherapy, iodine-125 seeds brachytherapy, transcatheter arterial chemoembolization, and antiangiogenic targeted therapy. Conclusion: MGTs occurring in the bladder are clinically rare and refractory. The case presented here highlights the importance of multidisciplinary diagnosis and treatment, providing evidence that radiotherapy and antiangiogenic therapy may play an important role in unresectable bladder MGT.

Efficacy and safety of second-line therapy by S-1 combined with sintilimab and anlotinib in pancreatic cancer patients with liver metastasis: a single-arm, phase II clinical trial.

Background: Pancreatic adenocarcinoma carries a grim prognosis, and there are few recognized effective second-line treatment strategies. We attempted to evaluate the efficacy and safety of a combination of S-1, sintilimab, and anlotinib as a second-line treatment in pancreatic cancer patients with liver metastasis. Methods: Pancreatic cancer patients with liver metastases were recruited. S-1 was administered orally at 25 mg/m2 bid, anlotinib was administered orally at 12 mg qd from day 1 to day 14, and sintilimab was administered intravenously at 200 mg on day 1. This method was repeated every 21 days, and the therapeutic effect was evaluated every 3 cycles. The primary outcome was the objective response rate (ORR). Results: Overall, 23 patients were enrolled in this study of whom 19 patients had objective efficacy evaluation. The ORR was 10.5% (95% CI 0.4%-25.7%) in the evaluable population. The progression-free survival (PFS) was 3.53 (95% CI 2.50-7.50) months, and the overall survival (mOS) was 8.53 (95% CI 4.97-14.20) months. Grade 3 adverse events were 26.1%, and no grade 4 or above adverse events occurred. High-throughput sequencing was performed on the tumor tissues of 16 patients; patients with HRD-H (n = 10) had shorter PFS than those with HRD-L (n = 6) (2.43 vs. 5.45 months; P = 0.043), but there was no significant difference in OS between the two groups (4.43 vs. 9.35 months; P = 0.11). Conclusions: This study suggests the advantage of S-1 combined with sintilimab and anlotinib in extending OS as a second-line therapy in pancreatic cancer patients with liver metastasis. Clinical Trial Registration: ChiCTR2000030659.

Camrelizumab combined with apatinib and nanoparticle albumin-bound paclitaxel in lung adenocarcinoma (CAPAP-lung): a single-arm phase II study.

Background: Platinum-doublet chemotherapy plus immunotherapy has been the standard of care for the first-line treatment of advanced non-small cell lung cancer lacking actional driver mutations. However, optimization of drug combinations is still needed to find a better balance between therapeutic efficacy and safety in the immunotherapy era. We aimed to investigate the efficacy and safety of platinum-free albumin bound paclitaxel (nab-paclitaxel) combined with camrelizumab and apatinib as first-line treatment for patients with advanced lung adenocarcinoma. Methods: In this multicenter open-label, single-arm phase II trial, patients with systemic treatment-naïve advanced lung adenocarcinoma without epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations received a rational-based combination of camrelizumab (200 mg intravenously, day one), apatinib (250 mg, q.d., five continuous days per week), and nab-paclitaxel (135 mg/m2 intravenously, days one and eight) every three weeks for four to six cycles in China. Patients with controlled disease were maintained with camrelizumab and apatinib. The primary end point was progression-free survival (PFS). This trial is registered with ClinicalTrials.gov (No. NCT04459078). Findings: Between August 26, 2020 and May 20, 2022, 64 patients were enrolled. The median PFS was 14.3 (95% CI: 9.9, not reached) months. The confirmed objective response rate was 64.1% (95% CI: 51.1, 75.7). The grade 3-4 hematologic treatment-related adverse events (TRAEs) were decreased neutrophil count (14.1%), decreased white blood cell count (7.8%), and anemia (3.1%). The most common non-hematologic TRAEs of grade 3-4 were increased alanine transaminase (18.8%) and aspartate transaminase (15.6%). No treatment-related death occurred. The quality of life was on average not clinically meaningful worse through treatment cycle 14. Interpretation: Nab-paclitaxel plus camrelizumab and apatinib showed clinically meaningful anti-tumor activity and manageable safety, with few hematologic toxicities, and might be a potential treatment option in patients with advanced lung adenocarcinoma lacking EGFR/ALK mutations. Funding: Heath Research Foundation of Chinese Society of Clinical Oncology, Hunan Provincial Natural Science Foundation of China, Hunan Cancer Hospital Climb Plan, Sister Institution Network Fund of The University of Texas MD Anderson Cancer Center, The Science and Technology Innovation Program of Hunan Province, and Suzhou Sheng Diya Biomedical Co., Ltd, a subsidiary of Jiangsu Hengrui Pharmaceuticals Co., Ltd. (Shanghai, China).

FRS2 regulated by miR-429 and miR-206 promotes angiogenesis in osteosarcoma.

FRS2 has demonstrated oncogenic roles in various malignancies, including liposarcoma and giant cell tumor of bone. However, its role in osteosarcoma remains less understood, and the upstream regulatory molecules influencing FRS2 remain unclear. This study aims to explore the clinical implications and biological function of FRS2 in osteosarcoma, and the potential regulatory microRNAs (miRNAs) governing its expression. Our study indicated significant upregulation of FRS2 in osteosarcoma cells and tissues by Western blotting and immunohistochemical staining. Elevated FRS2 expression correlated positively with increased angiogenesis and poor prognosis, possibly serving as an independent prognostic indicator for osteosarcoma patients. Functional assays revealed that attenuating FRS2 in osteosarcoma cells could mitigate proliferation, migration, and angiogenesis of vascular endothelial cells. Further investigations revealed that miR-429 and miR-206 directly targeted FRS2, exerting a negative regulation on its expression. Furthermore, FRS2 played a role in repressing osteosarcoma advancement influenced by miR-429 or miR-206. In summary, FRS2, influenced by miR-429 and miR-206, emerges as a promising therapeutic candidate for antiangiogenic osteosarcoma treatments.

A case report: A new promising treatment for pulmonary sarcomatoid carcinoma - Tislelizumab and Anlotinib combined with local radiotherapy.

Background: Pulmonary sarcomatoid carcinoma (PSC) is a rare pathological type of non-small cell lung cancer, only occurs in 0.1%-0.4 % of lung cancer patients. It has a poor prognosis and shows low response to conventional chemotherapy. Target therapy, immunotherapy, and other new approaches are worth exploring in PSC. Recently, patients with MET ex14 skipping mutation can obtain good therapeutic efficacy through target therapy. But there was no definitive treatment for patients without this special mutation. Case description: Now, we report a female PSC patient without MET ex14 skipping mutation in the cT4N2M1 stage treated with Tislelizumab and Anlotinib obtained remarkable effect for more than 2 years. Significantly, in this case, immunotherapy and antiangiogenic therapy continued to prolong the survival time of more than 10 months for the patient after being treated by local radiotherapy. This is the first case that reported the effectiveness of immunotherapy and antiangiogenic therapy combined with local radiotherapy in treating PSC and achieved more long-term clinical efficacy than other treatments. Conclusions: Thus, immunotherapy and antiangiogenic therapy combined with local radiotherapy may bring new hope to advanced PSC patients and is worth conducting further research. It provided an effective reference for the treatment of advanced PSC patients without METex14 skipping mutation. Moreover, this case also demonstrated the synergistic effect of radiotherapy and immunotherapy.

The E3 ubiquitin ligase RBCK1: Implications in the tumor immune microenvironment and antiangiogenic therapy of glioma.

E3 ubiquitin ligases (E3s) play a pivotal role in regulating the specificity of protein ubiquitination, and their significant functions as regulators of immune responses against tumors are attracting considerable interest. RBCK1-an RBR E3 ligase-is involved in immune regulation and tumor development. However, the potential effect of RBCK1 on glioma remains enigmatic. In the present study, we performed comprehensive analyses of multilevel data, which disclosed distribution characteristics of RBCK1 in pan-cancer, especially in glioma. Functional roles of RBCK1 were further confirmed using immunohistochemistry, cell biological assays, and xenograft experiments. Aberrant ascending of RBCK1 in multiple types of cancer was found to remodel the immunosuppressive microenvironment of glioma by regulating immunomodulators, cancer immunity cycles, and immune cell infiltration. Notably, the MES-like/RBCK1High cell population, a unique subset of cells in the microenvironment, suppressed T cell-mediated cell killing in glioma. Elevated expression levels of RBCK1 suggested a glioma subtype characterized by immunosuppression and hypo-responsiveness to immunotherapy but manifesting surprisingly increased responses to anti-angiogenic therapy. In conclusion, anti-RBCK1 target therapy might be beneficial for glioma treatment. Moreover, RBCK1 assisted in predicting molecular subtypes of glioma and response rates of patients to different clinical treatments, which could guide personalized therapy.

Multi-targeted tyrosine kinase inhibitor reverses resistance to immunotherapy in hepatic sarcomatoid carcinoma.

Hepatic sarcomatoid carcinoma (HSC) is characterized by its aggressive behavior and poor prognosis. As of now, no universally endorsed standard therapeutic approaches for HSC have been established. Herein, we describe the case of a 60-year-old individual diagnosed with HSC, subsequently presenting with multiple metastases postoperatively. Owing to the pronounced expression of programmed cell death protein 1 (PD-1), the individual was subjected to monotherapy utilizing sintilimab for a duration spanning 12 months. Following this regimen, a synergistic treatment approach comprising both anlotinib and sintilimab was instituted, culminating in an ensuing 11 months of efficacious therapeutic response. Throughout the course of treatment, the patient's quality of life remained satisfactory. This particular therapeutic strategy not merely reinforces the efficacy of PD-1 inhibitors in the realm of HSC management, but more pivotally, suggests that tyrosine kinase inhibitors (TKIs) might counteract resistance to PD-1 antagonists, thus offering a potentially augmented treatment paradigm for HSC.

Anlotinib as a third-line or further treatment for recurrent or metastatic nasopharyngeal carcinoma: a single-arm, phase 2 clinical trial.

BACKGROUND: Treatment options beyond the first-line setting for recurrent or metastatic nasopharyngeal carcinoma (RM-NPC) are limited. The role of the multitarget tyrosine kinase inhibitor anlotinib in RM-NPC is unclear. METHODS: In this prospective, single-arm, phase 2 trial, patients with histologically confirmed RM-NPC and failure of at least two lines of prior systemic treatments were eligible. Anlotinib was given at 12 mg once daily on days 1-14 every 3 weeks until disease progression or intolerable toxicities. The primary end point was disease control rate, defined as the percentage of patients achieving complete response, partial response, or stable disease by RECIST criteria. RESULTS: From April 2019 to March 2021, 39 patients were enrolled and received a median of 4 cycles (range, 0.5-20) of anlotinib treatment. Partial response and stable disease were observed in 8 and 20 patients, respectively. The disease control rate was 71.8%, and objective response rate was 20.5%. With a median follow-up of 17.2 months, the median progression-free survival was 5.7 months. The 12-month overall survival was 58.3%, and the median overall survival was not reached. The most frequent grade 3/4 treatment-related adverse events were hand-foot syndrome (23.7%), oral mucositis (21.0%), hypertension (7.9%), and triglyceride elevation (7.9%). Hemorrhage, all grade 1 or 2, occurred in 34.2% of the patients. CONCLUSIONS: Anlotinib monotherapy exhibited promising anti-tumor activities and disease control for heavily pretreated RM-NPC patients with a tolerable toxicity profile. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03906058.

Influence of antiresorptive/antiangiogenic therapy on changes in periodontal and oral tissue structures: a histomorphometrical analysis in rats.

OBJECTIVE: The objective of this study was to investigate the influence of various antiresorptive and antiangiogenic medications on morphological changes in periodontal and oral tissue structures. MATERIALS AND METHODS: Fifty-five Wistar rats randomly received dual application (i.e., at baseline and after 12-weeks) one of the following medications: (1) amino-bisphosphonate [zoledronate (Zo)], (2) RANKL inhibitor [denosumab (De)], (3) antiangiogenic [bevacizumab (Be)], (4) Zo + Be, (5) De + Be or (6) no medication [Control (Co)]. Periodontal and oral tissue biopsies were obtained at 17 (n = 21 animals, Phase 1, (De = 3, De + Be = 3, Zo = 5, Be = 3, Zo + Be = 2, Co = 5) and 29 (n = 34 animals, (De = 8, De + Be = 6, Zo = 2, Be = 7, Zo + Be = 4, Co = 7, Phase 2) weeks after the second drug application. The following outcomes were histomorphometrically assessed: periodontal space width in the coronal (PLS-C, mm) and apical sections (PLS- A), number of empty alveolar bone lacunae in the coronal, apical sections and at the apex at respective tooth sites (EL - C, EL- A, EL- Ap), mucosal thickness at edentulous alveolar ridge areas (MT, mm), and, when present, associated areas of inflammatory cell infiltrates (ICI, mm2). RESULTS: Comparable mean PLS-C, PLS-A, ET-A, ET-C, ET-Ap, and MT values were observed in all experimental groups after Phases 1 and 2. The presence of ICI was identified in 3 animals in the Co group (Phase 1: 1, Phase 2: 2), and 17 animals in the test groups (Phase 1: 4; Phase 2: 14). The estimated ICI surface area was significantly higher in the Zo + Be group, followed by the Zo and Be groups compared to that measured in the Co group. The time (i.e., Phases 1 and 2) was not found to be a predictor for the extent of the ICI area. In all groups, the EL-C, EL-A, and EL-Ap values were significantly higher after Phase 2 compared to those assessed after Phase 1. The MT values were significantly reduced in all groups after Phase 2 compared to those measured after Phase 1. CONCLUSIONS: The present evaluation was not able to find any morphological effects of different antiresorptive and antiangiogenic medications on periodontal and oral tissue structures. The presence of inflammatory cell infiltrates was more frequently observed in the animals administered with antiresorptive and antiangiogenic medications as well as combinations thereof. CLINICAL RELEVANCE: Administration of antiresorptive and antiangiogenic medications may be capable of inducing inflammatory reactions in periodontal tissues.

Influence of antiresorptive/antiangiogenic therapy on the surgical treatment outcomes of experimentally induced peri-implantitis lesions.

OBJECTIVE: To investigate the influence of various antiresorptive and antiangiogenic medications on the resolution of experimentally induced peri-implantitis lesions after different surgical treatment approaches. MATERIALS AND METHODS: Forty-eight albino rats randomly received a dual application of the following medications: (1) amino-bisphosphonate (zoledronate (Zo)) (n = 8), (2) RANKL inhibitor (denosumab (De)) (n = 8), (3) antiangiogenic (bevacizumab (Be)) (n = 8), (4) Zo + Be (n = 8), (5) De + Be (n = 8), or (6) no medication (control (Co)) (n = 8). Ligature-induced peri-implantitis lesions were established at 2 maxillary implants over 16 weeks. Afterward, animals were randomly treated either with open flap debridement (OFD) or reconstructive therapy (RT). Treatment procedures were followed by a 12-week healing period. The histological outcomes included residual defect length (DL); defect width (DW) at the bone crest (BC-DW); 25%, 50%, and 75% of the DL; and areas of inflammatory cell infiltrate (ICT). When present, areas of bone sequester (BS) were assessed considering the animal as a statistical unit. RESULTS: A total of 21 animals were analyzed (Zo: RT = 3, OFD = 1; De: RT = 3, OFD = 2; Be: OFD = 1; Zo + Be: RT = 2, OFD = 2; Co: RT = 3, OFD = 2). Implant loss rates were comparable among the experimental groups. Except for the 25% and 75% DW values that were significantly higher in the Zo + Be group compared to the Co group (p = 0.04 and p = 0.03, respectively), no significant differences were found among the experimental groups for the DL (lowest-Be: 0.56 mm; highest-Co: 1.05 mm), BC-DW (lowest-De: 0.86 mm, highest-Co: 1.07 mm), 50% DW (lowest-De: 0.86 mm; highest-Be + Zo: 1.29 mm), and ICT (lowest-Be: 0.56 mm2; highest-Be + Zo: 1.65 mm2). All groups, except for the Zo and Be following RT, showed presence of BS. CONCLUSIONS: The present findings did not reveal a marked effect of various antiresorptive/antiangiogenic medications on the resolution of experimentally induced peri-implantitis lesions, regardless of the surgical approach employed (OFD and RT). CLINICAL RELEVANCE: Resolution of peri-implantitis lesions may not be affected by the investigated antiresorptive/antiangiogenic medications.

Clinical outcomes of ramucirumab plus docetaxel in the treatment of patients with non-small cell lung cancer after immunotherapy: a systematic literature review.

Introduction: In the REVEL trial, ramucirumab plus docetaxel demonstrated significant improvements in overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) compared with placebo plus docetaxel for treatment of metastatic non-small cell lung cancer (NSCLC) that progressed during or after platinum-based chemotherapy. Since the approval of ramucirumab plus docetaxel, immune checkpoint inhibitors (ICIs), either as single agents or in combination with chemotherapy, have become the standard of care for first-line treatment of patients with advanced NSCLC. However, efficacy and safety data for ramucirumab plus docetaxel after prior ICI treatment from randomized controlled clinical studies are lacking. Methods: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a systematic literature review was performed. Electronic databases and select international oncology conference proceedings were searched. Studies published between 01 January 2014 and 01 July 2022, which evaluated 2 efficacy outcomes (and included at least 1 time-to-event endpoint) or safety outcomes of ramucirumab plus docetaxel in NSCLC that progressed after prior ICI treatment, were identified. Twelve studies were included in the analysis. Two treatment groups were selected: ramucirumab plus docetaxel after prior ICI ± chemotherapy (RAM + DTX ICI pre-treated) and ramucirumab plus docetaxel after prior chemotherapy only (RAM + DTX ICI naïve). OS, PFS, ORR, disease control rate (DCR), and safety data were extracted and descriptively summarized across both treatment groups. Results: The pooled weighted median PFS and median OS were 5.7 months (95% confidence interval [CI]: 3.9-6.8) and 11.2 months (95% CI: 7.5-17.5), respectively, in the RAM + DTX ICI pre-treated group and 3.8 months (95% CI: 2.3-4.1) and 13.5 months (95% CI: 8-24.0), respectively, in the RAM + DTX ICI naïve group. The ORR and DCR ranged from 20.9% to 60.0% and from 62.4% to 90.0%, respectively, in the RAM + DTX ICI pre-treated group and from 17.7% to 20.0% and from 57.1% to 75.0%, respectively, in the RAM + DTX ICI naïve group. The safety profile across studies was consistent between both treatment groups, and no new safety signals were reported. Conclusions: Cumulatively, these results support the combination of ramucirumab plus docetaxel as an effective and safe subsequent therapy for the treatment of patients with metastatic NSCLC with disease progression irrespective of previous ICI treatment.

Efficacy and safety of nintedanib and docetaxel in patients with previously treated lung non-squamous non-small cell lung cancer: a multicenter retrospective real-world analysis.

BACKGROUND: The standard first-line systemic treatment for patients with non-oncogene addicted advanced nonsquamous non-small cell lung cancer (NSCLC) is immunotherapy with immune checkpoint inhibitors (ICI) and/or chemotherapy (ChT). Therapy after failing ICI +/- ChT remains an open question, and docetaxel plus nintedanib represent a valid second line option. PATIENTS AND METHODS: A multicenter retrospective trial of real-life treatment patterns and outcomes of patients with advanced lung adenocarcinoma treated with docetaxel plus nintedanib after the failure of ICI and/or ChT was performed. Patients from 2 Slovenian and 1 Croatian oncological center treated between June 2014 and August 2022 were enrolled. We assessed objective response (ORR), disease control rate (DCR), median progression free survival (PFS), median overall survival (OS), and safety profile of treatment. RESULTS: There were 96 patients included in the analysis, with ORR of 18.8%, DCR of 57.3%, median PFS of 3.0 months (95% CI: 3.0-5.0 months), and a median OS of 8.0 months (95% CI: 7.0-10.0 months). The majority of patients (n = 47,49%) received docetaxel plus nintedanib as third-line therapy. The ORR for this subset of patients was 19.1%, with a DCR of 57.4%. The highest response rate was observed in patients who received second-line docetaxel plus nintedanib after first-line combination of ChT-ICI therapy (n = 24), with an ORR of 29.2% and DCR of 66.7% and median PFS of 4.0 months (95% CI: 3.0-8.0 months). Fifty-three patients (55.2%) experienced adverse events (AEs), most frequently gastrointestinal; diarrhea (n = 29, 30.2%), and increased liver enzyme levels (n = 17, 17.7%). CONCLUSIONS: The combination of docetaxel and nintedanib can be considered an effective therapy option with an acceptable toxicity profile for patients with advanced NSCLC after the failure of ICI +/- ChT.

Synergic vascular photodynamic activity by methylene blue-curcumin supramolecular assembly.

A supramolecular assembly was obtained by combining methylene blue (MB) with a natural plant extract, curcumin (Curc), in a stoichiometric ratio of 1:4 in aqueous solution (90% PBS + 10% ethanol) at room temperature. The MB-Curc supramolecular assembly was evidenced by absorption and fluorescence spectroscopies, and the stoichiometry and bonding constant were obtained using Cielens model. Its stability and photostability were evaluated by chromatographic analysis and UV-Vis absorption. The MB-Curc avoids the aggregation of both isolated compounds and efficiently produces singlet oxygen (ΦΔ= 0.52 ± 0.03). Its potential for photodynamic antiangiogenic treatments was evaluated through the vascular effect observed in chicken chorioallantoic membrane (CAM) assay. The results showed intense damage in CAM vascular network by MB-Curc after irradiation, which is higher than the effect of isolated compounds, indicating a synergistic vascular effect. This combination can be essential to prevent cancer revascularization after photodynamic application and improve the efficacy of this approach. The characteristics exhibited by MB-Curc make it a potential candidate for use in cancer treatments through photodynamic antiangiogenic therapy.

PD-1 Inhibitors Combined with Antiangiogenic Therapy with or Without Transarterial Chemoembolization in the Treatment of Hepatocellular Carcinoma: A Propensity Matching Analysis.

Background: At present, it is not known whether targeting plus immunotherapy combined with transarterial chemoembolization (TACE) can improve the efficacy of hepatocellular carcinoma (HCC). The aim of this retrospective experiment was to explore the difference in clinical efficacy between antiangiogenic drugs plus PD-1 inhibitors combined with and without TACE. Methods: Clinical data of 145 patients with HCC who received anti-angiogenesis therapy plus PD-1 inhibitor combined with TACE (TACE-P-T) (n = 62) or anti-angiogenesis therapy combined with PD-1 inhibitor (P-T) (n = 83) in China from October 2018 to December 2022 were collected and reviewed. We used propensity matching (PSM) to create two groups with comparable baseline scores, compared their median survival time (mOS) and median progression-free survival time (mPFS), and performed subgroup analysis. Results: Before PSM, the mOS and mPFS of patients were 20.3 and 5.0 months in the triple therapy group and 13.6 and 7.4 months in the control group, respectively. After PSM, the mOS and mPFS of patients were 19.7 and 6.6 months in the triple treatment group and 10.5 and 3.7 months in the control group, respectively. Therefore, the TACE-P-T group showed better survival outcomes than P-T. In the subgroup analysis, compared with the control group, the mOS was 10.7 vs 20.3 months in the alpha fetoprotein (AFP) (≥ 400ng/mL/<400ng/mL) group, 29.3 vs 7.4 months in the alkaline phosphatase (ALP) (≥ 125u/L/< 125u/L) group and 10.5 vs 20.0 months in the Portal vein invasion (PVTT) group. Conclusion: Antiangiogenic therapy combined with PD-1 inhibitors combined with TACE has significant survival benefits for HCC patients.

Combination of Targeted Therapies for Colorectal Cancer Treatment.

The design of innovative therapeutic strategies enabling the selective destruction of tumor cells while sparing healthy tissues remains highly challenging in cancer therapy. Here, we show that the combination of two targeted therapies, including bevacizumab (Bev), and a ß-glucuronidase-responsive albumin-binding prodrug of monomethyl auristatin E (MMAE), is efficient for the treatment of colorectal cancer implanted in mice. This combined therapy produces a therapeutic activity superior to that of the association of FOLFOX and Bev currently used to treat patients with this pathology. The increased anticancer efficacy is due to either a synergistic or an additive effect between Bev and MMAE selectively released from the glucuronide prodrug in the tumor microenvironment. Since numerous drug delivery systems such as antibody-drug conjugates employ MMAE as a cytotoxic payload, this finding may be of great interest for improving their therapeutic index by combining them with Bev, particularly for the therapy of colorectal cancer.

Vaccination against Extracellular Vimentin for Treatment of Urothelial Cancer of the Bladder in Client-Owned Dogs.

It was recently shown that targeting extracellular vimentin (eVim) is safe and effective in preclinical models. Here, we report the safety and efficacy in client-owned dogs with spontaneous bladder cancer of CVx1, an iBoost technology-based vaccine targeting eVim in combination with COX-2 inhibition. This was a single-arm prospective phase 1/2 study with CVx1 in 20 client-owned dogs with spontaneous UC which involved four subcutaneous vaccinations with CVx1 at 2-week intervals for induction of antibody titers, followed by maintenance vaccinations at 2-month intervals. Additionally, daily cyclooxygenase (COX)-2 inhibition with meloxicam was given. The response was assessed by antibody titers, physical condition, abdominal ultrasound and thorax X-ray. The primary endpoints were the development of antibody titers, as well as overall survival compared to a historical control group receiving carboplatin and COX-2 inhibition with piroxicam. Kaplan-Meier survival analysis was performed. All dogs developed antibodies against eVim. Titers were adequately maintained for the duration of this study. A median overall survival of 374 days was observed, which was 196 days for the historical control group (p < 0.01). Short-term grade 1-2 toxicity at the injection site and some related systemic symptoms peri-vaccination were observed. No toxicity was observed related to the induced antibody response. A limitation of this study is the single-arm prospective setting. CVx1 plus meloxicam consistently induced efficient antibody titers, was well tolerated and showed prolonged survival. The results obtained merit further development for human clinical care.