MRI features and whole-lesion apparent diffusion coefficient histogram analysis of brain metastasis from non-small cell lung cancer for differentiating epidermal growth factor receptor mutation status.

AIM: To explore the utility of magnetic resonance imaging (MRI) characteristics and whole-lesion apparent diffusion coefficient histogram analysis of brain metastasis from non-small cell lung cancer (NSCLC) in the differentiation of epidermal growth factor receptor (EGFR) mutation status. MATERIALS AND METHODS: Forty-eight patients with brain metastases from NSCLC were enrolled in this retrospective study. Patients were subtyped into EGFR mutation (23 cases) and wild-type (25 cases) groups. Whole-lesion histogram metrics were derived from the apparent diffusion coefficient (ADC) maps, and imaging features were evaluated according to conventional MRI. Student's t-test or Mann-Whitney U-test, chi-squared test, and receiver operating characteristic (ROC) curve analysis were performed to discriminate the two groups and to determine the diagnostic efficacy of ADC histogram parameters. RESULTS: EGFR mutation group had more multiple brain metastases, less peritumoural brain oedema (PTBO), and lower peritumoural brain oedema index (PTBO-I) than EGFR wild-type group (all p<0.05). In addition, 90th and 75th percentiles of ADC and maximum ADC in the EGFR mutation group were significantly higher than in the EGFR wild-type group (all p<0.05). Ninetieth percentile of ADC had the highest area under the curve (AUC; 0.711), and it was found to outperform 75th percentile of ADC (AUC, 0.662; p=0.039) and maximum ADC (AUC, 0.681). CONCLUSIONS: Whole-lesion ADC histogram analysis and MRI features of brain metastasis from NSCLC are expected to be potential biomarkers to non-invasively differentiate the EGFR mutation status.

Impact of pharmacist intervention on antibiotic use and prophylactic antibiotic use in urology clean operations.

WHAT IS KNOWN AND OBJECTIVE: The use of prophylactic antibiotics in clean operations was routine in China before 2011. Along with the appeal for using antibiotics rationally by WHO in 2011, China launched a national special rectification scheme on clinical use of antibiotics from April that year. The scheme, aimed at achieving rational use of antibiotics, made pharmacists part of the responsible medical team. Our objective was to describe the impacts of pharmacist intervention on the use of antibiotics, particularly in urology clean operations. METHODS: Pharmacists participated in antibiotic stewardship programmes of the hospital and urological clinical work and conducted real-time interventions at the same time from 2011 to 2013. Data on the use of antibiotics between 2010 and 2013 in urology were collected. RESULTS: Comparison of the 2013 data with those of 2010 showed that antibiotic use density [AUD= DDDs*100/(The number of patients who were treated the same period*Average days in hospital). DDDs = Total drug consumption (g)/DDD. DDD is the Defined Daily Dose] decreased by 57·8(58·8%); average antibiotic cost decreased by 246·94 dollars; the cost of antibiotics as a percentage of total drug cost decreased by 27·7%; the rate of use of antibiotics decreased from 100% to 7·3%. WHAT IS NEW AND CONCLUSION: The study illustrates how an antibiotic stewardship programme with pharmacist participation including real-time interventions can promote improved antibiotic-prescribing and significantly decrease costs.

Genetic features of a translation initiation system composed of IRES element, nucleotide context surrounding the initiation codon, and translation initiation region of classical swine fever virus RNA.

Nucleotide and codon usage are typically examined to investigate viral evolution. In this study, we analyzed the genetic information of 46 strains of classical swine fever virus (CSFV) RNA, nucleotide usage in the internal ribosome entry site (IRES), the nucleotide context surrounding the initiation codon, and synonymous codon usage in the translation initiation region. Phylogenetic analysis of the IRES element indicated that the genetic diversity of this element is generally similar to the phylogenetic clusters of CSFV genotypes. Nucleotides surrounding the initiation codon of CSFV RNA were generally more stable (ACAUGGCACAUGGAGUUG) compared to the internal AUG in the CSFV coding sequence. The second codon position after the initiation codon was generally selected to be GAG, which has lower tRNA abundance in pigs than its synonymous member (GAA). Regarding the synonymous codon usage bias in the CSFV translation initiation region, some codons showing low tRNA abundance in pigs are more frequently located in the translation initiation region than in the open reading frame of CSFV. Although CSFV, similarly to other RNA viruses, has a high mutation rate in nature, the regulatory features of nucleotide and synonymous codon usage of the IRES element, the nucleotide context surrounding the initiation codon and the translation initiation region in CSFV RNA have been 'branded' in the system of translation initiation to accommodate gene expression mediated by the cap-independent translation mechanism.

Synchronous primary adenocarcinoma of the lung and pancreas: a case series and review of the literature.

AIM: The frequency of pancreatic cancer in association with cancer of other organs ranges from 1 to 20%, with the most common ones being gastric, colon, thyroid and genitourinary. The presence of synchronous lung and pancreatic cancers is extremely rare. CASE SERIES: Two patients with extensive smoking history and variable presentations were found to have simultaneous lung and pancreatic masses both lesions being different histologically and on immunohistochemical staining. After individualized treatment plans, the first patient remains free of disease and the second patient is being treated with a palliative intent. CONCLUSION: The early recognition and treatment is important as there exists a significant survival difference in patients who have synchronous primaries as opposed to those with metastatic pancreatic adenocarcinoma.

Downregulated long non-coding RNA TRPM2-AS inhibits cisplatin resistance of non-small cell lung cancer cells via activation of p53- p66shc pathway.

OBJECTIVE: Non-small cell lung cancer (NSCLC), as an ordinary malignant tumor, presents with high death rate and poor prognosis. Few literatures have explored the association between NSCLC development and lncRNAs expression. This study focuses on the important role of a novel lncRNA TRPM2-AS in the development of chemo-resistance in NSCLC. MATERIALS AND METHODS: The expression level of lncRNA TRPM2-AS was identified by using qRT-PCR assay. The apoptosis rate and the alteration of the cell cycle were detected by the flow cytometric analysis. Cell Counting Kit-8 assay (CCK8) was utilized for detecting chemo-sensitivity of the cisplatin-resistant A549/DDP cells. The p53 and p66shc protein levels were detected by Western blotting assay. RESULTS: A549/DDP cells presented remarkably higher expression of lncRNA TRPM2-AS than paired A549 cells. Moreover, re-sensitization to cisplatin was seen in A549/DDP cells after lncRNA TRPM2-AS knockdown. On the contrary, the sensitivity of lncRNA TRPM2-AS-overexpressed A549 cells to cisplatin decreased obviously when compared with the control. Furthermore, downregulated lncRNA TRPM2-AS induced cell apoptosis and altered cell cycle distribution through activating the p53-p66shc pathway. CONCLUSIONS: We suggest that lncRNA TRPM2-AS participates in the resistance of NSCLC cells to cisplatin, which may provide a new therapeutic target of NSCLC.

Sertoli-Leydig cell tumor of the ovary: A diagnostic dilemma.

BACKGROUND: Sertoli-Leydig cell tumors are rare sex-cord stromal tumors of the ovary that can present with a variety of histological elements, which may complicate diagnosis and treatment. CASE: A 40-year-old female presenting with pelvic pain is found to have a large complex right adnexal mass and elevated alpha-fetoprotein. The mass was diagnosed as a Sertoli-Leydig cell tumor with heterologous elements including carcinoid and hepatoid components. She was treated with surgical resection followed by adjuvant chemotherapy and remains clear of disease. CONCLUSION: Prognostic indicators for Sertoli-Leydig cell tumors include degree and type of heterologous element differentiation. Thorough characterization of such elements is crucial for adequate diagnosis and treatment.

Intracerebroventricular Administration of Mineralocorticoid Receptor Antisense Oligonucleotides Attenuates Salt Appetite in the Rat.

The anterior ventral third ventricle (AV3V) region of the brain contains high concentrations of mineralocorticoid receptors (MR) and glucocorticoid receptors (GR) that are important in the maintenance of body fluid and electrolyte balance as well as other physiological processes. Daily intracerebroventricular pulse injections of MR antisense oligonucleotides significantly suppressed deoxycorticosterone acetate (DOCA) induced salt appetite in a dose-related manner. Similar administration of GR antisense or scrambled/sense oligonucleotide into the third ventricle failed to inhibit salt appetite. Salt appetite aroused after adrenalectomy was not suppressed by MR antisense oligonucleotide treatments but was suppressed by an antisense oligonucleotide directed against the angiotensin II AT1 receptor subtype. Receptor binding analysis demonstrated that MR and GR oligonucleotide treatments each reduced their respective receptor subtypes. Finally, although GR antisense oligonucleotide treatment was ineffective in suppressing DOCA-induced salt appetite, this treatment did increase stress induced corticosterone release as well as delayed the recovery of corticosterone to basal levels after stress.

Expression of estrogen-induced genes and estrogen receptor ß in pancreatic neuroendocrine tumors: implications for targeted therapy.

OBJECTIVE: The indolent nature and expression of progesterone receptor (PR), a well-known estrogen-induced gene, in a subset of pancreatic neuroendocrine tumors (PanNETs), raise the possibility of hormonal regulation in these tumors. METHODS: Immunohistochemical expression of estrogen receptors (ERs) α and ß as well as messenger RNA expression of estrogen-induced genes (PR, EIG121, IGF-1, IGF-1R, sFRP1, and sFRP4) by quantitative reverse transcription-polymerase chain reaction were examined in 131 World Health Organization grade G1 and G2 PanNETs and correlated their expression with clinicopathological features. RESULTS: Thirty-nine PanNETs (30%) showed high positive ERß staining, and 87 cases (66%) had low positive ERß staining; only 5 cases (4%) had no nuclear staining. Pancreatic neuroendocrine tumors with small size (P = 0.02), low World Health Organization grade (P = 0.02), and low American Joint Committee on Cancer stage (P = 0.006) more frequently showed high positive ERß staining. Among the estrogen-induced genes studied, PanNETs had significantly higher expression of PR, EIG121, IGF-1, sFRP1, and sFRP4 compared with normal pancreas, independent of age or sex. High positive ERß staining was associated with an increased expression of PR (P < 0.001) and EIG121 (P = 0.02). CONCLUSIONS: Our study showed that PanNETs with favorable prognostic features have higher ERß expression, which is associated with up-regulated PR and EIG121 messenger RNA expression. Estrogen regulation in PanNETs could potentially help in risk stratification and provide a rational target for novel treatment strategies.

Transformation of small B-cell lymphoma into large cell CD30⁺, CD4⁺, Epstein-Barr virus-negative lymphoma.

We report here 2 separate cases in which patients with known low-grade B-cell lymphomas presented with transformed lesions that were CD30⁺, CD4⁺, Epstein-Barr virus negative, and negative or focally weak for a wide range of B-cell, T-cell, and histiocytic/dendritic cell markers. In each case the transformed lymphoma possessed an identical pattern of immunoglobulin heavy chain and/or BCL2 rearrangement to the corresponding original low-grade B-cell lymphoma, confirming their identity as transformed B-cell lymphoma. A review of the relevant literature reveals that, to our knowledge, no transformed B-cell lymphomas with this immunophenotype have been previously reported, which creates the opportunity for potential errors of diagnosis. These cases highlight the importance of correlation with the patient's history and with molecular genetic results in rendering an accurate diagnosis.

Should high-risk adolescents have Papanicolaou tests?

BACKGROUND: The current American College of Obstetricians and Gynecologists guidelines state that cervical cancer screening should begin at age 21 years, regardless of sexual or obstetric history. However, previous studies have demonstrated that there is a small but significant subset of high-risk adolescents with extensive sexual and obstetric history who harbor a significant squamous cervical lesion. The objective of the current study was to use histologic and demographic data from adolescents (aged <21 years) who received Papanicolaou (Pap) tests to determine whether they benefited from early cervical cancer screening. METHODS: Adolescent girls who had Pap tests between 2000 and 2010 were included in the study. Demographic data, including obstetric history, number of sexual partners, age of first coitus, age at first pregnancy, menarche, smoking history, and Chlamydia and syphilis infection, were analyzed for associations with levels of cervical dysplasia. RESULTS: Of 56,785 adolescent Pap tests, 277 (0.5%) were diagnosed as high-grade squamous HSIL, and 56 of those Pap tests (20%) were from patients who had grade 3 cervical intraepithelial neoplasia (CIN-3) on subsequent biopsy and/or excision. One patient had microinvasive cervical carcinoma identified on loop electrosurgical excision procedure at age 27 years after an HSIL Pap test. Increased parity was associated significantly with higher rates of CIN-3. CONCLUSIONS: The study findings indicated that current American College of Obstetricians and Gynecologists guidelines to begin Pap testing at age 21 years are appropriate for the majority of adolescents, because the rate of HSIL is very low, and the risk for invasive carcinoma is minimal. Although higher parity was associated with a significantly increased grade of CIN, the conclusions are questionable because of the significant amount of missing demographic data points. That being said, this study should lead to other similar studies to determine any association of higher grade CIN with adolescent sexual and obstetric history.

BK virus as a potential co-factor for HPV in the development of cervical neoplasia.

Cervical cancer is the third most common type of cancer in women worldwide. A persistent infection with high risk (HR) human papillomavirus (HPV) is necessary for cervical cancer to occur. However, the great majority of women that are infected with HR-HPV will not develop cervical cancer, indicating that HR-HPV alone is not adequate to drive the development of cervical cancer, suggesting the involvement of cofactors. The BK polyomavirus (BKV) establishes latency near cervical tissue in the urogenital tract and is frequently detected in the urine, especially in immunosuppressed patients, and hence may coexist with HR-HPV. Current experimental evidence indicates that both HR-HPV and BKV are capable of altering cell-cycle control and inhibit apoptosis. Therefore, they may act additively or synergistically to promote malignant transformation. We hypothesize that BKV is a co-factor for HR-HPV in cervical cancer. In this study, we examined 249 cervical swabs that were submitted for routine HR-HPV screening test in the Molecular Diagnostics Laboratory at the University of Texas Medical Branch (UTMB). Our results showed that 107 samples contained HR-HPV at an overall rate of 43% (107/249); BKV was present in 4 (3.7%) of the 107 HR-HPV positive specimens and in 12 (8.5%) of the 142 HR-HPV negative samples with an overall positive rate of 6.4% (16/249). Although there was no statistical significance between HR-HPV and BKV co-infection (P=0.19, Fisher's exact test), our results support the hypothesis that BKV can co-exist with HR-HPV in cervical specimens.

Newly diagnosed acute lymphoblastic leukemia in China (II): prognosis related to genetic abnormalities in a series of 1091 cases.

The molecular characterization of cytogenetic abnormalities has not only provided insights into the mechanisms of leukemogenesis but also led to the establishment of new treatment strategies targeting these abnormalities and thereby further improve the prognosis of patients. We analyzed the prognosis of 1091 Chinese patients with newly diagnosed acute lymphoblastic leukemia (ALL) and explored the prognostic impacts of a large number of cytogenetic/molecular abnormalities. It was demonstrated that, in both B- and T-ALL settings, the prognosis was negatively correlated to the age as reported to date. For childhood T-ALL patients, it was also documented that the HOX11 expression represented a favorable prognostic factor as it was in adult ones. We identified CRLF2 overexpression as an intermediate-risk marker and Ik6 variant of IKZF1 gene as a high-risk one when stratifying pediatric B-ALL cases according to cytogenetic/molecular risks. We also found that Ik6 variant and CRLF2 overexpression had an important role in dictating the prognosis of Ph-negative patients, which may be useful markers in guiding the treatment of ALL in the future, with tyrosine kinase inhibitors on the other hand reversing the fate of Ph-positive ALL patients.

Calcitonin-negative neuroendocrine tumor of the thyroid: a distinct clinical entity.

BACKGROUND: Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor (NET) that arises from the parafollicular cells (C-cells) of the thyroid gland which produces calcitonin (CT) and is, therefore, a serum and immunohistochemical biomarker of MTC. Here, we describe a patient with another form of NET arising with the thyroid gland. PATIENT FINDINGS: This is a forty-year-old woman who underwent total thyroidectomy for a thyroid nodule that had features of an NET on fine needle aspiration. Her serum CT and carcinoembryonic antigen were normal. Surgical pathology showed a well-differentiated NET with immunohistochemical stains positive for markers of follicular cells (thyroglobulin and synaptophysin), positive for neuroendocrine markers (neuron specific enolase and chromogranin A), but negative for CT, the defining marker of MTC. CONCLUSIONS: We describe a rare case of a nonmedullary NET of the thyroid gland arising from thyroid follicular cells, not parafollicular cells. We suggest that calcitonin-negative neuroendocrine tumor of the thyroid gland (CNNETT) may be an entity that has not been recognized in the literature. This distinction between MTC and CNNETT may be important, as the treatment and prognosis may differ.

Epstein-Barr virus positive anaplastic large cell lymphoma: myth or reality?

The World Health Organization (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissue, 2008 edition, states that anaplastic large cell lymphoma (ALCL) is "consistently negative for Epstein-Barr virus (EBV)". The statement made by the WHO has led to the widespread belief that EBV can have no pathogenic role in ALCL. Herein we report a case of an immunocompetent 35-year-old male who presented with hemophagocytic syndrome secondary to lymphoma for which diagnostic material consisted solely of a bone marrow biopsy. The biopsy demonstrated large anaplastic cells which were uniformly positive for surface CD3, CD30 (strong membranous and Golgi expression), CD45, TIA-1 and Granzyme B but negative for ALK-1. In-situ hybridization was strongly positive for EBER in the large neoplastic cells. The uniformity of CD30 expression and positivity for cytotoxic markers on the anaplastic tumor cells raised the diagnostic possibility of an EBV-associated ALCL, ALK-. Discussion of this case as well as a retrospective review of 64 cases of reported of EBV+ ALCL are presented.