Current advances in nanoformulations of therapeutic agents targeting tumor microenvironment to overcome drug resistance.

The tumor microenvironment (TME) plays a pivotal role in cancer development and progression. In this line, revealing the precise mechanisms of the TME and associated signaling pathways of tumor resistance could pave the road for cancer prevention and efficient treatment. The use of nanomedicine could be a step forward in overcoming the barriers in tumor-targeted therapy. Novel delivery systems benefit from enhanced permeability and retention effect, decreasing tumor resistance, reducing tumor hypoxia, and targeting tumor-associated factors, including immune cells, endothelial cells, and fibroblasts. Emerging evidence also indicates the engagement of multiple dysregulated mediators in the TME, such as matrix metalloproteinase, vascular endothelial growth factor, cytokines/chemokines, Wnt/ß-catenin, Notch, Hedgehog, and related inflammatory and apoptotic pathways. Hence, investigating novel multitargeted agents using a novel delivery system could be a promising strategy for regulating TME and drug resistance. In recent years, small molecules from natural sources have shown favorable anticancer responses by targeting TME components. Nanoformulations of natural compounds are promising therapeutic agents in simultaneously targeting multiple dysregulated factors and mediators of TME, reducing tumor resistance mechanisms, overcoming interstitial fluid pressure and pericyte coverage, and involvement of basement membrane. The novel nanoformulations employ a vascular normalization strategy, stromal/matrix normalization, and stress alleviation mechanisms to exert higher efficacy and lower side effects. Accordingly, the nanoformulations of anticancer monoclonal antibodies and conventional chemotherapeutic agents also improved their efficacy and lessened the pharmacokinetic limitations. Additionally, the coadministration of nanoformulations of natural compounds along with conventional chemotherapeutic agents, monoclonal antibodies, and nanomedicine-based radiotherapy exhibits encouraging results. This critical review evaluates the current body of knowledge in targeting TME components by nanoformulation-based delivery systems of natural small molecules, monoclonal antibodies, conventional chemotherapeutic agents, and combination therapies in both preclinical and clinical settings. Current challenges, pitfalls, limitations, and future perspectives are also discussed.

Sodium-glucose co-transporter 2 inhibitor therapy reduces the administration frequency of anti-vascular endothelial growth factor agents in patients with diabetic macular oedema with a history of anti-vascular endothelial growth factor agent use: A cohort study using the Japanese health insurance claims database.

AIM: We assessed the effectiveness of sodium-glucose co-transporter 2 inhibitors (SGLT2is) in reducing the administration frequency of anti-vascular endothelial growth factor (VEGF) agents in patients with diabetic macular oedema (DMO) using a health insurance claims database. MATERIALS AND METHODS: This retrospective cohort study analysed health insurance claims data covering 11 million Japanese patients between 2005 and 2019. We analysed the frequency and duration of intravitreal injection of anti-VEGF agents after initiating SGLT2is or other antidiabetic drugs. RESULTS: Among 2412 matched patients with DMO, the incidence rates of anti-VEGF agent injections were 230.1 per 1000 person-year in SGLT2i users and 228.4 times per 1000 person-year in non-users, respectively, and the risk ratio for events was unchanged in both groups. Sub-analysis of each baseline characteristic of the patients showed that SGLT2is were particularly effective in patients with a history of anti-VEGF agent use [p = .027, hazard ratio (HR): 0.44, 95% confidence interval (CI): 0.22-0.91]. SGLT2is reduced the risk for the first (p = .023, HR: 0.45, 95% CI: 0.22-0.91) and second (p = .021, HR: 0.39, 95% CI: 0.17-0.89) anti-VEGF agent injections. CONCLUSIONS: There was no difference in the risk ratio for the addition of anti-VEGF therapy between the two treatment groups. However, the use of SGLT2is reduced the frequency of anti-VEGF agent administration in patients with DMO requiring anti-VEGF therapy. Therefore, SGLT2i therapy may be a novel, non-invasive, low-cost adjunctive therapy for DMO requiring anti-VEGF therapy.

A phase 1 trial utilizing a pharmacokinetic endpoint to determine the optimal dose of ramucirumab in children and adolescents with relapsed or refractory solid tumors, including central nervous system tumors.

BACKGROUND: Ramucirumab is a monoclonal antibody that binds the extracellular domain of vascular endothelial growth factor receptor (VEGFR-2) and prevents binding of VEGF ligands. Based on population pharmacokinetic (PK) analysis and correlation with efficacy in adults, a target steady state trough concentration (Css,min ) ≥ 50 µg/mL was established. PROCEDURES: This phase 1 trial (ADVL1416) used a rolling six design and a PK primary endpoint to define the recommended phase 2 dose (RP2D) of ramucirumab in children with recurrent/refractory solid tumors. Two dose levels (DL) were planned (DL1: 8 mg/kg, DL2: 12 mg/kg administered intravenously [IV] every 2 weeks). Toxicity during the initial 6 weeks was used to assess maximum tolerated dose (MTD). Cycle 1 Day 42 trough (Cmin ) ≥ 50 µg/mL was the target concentration for the PK endpoint. At the RP2D, cohorts for PK expansion and children with central nervous tumors were planned. RESULTS: Twenty-nine patients were enrolled; 28 were eligible; median age [range] = 13.5 [1-21] years; 22 were evaluable for the PK endpoint. Dose-limiting proteinuria occurred at both DLs; however, the MTD was not exceeded. At DL2 (12 mg/kg), the median Day 42 Cmin (n = 16) was 87.8 µg/mL; 15 of 16 patients achieved a Cmin  ≥ 50 µg/mL. CONCLUSION: Ramucirumab was well tolerated in children and adolescents with solid tumors. The RP2D for ramucirumab was 12 mg/kg IV every 2 weeks. This trial demonstrates the feasibility of incorporating a primary PK endpoint to determine dose escalation and the RP2D in children. Studies of ramucirumab in children with selected solid tumors are ongoing.

Simultaneous Tumor Shrinkage and Bronchial Perforation Induced by Nivolumab plus Cabozantinib Combination Therapy in a Patient with Collecting Duct Carcinoma.

Vascular endothelial growth factor receptor tyrosine kinase inhibitors are known to cause perforation as one of their severe side effects, and postoperative and postradiation therapy are known risk factors. However, there are few studies on perforation following tumor shrinkage. A 78-year-old woman with postoperative recurring left collecting duct carcinoma of the right hilar lymph nodes and mediastinum underwent eight courses of nivolumab plus cabozantinib, resulting in tumor shrinkage. Three days after the last administration, she developed fever and cough and was hospitalized for right lobar pneumonia. The patient received long-term antibiotics for bronchial fistula with the destruction of the bronchial wall and secondary lung abscess. When using nivolumab plus cabozantinib combination therapy for a tumor with bronchial invasion, physicians should be aware of bronchial perforation as the tumor shrinks.

Characteristics of macular edema associated with retinal vein occlusion showing poor anatomic response to three loading anti-vascular endothelial growth factor injections: an optical coherence tomography analysis.

PURPOSE: To analyze the clinical features of refractory cystoid macular edema related to retinal vein occlusion associated with the response to three consecutive loading doses of anti-vascular endothelial growth factor. METHODS: A retrospective chart review was performed on retinal vein occlusion patients treated by three anti-vascular endothelial growth factor injections. They were divided into a group according to resolution of macular edema in optical coherence tomography (Group 1) and with persistent macular edema (Group 2). We analyzed qualitative and quantitative morphologic features of optical coherence tomography. RESULTS: We enrolled a total of 120 eyes from 120 patients (Group 1: n = 54, Group 2: n = 66). The baseline choroidal thickness differed significantly between groups 1 and 2 (290.70 ± 19.58 µm and 311.06 ± 17.87 µm P < 0.001). The presence of Hyperreflective foci (16.70% vs. 36.40% P < 0.001), Disorganization of the retinal inner layers (14.80% vs. 87.90%) and external limiting membrane disruption (16.60% vs. 39.3% P < 0.001) differed significantly. Logistic regression analysis showed that the initial central macular thickness (B = 0.012; P = 0.006), baseline choroidal thickness (B = 0.232; P = 0.016) and presence of hyperreflective foci (B = 1.050; P = 0.019), disorganization of the retinal inner layers (B = 1.132; P = 0.001) and external limiting membrane disruption (B = 1.575; P = 0.012) significantly affected the anti-vascular endothelial growth factor treatment response. CONCLUSION: A thicker sub-fovea choroid and the presence of hyperreflective foci, disruption of the external limiting membrane and disorganization of the retinal inner layers associated with a poorer response to three loading anti-vascular endothelial growth factor injections in macular edema associated retinal vein occlusion.

Effectiveness Differences of Ranibizumab and Aflibercept Action in the Treatment of Diabetic Retinopathy.

Objective: To compare the difference in the effectiveness of ranibizumab (LU) and aflibercept (AF) in the treatment of diabetic retinopathy (DR). Methods: Ninety-four patients with DR admitted to Sunshine Union Hospital from August 2020 to February 2022 were selected for the study and were divided into LU group (n = 47) and AF group (n = 47) according to the random number table method. Both groups underwent 25G vitrectomy in our hospital, with LU injected into the vitreous before surgery in the LU group and AF in the AF group. Vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF) in the pre-and post-injection atrial water were compared between the two groups, and the operative time, intraoperative bleeding, and the occurrence of medically induced fissures were recorded in both groups. In addition, the expression of best corrected visual acuity (BCVA), Central Macular Thickness (CMT), and inflammatory factors were compared before and after surgery. Finally, patients were counted for adverse reactions and prognosis of DR recurrence during treatment. Results: After injection, VEGF decreased and PEDF increased in both groups (P < .001). There were no differences in operative time (P = .604), intraoperative bleeding rate (P = .694), the incidence of medically induced fissure (P = .557), BCVA [P = .665 (T0), P > .999 (T1), P = .727 (T2)], and CMT [P = .688 (T0), P = .065 (T1), P = .148 (T2)] between the two groups, while IL-6, IL-8, and MMP-9 were lower in the AF group than in the LU group at 2 months after surgery (P < .001). Finally, there was no difference between both groups in terms of adverse effects and prognosis of DR recurrence rate (P = 1.000, .478). Conclusion: Both vitreous cavity injections of LU and AF can effectively reduce the expression of vascular-related factors in the atrial fluid of DR patients, but AF has a more significant inhibitory effect on the level of inflammatory factors in patients in the short term after treatment.

Onco-Hypertension: A Continuously Developing Field between Cancer and Hypertension.

The prognosis of cancer patients has greatly improved in the last years, owing to the development of novel chemotherapeutic agents. However, this progress comes with an increasing occurrence of cardiovascular adverse reactions. A serious side effect is arterial hypertension (HT), which is the most frequent comorbidity encountered in cancer patients, influencing the outcomes in cancer survivors. Even though secondary HT related to specific chemotherapeutic agents, such as vascular endothelial growth factor inhibitors, is usually mild and reversible, in rare instances it can be severe, leading to discontinuation of chemotherapy. In addition, HT per se has been studied as a potential risk factor for cancer development. The relationship is even more complex than previously thought, as concerning evidence recently highlighted the potential oncogenic effects of antihypertensive drugs, particularly thiazide diuretics, which may increase the risk of skin cancer. As a result, in light of the similar risk factors and overlapping pathophysiological mechanisms between HT and cancer, a promising concept of onco-hypertension has emerged, aiming to improve the understanding of the complicated interplay between these two pathologies and maintain a balance between the efficacy and risks of both antihypertensive drugs and chemotherapy agents.

Efficient Assessment of Tumor Vascular Shutdown by Photodynamic Therapy on Orthotopic Pancreatic Cancer Using High-Speed Wide-Field Waterproof Galvanometer Scanner Photoacoustic Microscopy.

To identify the vascular alteration by photodynamic therapy (PDT), the utilization of high-resolution, high-speed, and wide-field photoacoustic microscopy (PAM) has gained enormous interest. The rapid changes in vasculature during PDT treatment and monitoring of tumor tissue activation in the orthotopic pancreatic cancer model have received limited attention in previous studies. Here, a fully two-axes waterproof galvanometer scanner-based photoacoustic microscopy (WGS-PAM) system was developed for in vivo monitoring of dynamic variations in micro blood vessels due to PDT in an orthotopic pancreatic cancer mouse model. The photosensitizer (PS), Chlorin e6 (Ce6), was utilized to activate antitumor reactions in response to the irradiation of a 660 nm light source. Microvasculatures of angiogenesis tissue were visualized on a 40 mm2 area using the WGS-PAM system at 30 min intervals for 3 h after the PDT treatment. The decline in vascular intensity was observed at 24.5% along with a 32.4% reduction of the vascular density at 3 h post-PDT by the analysis of PAM images. The anti-vascularization effect was also identified with fluorescent imaging. Moreover, Ce6-PDT increased apoptotic and necrotic markers while decreasing vascular endothelial growth factor (VEGF) expression in MIA PaCa-2 and BxPC-3 pancreatic cancer cell lines. The approach of the WGS-PAM system shows the potential to investigate PDT effects on the mechanism of angiographic dynamics with high-resolution wide-field imaging modalities.

Immunosuppressive mechanisms of oncofetal reprogramming in the tumor microenvironment: implications in immunotherapy response.

Both fetal and tumor tissue microenvironments display immunosuppressive features characterized by the presence of specific immunomodulatory stromal and immune cell populations. Recently, we discovered shared microenvironments between hepatocellular carcinoma (HCC) and fetal tissues and described this phenomenon as an oncofetal ecosystem. This ecosystem includes fetal-like immune (macrophage) and stromal (endothelial) cells within the tumor microenvironment (TME). This discovery highlights reciprocal interactions between fetal-like macrophages and T cells which result in the orchestration of an immunosuppressive TME. Importantly, VEGF-A protein expression by tumor cells and fetal-like macrophages plays an important role in oncofetal reprogramming of the TME in HCCs. Interestingly, recent clinical data indicate that blocking VEGF-A or CTLA4 alongside PD-L1 is effective in treating advanced HCC. Consequently, some immunotherapies may target and rely on oncofetal cells for clinical responsiveness. This understanding provides exciting opportunities to utilize oncofetal niche characteristics as biomarkers of immunotherapy response in HCC and might also have validity for predicting responses to immunotherapy in other cancers. In this review, we explore the immunosuppressive mechanisms and interactions of oncofetal cells in the TME of HCC and their potential implications for immunotherapy response.

The Effects of Drug Exposure and Single Nucleotide Polymorphisms on Aaptinib-Induced Severe Toxicities in Solid Tumors.

To investigate the value of drug exposure and host germline genetic factors in predicting apatinib (APA)-related toxicities. METHOD: In this prospective study, plasma APA concentrations were quantified using liquid chromatography with tandem mass spectrometry, and 57 germline mutations were genotyped in 126 advanced solid tumor patients receiving 250 mg daily APA, a vascular endothelial growth factor receptor II inhibitor. The correlation between drug exposure, genetic factors, and the toxicity profile was analyzed. RESULTS: Non-small cell lung cancer (NSCLC) was more prone to APA-related toxicities and plasma concentrations of APA, and its main metabolite M1-1 could be associated with high-grade adverse events (AEs) (P < 0.01; M1-1, P < 0.01) and high-grade antiangiogenetic toxicities (APA, P = 0.034; P < 0.05), including hypertension, proteinuria, and hand-foot syndrome, in the subgroup of NSCLC. Besides, CYP2C9 rs34532201 TT carriers tended to have higher levels of APA (P < 0.001) and M1-1 (P < 0.01), whereas CYP2C9 rs1936968 GG carriers were predisposed to higher levels of M1-1 (P < 0.01). CONCLUSION: Plasma APA and M1-1 exposures were able to predict severe AEs in NSCLC patients. Dose optimization and drug exposure monitoring might need consideration in NSCLC patients with CYP2C9 rs34532201 TT and rs1936968 GG. SIGNIFICANCE STATEMENT: Apatinib is an anti-VEGFR2 inhibitor for the treatment of multiple cancers. Though substantial in response, apatinib-induced toxicity has been a critical issue that is worth clinical surveillance. Few data on the role of drug exposure and genetic factors in apatinib-induced toxicity are available. Our study demonstrated a distinct drug-exposure relationship in NSCLC but not other tumors and provided invaluable evidence of drug exposure levels and single nucleotide polymorphisms as predictive biomarkers in apatinib-induced severe toxicities.

Factors affecting central macular thickness of diabetic macular oedema patients after an induction treatment of intravitreal ranibizumab.

OBJECTIVE: Intravitreal ranibizumab is one of the anti-vascular endothelial growth factors used for the treatment of diabetic macular oedema, not always successfully. We aimed to identify the factors affecting the changes of central macular thickness after induction treatment with intravitreal ranibizumab, to predict the treatment effect and facilitate early treatment decisions. METHODS: Cross-sectional study involving a retrospective record review of diabetic macular oedema patients who received an induction treatment of three monthly 0.5 mg intravitreal ranibizumab injections between 2016 and 2019. Central macular thickness was measured at baseline and 3 months post-treatment. Linear regression was applied to identify the factors associated with the changes of central macular thickness. RESULTS: A total of 153 diabetic macular oedema patients were involved in this study. Their mean age was 57.5 ± 7.7 years, 54.9% were female. The mean change of central macular thickness from baseline to 3 months after completed induction treatment of intravitreal ranibizumab was 155.5 ± 137.8 µm. Factors significantly associated with changes of central macular thickness were baseline central macular thickness [b = 0.73; 95% (CI): 0.63, 0.84; p = <0.001] and presence of subretinal fluid [b = 35.43; 95% CI: 3.70, 67.16; p = 0.029]. CONCLUSION: Thicker baseline central macular thickness and presence of subretinal fluid were the factors significantly associated with greater changes of central macular thickness in diabetic macular oedema patients after receiving three injections of intravitreal ranibizumab.

A Randomized Double-blind Clinical Trial of Weierkang Pills for the Treatment of Chronic Atrophic Gastritis.

BACKGROUND AND GOALS: There are currently no standard treatments for chronic atrophic gastritis and traditional Chinese medicine may be effective. This study aims to investigate the efficacy and safety of Weierkang pills in treating chronic atrophic gastritis. MATERIALS AND METHODS: There were 108 patients in our study. They were randomly assigned to 2 groups. In group A, patients received Weierkang pills and patients in group B received folic acid combined with teprenone. Symptoms, endoscopic scores, and biopsy specimens were compared at baseline and 3 months after treatment. Meanwhile, the expressions of vascular endothelial growth factor and trefoil factor 3 (TFF3) in biopsy specimens were also compared. RESULTS: Our study showed that the total effective rates of atrophy/intestinal metaplasia in group A reached the same level as group B (51.7% vs. 40.0%, P =0.419). Weierkang significantly improved the total effective rate of atrophy/intestinal metaplasia in gastric angle compared with group B (64.7% vs. 33.3%, P =0.024). Weierkang can significantly lower the total Kyoto risk score (2.6±1.1 vs. 3.3±1.0, P =0.002) and atrophy score (1.4±0.6 vs. 1.8±0.5, P =0.001) after treatment. In addition, Weierkang improves symptoms (1.3±1.3 vs. 2.3±1.8, P =0.003) and epigastric pain (0.2±0.4 vs. 0.5±0.6, P =0.041). The expression of TFF3 in gastric mucosa decreased significantly after treatment with Weierkang ( P =0.002). CONCLUSIONS: Weierkang can improve the endoscopic appearance and pathologic changes of chronic atrophic gastritis patients. Symptoms also improved. TFF3 may be involved the pathophysiology mechanism.

Lenvatinib in the treatment of unresectable hepatocellular carcinoma: a systematic review of economic evaluations.

PURPOSE: This aim of this study was to conduct a systematic review of economic evaluations comparing lenvatinib to other vascular endothelial growth factor (VEGF) inhibitors and other treatment options in the management of unresectable hepatocellular carcinoma (uHCC). METHODS: A comprehensive literature search was conducted using highly sensitive search syntax. The titles and abstracts of all records were studied and screened to identify eligible economic evaluations. To enable comparison across different countries, the results of economic evaluations make it possible to compare, the costs and ICER of all studies were converted into 2022 US dollars, and a 3% annual increase for inflation was applied. The quality of the studies was assessed using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist. This study is conducted and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. RESULTS: Lenvatinib was found to be cost-effective (ICER = dominant) compared to most drugs in the included studies, except in studies where it was compared with donafenib or when the price of sorafenib was significantly discounted (e.g., with a 90% discount, the value of ICER was + 104,669 USD). CONCLUSION: Lenvatinib was generally cost-effective in most studies, but not compared to donafenib or sorafenib (if the price sorafenib was significantly discounted).

Could the concomitant use of beta blockers with bevacizumab improve survival in metastatic colon cancer?

AIM: Drug-drug interactions are sometimes neglected in oncology practice. Due to drug pharmacokinetic and pharmacodynamic interactions, clinically increased or decreased drug effects and increased or decreased adverse effects may occur. Considering that the concomitant use of these two drugs that affect vascular endothelial growth factor receptor (VEGFR) may cause pharmacological potentiation or additive interaction, we aimed to evaluate the survival outcomes of concomitant use of bevacizumab and beta blockers in patients with metastatic colorectal cancer (mCRC). METHODS: In total, 181 patients with mCRC administered with bevacizumab plus cytotoxic chemotherapy regimen in a first-line setting were divided into two groups: concomitant beta-blocker user and nonuser. RESULTS: The median overall survival (mOS) was 35.9 (95% CI: 27.9-43.9) months in the beta-blocker-using group and 29.6 (95% CI: 27.9-43.9) months in the beta-blocker-non-using group (p = 0.054). The median progression-free survival (mPFS) was 16.1 (95% CI: 12.4-19.9) months in the beta-blocker-using group and 12.8 (95% CI: 10.6-15.0) months in the beta-blocker-non-using group (p = 0.006). The multivariate analysis revealed that beta-blocker use was an independent predictor of mPFS (HR: 0.66, 95% CI: 0.46-0.93, p = 0.018) and mOS (HR: 0.57, 95% CI: 0.36-0.91, p = 0.02). CONCLUSION: This study demonstrated that concomitant usage of beta blockers improved both survival outcomes, irrespective of the kind of beta blocker.

Evaluation of a Novel Combination Therapy, Based on Trifluridine/Tipiracil and Fruquintinib, against Colorectal Cancer.

INTRODUCTION: Trifluridine/tipiracil hydrochloride (FTD/TPI, Lonsurf®) is an oral antineoplastic agent that has been approved as late-stage chemotherapy for colorectal cancer. Its major mechanism of action is the dysfunction of tumoral DNA including DNA strand breaks and decreased replication. Fruquintinib (ELUNATE®) is a novel kinase inhibitor that selectively inhibits the vascular endothelial growth factor receptor-1, -2, and -3. In this study, we evaluated the antitumor activity of combination therapy with FTD/TPI and fruquintinib in vivo. METHODS: The enhancement of the antitumor effects with FTD/TPI and fruquintinib combination, compared to the single drugs given alone was evaluated using two human colorectal cancer xenografts in nude mouse models. FTD/TPI (200 mg/kg) was orally administered for 5 consecutive days followed by 2 days of rest in a 7-day period. Fruquintinib (10 mg/kg) was orally administered consecutively for 2 and 3 weeks in SW48 and HCT 116 tumor-bearing models, respectively. After treatment with these agents, the microvessel density was evaluated by CD31 immunohistochemical analyses. RESULTS: In both models, FTD/TPI and fruquintinib significantly inhibited tumor growth, and the activity of the combined treatment was significantly superior to that of either monotherapy. Body weight loss of greater than 20% was not observed in any group. A histochemical analysis showed nuclei enlargement, abnormal mitosis, and karyorrhexis in the FTD/TPI treatment group. The microvessel density in the HCT 116 tumors treated with FTD/TPI and fruquintinib was significantly lower than that in the control group. CONCLUSION: The combination of FTD/TPI and fruquintinib could be a promising treatment option for colorectal cancer.

Lung function and collagen 1a levels are associated with changes in 6 min walk test distance during treatment of TB among HIV-infected adults: a prospective cohort study.

BACKGROUND: Patients with tuberculosis (TB) and HIV often present with impairments in lung function and exercise capacity after treatment. We evaluated clinical and immunologic variables associated with a minimum clinically important difference (MCID) in the change in the 6 min walk test distance during the first 24 weeks of antiretroviral (ART) and anti-tubercular therapy. METHODS: Adults initiating ART and anti-TB treatment in the setting of newly-diagnosed HIV and pulmonary TB were enrolled in a prospective cohort study in South Africa. Patients underwent 6 min walk tests and spirometry at weeks 0, 4, 12, and 24 and biomarker level measurements early during treatment, at weeks 0, 4, and 12, when inflammation levels are typically elevated. Biomarkers included matrix metalloproteinases-1 (MMP-1), tissue inhibitor of MMP (TIMP)-1, collagen 1a, IL-6, IL-8, vascular cell adhesion molecule 1 (VCAM-1), C-X-C motif chemokine 10 (CXCL-10), CXCL-11, macrophage colony-stimulating factor (M-CSF), plasminogen activator, vascular endothelial growth factor, and chemokine (C-C) motif-2 (CCL-2). An MCID was derived statistically, and achievement of an MCID was modeled as the outcome using logistic regression model. RESULTS: Eighty-nine patients walked an average of 393 (± standard deviation = 69) meters at baseline, which increased by an average of 9% (430 ± 70 m) at week 24. The MCID for change in walk distance was estimated as 41 m. Patients experiencing an MCID on treatment had worse lung function, lower 6 min walk test distance, higher levels of proinflammatory biomarkers including TIMP-1 and M-CSF, and lower levels of collagen 1a at baseline. Experiencing an MCID during treatment was associated with increases in forced expiratory volume in 1-s [odds ratio (OR) = 1.17, 95% confidence interval (CI) = 1.05-1.33] and increases in blood collagen 1a levels (OR = 1.31, 95%CI 1.06-1.62). CONCLUSIONS: ART and TB treatment are associated with substantial improvements in 6 min walk test distance over time. Achievement of an MCID in the 6 min walk test in this study was associated with more severe disease at baseline and increases in collagen 1a levels and lung function during therapy.

Calcitonin Gene-Related Peptide, Vascular Endothelial Growth Factor, and Clinical Manifestations in Women With Fibromyalgia.

BACKGROUND: Fibromyalgia is a complex illness to diagnose and treat, which significantly impairs patients' quality of life. OBJECTIVES: The study aims were to compare levels of calcitonin gene-related peptide and vascular endothelial growth factor between patients with fibromyalgia and healthy controls and to examine their relationship with the main clinical manifestations of fibromyalgia. METHODS: This case-control study included 42 women diagnosed with fibromyalgia and 22 healthy women. Serum calcitonin gene-related peptide and vascular endothelial growth factor levels were spectrophotometrically analyzed by enzyme-linked immunosorbent assay. Clinical manifestations were assessed by means of self-administered questionnaires, including functional capacity in daily living activities, musculoskeletal pain, fatigue, anxiety, and sleep quality. The predictive value of these parameters in fibromyalgia was determined by receiver operating characteristic curve analysis. RESULTS: Serum calcitonin gene-related peptide levels significantly increased in the fibromyalgia group in comparison to the control group. However, there were no significant differences in vascular endothelial growth factor levels between patients and controls. No significant correlations were found between calcitonin gene-related peptide and vascular endothelial growth factor and the symptoms analyzed. DISCUSSION: Serum calcitonin gene-related peptide levels were dysregulated in women with fibromyalgia and may be a reliable parameter to help diagnose this complex syndrome.

A Systematic Review and Meta-Analysis of Clinical Outcomes of Small Gauge Vitrectomy with or without Intravitreal Anti-Vascular Endothelial Growth Factor Agents Pretreatment for Proliferative Diabetic Retinopathy.

BACKGROUND: Proliferative diabetic retinopathy (PDR) is a common visual threatening ocular disease, patients with nonclearing vitreous hemorrhage (VH), tractional retinal detachment (RD), or extensive fibrovascular proliferation are always in need for surgical treatment. Although several studies reported better surgical outcome in patients underwent surgery after anti-VEGF injection, the effect of anti-VEGF pretreatment for small gauge vitrectomy in PDR patients remains to be elucidated. OBJECTIVES: The objective of the study was to evaluate the benefits of preoperative anti-VEGF treatment in small gauge vitrectomy for PDR patients. METHODS: A comprehensive literature search in PubMed, Embase, and the Cochrane Central Register of Controlled Trials was performed to identify relevant studies. Meta-analyses were performed for intraoperative (including intraoperative bleeding, endodiathermy, iatrogenic retinal breaks, surgical time, etc.) and postoperative outcome parameters (including best-corrected visual acuity (BCVA), postoperative VH, postoperative RD, etc.). RESULTS: Ten randomized controlled trials were identified and used for comparing small gauge vitrectomy alone (344 eyes, control group) and small gauge vitrectomy with preoperative anti-VEGF injection (355 eyes). The intraoperative findings showed that the surgical time, the incidence of clinically significant intraoperative bleeding, iatrogenic retinal breaks, silicone oil tamponade, and the frequency of endodiathermy were significantly less in the anti-VEGF pre-treated group than in the vitrectomy alone group (p < 0.01). The postoperative findings showed that the incidences of early postoperative VH, postoperative RD were significantly less in the anti-VEGF pre-treated group than in the control group (p < 0.05). The pooled result of postoperative rubeosis iridis/neovascular glaucoma was borderline (p = 0.072) between cases and controls, while no statistically significant differences in BCVA at last follow-up and incidences of late postoperative VH were found between these two groups (p > 0.05). CONCLUSIONS: Anti-VEGF injection prior to small gauge vitrectomy in PDR patients might facilitate easier surgical procedure and reduce intra- and postoperative complications. Further studies are needed to verify our findings and evaluate the optimal interval and dosage for preoperative anti-VEGF injection.

Cost-effectiveness of the anti-vascular endothelial growth factor intravitreal injection and panretinal photocoagulation for patients with proliferative diabetic retinopathy in South Korea.

BACKGROUND: We determined the cost-effectiveness of the anti-vascular endothelial growth factor (VEGF) intravitreal injection versus panretinal photocoagulation (PRP) for patients with proliferative diabetic retinopathy (PDR) in South Korea. METHODS: We simulated four treatment strategies using PRP and the anti-VEGF injection by constructing a Markov model for a hypothetical cohort of 50-year-old PDR patients: (1) PRP only; (2) anti-VEGF injection only; (3) PRP first; and (4) anti-VEGF injection first. RESULTS: In this cost-effectiveness analysis, compared with only-PRP, the incremental cost-effectiveness ratio was $95,456 per quality-adjusted life-year (QALY) for PRP first, $34,375 per QALY for anti-VEGF injection first, and $33,405 per QALY for anti-VEGF injection only from a healthcare perspective. From the societal and payer perspective, strategy (2) was more cost-saving and effective than (1). In the probabilistic sensitivity analysis, only-PRP was cost-effective up to the willingness-to-pay (WTP) of about $42,000, while anti-VEGF injection only was cost-effective from a healthcare perspective. From the societal and payer perspectives, regardless of the value of WTP, anti-VEGF injection only was the most cost-effective strategy. CONCLUSION: In our study, the anti-VEGF injection for PDR was cost-effective from the payer and societal perspectives.

A review of vascular endothelial growth factor and its potential to improve functional outcomes following spinal cord injury.

Spinal cord injuries (SCI) are traumatic events with limited treatment options. Following injury, the lesion site experiences a drastic change to both its structure and vasculature which reduces its ability for tissue regeneration. Despite the lack of clinical options, researchers are investigating therapies to induce neuronal regeneration. Cell-based therapies have long been assessed in the context of SCI to promote neuronal protection and repair. Vascular endothelial growth factor (VEGF) not only demonstrates this ability, but also demonstrates angiogenic potential to promote blood vessel formation. While there have been numerous animal studies investigating VEGF, further research is still warranted to pinpoint its role following SCI. This review aims to discuss the literature surrounding the role of VEGF following SCI and its potential in promoting functional recovery.