Detection of lenalidomide metabolites in urine to discover drug-resistant compounds.

Lenalidomide is the first-line drug for the clinical treatment of multiple myeloma. However, its efficacy differs significantly among patients. Clinically, after lenalidomide treatment, few patients' conditions worsened, whereas others remained stable or improved. To clarify the reasons for this difference in efficacy, 20 patients with multiple myeloma who received maintenance treatment with lenalidomide were retrospectively included in this study. Lenalidomide metabolic compounds were detected in patient urine using mass spectrometry. A rapid and accurate ultra-performance liquid chromatography-time-of-flight tandem mass spectrometry (UPLC-TOF-MS/MS) method was used to characterize metabolites in the urine of different patients. Eleven metabolites, including four new compounds, were identified and characterized in all the samples. Among these, two metabolites were found to have obvious discrepancies in different groups of patients. One metabolite named Denitrified-2 glutarimide, a new potential compound, was only detected in the urine of ineffective and stable patients, whereas the other metabolite named 5-Hydroxy-lenalidomide was found only in the urine of effective patients.

Expression and prognosis of inducible T-cell co-stimulator and its ligand in Chinese stage I-III lung adenocarcinoma patients.

BACKGROUND: Immunotherapy has become the fastest-adopting treatment paradigm for lung cancer with improved survival. By binding with its ligand (inducible T-cell co-stimulator and its ligand [ICOSL]), an inducible T-cell co-stimulator (ICOS) could contribute to reversing immunosuppression and improving immune response and thus be a potential target for cancer immunotherapy. METHODS: We selected 54 formalin-fixed, paraffin-embedded tumor tissues from cases with stage I-III lung adenocarcinoma cancer. Immunohistochemical expression of ICOS and ICOSL was evaluated. The correlation with clinical parameters in Chinese patients was also compared with TCGA results. RESULTS: The positive rates of ICOS and ICOSL were 68% and 81.5%, respectively, in lung tumor tissues. Of these, 9 cases had a low expression of ICOS, and 22 cases had a high expression of ICOS; ICOSL expression was low in 20 cases and high in 24 cases. According to the International Association for the Study of Lung Cancer (8th edition), phase I lesions were detected in 21 cases, phase II lesions in 15 cases, and phase III lesions in 18 cases. The median survival time of all patients was 44.5 months, and the median disease-free survival was 32 months. Univariate analysis showed that the factors significantly associated with overall survival were tumor size, regional lymph node involvement, stage, and expression level of ICOS/ICOSL. Survival analysis using log-rank test indicated that the lower ICOS+ cell infiltration may predict poor prognosis, whereas lower ICOSL protein expression may be associated with better prognosis, but ICOSL data need further validation in larger samples due to inconsistency in TCGA mRNA prediction. CONCLUSION: ICOS/ICOSL might be associated with prognosis of lung cancer, and ICOS and its ligand may be potential therapeutic targets in non-small cell lung cancer.

Ixazomib-based maintenance therapy after bortezomib-based induction in patients with multiple myeloma not undergoing transplantation: A real-world study.

BACKGROUND: Maintenance therapy with proteasome inhibitors (PIs) can improve outcomes of multiple myeloma (MM) patients, however, the neurotoxicity and parenteral route of bortezomib limit its long-term use. An efficacious, tolerable, and convenient PI option is needed. METHODS: In this single-center, real-world study, we retrospectively analyzed the outcome and safety profile of ixazomib-based maintenance therapy in patients who plateaued with the responses of steady disease or better after bortezomib-based induction therapy in MM patients not undergoing transplantation. RESULTS: Of all the 71 patients, 37 cases (52.1%) were newly diagnosed MM (NDMM) and 34 cases (47.9%) were relapsed and/or refractory MM (RRMM). The overall response rate (ORR) was 81.7%, including 34 patients (47.9%) with a very good response rate or better (≥VGPR) after a median of nine cycles (6-14) of bortezomib-based induction therapy. Then the ORR was transformed to 74.6% including 39 patients of ≥VGPR (54.9%) after a median of six courses (2-25) of ixazomib-based maintenance therapy. Of these, 18 patients (25.4%) exhibited responses deepened. With 26.5 months median follow-up, median progression-free survival (PFS) was 28.4 and 16.5 months from the start of bortezomib and 16.2 and 10.0 months from the initiation of ixazomib in NDMM and RRMM group, respectively. Moreover, responses deepened during the maintenance phase (hazard ratio: 0.270, p = 0.007), and responses of ≥VGPR during the induction phase (hazard ratio: 0.218, p < 0.001) were confirmed to independently predict longer PFS after multivariate analyses. Severe adverse events (grade 3/4) were relatively rare. Bortezomib-emergent peripheral neuritis (PN) was significantly relived after the transition to ixazomib (p < 0.001). CONCLUSION: This real-world analysis has demonstrated oral ixazomib is a favorable option of long-term administration for maintenance with efficacy and feasibility and confirmed the association between deepening responses with ixazomib and prolonged PFS.

[Retracted] MicroRNA­718 serves a tumor­suppressive role in non­small cell lung cancer by directly targeting CCNB1.

Following the publication of this paper, the authors have contacted the Editorial Office to explain that they are unable to reproduce the results of their experiments designed to show the regulatory actions of miR­718 on the proliferation of non­small cell lung cancer, and consequently they wish to retract the paper. The Editor of International Jounal of Molecular Medicine has granted their request that the paper be retracted. All the authors agree to this retraction. The Editor and the authors apologize to the readership for any inconvenience caused. [the original article was published in International Journal of Molecular Medicine 45: 33­44, 2020; DOI: 10.3892/ijmm.2019.4396].

MicroRNA­718 serves a tumor­suppressive role in non­small cell lung cancer by directly targeting CCNB1.

MicroRNA­718 (miR­718) serves crucial roles in tumorigenesis and in the progression of a number of cancers. However, the expression profile, specific functions and mechanisms of action of miR­718 in non­small cell lung cancer (NSCLC) are still elusive. The aims of the present study were to quantify the expression of miR­718, determine its biological roles and elucidate the molecular mechanisms responsible for its activities in NSCLC cells. Reverse transcription­quantitative PCR was carried out to assess miR­718 expression in NSCLC tissue samples and cell lines. The Cell Counting Kit­8 assay, flow cytometry, cell migration and invasion assays, and a tumor xenograft experiment were performed to evaluate the effects of miR­718 overexpression on the malignant biological behaviors of NSCLC cells. miR­718 expression was demonstrated to be significantly decreased in NSCLC tissue samples and cell lines. This reduced expression was significantly associated with tumor, node, metastasis stage, tumor size, lymph node metastasis and poor overall survival among patients with NSCLC. Exogenous miR­718 expression suppressed NSCLC cell proliferation, migration and invasion, and promoted apoptosis in vitro; whereas it hindered tumor growth in vivo. Experiments to elucidate the mechanisms involved revealed that miR­718 functions by directly targeting cyclin B1 (CCNB1) mRNA. CCNB1 expression was found to be upregulated in NSCLC and inversely correlated with miR­718 levels. CCNB1 depletion had effects similar to those of miR­718 overexpression in NSCLC cells. Furthermore, restoration of CCNB1 expression attenuated the tumor­suppressive effects of miR­718 overexpression in NSCLC cells. These results indicated that miR­718 suppressed NSCLC progression in vitro and in vivo by directly targeting CCNB1 mRNA, which may indicate a potential target for the diagnosis and treatment of this fatal disease.

Betulinic acid exerts potent antitumor effects on paclitaxel-resistant human lung carcinoma cells (H460) via G2/M phase cell cycle arrest and induction of mitochondrial apoptosis.

Betulinic acid is a pentacyclic plant compound obtained from the bark of white birch trees and has been demonstrated to exhibit notable pharmacological properties. In the present study, the anticancer potential of betulinic acid on paclitaxel-resistant lung cancer cell line (H460) was evaluated. Cell viability was evaluated by an MTT assay, and a clonogenic assay was performed to assess the effects on cancer cell colony formation. DAPI staining using fluorescence microscopy and flow cytometry were employed to evaluate the effects of betulinic acid on apoptosis. The effects of betulinic acid on the cell cycle and mitochondrial membrane potential were also evaluated by flow cytometry. The effects of betulinic acid on the protein expression of B-cell lymphoma-2 (Bcl-2)/Bcl-2-associated X (Bax) were evaluated by western blot analysis. The results of the present study indicated that the half-maximal inhibitory concentration value of betulinic acid on paclitaxel-resistant H460 lung cancer cells was 50 µM. The treatment with betulinic acid was able to inhibit the colony formation potential in a dose-dependent manner. A lower cytoxicity by betulinic acid against normal human epithelial FR2 cells was observed compared with H460 cells. The betulinic acid exerted anticancer activity via the induction of apoptosis by regulating the Bcl-2/Bax signaling pathway. Additionally, treatment with betulinic acid resulted in cell cycle arrest of paclitaxel-resistant lung cancer H460 cells at the G2/M phase. Betulinic acid was also reported to cause reductions in the mitochondrial membrane potential in a dose-dependent manner. In conclusion, the results of the present study indicated that betulinic acid may be a useful drug candidate for the management of drug-resistant lung cancer.

[Clinical observations of lenalidomide combination chemotherapy for relapsing or refractory multiple myeloma].

OBJECTIVE: To explore the clinical efficacies and toxicities of lenalidomide combination chemotherapy in the treatment of relapsing or refractory multiple myeloma (MM) patients. METHODS: A total of 14 MM patients were recruited to receive lenalidomide combination chemotherapy in Beijing Chaoyang hospital from June 2013 to October 2014. Lenalidomide 25 mg was taken orally daily or every alternate day for 21 days and resting for 7 days. The regimens were RD (lenalidomide and dexamethasone, n = 6), RCD (lenalidomide, ifosfamide and dexamethasone, n = 4), RDD (lenalidomide, liposomal doxorubicinand dexamethasone, n = 1), PRD (lenalidomide, velcade and dexamethasone, n = 1) and R+DECP (lenalidomide, cisplatin, etoposide, ifosfamide and dexamethasone, n = 2). RESULTS: Among them, two patients died during the first cycle of lenalidomide. Ten patients finished 2 cycles of treatment and 2 patients attained near complete remission or complete remission (nCR/CR), 6 partial remission (PR) and 2 stable disease (SD) with an overall response rate (ORR) of 8/10. Ten patients finished 3 cycles of treatment and 3 attained CR, 5 PR and 2 SD. Nine patients finished 4 cycles of treatment and 3 attained CR, 5 PR and 1 progressive disease (PD). Six patients finished 5 cycles of treatment and 1 attained CR, 3 PR and 2 PD. Three patients finished 6 cycles of treatment and 1 attained CR, 1 PR and 1 PD. And the most common adverse reactions were fatigue, loss of appetite and hypocytosis. Six patients died. CONCLUSION: The lenalidomide combination chemotherapy is both efficacious and safe in the treatment of relapsing or refractory MM.

Clinicopathological characteristics and treatment outcomes of Chinese patients with genitourinary embryonal rhabdomyosarcoma.

BACKGROUND: Genitourinary embryonal rhabdomyosarcoma is rarely reported in China. This retrospective analysis aimed to characterize the clinicopathologic features and treatment outcomes of genitourinary embryonal rhabdomyosarcoma in a sample of Chinese patients. METHODS: Basic demographic and clinical data of 29 patients, who were diagnosed with genitourinary embryonal rhabdomyosarcoma between January 2000 and December 2011, were retrieved and analyzed. RESULTS: In these patients, 25 were males and 4 were females with a median age of 12 years. Paratesticule was the most common lesion site, followed by the prostate, bladder, and vagina. The median tumor size was 5.80 cm. Six patients had clinically positive regional nodes. At the initial diagnosis, patients had a metastatic disease. According to the TNM staging classification for the IRS-IV, phase I lesions were detected in ten cases, phase II lesions in six cases, phase III lesions in four cases, and phase IV lesions in nine cases. The median survival of all patients was 63 (range from 6 to 118) months. The 1-, 3-, and 5-year survival rates for these patients were 93%, 83%, and 52%, respectively. Multivariate analyses demonstrated that staging and anemia were significant predictors of prognosis. CONCLUSIONS: Our findings suggest that metastasis predicts a poor prognosis. Chemotherapy played an important role in comprehensive treatment. Palliative and neo-adjuvant chemotherapy could increase median survival time.

An open-labeled, randomized, multicenter phase IIa study of gambogic acid injection for advanced malignant tumors.

BACKGROUND: Gambogic acid is a pure active compound isolated from the traditional Chinese medicinal plant gamboge (Garcinia morella Desv.). Based on the preliminary results of a phase I study, this phase IIa study compared the efficacy and safety of different dosage schedules of gambogic acid in patients with advanced malignant tumors. METHODS: Patients with advanced or metastases cancer who had not received any effective routine conventional treatment or who had failed to respond to the existing conventional treatment were randomly assigned to receive either 45 mg/m(2) gambogic acid intravenously from Days 1 to 5 of a 2-week cycle (Group A), or 45 mg/m(2) every other day for a total of five times during a 2-week cycle (Group B). The primary endpoint was objective response rate (ORR). RESULTS: Twenty-one patients assigned to Group A and 26 to Group B were included in the final analysis. The ORRs were 14.3% in Group A and 0% in Group B. It was not possible to analyze the significant difference because one of the values was zero. The disease control rates (DCRs) were 76.2% in Group A and 61.5% in Group B (P = 0.0456). The observed adverse reactions were mostly Grades I and II, and occurred in most patients after administration of the trial drug. There was no significant difference in the incidence of adverse reactions between the two arms. CONCLUSIONS: The preliminary results of this phase IIa exploratory study suggest that gambogic acid has a favorable safety profile when administered at 45 mg/m(2). The DCR was greater in patients receiving gambogic acid on Days 1 - 5 of a 2-week cycle, but the incidence of adverse reactions was similar irrespective of the administration schedule.

[Clinical analysis of 81 cases with primary small cell carcinoma of the esophagus].

OBJECTIVE: To evaluate the clinical characteristics, treatment and prognostic factors in patients with primary small cell carcinoma (SmCC) of the esophagus. METHODS: Eighty-one esophageal SmCC patients were treated from 1999 to 2007 in our department, and their clinical data were retrospectively reviewed. RESULTS: Of the 81 patients, 52 (64.2%) were in limited stage (LS) and 23 (28.4%) in extensive stage (ES). The 1-, 3- and 5-year survival rates were 55.6%, 6.2% and 2.5%, respectively, with a median survival time of 13.5 months for the whole group; 69.2%, 7.3% and 3.6%, respectively, with a median survival time of 15 months for the LS group; while only 25.2%, 0 and 0, respectively, with a median survival time of 6 months for the ES group. Multivariate analysis showed that disease stage, performance status, multidisciplinary comprehensive therapy and mode of treatment were independent prognostic factors. CONCLUSION: Esophageal small cell carcinoma is a rare but highly aggressive malignant tumor. Disease stage and performance status are important prognostic factors. Appropriate treatment may play a key role in improving the survival of the patients.