This article reviews an emerging therapeutic agent, which is currently in phase III development for the treatment of anemia secondary to chronic kidney disease, covering promising phase II results, drug characteristics, and the current phase III trials, which, if approved, may significantly impact the management of anemia in this patient population.
Over the past year, the FDA has issued two letters to healthcare providers alerting them to adverse events associated with ORBERA and ReShape intragastric balloons (IGBs), including several deaths. Both IGB devices were FDA-approved for use in the US in the summer of 2015. Although the adverse events cited in the two letters occurred following FDA approval, there was already evidence prior to FDA approval that the safety and efficacy of ReShape and ORBERA were highly questionable. Since January 1, 2006, ORBERA and Reshape IGB have been implicated in 33 deaths. Given the cited evidence, we recommend FDA withdrawal of these two devices.
Photothermal therapy (PTT) and photodynamic therapy (PDT) both utilize light to induce a therapeutic effect. These therapies are rapidly gaining importance due to the noninvasiveness of light and the limited adverse effect associated with these treatments. However, most preclinical studies show that complete elimination of tumors is rarely observed. Combining PDT and PTT with chemotherapy or radiotherapy can improve the therapeutic outcome and simultaneously decrease side effects of these conventional treatments. Nanocarriers can help to facilitate such a combined treatment. Here, the most recent advancements in the field of photochemotherapy and photoradiotherapy, in which nanocarriers are employed, are reviewed.
Photothermal therapy and photodynamic therapy both utilize light to induce a therapeutic effect. These therapies will benefit tremendously if combined with other therapies such as chemotherapy and radiotherapy. Nanocarriers can help to facilitate such a combined treatment. In this paper, the most recent advancements in the field of photochemotherapy and photoradiotherapy in which nanocarriers are employed are reviewed.
Pheochromocytoma (PCC) and paraganglioma (PGL) are rare neuroendocrine tumors that are hereditary in up to 50% of patients. The gene encoding transmembrane-protein-127 (TMEM127) is one of the PCC/PGL susceptibility genes with an autosomal dominant inheritance pattern. Here we report two patients with bilateral PCC who both harbored a homozygous TMEM127-mutation. In a 31-year old mentally retarded patient the homozygous c.410-2A>G mutation was discovered during an update of DNA-analysis. A 26-year old mentally retarded patient was found to have a homozygous c.3G>A mutation. The parents of both patients were consanguineous. We reviewed previously reported clinical features of TMEM127-mutation carriers and compared our findings with case descriptions of homozygous mutations in other PGL/PCC susceptibility genes. Homozygosity for an autosomal dominant inherited disorder is an extremely rare phenomenon and has, to our knowledge, not been reported before for the gene encoding TMEM127. In the present cases, the clinical picture does not seem to be very different from heterozygous TMEM127-mutation carriers, except for a relatively large tumor size and more pronounced plasma metanephrines concentration. It is unclear whether the mental retardation is causally related to homozygosity of the TMEM127-mutations. Updating genetic screening in patients in whom PCC/PGL has been diagnosed in the past should be considered as it might provide clinically relevant information.
Current prognostic signatures need to be improved in identifying high-risk patients of gastric cancer (GC). Thus, we aimed to develop a reliable prognostic signature that could assess the prognosis risk in GC patients. Two microarray datasets of GSE662254 (n = 300, training set) and GSE15459 (n = 192, test set) were included into analysis. Prognostic genes were screened to construct prognosis-related gene pairs (PRGPs). Then, a penalized Cox proportional hazards regression model identified seven PRGPs, which constructed a prognostic signature and divided patients into high- and low-risk groups according to the signature score. High-risk patients showed a poorer prognosis than low-risk patients in both the training set (hazard ratios [HR]: 6.086, 95% confidence interval [CI]: 4.341–8.533) and test set (1.773 [1.107–2.840]). The PRGPs signature also achieved a higher predictive accuracy (concordance index [C-index]: 0.872, 95% CI: 0.846–0.897) than two existing molecular signatures (0.706 [0.667–0.744] for a 11-gene signature and 0.684 [0.642–0.726] for a 24-lncRNA signature) and TNM stage (0.764 [0.715–0.814]). In conclusion, our study identified a novel gene pairs signature in the prognosis of GC.
We used a novel method to identify a prognostic signature in gastric cancer, which removed the batch effects. The signature also showed a better predictive accuracy than other prognostic signatures.
Salivary gland cancer is an aggressive and painful cancer, but a rare tumor type accounting for only ~0.5% of cancer cases. Tumors of the salivary gland exhibit heterogeneous histologic and genetic features and they are subdivided into different subtypes, with adenoid cystic carcinomas (ACC) being one of the most abundant. Treatment of ACC patients is afflicted by high recurrence rates, the high potential of the tumors to metastasize, as well as the poor response of ACC to chemotherapy. A prerequisite for the development of targeted therapies is insightful genetic information for driver core cancer pathways. Here, we developed a transgenic mouse model toward establishment of a preclinical model. There is currently no available mouse model for adenoid cystic carcinomas as a rare disease entity to serve as a test system to block salivary gland tumors with targeted therapy. Based on tumor genomic data of ACC patients, a key role for the activation of the PI3K-AKT-mTOR pathway was suggested in tumors of secretory glands. Therefore, we investigated the role of Akt3 expression in tumorigenesis and report that Akt3 overexpression results in ACC of salivary glands with 100% penetrance, while abrogation of transgenic Akt3 expression could revert the phenotype. In summary, our findings validate a novel mouse model to study ACC and highlight the druggable potential of AKT3 in the treatment of salivary gland patients.
AKT3 expression is associated with bad prognosis in head and neck cancer. Taking advantage of a novel mouse model, we report that conditional Akt3 overexpression triggers adenoid cystic carcinomas in the salivary glands of mice with 100% penetrance. We further show that these adenoid cystic carcinomas are completely dependent on expression of the oncogene.
We conducted a surveillance epidemiology and end results (SEER)-based analysis to describe the incidence and characteristics of second primary acute lymphoblastic leukemia (sALL) among adults (≥18 years) with a history of primary malignancies (1M). Standardized incidence ratios (SIRs) of sALL cases were calculated by site and 1M stage. We also evaluated the differences in 5-year sALL survival by age, site, and extent of 1M, latency of sALL after 1M, and evidence of underlying racial/ethnic disparity. We identified 10,956 patients with de-novo/primary acute lymphoblastic leukemia (1ALL) and 772 with sALL. Women (49.1% vs. 42.9%), white patients (72.0% vs. 59.5%), older patients (58.8% vs. 25.2%; age ≥65 years), and patients diagnosed between 2003 and 2012 (66.8% vs. 53.9%) had a higher proportion of sALL compared with 1ALL. There was a significantly inferior median 5-year survival for sALL patients compared to 1ALL (6 vs. 15 months; HR 1.20, 95% CI 1.10–1.31, P < 0.001). The median latency period was 60.0 months; the most common 1M among sALL patients were breast (17.9%) and prostate (17.4%). Patients with any 1M were at increased risk of developing sALL (SIR 1.76, 95% CI 1.58–1.95, P < 0.001). Hematological-1M sites had significantly higher SIRs (hematological-SIR 7.35; solid-SIR 1.33; P < 0.001). We observed a significant increase in sALL incidence after a 1M and a significantly worse 5-year survival with different demographic characteristics from 1ALL. There is a need to define appropriate screening methods for patients surviving their primary cancer.
SEER analysis reveals a significant increase in incidence of second primary acute lymphoblastic leukemia (ALL) in adults, an underrecognized entity. Associated with a significantly worse 5-year survival with different demographic characteristics compared to de novo primary ALL.
In eukaryotic cells, autophagy is a process associated with programmed cell death. During this process, cytoplasmic proteins and organelles are engulfed by double-membrane autophagosomes, which then fuse with lysosomes to form autolysosomes. These autolysosomes then degrade their contents to recycle the cellular components. Autophagy has been implicated in a wide variety of physiological and pathological processes that are closely related to tumorigenesis. In recent years, an increasing number of studies have indicated that nonsteroidal anti-inflammatory drugs, such as celecoxib, meloxicam, sulindac, aspirin, sildenafil, rofecoxib, and sodium salicylate, have diverse effects in cancer that are mediated by the autophagy pathway. These nonsteroidal anti-inflammatory drugs can modulate tumor autophagy through the PI3K/Akt/mTOR, MAPK/ERK1/2, P53/DRAM, AMPK/mTOR, Bip/GRP78, CHOP/ GADD153, and HGF/MET signaling pathways and inhibit lysosome function, leading to p53-dependent G1 cell-cycle arrest. In this review, we summarize the research progress in autophagy induced by nonsteroidal anti-inflammatory drugs and the molecular mechanisms of autophagy in cancer cells to provide a reference for the potential benefits of nonsteroidal anti-inflammatory drugs in cancer chemotherapy.
Autophagy: Novel applications of nonsteroidal anti-inflammatory drugs for primary cancer.
The widespread use of high-dose therapy and autologous stem cell transplantation (ASCT) as well as the introduction of novel agents have significantly improved outcomes in multiple myeloma (MM) enabling long-term survival. We here analyze factors influencing survival in 865 newly diagnosed MM patients who underwent first-line ASCT at our center between 1993 and 2014. Relative survival and conditional survival were assessed to further characterize long-term survivors. Achievement of complete response (CR) post-ASCT was associated with prolonged progression-free survival (PFS) in the whole cohort and with significantly superior overall survival (OS) in the subgroup of patients receiving novel agent-based induction therapy. Landmark analyses performed at 1, 3, and 5 years post-ASCT revealed that sustainment of any response had a highly significant influence on survival with no significant differences between sustained CR and sustained inferior responses. Furthermore, outcome was independently improved by administration of maintenance therapy. A subset of patients did experience long-term survival >15 years. However, conditional survival demonstrated a persistent risk of myeloma-associated death and cumulative relative survival curves did not show development of a clear plateau, even in prognostically advantageous groups. In conclusion, in this large retrospective study, sustained response after first-line ASCT was found to be a major prognostic factor for OS independent of depth of sustained response. Administration of maintenance therapy further improved outcome, supporting the hypothesis that interventions to prolong responses achieved post-ASCT may be essential to reach long-term survival, especially in the setting of persisting residual disease.
Long-term analysis of 865 patients with newly diagnosed multiple myeloma treated with first-line autologous stem cell transplantation reveals sustained response after transplantation as a major prognostic factor for survival. Administration of maintenance therapy independently improves outcome, supporting the hypothesis that interventions to prolong responses achieved may be essential to reach long-term survival.
Intracellular Ca2+ concentration ([Ca2+]i) plays crucial roles in the regulation of ciliary beat frequency (CBF) and ciliary bend angle (CBA) of airway cilia. Moreover, Ca2+-dependent PDE1A exists in the CBF regulating metabolon of cilia. This study demonstrated that CBF is regulated by a direct and an indirect action of [Ca2+]i; the direct action changes CBF mediated via [Ca2+]i and the indirect action changes CBF mediated via cAMP, accumulation of which is controlled by the PDE1 activity. Upon reducing [Ca2+]i to various levels, the direct action decreases CBF and the indirect action increases CBF. The final CBF is determined by extents of cAMP accumulation, which are determined by PDE1 activities inhibited dependent on [Ca2+]i decreases; a slight decrease induced by a nominally Ca2+-free solution (no cAMP accumulation via PDE1) decreases CBF and an extreme decrease induced by 50 μm BAPTA-AM increases CBF via cAMP accumulation via inhibiting PDE1 similarly to a PDE1 inhibitor (8MmIBMX). CBA increase in response to [Ca2+]i decreases is smaller than CBF increase, because of no existence of PDE1A in the CBA regulating metabolon. Contrary, an [Ca2+]i increased by ionomycin, which decreases cAMP accumulation by PDE1A activation, caused a slower procaterol-stimulated CBF increase than that decreased by a Ca2+-free solution. A decrease in [Ca2+]i stimulates cAMP accumulation, while an increase in [Ca2+]i inhibits cAMP accumulation in airway ciliary cells. Thus, changes in [Ca2+]i modulate CBF and CBA via cAMP accumulation by controlling the PDE1 activity.
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The coordination of intramodal perceptual grouping and crossmodal interactions plays a critical role in constructing coherent multisensory percepts. However, the basic principles underlying such coordinating mechanisms still remain unclear. By taking advantage of an illusion called temporal ventriloquism and its influences on perceived speed, we investigated how audiovisual interactions in time are modulated by the spatial grouping principles of vision. In our experiments, we manipulated the spatial grouping principles of proximity, uniform connectedness, and similarity/common fate in apparent motion displays. Observers compared the speed of apparent motions across different sound timing conditions. Our results revealed that the effects of sound timing (i.e., temporal ventriloquism effects) on perceived speed also existed in visual displays containing more than one object and were modulated by different spatial grouping principles. In particular, uniform connectedness was found to modulate these audiovisual interactions in time. The effect of sound timing on perceived speed was smaller when horizontal connecting bars were introduced along the path of apparent motion. When the objects in each apparent motion frame were not connected or connected with vertical bars, the sound timing was more influential compared to the horizontal bar conditions. Overall, our findings here suggest that the effects of sound timing on perceived speed exist in different spatial configurations and can be modulated by certain intramodal spatial grouping principles such as uniform connectedness.
Globally, cancer is one of the leading causes of mortality. High treatment cost, partly owing to higher prices of anti-cancer drugs, presents a significant burden on patients and healthcare systems. The aim of the present study was to survey and compare retail prices of anti-cancer drugs between high, middle and low income countries in the South-East Asia, Western Pacific and Eastern Mediterranean regions.
Cross-sectional survey design was used for the present study. Pricing data from ten counties including one from South-East Asia, two from Western Pacific and seven from Eastern Mediterranean regions were used in this study. Purchasing power parity (PPP)-adjusted mean unit prices for 26 anti-cancer drug presentations (similar pharmaceutical form, strength, and pack size) were used to compare prices of anti-cancer drugs across three regions. A structured form was used to extract relevant data. Data were entered and analysed using Microsoft Excel®.
Overall, Taiwan had the lowest mean unit prices while Oman had the highest prices. Six (23.1%) and nine (34.6%) drug presentations had a mean unit price below US$100 and between US$100 and US$500 respectively. Eight drug presentations (30.7%) had a mean unit price of more than US$1000 including cabazitaxel with a mean unit price of $17,304.9/vial. There was a direct relationship between income category of the countries and their mean unit price; low-income countries had lower mean unit prices. The average PPP-adjusted unit prices for countries based on their income level were as follows: low middle-income countries (LMICs): US$814.07; high middle income countries (HMICs): US$1150.63; and high income countries (HICs): US$1148.19.
There is a great variation in pricing of anticancer drugs in selected countires and within their respective regions. These findings will allow policy makers to compare prices of anti-cancer agents with neighbouring countries and develop policies to ensure accessibility and affordability of anti-cancer drugs.
TP53 is the most frequently mutated gene in human cancers. Previous studies reported that TP53 mutations correlated with poor prognoses in patients with head and neck squamous cell carcinoma (HNSCC). However, the relationship between TP53 mutations and hypopharyngeal squamous cell carcinoma (HPSCC) is not known. The current study aimed to evaluate TP53 mutation status as a predictive biomarker in patients with HPSCC.
We retrospectively reviewed the clinical charts of 57 HPSCC patients treated with initial surgery between 2008 and 2014. TP53 mutation status was determined by Sanger sequencing, and patients were classified into wild-type, missense mutation, and truncating mutation groups. Additionally, p53 expression was determined using immunohistochemistry in surgical specimens.
TP53 mutations were identified in 39 (68%) patients. The 3-year disease-specific survival (DSS) rate of wild-type, missense mutation, and truncating mutation group were 94%, 61%, and 43%, respectively. The TP53 mutation group displayed significantly worse DSS and overall survival rates than the wild-type group (P = 0.01 and P = 0.007, respectively). Multivariate analyses revealed that the presence of TP53 mutations and ≥4 metastatic lymph nodes were independent adverse prognostic factors for HPSCC. p53 immunopositivity was detected in 22 patients, including 5 (28%) and 17 (71%) patients in the wild-type and missense mutation groups, whereas none of the patients with truncating mutation exhibited p53 immunopositivity (P = 0.0001).
The TP53 mutation status correlated with poor prognosis in surgically treated HPSCC patients. Specifically, truncating mutations which were not detected by p53 immunohistochemistry were predictive of worst survival.
This study provides a comprehensive examination of the histological features of non-neoplastic parenchyma in renal cell carcinoma (RCC). We prospectively collected radical nephrectomy (RN) specimens, to analyze the histological changes within peritumoral and distant parenchyma.
Data of patients who underwent RN and had no known history of diabetes, hypertension, hyperlipidemia, or chronic kidney disease etc., were prospectively collected. Tumor pseudo-capsule (PC), and parenchyma within 2 cm from tumor margin, were pathologically assessed. The parenchyma beyond PC or tumor margin was divided into 20 subsections of 1 mm in width. Histological changes, including chronic inflammation, glomerulosclerosis, arteriosclerosis and nephrosclerosis, were given scores of 0, 1, 2 or 3 for each subsection of each specimen, according to their severity. The 20 subsections of each specimen were further divided into four groups according to the distance from the tumor edge (group 1: 0–2 mm; group 2: 2–5 mm; group 3: 5–10 mm; group 4: 10–20 mm), to better compare the peritumoral parenchyma with the distant parenchyma.
In total, 53 patients were involved in this study. All tumors were confirmed RCCs (clear cell vs. papillary vs. chromophobe were 83% vs. 5.7% vs. 11.3%, respectively), with a mean size of 5.6 cm. Histological changes were more severe in peritumoral parenchyma close to PC or tumor edge (0–5 mm), and less common within parenchyma more distant from the tumor (5–20 mm) (p < 0.001). chronic inflammation and nephrosclerosis were the most common changes especially in peritumoral parenchyma (0-2 mm). PC was present in 49 tumors (92.5%), and PC invasion occurred in 5 cases (10.2%). Mean PC thickness was 0.7 mm. PCs were more likely to be present in clear cell RCC or papillary RCC than in chromophobe RCC (100% vs. 100% vs. 33.3%, respectively; p < 0.001).
Most RCCs have a well-developed PC, especially clear cell RCC. Histological changes mainly occur in peritumoral parenchyma, being rather uncommon in distant parenchyma. A compression band filled with severe histological changes was typically observed in renal parenchyma close to the tumor. Its preservation while performing an enucleation margin may not be entirely necessary.
In Denmark, national roll-out of a population-based, screening mammography program took place in 2007–2010. We report on outcome of the first four biennial invitation rounds.
Data on screening outcome were retrieved from the 2015 and 2016 national screening quality reports. We calculated coverage by examination; participation after invitation; detection-, interval cancer- and false-positive rates; cancer characteristics; sensitivity and specificity, for Denmark and for the five regions.
At the national level coverage by examination remained at 75–77%; lower in the Capital Region than in the rest of Denmrk. Detection rate was slightly below 1% at first screen, 0.6% at subsequent screens, and one region had some fluctuation over time. Ductal carcinoma in situ (DCIS) constituted 13–14% of screen-detected cancers. In subsequent rounds, 80% of screen-detected invasive cancers were node negative and 40% ≤10 mm. False-positive rate was around 2%; higher for North Denmark Region than for the rest of Denmark. Three out of 10 breast cancers in screened women were diagnosed as interval cancers.
High coverage by examination and low interval cancer rate are required for screening to decrease breast cancer mortality. Two pioneer local screening programs starting in the 1990s were followed by a decrease in breast cancer mortality of 22–25%. Coverage by examination and interval cancer rate of the national program were on the favorable side of values from the pioneer programs. It appears that the implementation of a national screening program in Denmark has been successful, though regional variations need further evaluation to assure optimization of the program.
Hepatocellular (HCC) and cholangiocellular carcinomas (CCC) display an exceptionally poor prognosis. Especially for advanced disease no efficient standard therapy is currently available. Recently, somatostatin analogs have been evaluated for the treatment of HCC, however, with contradictory results. Besides, for both malignancies the chemokine receptor CXCR4 has been discussed as a possible new target structure.
Expression of somatostatin receptor (SSTR) subtypes 1, 2A, 3, 4, and 5, and of CXCR4 was evaluated in a total of 71 HCCs and 27 CCCs by immunohistochemistry using well-characterized novel monoclonal antibodies.
In HCC tumor cells, frequency and intensity of expression of SSTRs and CXCR4 were only low. CXCR4 was present in about 40% of the HCCs, although at a low intensity. SSTR5, SSTR2, and SSTR3 were detected in about 15%, 8%, and 5% of the HCC tumors, respectively. SSTR and CXCR4 expression was much higher in CCC than in HCC. CXCR4 and SSTR1 were present in 60% and 67% of the CCC samples, respectively, followed by SSTR2 and SSTR5, which were detected in 30% and 11% of the tumors, respectively. Most notably, CXCR4 was intensely expressed on the tumor capillaries in about 50% of the HCCs and CCCs. CXCR4 expression on tumor vessels was associated with poor patient outcomes.
CCC, but not HCC, may be suitable for SSTR-based treatments. Because of the predominant expression of SSTR1, pan-somatostatin analogs should be preferred. In both HCC and CCC, indirect targeting of tumors via the CXCR4-positive tumor capillaries may represent a promising additional therapeutic strategy.
To examine the effects of recombinant human endostatin combined with radiotherapy on colorectal cancer HCT-116 cell xenografts in nude mice.
Forty male BALB/c nude mice were injected with human colorectal cancer HCT-116 cells to form xenografts and then randomized into the following 4 groups (each group comprised ten mice): a control group, an endostatin group (20 mg/kg endostatin once a day for 10 days), a radiotherapy group (a 6-Gy dose was administered via a 6-MV X-ray on day 5 post-inoculation), and a combination therapy group (radiotherapy with endostatin treatment). The tumor growth inhibition rate were detected. CD31, vascular endothelial growth factor (VEGF), and hypoxia inducible factor-1α (HIF-1α) expression and microvascular density (MVD) were evaluated by immunohistochemistry. The expression of VEGF protein was also detected by western blotting.
The tumor growth inhibition rate in the radiotherapy with endostatin treatment group was significantly higher than those in endostatin group or radiotherapy group (77.67% vs 12.31% and 38.59%; n = 8 per group, P < 0.05). The results of immunohistochemistry showed that treatment with radiotherapy induced significant increases in CD31, VEGF, and HIF-1α expression and MVD compared with treatment with saline, while treatment with endostatin or radiotherapy with endostatin induced reductions in CD31, VEGF, and HIF-1α expression and MVD compared with treatment with saline (n = 8 per group, P < 0.05). The results of western blotting showed that VEGF protein expression in radiotherapy group was significantly increased compared with that in the control group. However, VEGF protein expression in the endostatin or radiotherapy with endostatin groups was significantly decreased compared with that in the control group (n = 8 per group, P < 0.05).
Endostatin combined with radiotherapy can significantly inhibit HCT-116 cell xenograft growth, possibly by inhibiting angiogenesis and attenuating tumor cell hypoxia.
Associations between polymorphisms of UDP-glucuronosyltransferases (UGTs) or efflux transporters (e.g., P-glycoprotein and MRP2) and different types of cancer have been described, whereas the role of influx transporters (e.g. OATP1B1 and OATP2B1) has been seldom explored. The GenColon study investigated potential associations between variant alleles of UGTs, efflux and influx transporters and CRC.
Three hundred CRC cases were matched with 300 controls for age, sex and enrolment site. Fifteen SNPs in UGT1A6–9, UGT2B7, ABCB1, ABCC2, SLCO1B1 and SLCO2B1 genes were characterized using Taqman® PCR. Using multivariate conditional logistic regression, we investigated the relationships between CRC and "environmental" risk factors (physical activity, housing and working areas, consumption of red meat, tobacco, alcohol); genetic polymorphisms, in the study population and in the subgroups with "environmental" risk factors.
No significant association was observed for the analyzed SNPs (or haplotypes). However, an increased CRC risk was found in carriers of the UGT1A8 rs1042597-G variant allele (additive risk OR = 3.39[1.29–8.89], p = 0.02951) in the subgroup of meat-consumers (n = 84), and in carriers of the ABCB1 rs1045642-T (exon26) variant allele (additive risk; OR = 1.89[1.10–3.39], p = 0.0257) in the "never alcohol consumption subgroup" (n = 125). In addition, as previously reported, the following CRC risk factors were identified: absence of physical activity (OR = 6.35[3.70–10.9], p < 0.0001), living or working in rural or mix area (OR = 2.50[1.48–4.23], p = 0.0006 and OR = 2.99[1.63–5.48], p = 0.004, respectively) and tobacco exposure >30 years (3.37[1.63–6.96], p = 0.0010).
Variant genotypes of influx transporters (OATP1B1 and 2B1) were not associated with CRC. This study confirmed the influence of lifestyle factors, but not the previously reported detrimental effect of SNPs in intestinal UGTs or efflux transporters, except for a UGT1A8 variant in subjects consuming meat and the exon 26 SNP of ABCB1 in the never alcohol consumption subgroup.
Registered in Direction Générale de la Santé the 1st July 2008 under the number DGS2008–0144.
No consensus treatment has been reached for hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT). Hepatic resection (HR) and transarterial chemoembolization (TACE) have been recommended as effective options, but which is better remains unclear. This meta-analysis is to compare the effectiveness of HR and TACE for HCC with PVTT patients.
The PubMed, EMBASE, Cochrane Library, VIP, Wan Fang, and Sino Med databases were systematically searched for comparing HR and TACE treating PVTT.
Twelve retrospective studies with 3129 patients were included. A meta-analysis of 11 studies suggested that the 1-, 2-, 3-, and 5-year overall survival (OS) rates (OR = 0.48, 95% CI = 0.41–0.57, I2 = 37%, P < 0.00001; OR = 0.21, 95% CI = 0.12–0.38, I2 = 43%, P < 0.00001; OR = 0.35, 95% CI = 0.28–0.44, I2 = 53%, P < 0.00001; OR = 0.28, 95% CI = 0.14–0.54, I2 = 72%, P = 0.0001, respectively) favored HR over TACE. In a subgroup analysis, HR had better 1-, 2-,3, 5-year OS for type I PVTT (OR = 0.33, 95% CI = 0.17–0.64, I2 = 20%, P = 0.001; OR = 0.32, 95% CI = 0.16–0.63, I2 = 0%, P = 0.001; OR = 0.18, 95% CI = 0.09–0.36, I2 = 0%, P < 0.00001; OR = 0.07, 95% CI = 0.01–0.32, I2 = 0%, P = 0.0006, respectively) and better 1-, 3-, and 5-year OS for type II PVTT (OR = 0.37, 95% CI = 0.20–0.70, I2 = 59%, P = 0.002; OR = 0.22, 95% CI = 0.13–0.39, I2 = 0%, P < 0.00001; OR = 0.16; 95% CI = 0.03–0.91; I2 = 51%, P = 0.04, respectively). There was no difference in 1-, 3-, or 5-year OS between HR and TACE for type III PVTT (OR = 0.86, 95% CI = 0.61–1.21, I2 = 0%, P = 0.39; OR = 0.83, 95% CI = 0.42–1.64, I2 = 0%, P = 0.59; OR = 0.59, 95% CI = 0.06–-6.04, I2 = 65%, P = 0.66, respectively).
HR may lead to longer OS for some selected HCC patients with PVTT than TACE, especially for type I or II PVTT, with less difference being observed for type III or IV PVTT.
Golgi Membrane Protein 1 (GOLM1), a protein involved in the trafficking of proteins through the Golgi apparatus, has been shown to be oncogenic in a variety of human cancers. Here, we examined the role of GOLM1 in the development of human glioma.
qRT-PCR, immunohistochemistry, and western blot analysis were performed to evaluate GOLM1 levels in cell lines and a cohort of primary human glioma and non-neoplastic brain tissue samples. Glioma cell lines were modified with lentiviral constructs expressing short hairpin RNAs targeting GOLM1 or overexpressing the protein to assess function in proliferation, viability, and migration and invasion in vitro using EdU, CCK8, clone-forming, Transwell assays, 3D tumor spheroid invasion assay and in vivo in orthotopic implantations. Protein lysates were used to screen a membrane-based antibody array to identify kinases mediated by GOLM1. Specific inhibitors of PDGFRα (AG1296) and AKT (MK-2206) were used to examine the regulation of PDGFA/PDGFRα on GOLM1 and the underlying pathway respectively.
qRT-PCR, immunohistochemistry and western blot analysis revealed GOLM1 expression to be elevated in glioma tissues and cell lines. Silencing of GOLM1 attenuated proliferation, migration, and invasion of U251, A172 and P3#GBM (primary glioma) cells, while overexpression of GOLM1 enhanced malignant behavior of U87MG cells. We further demonstrated that activation of AKT is the driving force of GOLM1-promoted glioma progression. The last finding of this research belongs to the regulation of PDGFA/PDGFRα on GOLM1, while GOLM1 was also a key element of PDGFA/PDGFRα-mediated activation of AKT, as well as the progression of glioma cells.
PDGFA/PDGFRα-regulated GOLM1 promotes glioma progression possibly through activation of a key signaling kinase, AKT. GOLM1 interference may therefore provide a novel therapeutic target and improve the efficacy of glioma treatment, particularly in the case of the proneural molecular subtype of human glioma.
Patients with gastric cancer commonly have a poor prognosis, owing to its invasiveness and distant metastasis. Recent studies have confirmed the pivotal role of long non-coding RNAs (lncRNAs) in tumorigenesis and the progression of malignant tumors, including gastric cancer. However, little is known about the molecular mechanism by which lncRNA AK023391 contributes to gastric cancer.
A lncRNA microarray was used to identify the differentially expressed lncRNA AK023391 in gastric cancer and adjacent normal tissues. In addition, RNA fluorescence in situ hybridization (FISH) was used to investigate the association between AK023391 expression and the clinicopathological characteristics and prognosis of patients with gastric cancer. Subsequently, a series of in vitro assays and a xenograft tumor model were used to observe the functions of lncRNA AK023391 in gastric cancer cells. A cancer pathway microarray, bioinformatic analysis, western blotting, and immunochemistry were carried out to verify the regulation of AK023391 and its downstream PI3K/Akt signaling pathway.
Expression of lncRNA AK023391 was significantly upregulated in gastric cancer samples and cell lines in comparison to adjacent normal tissues, and was positively correlated with poor survival in patients with gastric cancer. The multivariate Cox regression model revealed that AK023391 expression acted as an independent prognostic factor for survival in patients with gastric cancer. Knockdown of AK023391 inhibited cell growth and invasion both in vitro and in vivo, and induced apoptosis and cell cycle arrest in gastric cancer cells, whereas its overexpression reversed these effects. Mechanistically, PI3K/Akt signaling mediated the NF-κB, FOXO3a, and p53 pathways. Moreover, downstream transcription factors, such as c-myb, cyclinB1/G2, and BCL-6 might be involved in AK023391-induced tumorigenesis in gastric cancer.
The novel oncogenic lncRNA AK023391 in gastric cancer exerts its effects through activation of the PI3K/Akt signaling pathway, and may act as a potential biomarker for survival in patients with gastric cancer.
The aim of this study was to compare the short-term and mid-term effects of laparoscopic intersphincteric resection with the conventional open approach for patients with low rectal cancer through a meta-analysis.
The PubMed, EMBASE, Cochrane, and Ovid databases were searched for eligible studies until March 2017. Operation time, blood loss, circumferential resection margin-positive rate, distal margin length, number of resected lymph nodes, diverting stoma rate, postoperative overall morbidity, anastomotic leakage, and hospital stay were the main short-term effect endpoints. We also examined disease-free survival, overall survival, local recurrence, and post-operational anal function as secondary outcomes to evaluate the mid-term effects of laparoscopic surgery.
Five studies involving 620 patients were included in the analyses. Compared with the open approach, the laparoscopic ISR had less blood loss (weighted mean difference [WMD] = − 214.65 ml, 95% CI [− 370.44, − 196.13], p < 0.01), less postoperative overall morbidity (OR = 0.58, 95% CI [0.40, 0.86], p < 0.01), and shorter duration of hospital stay (WMD = − 5.87 days, 95% CI [− 11.35, − 0.40], p < 0.05); however, the operation time was significantly longer in the laparoscopic group (WMD = 47.34 min, 95% CI [4.10, 90.58], p < 0.05). No other significant differences were observed.
Laparoscopic ISR for low rectal cancer offers fewer complications and faster recovery, with similar operation quality and mid-term oncological results than the conventional approach. Although this technique is comparatively more complex than the conventional approach and requires practice, laparoscopic ISR shows great potential as a surgical option and deserves further clinical study.
Preclinical radiation biology has become increasingly sophisticated due to the implementation of advanced small animal image guided radiation platforms into laboratory investigation. These small animal radiotherapy devices enable state-of-the-art image guided therapy (IGRT) research to be performed by combining high-resolution cone beam computed tomography (CBCT) imaging with an isocentric irradiation system. Such platforms are capable of replicating modern clinical systems similar to those that integrate a linear accelerator with on-board CBCT image guidance.
In this study, we present a dosimetric evaluation of the small animal radiotherapy research platform (SARRP, Xstrahl Inc.) focusing on small field dosimetry. Physical dosimetry was assessed using ion chamber for calibration and radiochromic film, investigating the impact of beam focus size on the dose rate output as well as beam characteristics (beam shape and penumbra). Two film analysis tools) have been used to assess the dose output using the 0.5 mm diameter aperture.
Good agreement (between 1.7–3%) was found between the measured physical doses and the data provided by Xstrahl for all apertures used. Furthermore, all small field dosimetry data are in good agreement for both film reading methods and with our Monte Carlo simulations for both focal spot sizes. Furthermore, the small focal spot has been shown to produce a more homogenous beam with more stable penumbra over time.
FilmQA Pro is a suitable tool for small field dosimetry, with a sufficiently small sampling area (0.1 mm) to ensure an accurate measurement. The electron beam focus should be chosen with care as this can potentially impact on beam stability and reproducibility.
The aim of this work is to validate the Dynamic Planning Module in terms of usability and acceptance in the treatment planning workflow.
The Dynamic Planning Module was used for decision making whether a plan adaptation was necessary within one course of radiation therapy. The Module was also used for patients scheduled for re-irradiation to estimate the dose in the pretreated region and calculate the accumulated dose to critical organs at risk. During one year, 370 patients were scheduled for plan adaptation or re-irradiation. All patient cases were classified according to their treated body region. For a sub-group of 20 patients treated with RT for lung cancer, the dosimetric effect of plan adaptation during the main treatment course was evaluated in detail. Changes in tumor volume, frequency of re-planning and the time interval between treatment start and plan adaptation were assessed.
The Dynamic Planning Tool was used in 20% of treated patients per year for both approaches nearly equally (42% plan adaptation and 58% re-irradiation). Most cases were assessed for the thoracic body region (51%) followed by pelvis (21%) and head and neck cases (10%). The sub-group evaluation showed that unintended plan adaptation was performed in 38% of the scheduled cases. A median time span between first day of treatment and necessity of adaptation of 17 days (range 4–35 days) was observed. PTV changed by 12 ± 12% on average (maximum change 42%). PTV decreased in 18 of 20 cases due to tumor shrinkage and increased in 2 of 20 cases. Re-planning resulted in a reduction of the mean lung dose of the ipsilateral side in 15 of 20 cases.
The experience of one year showed high acceptance of the Dynamic Planning Module in our department for both physicians and medical physicists. The re-planning can potentially reduce the accumulated dose to the organs at risk and ensure a better target volume coverage. In the re-irradiation situation, the Dynamic Planning Tool was used to consider the pretreatment dose, to adapt the actual treatment schema more specifically and to review the accumulated dose.
Historical data indicate that surgical resection may benefit select patients with metastatic gastric and gastroesophageal junction cancer. However, randomized clinical trials are lacking. The current RENAISSANCE trial addresses the potential benefits of surgical intervention in gastric and gastroesophageal junction cancer with limited metastases.
This is a prospective, multicenter, randomized, investigator-initiated phase III trial. Previously untreated patients with limited metastatic stage (retroperitoneal lymph node metastases only or a maximum of one incurable organ site that is potentially resectable or locally controllable with or without retroperitoneal lymph nodes) receive 4 cycles of FLOT chemotherapy alone or with trastuzumab if Her2+. Patients without disease progression after 4 cycles are randomized 1:1 to receive additional chemotherapy cycles or surgical resection of primary and metastases followed by subsequent chemotherapy. 271 patients are to be allocated to the trial, of which at least 176 patients will proceed to randomization. The primary endpoint is overall survival; main secondary endpoints are quality of life assessed by EORTC-QLQ-C30 questionnaire, progression free survival and surgical morbidity and mortality. Recruitment has already started; currently (Feb 2017) 22 patients have been enrolled.
If the RENAISSANCE concept proves to be effective, this could potentially lead to a new standard of therapy. On the contrary, if the outcome is negative, patients with gastric or GEJ cancer and metastases will no longer be considered candidates for surgical intervention.
The article reports of a health care intervention on human participants and is registered on October 12, 2015 under ClinicalTrials.gov Identifier: NCT02578368; EudraCT: 2014–002665-30.
A wide range of studies has investigated the diagnostic proficiency of extracellular microRNAs (miRNAs) in hepatocellular cancer (HCC). HCC is expected to increase in Sub-Saharan Africa (SSA), due to endemic levels of viral infection (HBV/HIV), ageing and changing lifestyles. This unique aetiological background provides an opportunity for investigating potentially novel circulating miRNAs as biomarkers for HCC in a prospective study in South Africa.
This study will recruit HCC patients from two South African cancer hospitals, situated in Durban and Pietermaritzburg in the province of KwaZulu-Natal. These cases will include both HBV mono-infected and HBV/HIV co-infected HCC cases. The control group will consist of two (2) age and sex-matched healthy population controls per HCC case randomly selected from a Durban based laboratory. The controls will exclude patients if they have any evidence of chronic liver disease. A standardised reporting approach will be adopted to detect, quantify and normalize the level of circulating miRNAs in the blood sera of HCC cases and their controls. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) will be employed to quantity extracellular miRNAs. Differences in concentration of relevant miRNA by case/control status will be assessed using the Wilcoxon rank-sum (Mann-Whitney U) test. Adjustment for multiple testing (Bonferroni correction), receiver operating curves (ROC) and optimal breakpoint analyses will be employed to identify potential thresholds for the differentiation of miRNA levels of HCC cases and their controls.
Although there is a growing base of literature regarding the role of circulating miRNAs as biomarkers, this promising field remains a 'work in progress'. The aetiology of HBV infection in HCC is well understood, as well as it's role in miRNA deregulation, however, the mediating role of HIV infection is unknown. HCC incidence in SSA, including South Africa, is expected to increase significantly in the next decade. A combination of factors, therefore, offers a unique opportunity to identify candidate circulating miRNAs as potential biomarkers for HBV/HIV infected HCC.
Use of dietary supplements among cancer survivors is common and controversial, but information on the amount of nutrients from supplements among cancer survivors is limited. We examined the amount of nutrients and their contribution to total nutrient intake from supplements and compared these data between cancer survivors and cancer-free individuals. We also identified factors associated with supplement use among cancer survivors.
We identified 400 cancer survivors and 10,387 cancer-free individuals, aged ≥ 19 years, from the fifth Korea National Health and Nutrition Examination Survey (KNHANES) V-1, 2 (2010, 2011). We calculated the amount of nutrients consumed from foods and supplements, the percent contributions of supplement nutrients to total nutrient intakes and cancer survivors' nutrient intakes relative to the Estimated Average Requirements (EARs) and the Tolerable Upper Intake Levels (ULs). We examined factors associated with supplement use among cancer survivors.
We found that 33.3% of cancer survivors and 22.1% of cancer-free individuals reported the use of dietary supplements. Compared to cancer-free individuals, cancer survivors had higher intakes of riboflavin, folate, and iron from foods (p < 0.05 for each), and higher intakes of calcium (p = 0.05) and vitamin C (p = 0.01) from foods and supplements. The similar pattern was observed for the percent contributions to total nutrient intake. Cancer survivors had higher proportion of participants below EARs than cancer-free individuals for thiamin and niacin (p < 0.05 for each). The proportions of cancer survivors below the EARs were 61.2% for calcium, 49.1% for riboflavin, and 43.5% for folate and the proportions of cancer survivors above the ULs were 3.3% for iron, and 2.3% for vitamin A. For female cancer survivors, education above an elementary school level, moderate physical activity, low vegetable intake, and high circulating vitamin D levels were associated with supplement use. For male cancer survivors, living in an urban area, no consumption of alcohol, and lower energy intake, were associated with supplement use.
Korean cancer survivors have higher rate of dietary supplement use and higher contribution from supplements to total nutrient intake than cancer-free individuals. Demographic and lifestyle factors were associated with supplement use among cancer survivors.
Adoptive immunotherapy offers great potential for treating many types of cancer but its clinical application is hampered by cross-reactive T cell responses in healthy human tissues, representing serious safety risks for patients. We previously developed a computational tool called Expitope for assessing cross-reactivity (CR) of antigens based on tissue-specific gene expression. However, transcript abundance only indirectly indicates protein expression. The recent availability of proteome-wide human protein abundance information now facilitates a more direct approach for CR prediction. Here we present a new version 2.0 of Expitope, which computes all naturally possible epitopes of a peptide sequence and the corresponding CR indices using both protein and transcript abundance levels weighted by a proposed hierarchy of importance of various human tissues.
We tested the tool in two case studies: The first study quantitatively assessed the potential CR of the epitopes used for cancer immunotherapy. The second study evaluated HLA-A*02:01-restricted epitopes obtained from the Immune Epitope Database for different disease groups and demonstrated for the first time that there is a high variation in the background CR depending on the disease state of the host: compared to a healthy individual the CR index is on average two-fold higher for the autoimmune state, and five-fold higher for the cancer state.
The ability to predict potential side effects in normal tissues helps in the development and selection of safer antigens, enabling more successful immunotherapy of cancer and other diseases.
Invasive micropapillary carcinoma of the breast (IMPC) is a histological tumor variant that occurs with low frequency characterized by an inside-out formation of tumor clusters with a pseudopapillary arrangement. IMPC is an aggressive tumor with poor clinical outcome. In addition, this histological subtype usually expresses human epidermal growth factor receptor 2 (HER2) which also correlates with a more aggressive tumor. In this work we studied the clinical significance of IMPC in HER2-positive breast cancer patients treated with adjuvant trastuzumab. We also analyzed mucin 4 (MUC4) expression as a novel biomarker to identify IMPC.
We retrospectively studied 86 HER2-positive breast cancer patients treated with trastuzumab and chemotherapy in the adjuvant setting. We explored the association of the IMPC component with clinicopathological parameters at diagnosis and its prognostic value. We compared MUC4 expression in IMPC with respect to other histological breast cancer subtypes by immunohistochemistry.
IMPC, either as a pure entity or associated with invasive ductal carcinoma (IDC), was present in 18.6% of HER2-positive cases. It was positively correlated with estrogen receptor expression and tumor size and inversely correlated with patient's age. Disease-free survival was significantly lower in patients with IMPC (hazard ratio = 2.6; 95%, confidence interval 1.1–6.1, P = 0.0340). MUC4, a glycoprotein associated with metastasis, was strongly expressed in all IMPC cases tested. IMPC appeared as the histological breast cancer subtype with the highest MUC4 expression compared to IDC, lobular and mucinous carcinoma.
In HER2-positive breast cancer, the presence of IMPC should be carefully examined. As it is often not informed, because it is relatively difficult to identify or altogether overlooked, we propose MUC4 expression as a useful biomarker to highlight IMPC presence. Patients with MUC4-positive tumors with IMPC component should be more frequently monitored and/or receive additional therapies.
Adoptive transfer of donor NK cells has the potential of mediating graft-versus-leukemia (GVL) effect while suppressing acute graft-versus-host-disease (aGVHD) during allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, these beneficial effects are limited by the transient function of adoptively transferred NK cells. Previous studies demonstrate that cytokine-induced memory-like NK cells that are preactivated by IL-12, IL-15, and IL-18 have enhanced effector functions and long life span in vivo. Here, we investigated the effects of IL-12/18-preactivated and IL-12/15/18-preactivated donor NK cells on GVL and aGVHD in a murine model of allo-HSCT. We found that both IL-12/18- and IL-12/15/18-preactivated NK cells mediated stronger GVL effect than control NK cells mainly due to their elevated activation/cytotoxicity and sustained proliferative potential. Interestingly, we observed that although both IL-12/18- and IL-12/15/18-preactivated NK cells significantly inhibited severe aGVHD, only the IL-12/18-preactivated NK cells maintained the beneficial effect of donor NK cells on mild aGVHD. The IL-12/15/18-preactivated NK cell infusion accelerated aGVHD in the fully-mismatched mild aGVHD model. Our results demonstrated that IL-12/18-preactivated NK cells displayed sustained and enhanced GVL functions, and could mitigate aGVHD despite the severity of the disease. IL-12/18-preactivated donor NK cell infusion may be an effective and safe adoptive therapy after allo-HSCT.
This article is protected by copyright. All rights reserved
FHIT is a genome caretaker/tumor suppressor that is silenced in >50% of cancers. Although it was identified more than 20 years ago, questions remain as to how FHIT loss contributes to cancer, and conversely, how FHIT acts to maintain genome integrity and suppress malignancy. Fhit belongs to the histidine triad family of enzymes that catalyze the degradation of nucleoside 5′,5′-triphosphates, including the m7GpppN 'caps' that are generated when mRNAs undergo 3′-5′ decay. This raised the possibility that Fhit loss might affect changes in the translation of cancer-associated mRNAs, possibly as a consequence of increased intracellular concentrations of these molecules.
Ribosome profiling identified several hundred mRNAs for which coding region ribosome occupancy changed as a function of Fhit expression. While many of these changes could be explained by changes in mRNA steady-state, a subset of these showed changes in translation efficiency as a function of Fhit expression. The onset of malignancy has been linked to changes in 5'-UTR ribosome occupancy and this analysis also identified ribosome binding to 5′-untranslated regions (UTRs) of a number of cancer-associated mRNAs. 5'-UTR ribosome occupancy of these mRNAs differed between Fhit-negative and Fhit-positive cells, and in some cases these differences correlated with differences in coding region ribosome occupancy.
In summary, these findings show Fhit expression impacts the translation of a number of cancer associated genes, and they support the hypothesis that Fhit's genome protective/tumor suppressor function is associated with post-transcriptional changes in expression of genes whose dysregulation contributes to malignancy.
I recently cared for a middle-aged woman, Ms. G. who presented with an acute coronary syndrome. Some years ago, she'd had a cardiac arrest and was found to have extensive coronary artery disease, for which she underwent urgent multivessel coronary-artery bypass surgery. Though we often assume that…
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In the past decade, the oncology community has witnessed major advances in the understanding of cancer biology and major breakthroughs in several different therapeutic areas, from solid tumors to hematological malignancies; moreover, the advent of effective immunotherapy approaches, such as immune-checkpoint blockade, is revolutionizing treatment algorithms in almost all oncology disease areas. As knowledge evolves and new weapons emerge in the "war against cancer", clinical and translational research need to adapt to a rapidly changing environment to effectively translate novel concepts into sustainable and accessible therapeutic options for cancer patients.
With this in mind, translational cancer researchers, oncology professionals, treatment experts, CRO and industry leaders, as well as patient representatives gathered in London, 16-17 March 2017, for The International Congress on Clinical Trials in Oncology and Hemato-Oncology (ICTO2017), to discuss the changing face of oncology clinical trials in the new era of personalized medicine and immuno-oncology. A wide range of topics, including clinical trial design in immuno-oncology, biomarker-oriented drug development paths, statistical design and endpoint selection, challenges in the design and conduct of personalized medicine clinical trials, risk-based monitoring, financing and reimbursement, as well as best operational practices, were discussed in an open, highly interactive format, favoring networking among all relevant stakeholders. The most relevant data, approaches and issues emerged and discussed during the conference are summarized in this report.
Pancreatic cancer, especially in case of locally advanced stage has a poor prognosis. Radiotherapy in general can lead to tumor volume reduction, but further improvements, such as ion beam therapy have to be promoted in order to enable dose escalation, which in turn results in better local control rates and downsizing of the tumor itself. Ion beam therapy with its highly promising physical properties is also accompanied by distinct inter- and intrafractional challenges in case of robustness. First clinical results are promising, but further research in motion mitigation and biological treatment planning is necessary, in order to determine the best clinical rationales and conditions of ion beam therapy of pancreatic cancer. This review summarizes the current knowledge and studies on ion beam therapy of pancreatic cancer.
Ralph Northam, a pediatric neurologist who was recently elected governor of Virginia, distinguished himself during the gubernatorial race by calling President Donald Trump a "narcissistic maniac." Northam drew criticism for using medical diagnostic terminology to denounce a political figure, though…
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I recently cared for a middle-aged woman, Ms. G. who presented with an acute coronary syndrome. Some years ago, she'd had a cardiac arrest and was found to have extensive coronary artery disease, for which she underwent urgent multivessel coronary-artery bypass surgery. Though we often assume that…
http://ift.tt/2CeAFuU
In this study, we assessed the precision and trueness of dental models printed with 3-dimensional (3D) printers via different printing techniques.
http://ift.tt/2zE9bw0
Little is known regarding how the mandible rotates in facial asymmetry. The purpose of this study was to study mandibular misalignment with a new plane-to-plane analysis method in patients with facial asymmetry.
http://ift.tt/2C1Afve
Thank you for your comments on our study published in the AJO-DO (Ohiomoba H, Sonis A, Yansane A, Friedland B. Quantitative evaluation of maxillary alveolar cortical bone thickness and density using computed tomography imaging Am J Orthod Dentofacial Orthop 2017;151:82-91), and we are pleased to respond to those comments.
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In this study, we investigated volumetric and dimensional changes to the pharyngeal airway space after isolated mandibular setback surgery for patients with Class III skeletal dysplasia.
http://ift.tt/2C28DpK
We have previously discussed the use of conventional logistic regression when our aim is to assess binary or, in other words, dichotomous categorical outcomes.1,2 That is when the possible answers after examining the outcome variable can be either "yes" or "no." One such example in orthodontics is crowding alleviation after the use of different therapeutic approaches. Crowding alleviation can be either resolved—"yes"—or not resolved—"no."
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The aim of this study was to analyze the time-dependent in-vitro behavior of the periodontal ligament (PDL) by determining the material parameters using specimens of porcine jawbone. Time-dependent material parameters to be determined were expected to complement the results from earlier biomechanical studies.
http://ift.tt/2C258iY
More than 45 years ago, in the first edition of this book, Dr T. M. Graber noted that "there is no single text that adequately serves the needs and interests of clinicians, orthodontic specialists and students" and "the profession needs one badly." Now in its sixth edition, Orthodontics: Current principles and techniques, understandably remains the most globally used graduate orthodontic textbook. Thoroughly updated, this edition ensures a mastery of the latest scientific and clinical information available in our specialty.
http://ift.tt/2zEyWvZ
The purpose of this 2-arm parallel trial was to assess the effect of the AcceleDent Aura appliance (OrthoAccel Technologies, Houston, Tex) on the rate of maxillary premolar extraction space closure in adolescent patients.
http://ift.tt/2C1FniX
Orthodontics has progressed greatly in the last decade. Many new devices and concepts have been developed, whereas others have disappeared. Randomized trials, systematic reviews, and meta-analyses have shown that some things we believed to be true are actually false, or at least not as simple as we once thought. There is an abundance of information, but it is not always easy to find credible references. The emphasis on evidence-based practice is becoming increasingly important, since commercially driven claims are readily available.
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In this study, we aimed to analyze craniofacial morphology by assessing the skeletal cephalometric profiles of HIV-positive patients receiving antiretroviral therapy.
http://ift.tt/2BZBOcQ
In 2015, the American Association of Orthodontists (AAO) established a new award, the Lifetime Achievement Award for Orthodontic Research. The first recipient of this award was Dr William R. Proffit, who received his award at the AAO Annual Session in 2017. Also that year, nominations were solicited for the next year's award. Nominees should be those who have made significant contributions to the science related to the specialty of orthodontics. Their research should be considered original, outstanding, or innovative.
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This case report describes the orthodontic retreatment a patient with a skeletal Class III malocclusion. The clinical examination showed a concave profile caused by a retruded maxilla and a prognathic mandible, an occlusal cant, and absence of all first premolars. A surgery-first approach was combined with skeletal anchorage implants in the maxillary arch and tandem mechanics. The esthetic facial profile, pleasant smile, appropriate occlusion, and overall good treatment outcomes remained stable 5 years after active orthodontic treatment.
http://ift.tt/2C1mqwO
Issued by the Dental Council on 7 April 2017
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I read the article by Ohiomoba et al in the January issue and appreciated the accomplishment and results of this retrospective clinical study (Ohiomoba H, Sonis A, Yansane A, Friedland B. Quantitative evaluation of maxillary alveolar cortical bone thickness and density using computed tomography imaging. Am J Orthod Dentofacial Orthop 2017;151:82-91). The authors proposed to characterize alveolar cortical bone thickness and density in the maxilla and to explore patient factors that may significantly affect these bone properties.
http://ift.tt/2C256rm
Amini F, Shariati M, Sobouti F, Rakhshan V. Effects of fixed orthodontic treatment on nickel and chromium levels in gingival crevicular fluid as a novel systemic biomarker of trace elements: A longitudinal study. Am J Orthod Dentofacial Orthop 2016;149:666-72.
http://ift.tt/2zE97wg
Skeletal and dental discrepancies cause asymmetric malocclusions in orthodontic patients. It is difficult to achieve adequate functional occlusion and guidance in patients with congenital absence of a mandibular incisor due to the tooth-size discrepancy. Here, we describe the orthodontic treatment of a 22-year-old woman with an asymmetric Angle Class II malocclusion, mandibular deviation to the left, and 3 mandibular incisors. The anterior teeth and maxillary canines were crowded. We used an improved superelastic nickel-titanium alloy wire (Tomy International, Tokyo, Japan) to compensate for the asymmetric mandibular arch and an asymmetrically bent archwire to move the maxillary molars distally.
http://ift.tt/2BZBM4I
Irritable bowel syndrome and endometriosis are two diseases affecting a significant part of the female population, either together or individually, with remarkable consequences in the quality of life. Several studies suggest an epidemiological association between them. Their association may not be just an epidemiological phenomenon, but the manifestation of a pathophysiological correlation, which probably generates a mutual promotion phenomenon. In particular, both clinical entities share the presence of a chronic low-grade inflammatory state at the basis of the disease persistence.
http://ift.tt/2BMGL4L
Non-alcoholic fatty liver disease (NAFLD) is associated with substantial cardiometabolic morbidity.
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Investigators need novel methods for timely identification of patients with serious illness to test or implement new palliative care models.
http://ift.tt/2C029Yq
Providing care to cancer patients in resource-poor settings often demands complex trade-offs regarding resource allocation. It is estimated that over 60% of all cancer deaths worldwide occur in low- and middle-income countries (LMICs), where channels to care and appropriate symptom management interventions are overstressed or obsolete. Concepts of distributive justice underlie much of global health policy. As appetites for expanding global palliative care services increase so do questions of fair and culturally appropriate distribution.
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Thousands of family members worldwide are annually involved in assisted dying. Family participation in assisted dying has rarely been investigated and families' needs typically are not considered in assisted dying legislation and clinical guidelines.
http://ift.tt/2BZvQbT
Pediatric palliative care has no evidence-based needs assessment measure. The Parent and Child Needs Survey (PCNeeds) is a new instrument designed to assess the needs of children in palliative care, including children receiving end-of-life care, and their families.
http://ift.tt/2zEsxB2
The extremity edema of advanced disease is a common, multifactorial feature, which impairs patient activities and quality of life. The most frequently chosen management is based on combined decongestive physiotherapy or pharmacotherapy (with diuretics or steroids). Subcutaneous lymphatic drainage in refractory edema may decrease the swelling, prevent spontaneous lymphorrhoea but also increase the risk of infection. Safe and effective conservative management in diuretics resistant edemas is lacking.
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Although several publications document the healthcare disparities experienced by sexual and gender minorities (SGMs), including lesbian, gay, bisexual, and transgender (LGBT) individuals,1-4 less is known about the experiences and outcomes for SGM families and individuals in hospice and palliative care (HPC) settings. This article provides a brief overview of issues pertaining to SGMs in HPC settings, highlighting gaps in knowledge and research. Current and best practices for SGM individuals and their families in HPC settings are described, as are recommendations for improving the quality of such care.
http://ift.tt/2zDsxBn
Oral lichen planus (OLP) is an autoimmune inflammatory disease of the oral mucosa whose etiology remains unknown. Moreover, the possibility of OLP being a premalignant change is under debate. Various types of immune cells infiltrate the OLP lesion and affect its clinicopathological features. However, the diversity of infiltrating immune cells has not been fully clarified in relation to OLP diagnosis. In this study, we quantitatively examined CD8 (+) lymphocyte infiltration by immunohistochemistry, which is the principal effector of cytotoxic immune reaction in 123 cases of OLP specimens.
http://ift.tt/2BLps46
Mixed adenoneuroendocrine carcinoma (MANEC) is a rare pathologic entity defined as a tumor exhibiting both adenocarcinoma and neuroendocrine carcinoma components. Though uncommon, these tumors show aggressive behavior and generally portend a poor prognosis. This study seeks to further define clinicopathological characteristics of MANEC to aid in accurate diagnosis and properly direct clinical management. Thirty-four confirmed MANECs were identified in our twenty-five year retrospective review of cases arising in the gastrointestinal tract.
http://ift.tt/2BKuHRq
We thank the authors for their interests in our article [1]. As the authors pointed out, parotid gland is the most common site of epithelial salivary gland neoplasms in adult and pediatric populations, which has been confirmed by the results of our study where we found 36 of 57 tumors (63%) to be located in the parotid gland. Unlike the reported data from tumor registries, the histology of all tumors included in the current study was reviewed and classified by three specialized head and neck pathologists, using the most up-to-date classification and diagnostic criteria.
http://ift.tt/2C1v2nf
We recently identified a novel histological subtype of hepatocellular carcinoma, designated as "macrotrabecular-massive" (MTM-HCC) and associated with specific molecular features. In order to assess the clinical relevance of this novel variant, we aimed to investigate its prognostic value in two large series of patients with HCC treated either by surgical resection or radiofrequency ablation (RFA).
We retrospectively included 237 HCC surgical samples and 284 HCC liver biopsies from patients treated by surgical resection and RFA, respectively. Histological slides were reviewed by pathologists specialized in liver disease, and the MTM-HCC subtype was defined by the presence of a predominant (>50%) macrotrabecular architecture (more than 6 cells thick). The main clinical and biological features were recorded at baseline. Clinical endpoints were early and overall recurrence.
The MTM-HCC subtype was identified in 12% of the whole cohort (16% of surgically resected samples, 8.5% of liver biopsy samples). It was associated at baseline with known poor prognostic factors (tumor size, AFP level, satellite nodules and vascular invasion). Multivariate analysis showed that MTM-HCC subtype was an independent predictor of early and overall recurrence (surgical series: OR 3.03 (1.38-6.65), p=0.006 and 2.76 (1.63-4.67), p<0.001); RFA series: 2.37 (1.36-4.13), p=0.002 and 2.19 (1.35-3.54), p=0.001, respectively). Its prognostic value was retained even after patients stratification according to common clinical, biological and pathological features of aggressiveness. No other baseline parameter was independently associated to recurrence in the RFA series.
Conclusion: The MTM-HCC subtype, reliably observed in 12% of patients eligible for a curative treatment, represents an aggressive form of HCC that may require more specific therapeutic strategies. This article is protected by copyright. All rights reserved.
Obtaining feedback from our environment and estimating the internal states of our body is essential for decision making and survival. Humans constantly integrate inputs from multiple sensory sources in an unconscious fashion over all available channels. Millions of sensors located in the eye, ear, and skin collect hundreds of thousands of bits per second (Küpfmüller, 1974). Unconscious sensory integration and processing is necessary to prevent information overload from these sensory inputs. This intrinsic mechanism is essential to function, yet, overlooked under normal physiological conditions.
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New England Journal of Medicine, Ahead of Print.
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New England Journal of Medicine, Ahead of Print.
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The hydraulic capacitance of biomass is a key component of the vegetation water budget, which serves as a buffer against short and long-term drought stresses. Here, we present a protocol for the calibration and use of soil moisture capacitance sensors to monitor water content in the stems of large trees.
http://ift.tt/2E2ZwlW
Age is the single greatest risk factor for many diseases, including oral diseases. Despite this, a majority of preclinical oral health research has not adequately considered the importance of aging in research aimed at the mechanistic understanding of oral disease. Here, we have attempted to provide insights from animal studies in the geroscience field and apply them in the context of oral health research. In particular, we discuss the relationship between the biology of aging and mechanisms of oral disease. We also present a framework for defining and utilizing age-appropriate rodents and present experimental design considerations, such as the number of age-points used and the importance of genetic background. While focused primarily on rodent models, alternative animal models that may be particularly useful for studies of oral health during aging, such as companion dogs and marmoset monkeys, are also discussed. We hope that such information will aid in the design of future preclinical studies of geriatric dental health, thus allowing more reliability for translation of such studies to age-associated oral disease in people.
A highly pure population of megakaryocytes can be obtained from cord blood-derived CD34+ cells. A method for CD34+ cell isolation and megakaryocyte differentiation is described here.
http://ift.tt/2Dmcfin
Publication date: Available online 26 December 2017
Source:Women and Birth
Author(s): Billie Bradford, Robyn Maude
ProblemDecreased fetal movements is a common reason for unscheduled antenatal assessment and is associated with adverse pregnancy outcome.BackgroundFetal movement counting has not been proven to reduce stillbirths in high-quality studies.AimsThe aim was to explore a qualitative account of fetal movements in the third trimester as perceived by pregnant women themselves.MethodsUsing qualitative descriptive methodology, interviews were conducted with 19 women experiencing an uncomplicated first pregnancy, at two timepoints in their third trimester. Interview transcripts were later analysed using qualitative content analysis.FindingsPregnant women described a sustained increase in strength, frequency and variation in types of fetal movements from quickening until 28–32 weeks. Patterns of fetal movement were consistently described as involving increased movement later in the day and as having an inverse relationship to the women's own activity and rest. At term, the most notable feature was increased strength. Kicking and jolting movements decreased whilst pushing and rolling movements increased.DiscussionMaternal descriptions of fetal activity in this study were consistent with other qualitative studies and with ultrasound studies of fetal development.ConclusionPregnant women observe a complex range of fetal movement patterns, actions and responses that are likely to be consistent with normal development. Maternal perception of a qualitative change in fetal movements may be clinically important and should take precedence over any numeric definition of decreased fetal movement. Midwives may inform women that it is normal to perceive more fetal movement in the evening and increasingly strong movements as pregnancy advances.
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Colorectal cancer (CRC) is driven by the accumulation of driver mutations, but the contributions of specific mutations to different steps in malignant progression is not fully understood. In this study, we generated mouse models harboring different combinations of key CRC driver mutations (Apc, Kras, Tgfbr2, Trp53, Fbxw7) in intestinal epithelial cells to comprehensively investigate their roles in the development of primary tumors and metastases. Apc∆716 mutation caused intestinal adenomas and combination with Trp53R270H mutation or Tgfbr2 deletion induced submucosal invasion. The addition of KrasG12D mutation yielded EMT-like morphology and lymph vessel intravasation of the invasive tumors. In contrast, combinations of Apc∆716 with KrasG12D and Fbxw7 mutation was insufficient for submucosal invasion but still induced EMT-like histology. Studies using tumor-derived organoids showed that KrasG12D was critical for liver metastasis following splenic transplantation, when this mutation was combined with either Apc∆716 plus Trp53R270H or Tgfbr2 deletion, with the highest incidence of metastasis displayed by tumors with a Apc∆716 KrasG12D Tgfbr2-/- genotype. RNAseq analysis of tumor organoids defined distinct gene expression profiles characteristic for the respective combinations of driver mutations, with upregulated genes in Apc∆716 KrasG12D Tgfbr2-/- tumors found to be similarly upregulated in specimens of human metastatic CRC. Our results show how activation of Wnt and Kras with suppression of TGF-β signaling in intestinal epithelial cells is sufficient for CRC metastasis, with possible implications for the development of metastasis prevention strategies.
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The H3K4 demethylase KDM5B is amplified and overexpressed in luminal breast cancer, suggesting it might constitute a potential cancer therapy target. Here we characterize, in breast cancer cells, the molecular effects of a recently developed small-molecule inhibitor of the KDM5 family of proteins (KDM5i), either alone or in combination with the DNA demethylating agent 5-aza-2'-deoxycytidine (DAC). KDM5i treatment alone increased expression of a small number of genes, whereas combined treatment with DAC enhanced the effects of the latter for increasing expression of hundreds of DAC-responsive genes. ChIP-seq studies revealed that KDM5i resulted in the broadening of existing H3K4me3 peaks. Furthermore, cells treated with the drug combination exhibited increased promoter and gene body H3K4me3 occupancy at DAC-responsive genes compared to DAC alone. Importantly, treatment with either DAC or DAC+KDM5i induced a dramatic increase in H3K27ac at enhancers with an associated significant increase in target gene expression, suggesting a previously unappreciated effect of DAC on transcriptional regulation. KDM5i synergized with DAC to reduce the viability of luminal breast cancer cells in in-vitro assays. Our study provides the first look into the molecular effects of a novel KDM5i compound and suggests that combinatorial inhibition along with DAC represents a new area to explore in translational epigenetics.
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Glioblastoma (GBM) tumors exhibit potentially actionable genetic alterations against which targeted therapies have been effective in treatment of other cancers. However, these therapies have largely failed in GBM patients. A notable example is EGFR kinase inhibitors, which display poor clinical efficacy despite overexpression and/or mutation of EGFR in >50% of GBM. In addressing this issue, preclinical models may be limited by the inability to accurately replicate pathophysiological interactions of GBM cells with unique aspects of the brain extracellular matrix (ECM), which is relatively enriched in hyaluronic acid (HA) and flexible. In this study, we present a brain-mimetic biomaterial ECM platform for 3D culturing of patient-derived GBM cells, with improved pathophysiological properties as an experimental model. Compared to orthotopic xenograft assays, the novel biomaterial cultures we developed better preserved the physiology and kinetics of acquired resistance to the EGFR inhibition than gliomasphere cultures. Orthogonal modulation of both HA content and mechanical properties of biomaterial scaffolds was required to achieve this result. Overall, our findings show how specific interactions between GBM cell receptors and scaffold components contribute significantly to resistance to the cytotoxic effects of EGFR inhibition.
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Inflammasomes are key regulators of innate immunity in chronic inflammatory disorders and autoimmune diseases, but their role in inflammation-associated tumorigenesis remains ill-defined. Here we reveal a pro-tumorigenic role in gastric cancer (GC) for the key inflammasome adaptor ASC and its effector cytokine IL-18. Genetic ablation of ASC in the gp130F/F spontaneous mouse model of intestinal-type GC suppressed tumorigenesis by augmenting caspase-8-like apoptosis in the gastric epithelium, independently from effects on myeloid cells and mucosal inflammation. This phenotype was characterized by reduced activation of caspase-1 and NF-κB activation and reduced expression of mature IL-18, but not IL-1β, in gastric tumors. Genetic ablation of IL-18 in the same model also suppressed gastric tumorigenesis, whereas blockade of IL-1β and IL-1α activity upon genetic ablation of the IL-1 receptor had no effect. The specific pro-tumorigenic role for IL-18 was associated with high IL-18 gene expression in the gastric tumor epithelium compared to IL-1β, which was preferentially expressed in immune cells. Supporting an epithelial-specific role for IL-18, we found it to be highly secreted from human GC cell lines. Moreover, IL-18 blockade either by a neutralizing anti-IL-18 antibody or by CRISPR/Cas9-driven deletion of ASC augmented apoptosis in human GC cells. In clinical specimens of human GC tumors, we observed a significant positive correlation between elevated mature IL-18 protein and ASC mRNA levels. Collectively, our findings reveal the ASC/IL-18 signaling axis as a candidate therapeutic target in GC.
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The new standard makes Kansas the 38th state in the country to have CPR training as a high school graduation requirement
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This protocol describes a method to image resident tumor-infiltrating CD8 T cells labeled with fluorescently coupled antibodies within human lung tumor slices. This technique permits real-time analyses of CD8 T cell migration using confocal microscopy.
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