Efficacy and safety evaluation of the regimen containing Bedaquiline in elderly patients with drug-resistant pulmonary tuberculosis / 中华老年医学杂志

Objective:To evaluate the efficacy and adverse reactions of the regimen containing Bedaquiline in elderly patients with multi-drug resistant tuberculosis.Methods:From March 2019 to June 2022, patients with multi-drug resistant pulmonary tuberculosis admitted to Anhui Chest Hospital were randomly divided into two groups: the observation group was given a treatment containing Bedaquiline, and the control group was given a treatment without Bedaquiline.Patients were also divided into elderly patients(age ≥60 years old)and non-elderly patients(age <60 years old)according to age.Sputum culture conversion, lesion absorption and adverse reactions were compared between the observation group and the control group in general, elderly and non-elderly patients, respectively.Results:A total of 170 cases were collected, including 79 in the observation group and 91 in the control group.Sputum culture conversion: The sputum culture conversion rates of observation groups in general, non-elderly and elderly patients were better than that of control groups at the 3rd month after treatment(the general, 96.2% vs.75.8%, χ2=14.001, P<0.001; the non-elderly, 94.9% vs.82.1%, χ2=4.675, P=0.031; the elderly, 100.0% vs. 65.7%, χ2=8.771, P=0.003), and at the 6th month, the rates of overall observation group was better than that of control group(98.7% vs.92.3%, χ2=3.895, P=0.048); the rates of non-elderly and elderly observation group and control group were all greater than 90%, with no statistical significance( P>0.05). Lesion absorption: Overall and non-elderly observation groups were better than control group in lesion absorption at the 3rd month(the general, 84.8% vs.68.1%, χ2=12.962, P=0.002; the non-elderly, 88.1% vs.71.4%, χ2=9.832, P=0.007; and the 6th month(the general, 88.6% vs.76.9%, χ2=14.888, P=0.001; the non-elderly, 89.8% vs.82.1%, χ2=8.618, P=0.013). The focal absorptivity of senile observation group at the end of March and June were 75.0% and 85.0%, respectively, both better than control group, but the difference was not statistically significant( P>0.05). Adverse reactions: Overall and non-senile observation groups had longer QT interval than control groups( P<0.05), but no patients stopped bedaquiline because of this, and there was no significant difference in QT interval between the two groups( P>0.05). Conclusions:In elderly patients with multi-drug resistant pulmonary tuberculosis, early sputum culture conversion turns fast after treatment with Bedaquiline, which has good therapeutic effect, good tolerance and controllable adverse reactions.

Efficacy and safety analysis of anlotinib in the treatment of distant metastatic radioactive iodine-refractory differentiated thyroid cancer / 中华核医学与分子影像杂志

Objective:To investigate the efficacy and safety of anlotinib in distant metastatic radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC).Methods:Retrospective analysis was performed on 17 patients with distant metastatic RAIR-DTC (6 males, 11 females, age: 57.0(45.5, 63.0) years) from Affiliated Hospital of Qingdao University between October 2018 and February 2023, including 13 patients receiving first-line treatment and 4 patients receiving second-line treatment with anlotinib. The changes of serum thyroglobulin (Tg) during the treatment of anlotinib, the changes of maximum diameter of the target lesion at the last follow-up compared with the diameter at baseline, the imaging efficacy, and treatment-related adverse events were analyzed. The serological and imaging effects of the first-line treatment group and the second-line treatment group were compared. The Fisher exact test was used to analyze the differences between groups.Results:The follow-up time of 17 patients was 17.3(9.5, 21.4) months, and the objective response rate (ORR) and disease control rate (DCR) were 7/17 and 16/17, respectively. There were no significant differences of ORR (6/13 vs 1/4; P=0.603) and DCR (13/13 vs 3/4; P=0.235) between the first-line and second-line treatment groups. The change rates of serum Tg at 3, 6 weeks and the last follow-up were -30.2%(-61.2%, -15.5%), -64.8%(-90.6%, -32.3%), and -85.8%(-96.1%, -50.7%), respectively. At the last follow-up, the change rate of maximum diameter of target lesions was -20.0%(-45.0%, -5.2%). The incidence of treatment-related adverse reactions was 14/17, and 2 patients (2/17) had grade 3 or above adverse reactions. Conclusion:Anlotinib shows superior efficacy with tolerable toxicity in the first-line treatment of distant metastatic RAIR-DTC, and hopefully plays an important role in second-line treatment for RAIR-DTC resistant to sorafenib.

Uptake characteristics of 68Ga-FAPI-04 and 18F-FDG in surgical wounds after radical surgery for gastrointestinal adenocarcinoma / 中华核医学与分子影像杂志

Objective:To explore the uptake characteristics and temporal changes of 68Ga-fibroblast activation protein inhibitors (FAPIs) and 18F-FDG in the anastomotic site of reconstructed digestive tracts after radical surgery for gastrointestinal adenocarcinoma. Methods:A cohort of 43 patients (28 males, 15 females; age range 28-79 years) who underwent radical surgery for gastrointestinal adenocarcinoma and underwent 18F-FDG PET/CT follow-up between November 2020 and June 2022 in the First Affiliated Hospital of the Air Force Medical University was prospectively included. One week after the 18F-FDG PET/CT examination, 68Ga-FAPI-04 PET/CT imaging was performed. ROIs were drawn on the PET images at the highest uptake level of anastomotic sites of reconstructed digestive tract and abdominal wall incisions, and SUV max and target-to-background ratio (TBR) were determined. χ2 test, one-way analysis of variance, Kruskal-Wallis rank sum test (Bonferroni correction) and Wilcoxon signed-rank test were supplied. Results:There were 86 surgical wounds (13 gastric-intestinal anastomotic sites, 14 esophagus-intestinal anastomotic sites, 16 intestinal-intestinal anastomotic sites, and 43 abdominal wall incisions) included. In 68Ga-FAPI-04 PET imaging, SUV max of gastric-intestinal anastomotic sites was higher than that of abdominal wall incisions, with a statistically significant difference (adjusted P=0.014). The TBR did not show statistically significant differences among different types of surgical wounds ( H=3.88, P=0.275). In 18F-FDG PET imaging, SUV max of gastric-intestinal, esophagus-intestinal, and intestinal-intestinal anastomotic sites were all higher than that of abdominal wall incisions, with statistically significant differences (adjusted all P<0.001). There were no statistically significant differences in TBR among different types of surgical wounds ( H=3.02, P=0.388). In 68Ga-FAPI-04 PET imaging, the TBR of all types of anastomotic sites exhibited a decreasing trend with increasing postoperative time. Except for intestinal-intestinal anastomotic sites, the differences in TBR between < 0.5-year and ≥ 1.5-year groups were statistically significant for other types of surgical wounds (adjusted P<0.05). In 18F-FDG PET imaging, the TBR of abdominal wall incisions showed a decreasing trend with increasing postoperative time. However, the TBR of other types of surgical wounds did not show a decreasing trend, and the differences in TBR among different time groups were not statistically significant ( H values: 0.53-2.75, P values: 0.252-0.768). In comparing the two PET imaging agents, for all surgical wounds within the <0.5-year and 0.5-1.5-year groups, the 68Ga-FAPI-04 TBR was consistently higher than the 18F-FDG TBR ( z values: -3.17 and -2.55, P values: 0.002 and 0.011). However, in the ≥1.5-year group, the TBR values tended to be consistent, and the differences were not statistically significant ( z=-0.70, P=0.485). Conclusions:The 18F-FDG uptake in the anastomotic sites of reconstructed digestive tracts reaches a low level under half a year after surgery and does not significantly change over time, while the 68Ga-FAPIs uptake remains relatively high within the first 1.5 years after surgery but decreases over time. These patterns suggest that clinical attention should be paid to the differential diagnosis of anastomotic inflammation or fibrosis, which resulting in agent uptake and local tumor recurrence.

Diagnostic and prognostic value of 68Ga-FAPI PET for malignant tumors of the liver and biliary tract / 中华核医学与分子影像杂志

Objective:To investigate the diagnostic and prognostic value of 68Ga-fibroblast activation protein inhibitor (FAPI) PET for hepatobiliary malignancies. Methods:From July 2020 to February 2023, 33 patients (23 males, 10 females; age (55.4±13.5) years) with suspected or confirmed liver or biliary tract malignancies who underwent 68Ga-FAPI PET in Union Hospital, Tongji Medical College, Huazhong University of Science and Technology were retrospectively analyzed. PET images were evaluated by 3 experienced nuclear medicine physicians, and the results of biopsy or postoperative pathology, clinical and imaging follow-up were used as the gold standard. One-way analysis of variance and least significant difference t test were used to compare the differences among groups. Survival analysis was performed using Kaplan-Meier curves and the log-rank test. Results:Of 33 patients, 14 performed PET for initial diagnosis and staging, and 19 for restaging. There were 14 patients with hepatocellular carcinoma (HCC), 13 patients with cholangiocarcinoma (CCA), and 6 patients with gallbladder carcinoma (GBC). The primary tumor of HCC, CCA and GBC all showed significant 68Ga-FAPI uptake, with no statistically significant difference in SUV max among groups ( F=1.58, P=0.250). The sensitivities of 68Ga-FAPI PET for initial diagnosis and restaging of hepatobiliary malignancies were 14/14 and 15/15, respectively. Compared with conventional imaging, 68Ga-FAPI PET changed the diagnosis and staging in 29.2%(7/24) patients. The treatment strategy was changed in 30.3%(10/33) patients with malignant tumors due to 68Ga-FAPI PET findings. Follow-up showed 22 cases survived and 11 cases died, with the overall survival of 355.56(80.00, 516.97) d, and 1- and 2-year survival rates were 68.2% and 57.9%, respectively. Semi-quantitative 68Ga-FAPI PET parameters such as SUV max, target-liver ratio (TLR), and target-blood ratio (TBR) had no significant prognostic value, but the prognosis of the group without distant metastases diagnosed by 68Ga-FAPI PET was significantly better than that of the group with distant metastasis ( P=0.032). Conclusion:68Ga-FAPI PET has high sensitivity for the diagnosis of hepatobiliary malignancies, which can help guide treatment decisions and prognosis evaluation.

Comparison of 68Ga-FAPI and 18F-FDG PET/CT for the diagnosis of primary and metastatic gastric signet-ring cell carcinoma / 中华核医学与分子影像杂志

Objective:To investigate the clinical utility of 68Ga-labeled fibroblast activation protein inhibitor (FAPI) PET/CT in the detection of primary and metastatic gastric signet-ring cell carcinoma (GSRCC) and compared the results with those of 18F-FDG PET/CT. Methods:A total of 21 patients (10 males, 11 females, average age 52 years) with primary and metastatic GSRCC who underwent 68Ga-FAPI and 18F-FDG PET/CT at the First Affiliated Hospital of Xiamen University from June 2020 to May 2022 were retrospectively analyzed. Pathological results of surgery and (or) biopsy were used as the " gold standard" for final diagnosis. In cases whose surgery or tissue biopsies were not available, clinical and radiographic follow-up results were used as the reference standards. Wilcoxon signed-rank test was used to compare the SUV max of 18F-FDG and 68Ga-FAPI. McNemar χ2 test was used to compare the detection rate between 18F-FDG and 68Ga-FAPI PET/CT. Results:68Ga-FAPI PET/CT showed higher SUV max than 18F-FDG in primary tumors (5.3(2.4, 15.7) vs 2.4(1.8, 2.5); z=2.31, P=0.021), local recurrences (7.8(6.0, 8.9) vs 2.4(1.9, 3.4); z=2.20, P=0.028), lymph nodes metastases (7.7(4.5, 12.2) vs 2.4(1.9, 3.6); z=6.01, P<0.001) and bone/visceral metastases (6.7(5.3, 11.1) vs 2.4(2.0, 3.4); z=11.36, P<0.001). Regarding diagnostic accuracy, 68Ga-FAPI PET/CT showed higher sensitivities than 18F-FDG for primary tumors (7/9 vs 2/9; χ2=3.20, P=0.063) and local recurrences (7/7 vs 2/7; χ2=3.20, P=0.063). It also demonstrated higher lesion detection rates than 18F-FDG for suspicious lymph node metastases (86%(65/76) vs 32%(24/76); χ2=31.37, P<0.001) and bone/visceral metastases (99%(184/185) vs 39%(73/185); χ2=107.08, P<0.001). Conclusions:68Ga-FAPI PET/CT showed higher tumor uptake and lesion detection rate than 18F-FDG in the primary and metastatic GSRCC. 68Ga-FAPI PET/CT demonstrates good diagnostic performance for tumor detection, staging, and restaging of GSRCC, which is helpful to further guide clinical treatment strategy.

Kinetic metrics of 68Ga-FAPI-04 in patients with pancreatic cancer identified by total-body PET/CT dynamic imaging / 中华核医学与分子影像杂志

Objective:To investigate the kinetic metrics of 68Ga-fibroblast activation protein inhibitor (FAPI)-04 in pancreatic cancers and normal organs by using total-body PET dynamic imaging. Methods:From December 2020 to December 2021, 68Ga-FAPI-04 total-body PET/CT dynamic imaging were performed on 6 pancreatic cancer patients (3 males, 3 females, median age 55.5 years) in Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University. Images were respectively analyzed. Manual delineations of volume of interests (VOIs) on multiple normal organs and pathological lesions were performed and time-to-activity curves (TACs) were generated. A reversible two-tissue compartment model (2TCM) was fitted for each tissue TAC. Rate constants including K1, k2, k3 and k4, and the total volume of distribution ( Vt) were obtained and compared by tissue types. Wilcoxon rank sum test and Spearman correlation analysis were used for data analysis. Results:Kinetic metrics varied significantly among normal organs and pancreatic cancer lesions ( z values: 2.00-1 240.00, all P<0.05). The highest K1 among lesions was observed in primary tumor (0.30 min -1), which was observed in the spleen (1.42 min -1) among normal organs. The highest k2 among lesions was observed in peritoneal metastases (0.24 min -1), which was observed in the spleen (2.59 min -1) among normal organs. Primary tumor showed the highest k3 of 0.17 min -1 among lesions, and the pancreas had the highest k3 of 0.16 min -1 among normal organs. Primary tumor had the highest k4 of 0.03 min -1 among lesions, and the heart, lungs, parotid glands had high k4(0.06 min -1) among normal organs. Vt were higher in pathological lesions compared to normal organs, with the highest in primary tumor (13.78 ml/cm 3). There were correlations between Vt in lesions and SUV mean( rs=0.86, P<0.001) or SUV max ( rs=0.77, P<0.001). Conclusion:The rate constants including K1, k2, k3 and k4, and Vt of 68Ga-FAPI-04 vary among normal organs and lesions.

Research progress of radiolabeled FAPIs in the tumor targeted diagnosis and therapy / 中华核医学与分子影像杂志

Cancer-associated fibroblasts (CAFs) are essential parts of tumor stroma. Fibroblast activation protein (FAP), overexpressed in CAFs, is closely related to tumor growth, invasion, metastasis, immunosuppression and prognosis, which is a vital target for tumor targeted diagnosis and therapy. In recent years, a variety of new radiolabeled quinoline-based FAP inhibitors (FAPIs) have been used for tumor targeted diagnostic and therapeutic research. A number of studies have confirmed that radiolabeled FAPIs plays an important role in tumor diagnosis, staging and treatment, which have a good clinical application prospect. This review summarizes the research status of radiolabeled FAPIs and discusses their potential in the accurate diagnosis and therapy of tumors.

Quinolinotriazole antiplasmodials via click chemistry: synthesis and in vitro studies of 7-Chloroquinoline-based compounds

Malaria is nowadays one of the most serious health concerns in a global scale and, although there is an evident increase in research studies in this area, pointed by the vast number of hits and leads, it still appears as a recurrent topic every year due to the drug resistance shown by the parasite exposing the urgent need to develop new antimalarial medications. In this work, 38 molecules were synthesized via copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC) or "click" chemistry, following different routes to produce 2 different organic azides, obtained from a 4,7 dicholoquinoline, reacted with 19 different commercially available terminal alkynes. All those new compounds were evaluated for their in vitro activity against the chloroquine resistant malaria parasite Plasmodium falciparum (W2). The cytotoxicity evaluation was accomplished using Hep G2 cells and SI index was calculated for every molecule. Some of the quinoline derivatives have shown high antimalarial activity, with IC50 values in the range of 1.72-8.66 µM, low cytotoxicity, with CC50>1000 µM and selectivity index (SI) in the range of 20-100, with some compounds showing SI>800. Therefore, the quinolinotriazole hybrids could be considered a very important step on the development of new antimalarial drugs

Anti-cancer Effects of a Novel Quinoline Derivative 83b1 on Human Esophageal Squamous Cell Carcinoma through Down-Regulation of COX-2 mRNA and PGE₂ / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: 83b1 is a novel quinoline derivative that has been shown to inhibit cancer growth in human esophageal squamous cell carcinoma (ESCC). This study was conducted to comprehensively evaluate the cytotoxic effects of 83b1 on a series of ESCC cell lines and investigate the mechanisms by which 83b1 suppresses cancer growth based on molecular docking analysis. MATERIALS AND METHODS: A series of ESCC and nontumor immortalized cell lines were exposed to 83b1 and cisplatin (CDDP) in a dose-dependent manner, and the cytotoxicity was examined by a MTS assay kit. Prediction of the molecular targets of 83b1 was conducted by molecular docking analysis. Expression of cyclooxygenase 2 (COX-2) mRNA and COX-2–derived prostaglandin E₂ (PGE₂) were measured by quantitative real-time polymerase chain reaction and enzymelinked immuno-sorbent assay, respectively. In vivo anti-tumor effect was determined using a nude mice xenografted model transplanted with an ESCC cell line, KYSE-450. RESULTS: 83b1 showed the significant anti-cancer effects on all ESCC cell lines compared to CDDP; however, 83b1 revealed much lower toxic effects on non-tumor cell lines than CDDP. The predicted molecular target of 83b1 is peroxisome proliferator-activated receptor delta (PPARδ), which is a widely known oncoprotein. Additionally the expression of COX-2 mRNA and COX-2–derived PGE2 were down-regulated by 83b1 in a dose-dependent manner in ESCC cell lines. Furthermore, 83b1 was shown to significantly reduce the tumor size in nude mice xenograft. CONCLUSION: The results of this study suggest that the potential anti-cancer effects of 83b1 on human esophageal cancers occur through the possible oncotarget, PPARδ, and down-regulation of the cancer related genes and molecules.

Derivados quiolínicos: compustos sintéticos con propiedades antitumorales sobre líneas de cáncer humano / Quinolinic derivates: synthetic compounds with antitumor proprieties against human line cell cancer

El cáncer es una enfermedad multifactorial caracterizada por anormalidad en el crecimiento celular provocado por factores ambientales y múltiples cambios en la expresión de los genes. El cáncer de mama representa una de las enfermedades que más afecta a la población femenina mundial. Actualmente, se ha mostrado un auge en las investigaciones sobre compuestos extraídos de diversas plantas y origen sintético con posibles agentes antitumorales, entre los que se pueden nombrar los derivados sintéticos de quinolinas. Realizado estudio del grupo sintético indeno (2,1-c) quinolinas y sus efectos citotóxicos sobre líneas de cáncer de mama SKBr3 yMCF-7. La evaluación de la actividad citotóxica de estos compuestos fue determinada a través del método del MTT, se calcularon los valores de concentración inhibitoria, los índices de selectividad y combinaciones con taxanos. Los resultados obtenidos muestran una alta selectividad de los compuestos sintéticos y natural evaluados hacia las líneas celulares MCF-7 y SKBr3 con respecto a las células control (fibroblastos dérmicos humanos); además de una interacción de tipo potenciación en la combinación de un derivado quinolínico y la drogataxano. Con todo esto se puede inferir que solo ciertos compuestos que tuvieron modificaciones químicas realizadas sobre el compuesto patrón del grupo sintético indeno (2,1-c) quinolinas mostraron una inhibición sobre la viabilidad celular sobre las líneas tumorales SKBr3 y MCF-7, conforme aumenta la dosis de los compuestos, además de evidenciar la efectividad de compuestos derivados de quinolinas como moléculas con características antineoplásicas

The cancer is a multifactorial disease characterized by abnormal cell growth caused by environmental factors and for multiple changes in the gene expression. The breast cancer is a disease that affects the female population in worldwide. Currently, there is shown an increment in the research on compounds that we extracted from various plants and synthetic origin with potential antitumor agents, among which can be namedthe synthetic derivatives of the quinolines. A study was performed on an group of synthetic indeno (2,1-c) quinolines and their cytotoxic effects on breast cancer cell lines SKBR3 and MCF-7 was performed. The evaluation of the cytotoxic activity of these compounds was determined through the MTT method; we were calculated inhibitory concentration values, the rates of selectivity and the drug combinations with taxanes. The results show a high selectivity of the natural and the synthetic compounds evaluated towards the cell lines MCF-7 and SKBR3 cells with respect to control (dermal fibroblasts human), besides an enhancement type interaction in the combination of a drug derivative and the quinolinic taxanes. With all this we can infer that only certain compounds had chemical modifications performed on the composite pattern of synthetic group indeno (2, 1-c) quinolines showed an inhibition on cell viability on tumor cell lines SKBR3 and MCF-7, with increasing dose of the compounds, also showing the effectiveness of compounds derived from the quinolines as molecules with the antineoplastic properties and his characteristics

Combined therapeutic effects of Huaiqihuang and Montelukast sodium on airway inflammation and expression of IL-17 in asthmatic rat / 中国医师杂志

ObjectiveTo explore the mechanism of Montelukast combined with Huang Qi Huai in the treatment of asthma.MethodsForty male Sprague-Dawley (SD) rats were chosen and randomly divided into five groups:control group (Control),model group (Model),Montelukast group (MK),Huang Qi Huai group (H),Montelukast + Huang Qi Huai group (MK + H),each group has 8 rats.The other four groups except the control group were built to chronic rat asthma model.The treatment groups were administered intragastrically with Montelukast,Huang Qi Huai and Montelukast + Huang Qi Huai respectively.All animals were sacrificod; plasma and bronchoalveolar lavage fluid (BALF) and superior lobe of right lung tissues were collected.Superior lobes of right lung tissues were used to measure the expression of IL-17 in lung tissue by immunohistochemistry.The airway inflammation was analyzed by histochemistry staining with H.E.Total cells score and differential score in BALF were counted.The levels of IL-17 in the plasma and BALF were measured by Enzyme-linked immunosorbent assay (ELISA).ResultsCompared with the control group,the degree of inflammatory cell around the airway in the model group were significantly higher (P ＜ 0.05).Compared with group model,the degree of inflammatory cell around the airway in the Group MK,group H and group MK + H were significantly ameliorated ( P ＜0.05).Compared with Group MK,the degree of inflammatory cell around the airway in group MK + H was significantly ameliorated ( P ＜O.05),the expression of IL-17 in lung tissues was significantly lower ( P ＜0.05),the numbers of total cells and the concentration of IL-17 in plasma and BALF were decreased too ( P ＜0.05).Correlation analysis showed that the level of IL-17 in the plasma and BALF was positively correlated with the level of IL-17 in the lung tissue( P ＜ 0.05 ).ConclusionsCombined Huang Qi Huai adjuvant Montelukast treatment of asthmatic rat further reduced the concentration of IL-17 in the plasma and BALF,reduced the expression of IL-17 in lung tissue,improved the airway inflammation.Down regulation the expression of IL-17 was probably one of the mechanisms of anti-inflammatory.

Environmental Pollution by Quinolines Antibiotics from Human and Animal Excreta / 环境与健康杂志

Quinolines antibiotics present stable chemical properties ,higher excretion of prototype drug. Most of quinolines antibiotics used by human and animals show original and various biological activity forms in the excrement,which is important to ecological environment and human health. The data indicate that the present clinical treatment is facing frequent occurrence and higher rates of quinolines antibiotics-resistance, which is related to environmental pollution by quinolines antibiotics. So far as little research is focused on the management of the excrement from human and animals using quinolines antibiotics, and the control, management of the residues of excrement are very important for reducing the risk of antibiotic-resistance in human.