Small Set Of Patients Research Articles

Přínos tenkojehlové aspirační bio psie a klasifi kace Bethesda v diagnostice tumorů štítné žlázy – retrospektivní studie

Introduction: Thyroid nodule is a pathology with a prevalence of 19–68% of the population, with a thyroid gland carcinoma proven in 7–15% of these cases. Bethesda classifi cation is a standardized system for cytology fi ndings evaluation. Aim of work: The aim of our work was to compare a predicted preoperative dia gnosis including Bethesda classifi cation and the fi nal histology results, to defi ne malignancy risk for Bethesda categories and to compare our fi ndigs with foreign papers. Material and methods: A retrospective, observational study. In a group of 330 patients with performed operation on the thyroid gland (total thyroidectomy or hemithyroidectomy) at the ENT department of the University hospital in Pilsen between 2016 and 2017 there was a group of 180 patients (147 female and 33 male patients) with preoperatively known Bethesda category. We have compared an expected dia gnosis and postoperatively known histology dia gnosis, determined a risk of malignancy rate for each category of Bethesda classifi cation and compared our results with a foreign literature. Results: In the group of our patients, we have determined a risk of malignancy rate for Bethesda I. category as 14.29%, same as for Bethesda II. For Bethesda III. as 15.79%, Bethesda IV. as 10.64%, Bethesda V. as 52.17% and Bethesda VI. category as 100%. Conclusion: Fine- -needle aspiration bio psy of thyroid gland nodules is a basic dia gnostic method, which facilitates categorization and stratifi cation of a risk of malignancy in cytological fi ndings. In our group of patients, a risk of malignancy rate diff ers in Bethesda I. and II. category, our risk of malignancy rate is higher compared to foreign literature, which, we believe, is a statistical error due to a rather small set of patients. Key words thyroid nodule – fine-needle aspiration bio psy – Bethesda classifi cation – risk of malignancy rate

Recent Improvements in the Treatment of High-Risk Thyroid Cancer

Thyroid cancer is one of the slow-growing tumors with excellent oncological outcomes. However, a small set of patients with unexpectedly severe outcomes are usually ignored. Anaplastic thyroid cancer (ATC) remains one of the most aggressive and lethal solid tumors. Recently, dabrafenib and trametinib combination therapy or neoadjuvant BRAF induction therapy has shown promising results. In addition, a combination of targeted drugs, immunotherapy, surgery, and radiation therapy can improve overall survival in ATC patients. Another disease for which there is no breakthrough treatment is radioactive iodine-refractory differentiated thyroid cancer (DTC). To date, multikinase inhibitors (sorafenib, lenvatinib) targeting the growth factor signaling pathway have been developed and approved as anticancer agents for patients with advanced DTC. This review includes results from multikinase inhibitors to the emergence of new target molecules, including rearrangements during transformation (RET) and tropomyosin receptor kinase (TRK).

Inflamatorní myofibroblastický tumor v otorinolaryngologii

Introduction: Inflammatory myofibroblastic tumour (IMT) is a rare tumour with borderline biological behaviour composed of fibroblasts and myofibroblasts and accompanied by non-neoplastic inflammatory cells. It occurs mostly in children and young adults. The disease is most commonly seen in abdominal soft tissues (omentum, mesentery, etc.), in the lungs and also has been reported in other parts of gastrointestinal tract and other organs. In the head and neck region IMT is not so common, it may occur in larynx, trachea or nasal sinuses. The primary therapeutic approach is a complete surgical excision. Radiation, chemotherapy or biological treatment modalities are used in aggressive, non-resectable, and recurrent tumours or in case of metastases. Aims: Through a case report on a small set of patients and up-to-date information from the literature, the authors want to share knowledge about the rare diagnosis of IMT in ENT, its possible clinical manifestations, differential diagnosis and appropriate treatment. The group of patients, the case report: The paper presents patients with IMT treated at the Department of Otorhinolaryngology and Head and Neck Surgery, University Hospital Hradec Kralove in the years 2013–2020. The case of a 11-year-old boy with progressive dyspnoea caused by polypoid tracheal tumour is discussed in more detail. The tumour was removed by external surgical approach with bronchoscopy assistance. Histological examination proved an IMT. Conclusion: IMT is a rare neoplasm which must be included in the differential diagnosis of tumours of the respiratory tract, especially in children and young adults. The treatment consists of complete surgical removal and regular follow-up due to the risk of local recurrence. Keywords: inflammatory myofibroblastic tumour – dyspnoea in a child – tracheal tumour

Identifying gene expression-based biomarkers in online learning environments.

Gene expression-based classifiers are often developed using historical data by training a model on a small set of patients and a large set of features. Models trained in such a way can be afterwards applied for predicting the output for new unseen patient data. However, very often the accuracy of these models starts to decrease as soon as new data is fed into the trained model. This problem, known as concept drift, complicates the task of learning efficient biomarkers from data and requires special approaches, different from commonly used data mining techniques. Here, we propose an online ensemble learning method to continually validate and adjust gene expression-based biomarker panels over increasing volume of data. We also propose a computational solution to the problem of feature drift where gene expression signatures used to train the classifier become less relevant over time. A benchmark study was conducted to classify the breast tumors into known subtypes by using a large-scale transcriptomic dataset (∼3500 patients), which was obtained by combining two datasets: SCAN-B and TCGA-BRCA. Remarkably, the proposed strategy improves the classification performances of gold-standard biomarker panels (e.g. PAM50, OncotypeDX and Endopredict) by adding features that are clinically relevant. Moreover, test results show that newly discovered biomarker models can retain a high classification accuracy rate when changing the source generating the gene expression profiles. github.com/UEFBiomedicalInformaticsLab/OnlineLearningBD. Supplementary data are available at Bioinformatics Advances online.

Acute dacryocystitis in pediatric patients and frequency of nasolacrimal duct patency

ABSTRACT Purpose: To study acute dacryocystitis in a pediatric age group, focusing on patients’ demographic profiles, clinical presentation, and management outcome. Methods: A retrospective case series of all acute dacryocystitis in pediatric patients (0–17 years) from two tertiary-care eye centres in Riyadh, Saudi Arabia was conducted. Demographic profile, risk factors, initial clinical presentation, management regimens, and final outcome were analysed. Results: A total of 51 patients were included in the study. The mean age of presentation was 3.9 ± 4 years (1 month–13 years). Thirty-eight patients (74.5%) reported symptoms of congenital nasolacrimal duct obstruction (NLDO) prior to presentation, four patients (7.8%) had congenital dacryocystocele, two (3.9%) had a history of traumatic NLDO, and ten (19.6%) had an attack of acute dacryocystitis in the absence of NLDO or any other known risk factors. Four patients (7.8%) progressed to orbital cellulitis while another three (5.8%) had lacrimal sac fistula secondary to acute dacryocystitis. Systemic antibiotics were the initial management in all 51 patients. Twenty-five (49%) underwent probing after the resolution of the acute attack while 12 (23.5%) patients underwent dacryocystorhinostomy (DCR). Conclusions: Early recognition and urgent management for acute dacryocystitis are required to prevent further potential complications and achieve excellent outcomes. Congenital NLDO is the main risk factor for the development of acute dacryocystitis in the pediatric age group. In a small set of patients, acute dacryocystitis can develop despite the presence of a patent lacrimal drainage system on clinical evaluation with lack of tearing and discharge before and after the attack of acute dacryocystitis.

Serum PD-1 Is Elevated after Pembrolizumab Treatment but Has No Predictive Value.

Immune-checkpoint blockade (ICB) uses antibody targeting of specific inhibitory receptors and ligands. The major limitations of ICB, such as high cost, limited success rate, and immune-related adverse events (irAE), highlight the need for predictive biomarkers. We analyzed pre-immunotherapy and post-immunotherapy serum samples of 24 patients treated with pembrolizumab for changes in PD-1 and over 1,000 additional protein markers using a multiplex proximity extension assay (PEA) to identify potential predictive biomarkers of response and/or toxicity. Candidates were selected based on the criteria that at least 2 patients within any of 3 patient groups (responders without irAEs, responders with irAEs, or nonresponders with irAEs) had either a ≥4-fold increase or 4-fold decrease in expression post-immunotherapy. Female and male control samples were used as technical duplicates. A patient group with no response and no irAEs was used to exclude candidates. Following treatment with pembrolizumab, there was a relative increase of PD-1 in the serum of all patients, compared with controls (average 4.4-fold). We identified 7 additional serum proteins that met our candidate selection criteria. These candidate markers did not have any significant association with response or toxicity to pembrolizumab. Overall, we show that serum PD-1 increases post-therapy with pembrolizumab treatment but has no predictive value for response or toxicity in this small set of patients.

Expression profile of Epstein-Barr virus and human adenovirus small RNAs in tonsillar B and T lymphocytes.

We have used high-throughput small RNA sequencing to characterize viral small RNA expression in purified tonsillar B and T lymphocytes isolated from patients tested positive for Epstein-Barr virus (EBV) or human adenovirus (HAdV) infections, respectively. In the small set of patients analyzed, the expression profile of EBV and HAdV miRNAs could not distinguish between patients diagnosed with tonsillar hypertrophy or chronic/recurrent tonsillitis. The EBV miR-BART expression profile among the patients diagnosed with tonsillar diseases resembles most closely the pattern seen in EBV+ tumors (Latency II/I). The miR-BARTs that appear to be absent in normal EBV infected cells are essentially all detectable in the diseased tonsillar B lymphocytes. In the EBV+ B cells we detected 44 EBV miR-BARTs derived from the proposed BART precursor hairpins whereof five are not annotated in miRBase v21. One previously undetected miRNA, BART16b-5p, originates from the miR-BART16 precursor hairpin as an alternative 5´ miR-BART16 located precisely upstream of the annotated miR-BART16-5p. Further, our analysis revealed an extensive sequence variation among the EBV miRNAs with isomiRs having a constant 5´ end but alternative 3´ ends. A range of small RNAs was also detected from the terminal stem of the EBER RNAs and the 3´ part of v-snoRNA1. During a lytic HAdV infection in established cell lines the terminal stem of the viral non-coding VA RNAs are processed to highly abundant viral miRNAs (mivaRNAs). In contrast, mivaRNA expression in HAdV positive tonsillar T lymphocytes was very low. The small RNA profile further showed that the 5´ mivaRNA from VA RNAI and the 3´ mivaRNA from VA RNAII were as predicted, whereas the 3´ mivaRNA from VA RNAI showed an aberrant processing upstream of the expected Dicer cleavage site.

A mobile application supporting outpatient treatment and follow-up.

An increasing prevalence of chronic diseases is observed, among which cancer is now included because of its survival rates. That trend requires new ways of supporting outpatients and improving their compliance to treatments. This paper introduces HeNeA, a mobile application designed to support patients affected by Head and Neck cancer during their treatments. The application leverages on the mHealth features described in the literature and has been reviewed by a small set of patients during its development. Further evaluation is expected to occur when it will be offered to every eligible patient discharged from the Head and Neck division of a major Italian cancer centre.

Ultrasound-guided Ethanol Ablation: Where does It fit in the Treatment of Recurrent Metastatic Papillary Thyroid Cancer?

ABSTRACT Introduction Ethanol (ETOH) ablation of metastatic neck nodes has been described as a potentially safe and effective alternative to surgical excision. We sought to describe a subset of these patients well suited for ETOH ablation. Materials and methods We report ultrasound-guided ETOH ablation of metastatic papillary thyroid cancer (PTC) at a Tertiary Care Endocrine Surgery Unit over 5 years. A retrospective review of all reoperative lymph node dissections was undertaken. Ethanol injection was used as second-line treatment to operative excision and was standardized with ultrasound guidance and the use of 1 cc/cm3 of 100% ETOH solution. Results Five treatments of ultrasound-guided ETOH ablation were studied. All patients had been previously treated with radioactive iodine (RAI) (mean: 1.25 treatments of 174mCi), however, in three cases with pretreatment I-131 scan, no uptake of radioiodine was seen in the treated disease. In four cases with pretreatment fludeoxyglucose-positron emission tomography (FDG-PET), treated lesions were avid. Median follow-up time for treatment was 28.5 months, with no disease progression in all ablated lesions. Serum thyroglobulin (Tg) values in patients without Tg-antibody were lower after treatment. There were no complications. Conclusion Surgeons seeking a less-invasive approach for nodal metastases in the neck can consider ETOH ablation. Small ultrasound detectable lesions in scarred necks (irradiated and/or reoperative) which are radioiodine non-avid and FDG-PET avid may be best suited for this treatment. As demonstrated by a small set of patients in a Tertiary Care Endocrine Surgery Unit, ETOH ablation is safe and effective at controlling progression of targeted local disease. How to cite this article Pasternak JD, Kluijfhout W, Seiser N, Gosnell JE, Suh I, Duh Q-Y, Shen WT. Ultrasound-guided Ethanol Ablation: Where does It fit in the Treatment of Recurrent Metastatic Papillary Thyroid Cancer? World J Endoc Surg 2016;8(3):199-202.

Impact of metformin use on survival in locally-advanced, inoperable non-small cell lung cancer treated with definitive chemoradiation.

We investigated survival outcomes in diabetic patients with non-small cell lung cancer (NSCLC) treated with concurrent metformin and definitive chemoradiation. This single-institution, retrospective cohort study included 166 patients with NSCLC who were treated definitively with chemoradiation between 1999 and 2013. Of 40 patients who had type II diabetes, 20 (50%) were on metformin, and 20 (50%) were not on metformin. The primary outcome was overall survival (OS), and secondary outcomes included progression-free survival (PFS), locoregional recurrence-free survival (LRRFS) and distant metastasis-free survival (DMFS). Kaplan Meier method and log-rank test were performed in survival analysis. Cox regression was utilized in univariate analysis of potential confounders. Median follow-up was 17.0 months. Compared with non-diabetic patients, diabetic patients on metformin demonstrated similar OS (16.3 vs. 14.3 mo, P=0.23), PFS (11.6 vs. 9.7 mo, P=0.26), LRRFS (14.1 vs. 11.9 mo, P=0.78), and DMFS (13.4 vs. 10.0 mo, P=0.69). Compared with diabetic patients not on metformin, diabetic patients on metformin also exhibited similar OS (14.3 vs. 19.2 mo, P=0.18), PFS (19.7 vs. 10.1 mo, P=0.38), LRRFS (11.9 vs. 15.5 mo, P=0.69), and DMFS (10.0 vs. 17.4 mo, P=0.12). Identified negative prognostic factors on included squamous cell histology, lower performance status, higher T stage, and non-caucasian ethnicity. No statistically significant differences in survival or patterns of failure were found among the three cohorts in this small set of patients. No statistically significant differences in survival or patterns of failure were found between the three cohorts in this small set of patients. Though it is possible that metformin use may in fact have no effect on survival in NSCLC patients treated with definitive RT, larger-scale retrospective and prospective studies are implicated for clarification.

Immune infiltrates impact on the prediction of prognosis and response to immunotherapy of melanoma patients

Background Melanoma is a highly malignant melanocyte-derived tumor and its incidence is increasing at outstanding rate. Despite specific therapies have been explored for many years, no effective therapeutic options have been developed. Vaccination strategies, including Dendritic Cells (DC) based immunotherapy, are consistently increasing the proportion of cancer patients with anti-vaccine immune responses although the number of patients with increased overall survival is still limited. The efficacy of the immunotherapy is mainly dependent on tumor microenvironment –immune system interactions. Our aim is to evaluate the host immune response to melanoma by quantifying the density and location of T cells in primary tumors of patients treated with DC immunotherapy and correlate them with clinical variables such as overall survival (OS). Materials and methods We collected 60 FFPE primary tumors from melanoma patients treated with DC immunotherapy. Serial sections (4 micron in thickness) were stained with CD3, CD8 and CD45RO antibodies. Haematoxylin was used as a counterstain and Nova Red for the immunohistochemical stain. All the slides were digitalized and an automated quantitative analysis was performed in order to evaluate the density and location of two lymphocyte populations, cytotoxic (CD8) and memory (CD45RO) T cells. Of all samples the clinical outcome of the patient is known. Results The immunohistochemical analysis of primary melanoma using a small set of patients resulted in significant differences between short (OS 24 months). A high degree of T cells infiltration was seen in the tumor area of both patients, responding and non-responding to DC immunotherapy. However, the location but not the density of TILs was significantly different in the two cohorts of patients and showed a strong correlation with clinical response to DC vaccination. Conclusions Immune cells within melanoma tumors may have a prognostic value and clinical significance as a predictor of patient outcome and response to DC immunotherapy in melanoma patients.

Promotor methylation: Does it affect response to therapy in chronic hepatitis C (G4) or fibrosis?

Background and aim. DNA methylation plays a critical role in the control of important cellular processes. The present study assessed the impact of promoter methylation (PM) of some genes on the antiviral response to antiviral therapy and it’s relation to the presence of fibrosis in HCV-4 infected patients from Egypt.Material and methods. Clinical, laboratory and histopathological data of 53 HCV-4 infected patients who were subjected to combined antiviral therapy were collected; patients were classified according to their response to treatment and the fibrosis status. The methylation profiles of the studied groups were determined using the following genes: APC, P14ARF, P73, DAPK, RASSF1A, and O6MGMT in patients’ plasma.Results.O6MGMT and P73 showed the highest methylation frequencies (64.2 and 50.9%) while P14 showed the lowest frequency (34%). Sustained virological response (SVR) was 54.7%with no significant difference in clinico-pathological or laboratory features between the studied groups. PM of O6MGM was significantly higher in non-responders (p value 0.045) while DAPK showed high methylation levels in responders with no significance (p value: 0.09) andPM of RASSF1A was significantly related to mild fibrosis (p value: 0.019). No significant relations were reported between PM of any of the studied genes and patients’ features.Conclusion. PM of some Tumor Suppressor genes increases in chronic active HCV-4. However, only 06MGMT can be used as a predictor of antiviral response and RASSF1A as a marker of marked fibrosis in this small set of patients. An extended study, including more patients is required to validate the results of this preliminary study.

Development of synchronous VHL syndrome tumors reveals contingencies and constraints to tumor evolution.

BackgroundGenomic analysis of multi-focal renal cell carcinomas from an individual with a germline VHL mutation offers a unique opportunity to study tumor evolution.ResultsWe perform whole exome sequencing on four clear cell renal cell carcinomas removed from both kidneys of a patient with a germline VHL mutation. We report that tumors arising in this context are clonally independent and harbour distinct secondary events exemplified by loss of chromosome 3p, despite an identical genetic background and tissue microenvironment. We propose that divergent mutational and copy number anomalies are contingent upon the nature of 3p loss of heterozygosity occurring early in tumorigenesis. However, despite distinct 3p events, genomic, proteomic and immunohistochemical analyses reveal evidence for convergence upon the PI3K-AKT-mTOR signaling pathway. Four germline tumors in this young patient, and in a second, older patient with VHL syndrome demonstrate minimal intra-tumor heterogeneity and mutational burden, and evaluable tumors appear to follow a linear evolutionary route, compared to tumors from patients with sporadic clear cell renal cell carcinoma.ConclusionsIn tumors developing from a germline VHL mutation, the evolutionary principles of contingency and convergence in tumor development are complementary. In this small set of patients with early stage VHL-associated tumors, there is reduced mutation burden and limited evidence of intra-tumor heterogeneity.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-014-0433-z) contains supplementary material, which is available to authorized users.

Progress in inferring desmoplastic stromal tissue microstructure noninvasively with ultrasound nonlinear elasticity imaging

Desmoplasia is the abnormal growth of fibrous tissue that is often associated with malignancy in breast and other solid tumors. The collagen comprising the extracellular tissue matrix tends to be more dense than in normal breast tissue, and to exhibit altered microstructure. The distinctive mechanical properties of solid tumors are often attributed to the abnormal density and microstructure of their collagen extracellular matrices. For example, a higher concentration of collagen implies a larger linear elastic modulus, while a decrease in fiber tortuosity would mean a smaller “toe” region in the stress-strain curve. This talk describes progress of inferring local tissue microstructural properties from noninvasive, in vivo measurement of nonlinear elastic properties of breast tissue. An ultrasound elasticity-imaging based approach for determining the average local micro-structural properties of tissue was developed and implemented. It utilizes multiscale homogenization methods to determine effective macroscopic properties from assumed microstructural arrangements of collagen fibers. The resulting nonlinear constitutive equation is then used in a model-based elastic inverse problem solver to obtain local microstructural tissue properties from macroscopic observations of tissue deformation. Its potential in diagnosing malignant breast tumors in a small set of patients was also examined. [NSF Grant 50201109; NIH NCI-R01CA140271.]

Surgical Treatment of Subacute and Chronic Valgus Instability in Multiligament-Injured Knees With Superficial Medial Collateral Ligament Reconstruction Using Achilles Allografts

Background: Symptomatic medial collateral ligament (MCL) instability is rare, and it is frequently associated with multiligament injuries. Most clinical investigations have failed to clearly define the specific objective outcome measures assessing the stability of the MCL quantitatively before and after the reconstruction procedure. Purpose: To quantitatively evaluate the early clinical outcomes of patients with valgus instability of knee joints who had undergone superficial MCL reconstruction using Achilles tendon allografts. Study Design: Case series; Level of evidence, 4. Methods: From August 2005 to December 2010, 19 consecutive patients with MCL injuries were included in this study. The inclusion criteria were (1) a subacute or chronic MCL injury, with a time from initial injury to surgery of longer than 3 weeks, and (2) valgus laxity graded C or D according to the International Knee Documentation Committee (IKDC). All patients underwent superficial MCL reconstruction using Achilles tendon allografts. To evaluate the laxity of the MCL preoperatively and postoperatively, valgus stress radiographs using a Telos device were used. Other assessments included the IKDC subjective functional evaluation and Lysholm score estimation. Results: Sixteen of the 19 patients (12 men and 4 women) were available for final follow-up. The median age of the patients was 37 years (range, 19-53 years); mean body mass index (BMI) was 26.4 (range, 21.7-29.4). The mean time from injury to surgery was 15.9 months (range, 24 days to 84 months), and median follow-up period was 34 months (range, 24-67 months). The mean medial knee laxity (side-to-side difference) was 8.9 ± 3.2 mm (range, 6-15.9 mm) preoperatively and 1.1 ± 0.9 mm (range, –1.1 to 3.2 mm) postoperatively (P < .001). The preoperative mean IKDC subjective knee functional score was 49.8 ± 6.9 (range, 31-57.5), while the postoperative functional score was 84.3 ± 6.0 (range, 71.3-93.1) (P < .001). The mean Lysholm score was 69.3 ± 5.9 (range, 55-78) preoperatively and 88.6 ± 5.0 (range, 75-95) postoperatively (P < .001). There was no significant correlation between patients’ BMI and the final clinical outcome scores (P = .311). Conclusion: In a small set of patients with multiligament-injured knees, valgus laxity can be effectively restored through surgical management with superficial MCL reconstruction, when the other associated ligament injuries are reconstructed as well. The subjective functional results were significantly improved postoperatively at short-term follow-up.

Potentials of Plasma NGAL and MIC-1 as Biomarker(s) in the Diagnosis of Lethal Pancreatic Cancer

Pancreatic cancer (PC) is lethal malignancy with very high mortality rate. Absence of sensitive and specific marker(s) is one of the major factors for poor prognosis of PC patients. In pilot studies using small set of patients, secreted acute phase proteins neutrophil gelatinase associated lipocalin (NGAL) and TGF-β family member macrophage inhibitory cytokine-1 (MIC-1) are proposed as most potential biomarkers specifically elevated in the blood of PC patients. However, their performance as diagnostic markers for PC, particularly in pre-treatment patients, remains unknown. In order to evaluate the diagnostic efficacy of NGAL and MIC-1, their levels were measured in plasma samples from patients with pre-treatment PC patients (n = 91) and compared it with those in healthy control (HC) individuals (n = 24) and patients with chronic pancreatitis (CP, n = 23). The diagnostic performance of these two proteins was further compared with that of CA19-9, a tumor marker commonly used to follow PC progression. The levels of all three biomarkers were significantly higher in PC compared to HCs. The mean (± standard deviation, SD) plasma NGAL, CA19-9 and MIC-1 levels in PC patients was 111.1 ng/mL (2.2), 219.2 U/mL (7.8) and 4.5 ng/mL (4.1), respectively. In comparing resectable PC to healthy patients, all three biomarkers were found to have comparable sensitivities (between 64%-81%) but CA19-9 and NGAL had a higher specificity (92% and 88%, respectively). For distinguishing resectable PC from CP patients, CA19-9 and MIC-1 were most specific (74% and 78% respectively). CA19-9 at an optimal cut-off of 54.1 U/ml is highly specific in differentiating resectable (stage 1/2) pancreatic cancer patients from controls in comparison to its clinical cut-off (37.1 U/ml). Notably, the addition of MIC-1 to CA19-9 significantly improved the ability to distinguish resectable PC cases from CP (p = 0.029). Overall, MIC-1 in combination with CA19-9 improved the diagnostic accuracy of differentiating PC from CP and HCs.

DNA Methylation as a Target of Epigenetic Therapeutics in Cancer

Epigenetic alterations have been implicated in the development and progression of human cancer. It is noteworthy that epigenetic modifications, in contrast to genetic mutations, are intrinsically reversible. This triggers an impressive interest of researchers in treatment of cancer patients via targeting epigenetic mechanisms, leading to subsequent intensive investigations of epigenetic drugs as a novel therapeutic intervention. DNA methylation, the major form of epigenetic modifications, is catalyzed by the maintenance DNA methyltransferase (DNMT) 1 and/or the de novo methyltransferases DNMT3A and DNMT3B. Aberrant expression of DNMTs and disruption of DNA methylation are closely associated with multiple forms of cancer, although the exact mechanisms underlying this link remain elusive. An array of tumor suppressor genes (TSGs) frequently sustain promoter hypermethylation, which results in epigenetic silencing of these genes and makes cancer cells acquire growth advantages. DNA demethylating agents, re-activating TSGs via inhibiting hypermethylation of their promoter regions, are currently being tested in clinical trials, and several of them are already applied in clinics. DNA demethylating agents, used either alone or in combination with other agents, such as chemotherapeutic drugs and the histone deacetylase inhibitors, have shown to be effective in treatment of cancer, although only in a small set of patients. In this review, we examine and discuss the most recent advances in epigenetic therapy of cancer, with a focus on DNA demethylating agents.

A Novel Method to Calculate Mean Survival Time for Time-to-Event Data

In the analysis of time-to-event data, restricted mean survival time has been well investigated in the literature and provided by many commercial software packages, while calculating mean survival time remains as a challenge due to censoring or insufficient follow-up time. Several researchers have proposed a hybrid estimator of mean survival based on the Kaplan–Meier curve with an extrapolated tail. However, this approach often leads to biased estimate due to poor estimate of the parameters in the extrapolated “tail” and the large variability associated with the tail of the Kaplan–Meier curve due to small set of patients at risk. Two key challenges in this approach are (1) where the extrapolation should start and (2) how to estimate the parameters for the extrapolated tail. The authors propose a novel approach to calculate mean survival time to address these two challenges. In the proposed approach, an algorithm is used to search if there are any time points where the hazard rates change significantly. The survival function is estimated by the Kaplan–Meier method prior to the last change point and approximated by an exponential function beyond the last change point. The parameter in the exponential function is estimated locally. Mean survival time is derived based on this survival function. The simulation and case studies demonstrated the superiority of the proposed approach.

A panel of five circulating microRNAs as potential biomarkers for prostate cancer

Circulating microRNA (miRNAs) have been shown to have the potential as noninvasive diagnosis markers in several types of cancers. In this study, we investigated whether circulating miRNAs could be used in the diagnosis of prostate cancer (CaP) in a Chinese patient population. Illumina's Human v2 miRNA microarray was used to analyze miRNAs levels in a small set of patients [25 CaP, 17 benign prostatic hyperplasia (BPH)] in an effort to identify CaP-specific miRNAs. The identified miRNAs were further examined by quantitative real-time PCR (qRT-PCR) in the same small set of patients. After the training phase of screening and selecting, the candidate miRNAs were validated in a larger independent cohort (80 CaP, 44 BPH, and 54 healthy controls) with qRT-PCR in the verification phase. Five miRNAs were confirmed by qRT-PCR analysis in validation sets. Receiver operating characteristic (ROC) curve analysis showed all 5 miRNAs had diagnostic value. More importantly, further principal component analysis indicated component 1 extracted from expression data of the 5 miRNAs could differentiate CaP from BPH and healthy controls with high diagnosis performance, with an AUC of 0.924 and 0.860, respectively. Our data suggested that circulating miRNAs could serve as biomarkers for CaP, and compared to single miRNA, the 5 miRNAs panel can accurately discriminate CaP from BPH and healthy controls with high sensitivity and specificity, and therefore, combined with routine PSA test, these 5 CaP-specific miRNAs may help improve CaP diagnosis in clinical application.

Three-wire Fixation Technique for Displaced Fifth Metatarsal Base Fractures

Fractures of the tuberosity of the fifth metatarsal are the most common type of fifth metatarsal fractures. This particular fracture usually produces low morbidity and low rates of nonunion when treated nonoperatively. However, on occasion, significant displacement, comminution, or significant intra-articular involvement may warrant operative intervention. Multiple techniques have been described for the operative care of this fracture. We present a somewhat simplified fixation method for displaced fifth metatarsal fractures in a small set of patients who were all followed up to final healing of the fracture.