Which novel agents hold the greatest promise in AML?

The therapeutic landscape for acute myeloid leukemia (AML) has changed dramatically with the approval of targeted agents, including venetoclax, midostaurin, gilteritinib, ivosidenib, and enasidenib, among others. However, older patients with AML continue to experience poorer outcomes and are in ongoing need of more effective and less toxic regimens. This review examines the efficacy of novel therapeutics and promising combination approaches to further improve outcomes in the treatment of patients with AML.     

Association of specific metastatic organs with the prognosis and chemotherapeutic response in patients with advanced lung cancer

BackgroundThis study was performed to investigate the influence of specific metastatic organs on the prognosis and therapeutic effect in patients with advanced lung cancer.MethodsWe retrospectively analyzed 400 patients with pathologically diagnosed advanced lung cancer to determine the association of the patients’ metastatic status with their prognoses and responses to first-line therapy. Metastases within the chest cavity (pulmonary metastasis, pleural effusion, and pericardial effusion) were counted as one organ.ResultsThe numbers of metastatic organs in the patients were as follows: one (n=199 patients), two (n=99), three (n=61), and four or more (n=41). A multivariate analysis showed that liver and muscle metastases were independently associated with shorter overall survival (median of 207 and 120 days, respectively) and shorter progression-free survival (median of 125 and 53 days, respectively). Chest cavity, bone, brain, and lymph node metastases were not associated with survival. The presence of either muscle or skin metastasis was associated with a lower response rate to first-line therapy than was the absence of each metastasis (14.3% vs. 49.4% and 11.1% vs. 48.9% in patients with vs. without muscle or skin metastasis, respectively).ConclusionsMuscle and liver metastases were associated with poor outcomes. Muscle and skin metastases were associated with a lower response rate to treatment. For patients with advanced lung cancer, oncologists should select treatment strategies considering the patients’ metastatic statuses as well as other clinical characteristics.     

MAPK7 and MAP2K4 as prognostic markers in osteosarcoma

Osteosarcoma is a class of cancer originating from the bone, affecting mainly children and young adults. Cytogenetic studies showed the presence of rearrangements and recurrent gains in specific chromosomal regions, indicating the possible involvement of genes located in these regions during the pathogenesis of osteosarcoma. These studies investigated expression of 10 genes located in the chromosomal region involved in abnormalities in osteosarcoma, 1p36, 17p, and chromosome 19. The purpose of this study was to investigate the expression profile of genes located in regions involved in chromosomal rearrangements in osteosarcoma. We used quantitative real-time polymerase chain reaction to investigate the expression of 10 genes located in 1p36.3 (MTHFR, ERRFI1, FGR, E2F2), 17p (MAPK7, MAP2K4), and chromosome 19 (BBC3, FOSB, JUND, and RRAS), in 70 samples taken from 30 patients (30 prechemotherapy, 30 postchemotherapy, and 10 metastases specimens) and 10 healthy bones as a control sample. The most interesting results showed a strong association between the expression levels of MAPK7 and MAP2K4 genes and clinical parameters of osteosarcoma. Overexpression of these genes was significantly associated to a poor response to treatment (P = .0001 and P = .0049, respectively), tumor progression, and worse overall survival (P = .0052 and P = .0085, respectively), suggesting that MAPK7 and MAP2K4 could play an important role in osteosarcoma tumorigenesis. Thus, these genes could be good markers in assessing response to treatment and development of osteosarcoma.     

Novel quinazoline HMJ‐30 induces U‐2 OS human osteogenic sarcoma cell apoptosis through induction of oxidative stress and up‐regulation of ATM/p53 signaling pathway

Human osteogenic sarcoma is the most common primary bone tumor. Despite of the success of frontline therapy, about 40% of patients have disease progression and further therapy is palliative and toxic. In this study, we developed a novel quinazoline HMJ‐30 to investigate the cell growth inhibition and apoptotic responses in U‐2 OS human osteogenic sarcoma cells. Our results demonstrated that HMJ‐30 significantly reduced cell viabilities of U‐2 OS, HOS, and 143B cells in a dose‐dependent manner, but it exhibited low cytotoxicity in normal hFOB cells. HMJ‐30 induced DNA damage and apoptosis in U‐2 OS cells as revealed by morphologic changes, comet assay and DAPI staining. Immuno‐staining, colorimetric assays, and Western blotting analyses indicated that activities of caspase‐8, caspase‐9, and caspase‐3 and the levels of Bcl‐2 family‐related proteins (Bcl‐2, Mcl‐1, Bax, BAD, and t‐Bid) were altered in HMJ‐30‐treated U‐2 OS cells. Pretreatment of cells with caspase‐8, ‐9, and ‐3 specific inhibitors significantly reduced the cell growth inhibition. HMJ‐30‐induced apoptosis was mediated through both death‐receptor and mitochondria‐dependent apoptotic pathways in U‐2 OS cells. HMJ‐30 induced early phosphorylation of p53^Ser18 was through the activation of ataxia telangiectasia mutated (ATM) in U‐2 OS cells. The cell growth inhibition by HMJ‐30 was substantially attenuated either by the pre‐incubation of U‐2 OS cells with N‐acetylcysteine (NAC, an antioxidant) and caffeine (an ATM kinase inhibitor) or by p53 knockdown via RNAi. In conclusion, ROS dependent‐ATM/p53 signaling pathway is involved in HMJ‐30‐induced apoptosis in U‐2 OS cells. © 2011 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 29: 1448–1456, 2011     

Panax notoginseng saponins promotes proliferation and osteogenic differentiation of rat bone marrow stromal cells

Aim of the study

Panax notoginseng saponins (PNS) is the main effective component of Panax notoginseng, have various pharmacologic activities such as antioxidant, anti-inflammatory, and estrogen-like bioactivities, have been shown to be an effective agent on anti-osteoporosis. Bone marrow stromal cells (BMSCs) play a crucial homeostatic role in skeletal modeling and remodeling due to their capability to differentiate into osteooblasts. Whether PNS has effect on osteogenic differentiation of BMSCs are unknown.This study was designed to investigate the effects of PNS on the proliferation and osteogenic differentiation of BMSCs in vitro.

Materials and methods

When BMSCs cultivated in the basal medium or the osteogenic induction medium (OS with or without PNS), cell proliferation was analyzed using an MTT assay, the mineralization was assessed using Alizarin red S staining, the alkaline phosphatase activity was measured using a commercial kit, the mRNA level of osteogenic gene and PPARγ2 gene were determined using RT-PCR, the protein level of PPARγ2 was analyzed by Western blotting.

Results

BMSCs cultured in the basal medium with PNS caused a significant increase in proliferation. PNS treatment increased ALP activity, Alizarin red S staining and mRNA level of ALP, Cbfa 1, OC, and BSP, whereas decreased the mRNA level and protein expression of PPARγ2 during osteogenic induction. In addition, the effects of PNS treatment were dose-dependent relationship.

Conclusion

PNS could stimulate BMSCs proliferation and promote their osteogenic differentiation by up-regulation expression of osteogenic marker gene and down-regulation expression of adipogenic marker gene in a dose-dependent manner. Thus, PNS may play an important therapeutic role in osteoporosis patients by improving osteogenic differentiation of BMSCs.     

Quantitative analysis of multiple methylated genes in plasma for the diagnosis and prognosis of hepatocellular carcinoma

This study was aimed to evaluate the clinical value of plasma methylation analysis of a panel of four genes (APC, GSTP1, RASSF1A, and SFRP1), which was identified by our previous work, for the noninvasive diagnosis of hepatocellular carcinoma (HCC). The methylation status of these four genes in 150 plasma samples from 72 patients with HCC, 37 benign live diseases and 41 normal controls was detected with methylation-sensitive restriction enzymes-based quantitative PCR (MSRE-qPCR) method. The plasma methylation levels of APC, GSTP1, RASSF1A, and SFRP1 were significantly higher in HCCs than those in normal or benign controls (P < 0.05). Although the area under the receiver-operation characteristic curve (AUC-ROC) for individual gene was moderate (range, from 0.800 to 0.881), the combination analysis of these four genes resulted in an increased AUC of 0.933 with 92.7% sensitivity, 81.9% specificity, 90.5% positive predictive value (PPV), and 87.2% negative predictive value (NPV) in discriminating HCC from normal control. The combination analysis also indicated an increased AUC of 0.877 when compared with individual gene (from 0.666 to 0.850) in discriminating HCC from benign control, and the consultant sensitivity, specificity, PPV, and NPV was 84.7%, 81.1%, 89.7%, and 73.2%, respectively. Patients with elevated plasma methylation levels of APC or RASSF1A showed poorer overall survival than those with low levels (P < 0.05). Cox multivariate analysis demonstrated methylated RASSF1A in plasma to be an independent prognostic factor for overall survival (hazard ratio = 3.262, 95% CI: 1.476–7.209, P = 0.003). These data showed that quantitative analysis of multiple methylated genes in plasma may be a promising tool for noninvasive diagnosis of HCC; and methylated plasma RASSF1A appears to be a prognostic marker of HCC.     

The impact of age at the time of radiotherapy for localized prostate cancer on the development of second primary malignancies

Purpose

There is a known increased risk of second primary malignancy (SPM) in patients with prostate cancer (CaP) treated with radiotherapy (RT). It is unclear how age at diagnosis influences the risk of SPMs.

Propensity-matched comparison of video-assisted thoracoscopic with thoracotomy lobectomy for locally advanced non–small cell lung cancer

Objective

We evaluated whether video-assisted thoracoscopic lobectomy for locally advanced non–small cell lung cancer could be performed safely and with acceptable long-term outcomes by our improved technique and compared with standard thoracotomy lobectomy in a well-balanced population.

Detection of disseminated tumor cells in locally advanced breast cancer patients before primary systemic therapy

AimTo assess the prevalence and prognostic power of disseminated tumor cells (DTC) in patients with locally advanced breast cancer (LABC) before primary systemic therapy (PST).Materials and methodsLABC patients attending our Breast Unit were studied between 2002 and 2012, all of them being considered for PST. To determine the presence of DTC, posterior iliac crest aspirates were obtained and marrow samples were processed by gradient separation with Ficoll (Lymphoprep^®) and immunohistochemical staining using the antiCK A45-B/B3 (EPIMET) antibody. Clinicopathologic variables were recorded before and after PST to assess response. Disease-free survival (DFS) and overall survival (OS) were determined after follow-up. The presence of DTC as a predictor of response to PST and as a prognostic tool for OS and DSF was evaluated.ResultsDTC were observed in 26% of 47 patients included in the study. PST consisted of chemotherapy in 94% and hormone therapy in 6%. Breast-conserving therapy was attained in 33%. Mean follow-up was 68 months. Complete clinical response (CR) after PST was seen in 26%, disease recurrence in 38%, and cancer-related death in 8%; tumor size and negative estrogen receptors were significant predictors of CR and mastectomy was associated with DFS. Persistent axillary disease after PST and previous recurrence were predictive of OS. DTC were detected more often in patients who did not achieve CR and those who presented recurrence. DTC detection was a significant prognostic factor for a worse OS (OR = 7.62; CI95%: 1.46–39.61; p = 0.009) and a decreased survival time (62 versus 82 months, p = 0.004).ConclusionPresence of DTC before PST was found in a significant number of patients with LABC. DTC were found to be a significant prognostic factor for cancer-related death. DTC could be a surrogate predictor of response to PST and also of disease recurrence in LABC patients.