Clinical Significance of the Immunohistochemical Expression of Histone Deacetylases (HDACs)-2, -4, and -5 in Ovarian Adenocarcinomas.

BACKGROUND: Histone deacetylases (HDACs) are implicated in carcinogenesis, and HDAC inhibitors (HDACis) are explored as a therapeutic tool in several tumors. The aim of this study was to evaluate the clinical significance of HDAC-2, -4, and -5 expression in epithelial ovarian carcinoma (EOC). METHODS: HDAC-2, -4, and -5 immunohistochemical expression was examined in 92 EOC tissue specimens and was correlated with clinicopathological characteristics. RESULTS: HDAC-2 was the most frequently (94.4%) expressed isoform, being marginally higher in serous tumors compared with other types (p = 0.08). HDAC-5 was the less frequently expressed (28.1%), being positively associated with HDAC-4. HDAC-4 positivity was associated with lower FIGO-stage (p = 0.045) and T-category (p = 0.043) and the absence of lymph node (p = 0.05) or distant metastasis (p = 0.09) in serous carcinomas. HDAC-2 positivity was correlated with the absence of lymph node metastasis in serous tumors (p = 0.045). On the contrary, HDAC-5 nuclear positivity was correlated with lymph node metastasis in the entire cohort (p = 0.048). HDAC-4 positivity was marginally associated with favorable prognosis in serous carcinomas in univariate survival analysis (p = 0.086), but this correlation was not significant in multivariate analysis. CONCLUSIONS: These findings suggest a differential expression among HDAC-2, -4, and -5 in ovarian adenocarcinomas in terms of immunolocalization, positivity rate, and associations with clinicopathological parameters, providing evidence for a potential role in the pathobiology of EOC.

Six-Year Time-Series Data on Multidrug-Resistant Bacteremia, Antibiotic Consumption, and Infection Control Interventions in a Hospital.

Background: Multidrug-resistant (MDR) bacteremia is a serious health care-associated infection with significant morbidity and excess hospitalization costs. Our aim is to study the association between incidences of MDR bacteremia, antibiotic consumption, and infection control measures in a hospital from 2013 to 2018. Methods: We analyzed the following indices: (1) incidence of bacteremia (carbapenem-resistant Acinetobacter baumanii, Pseudomonas aeruginosa, and Klebsiella pneumoniae, methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococci); (2) use of antibiotics; (3) consumption of disinfectant solutions for hand hygiene; and (4) isolation rates of MDR carrier patients. Findings: The use of advanced antibiotics (p = 0.001) and carbapenems (p = 0.008) decreased significantly in all hospital departments but the incidence of total MDR bacteremia did not change significantly. Increased use of hand disinfectant solutions was statistically associated with decreased incidence of total MDR bacteremia (incidence rate ratio [IRR]: 0.94, confidence interval [95% CI]: 0.90-0.99, p: 0.020) in all hospital. Also, increased isolation rates of MDR carrier patients 2 months before correlated with decreased incidence of bacteremia due to carbapenem-resistant gram-negative pathogens (IRR: 0.35, 95% CI: 0.18-0.66, p: 0.001) in adults intensive care unit. Conclusion: In our hospital, hand hygiene and isolation of MDR carrier patients controlled MDR bacteremia.

A case of multiple familial trichoepitheliomas responding to treatment with the Hedgehog signaling pathway inhibitor vismodegib.

Multiple familial trichoepitheliomas (MFT) is an autosomal dominantly inherited disease characterized by multiple skin appendage tumors. We describe a patient showing a continuous spectrum of follicular differentiated neoplasms including classical trichoepitheliomas but also infiltrative growing and finally metastasizing malignant follicular differentiated tumors. Germline mutation analysis revealed a nonsense mutation in the cylindromatosis (CYLD) gene. Gene expression analysis by real-time PCR of tumor tissue showed overexpression of glioma-associated oncogene Gli1 mRNA. Treatment with the Hedgehog pathway inhibitor vismodegib resulted in a significant regression of the highly differentiated trichoepitheliomas. Gli upregulation is indicative of an active Hedgehog signaling pathway. We hypothesize that its upregulation is indirectly caused by CYLD mutation which promotes tumor development. Vismodegib treatment could thus provide a new treatment option for patients with this debilitating disorder.

Association of Plane of Total Mesorectal Excision With Prognosis of Rectal Cancer: Secondary Analysis of the CAO/ARO/AIO-04 Phase 3 Randomized Clinical Trial.

Importance: Previous retrospective studies have shown that surgical quality affects local control in rectal cancer.. Objective: In this secondary end point analysis, we evaluated the prognostic effect of the total mesorectal excision (TME) plane in the CAO/ARO/AIO-04 phase 3 randomized clinical trial. Design, Setting, and Participants: The CAO/ARO/AIO-04 trial enrolled 1236 patients with cT3-4 and/or node-positive rectal adenocarcinoma from 88 centers in Germany between July 25, 2006, and February 26, 2010. Interventions: Patients were randomized to receive treatment with standard fluorouracil-based preoperative chemoradiotherapy (CRT) alone (control arm) or oxaliplatin (experimental arm) followed by TME and adjuvant chemotherapy. Main Outcomes and Measures: The TME quality (mesorectal, intramesorectal, and muscularis propria plane) was prospectively assessed in 1152 operation specimens. An assessment was performed independently by pathologists and surgeons. The results were correlated with clinicopathologic data and the clinical outcome was tested, including multivariable analysis with the Cox regression model. Results: Of 1152 German Caucasian participants, 332 (28.8) were women and the mean age was 63 years. The plane of TME was mesorectal in 930 patients (80.7%), intramesorectal in 169 (14.7%), and muscularis propria in 53 (4.6%). In a univariable analysis, the TME plane was significantly associated with 3-year disease-free survival (mesorectal vs intramesorectal vs muscularis propria, 95% CI, 73.1-78.8 vs 61.6-76.0 vs 55.6-81.3, respectively; P = .01), cumulative incidence of local and distant recurrences (mesorectal vs intramesorectal vs muscularis propria, 95% CI, 2.0-4.5 vs 1.2-8.1 vs 2.5-20.5, respectively; P < .001; and mesorectal vs intramesorectal vs muscularis propria, 95% CI, 17.0-22.4 vs 18.3-32.0 vs 14.2-39.0, respectively; P = .03, respectively), and overall survival (mesorectal vs intramesorectal vs muscularis propria, 95% CI, 88.3-92.3 vs 79.7-91.0 vs 81.6-98.7, respectively; P = .02). In contrast to the pathologist-based evaluation, the assessment of TME plane by the operating surgeon failed to demonstrate prognostic significance for any of these clinical end points. In a multivariable analysis, the plane of surgery (mesorectal vs muscularis propria TME) constituted an independent factor for local recurrence (P = .002). Conclusions and Relevance: This phase 3 randomized clinical trial confirms the long-term clinical effect of TME plane quality on local recurrence, as initially reported in the MRC CR07 study. The data highlight the key role of pathologists and surgeons in the multidisciplinary management of rectal cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT00349076.

Clinical Significance and Biological Role of HuR in Head and Neck Carcinomas.

BACKGROUND: Hu-antigen R (HuR) is a posttranscriptional regulator of several target mRNAs, implicated in carcinogenesis. This review aims to present the current evidence regarding the biological role and potential clinical significance of HuR in head and neck carcinomas. METHODS: The existing literature concerning HuR expression and function in head and neck carcinomas is critically presented and summarised. RESULTS: HuR is expressed in the majority of the examined samples, showing higher cytoplasmic levels in malignant or premalignant cases. Moreover, HuR modulates several genes implicated in biological processes important for malignant transformation, growth, and invasiveness. HuR seems to be an adverse prognosticator in patients with OSCCs, whereas a correlation with a more aggressive phenotype is reported in several types of carcinomas. CONCLUSIONS: A consistent role of HuR in the carcinogenesis and progression of head and neck carcinomas is suggested; nevertheless, further studies are warranted to expand the present information.

MIBI scintigraphy of parathyroid adenomas: correlation with biochemical and histological markers.

PURPOSE: In this study, we tested the hypothesis that MIBI-positive and MIBI-negative adenomas of parathyroid glands (APGs) have distinct biochemical and histological markers that could help differentiate MIBI-positive from MIBI-negative APGs. PATIENTS AND METHODS: 40 patients with 41 APGs were included in the study. Patients were enrolled in the study after MIBI scintigraphy examinations had been carried out. Biochemical analyses included serum levels of calcium (Ca), intact parathyroid hormone (iPTH), and 25-hydroxyvitamin D3 (25-OH-D3). All patients had neck ultrasound and MIBI examinations. After surgical resection the APGs were examined histologically. RESULTS: In each of 39 patients one APG could be confirmed by histology, and in one patient, two contralateral APGs were identified. MIBI studies were positive in 73 % and negative in 27 % of the APGs. False-positive cases were not observed. MIBI-negative APGs were only present in patients with iPTH values below 150 pg/ml. In 82 % of MIBI negative studies oxyphilic cells were absent, and this cell type was present in only 18 % of MIBI negative cases (p < 0.001). Regarding cysts within the APGs, no differences were demonstrated between MIBI positive or negative studies (p = 0.32). Fat cells were seen in none of the MIBI -negative studies and in only 3 % of MIBI positive studies (p = 0.08). CONCLUSIONS: For APGs, MIBI positivity correlates with serum iPTH concentration. The absence of oxyphilic cells with large numbers of mitochondria in APGs contributes to MIBI negativity, probably because of the reduced binding sites for the radiotracer.

Seromucinous borderline tumor of the testis-A case report.

Tumors of ovarian epithelial type of testis are rare entities. After ruling out metastasis, especially from gastrointestinal origins, these neoplasms are categorized according to their ovarian correspondents, now including a new group of seromucinous tumors, which was introduced by the World Health Organization in 2013. Here we present the case of a 60-year-old man with a testicular tumor, showing focally stratified, immunohistochemical PAX8-positive epithelium and endometrioid-like stroma, supporting the diagnosis of seromucinous borderline tumor of ovarian-type surface epithelium. The two main competing hypotheses for the etiology of these neoplasms are development either by metaplasia of the mesothelium of the tunica vaginalis testis, or from remnants of Mullerian duct, which is supported by the notable positivity for PAX8 in our case. To our knowledge, we are the first to describe this newly defined entity of seromucinous borderline tumor of the testis in the English-speaking literature.

Afatinib-associated Stevens-Johnson syndrome in an EGFR-mutated lung cancer patient.

INTRODUCTION: Afatinib is a tyrosine kinase inhibitor (TKI), that has been approved for treating patients with epidermal growth factor receptor (EGFR) mutated advanced non-small-cell lung cancer (NSCLC). Stevens-Johnson syndrome (SJS) related to EGFR directed TKIs is a rare adverse event. CASE PRESENTATION: We report a case of a 79-year-old white female with EGFR-mutated, metastatic non-small-cell lung cancer treated with afatinib as first-line palliative treatment, who developed a SJS after two months of treatment. Discontinuation of the TKI and systemic glucocorticoid treatment led to improvement of symptoms and recovery. CONCLUSION: Severe adverse cutaneous drug reactions that predominantly involve the skin and mucous membranes during treatment with afatinib should alert clinicians to suspect SJS and react appropriately.

Solitary and small (≤3 mm) apical positive surgical margins are related to biochemical recurrence after radical prostatectomy.

OBJECTIVES: To evaluate the prognostic value of positive surgical margins (PSM) in radical prostatectomy (RPE) specimens in relation to multifocality, localization and size. METHODS: A total of 1036 patients who underwent RPE and staged pT2-3a,pN0,M0 were evaluated. None had received adjuvant or neoadjuvant therapy. All specimens were routinely processed by complete whole mount sectioning. Exact number, localization and size of PSM were reassessed, and patients were followed up for a mean of 60 months. RESULTS: A total of 267 patients (26%) showed PSM (20% pT2, 48% pT3a). Preoperative prostate-specific antigen, Gleason score (GS) and PSM were independent predictors of biochemical recurrence (BCR). BCR-free survival rates for patients with and without PSM were 59% and 80%, respectively (HR 2.1; P < 0.001). PSM were related to biochemical failure in pT2 and pT3a tumors (P = 0.001 and P = 0.015). A total of 64% of solitary PSM were apical. Multifocality, localization and size of PSM had no significant impact on BCR. CONCLUSIONS: Solitary apical and small PSM in RPE have a significant impact on BCR-free survival in localized stages.

Coronary ostial stenosis after aortic valve replacement: successful treatment of 2 patients with drug-eluting stents.

Coronary ostial stenosis is a rare but potentially serious sequela after aortic valve replacement. It occurs in the left main or right coronary artery after 1% to 5% of aortic valve replacement procedures. The clinical symptoms are usually severe and may appear from 1 to 6 months postoperatively. Although the typical treatment is coronary artery bypass grafting, patients have been successfully treated by means of percutaneous coronary intervention.Herein, we present the cases of 2 patients in whom coronary ostial stenosis developed after aortic valve replacement. In the 1st case, a 72-year-old man underwent aortic valve replacement and bypass grafting of the saphenous vein to the left anterior descending coronary artery. Six months later, he experienced a non-ST-segment-elevation myocardial infarction. Coronary angiography revealed a critical stenosis of the right coronary artery ostium. In the 2nd case, a 78-year-old woman underwent aortic valve replacement and grafting of the saphenous vein to an occluded right coronary artery. Four months later, she experienced unstable angina. Coronary angiography showed a critical left main coronary artery ostial stenosis and occlusion of the right coronary artery venous graft. In each patient, we performed percutaneous coronary intervention and deployed a drug-eluting stent. Both patients were asymptomatic on 6-to 12-month follow-up. We attribute the coronary ostial stenosis to the selective ostial administration of cardioplegic solution during surgery. We conclude that retrograde administration of cardioplegic solution through the coronary sinus may reduce the incidence of postoperative coronary ostial stenosis, and that stenting may be an efficient treatment option.

Comparability of microarray data between amplified and non amplified RNA in colorectal carcinoma.

Microarray analysis reaches increasing popularity during the investigation of prognostic gene clusters in oncology. The standardisation of technical procedures will be essential to compare various datasets produced by different research groups. In several projects the amount of available tissue is limited. In such cases the preamplification of RNA might be necessary prior to microarray hybridisation. To evaluate the comparability of microarray results generated either by amplified or non amplified RNA we isolated RNA from colorectal cancer samples (stage UICC IV) following tumour tissue enrichment by macroscopic manual dissection (CMD). One part of the RNA was directly labelled and hybridised to GeneChips (HG-U133A, Affymetrix), the other part of the RNA was amplified according to the "Eberwine" protocol and was then hybridised to the microarrays. During unsupervised hierarchical clustering the samples were divided in groups regarding the RNA pre-treatment and 5.726 differentially expressed genes were identified. Using independent microarray data of 31 amplified vs. 24 non amplified RNA samples from colon carcinomas (stage UICC III) in a set of 50 predictive genes we validated the amplification bias. In conclusion microarray data resulting from different pre-processing regarding RNA pre-amplification can not be compared within one analysis.

Downstaging of pancreatic carcinoma after neoadjuvant chemoradiation.

BACKGROUND AND PURPOSE: Neoadjuvant chemoradiation could improve survival in patients with pancreatic cancer because of a higher rate of R0 resections, lower rate of nodal metastasis (ypN) and of local recurrence. This approach was tested in a cohort to estimate its effect on survival. PATIENTS AND METHODS: Three-dimensional, conformal radiation to the primary tumor (55.8 Gy) and the lymphatics (50.4 Gy) was combined with chemotherapy. Resection was performed 6 weeks after completion of chemoradiation. RESULTS: 38 of 120 patients with locally advanced cancer underwent tumor resection thereafter. Three patients (8%) had pathologic complete response. Median tumor-specific survival was 29 months and overall survival 25 months. Patients with clear margins (35/38; 89%) had a 3-year disease-specific survival rate of 51% versus 0% with positive margins (p = 0.008). Nodal disease rate decreased from 50% at pretherapeutic imaging to 32% at resection. Patients with ypN0 status (n = 26/38) had a 3-year tumor-specific survival rate of 50% compared to 31% in patients with ypN1 status. At multivariate analysis, resection status and nodal spread significantly predicted tumor-specific survival. Chemoradiation was generally well tolerated. CONCLUSION: The current results support randomized testing of neoadjuvant chemoradiation to prove survival prolongation. Compared to the literature this approach seems to reduce the number of positive nodes.

Multivisceral resection for colon carcinoma.

PURPOSE: The aim of curative surgery for colon carcinoma is the complete resection of the neoplasm. In locally advanced colon carcinomas with adhesion to neighboring organs, standard surgical procedures often turn into multivisceral resections. The purpose of this study was to investigate the value of multivisceral resection in primary colon carcinomas and factors influencing its success. METHODS: Prospectively collected data for 174 patients from the Erlangen Registry for Colorectal Carcinomas who underwent multivisceral resection for colon carcinoma from 1978 through 2002 were analyzed. Multivisceral resection was defined as the excision or resection of at least one further organ in addition to the carcinoma-affected colon. Postoperative complications, locoregional tumor recurrence, distant metastases, and cancer-related survival were evaluated after a five-year follow-up. RESULTS: Multivisceral resection most commonly involved parts of the small intestine (31.6%), urinary bladder (27.0%), and the abdominal wall (15.5%). R0 resection (no residual tumor) was achieved in 93.1%. Overall, postoperative complications occurred in 25.8%, and the postoperative mortality rate was 6.9%. For patients with R0 resection, the Kaplan-Meier estimate of five-year cancer-related survival was 80.7%; no patient with R1 or R2 resection survived for 5 years. The five-year rate of locoregional tumor recurrence was 6.5%, and the five-year rate of distant metastases was 24.2%. The presence of lymphatic metastases was a significant prognostic factor for locoregional tumor recurrence, distant metastases, and cancer-related survival. CONCLUSION: The high percentage of R0 resections achieved through multivisceral resection justifies this procedure for locally advanced colon carcinomas and highlights the importance of experienced, well-trained surgeons to decrease the incidence of locoregional recurrence.

Comparison of clinical risk scores predicting prognosis after resection of colorectal liver metastases.

BACKGROUND: The aim of this study was to compare the risk scores of Fong et al., Nordlinger et al., and the TNM classification of colorectal liver metastases proposed by the UICC. METHODS: Data from 282 consecutive patients undergoing 303 liver resections for metastatic colorectal cancer between 1995 and 2006 at the Department of Surgery, University of Erlangen were analyzed. The median follow-up time was 34 months. A curative (R0) resection was performed in 92% of the patients. RESULTS: Applying the clinical risk score of Fong with preoperative data identified three risk groups. The survival rates between "low risk" (n = 22) and "intermediate risk" (n = 222) diverged (P = 0.073). The survival rates between "intermediate risk" and "high risk" (n = 59) differed significantly (P = 0.030). Using the risk scoring system of Nordlinger, patients were divided into two risk groups (i.e., "low risk" (n = 218) and "intermediate risk" (n = 68)). Significant differences in survival between the groups were noted (P = 0.012). Applying the clinical TNM classification of colorectal liver metastases revealed no significant differences in survival between the risk groups. CONCLUSIONS: Our study found the clinical risk score developed by Fong et al. to be a reliable preoperative prognostic tool for selecting patients for surgical resection of colorectal liver metastases.

Quality management in rectal carcinoma: what is feasible?

PURPOSE: A cohort study was carried out to analyse quality indicators in the diagnosis and treatment of rectal carcinoma. METHODS: A total of 2,470 patients with rectal carcinoma treated between 1985 and 2007 at the Department of Surgery, University of Erlangen, were analysed and compared within four time intervals. RESULTS: Most of the indicators analysed from 2004 to 2007 fulfilled the defined target values. The indicators for process quality of surgical treatment and the surrogate indicators of outcome quality in surgery showed excellent results. Comparing this to previous data, it displays the new developments such as introduction of multimodal treatment for high-risk patients. While the rate of locoregional recurrences decreased, no significant improvement in survival was found. CONCLUSIONS: Careful analysis of quality indicators is important for both quality management and comparison of treatment results. The progress in diagnosis and treatment requires a continuous update of definitions and target values.

Malignant progression of invasive tumour cells seen in hypoxia present an accumulation of beta-catenin in the nucleus at the tumour front.

Of all processes involved in tumour progression, local invasion and formation of metastases are the clinically most relevant but the scientifically least well understood at their molecular level. The loss of cell adhesion, then tumour cell migration with changes in the cytoskeleton, invasion and metastatic dissemination are the steps of the "metastatic cascade". The E-cadherin-catenin complex plays a key role in cell adhesion thus building the first step in malignant progression. In many epithelial cancers, E-cadherin is lost concomitantly with tumour progression. Thus beta-catenin dissociates in the cytoplasm and accumulates in the nucleus as a transcription factor. Recent experimental progress has identified that tumour hypoxia not only induces tumour angiogenesis, but also modulates malignant progression to initiate tumour invasion and metastasis. It was hypothesised that hypoxia within tumours causes dysfunction of the E-cadherin-catenin complex with an accumulation of beta-catenin in the nucleus and produces an invasive phenotype of tumour cells. For this purpose fertilized chicken eggs were incubated for ten days in normoxic conditions. Subsequently colon carcinoma cells (SW-480) were placed on the chorioallantoic membrane. During the following six days the eggs were incubated either in normoxic conditions or in stepwise decreasing hypoxic conditions. SW-480 colon carcinoma cells did not invade the epithelial layer in normoxic conditions. beta-catenin was membrane bound or in the cytoplasm. The nuclei were regularly omitted. In contrast, an invasion through the epithelial layer into the mesoderm was already seen after three days when incubated in hypoxic conditions. beta-catenin was membrane bound in non-invasive regions of the tumour nodule but there was an accumulation of beta-catenin in the nucleus in the invasive tumour front. Hypoxia seems to be responsible for accumulation of beta-catenin in the nucleus which is accompanied by a more invasive phenotype of tumour cells at the tumour front.

Transvaginal-laparoscopic anterior rectum resection in a hysterectomized woman with deep-infiltrating endometriosis: Description of a gynecologic natural orifice transendoluminal surgery approach.

Deep-infiltrating endometriosis may affect the vagina, the rectum, and the cervicoisthmic part of the uterus, resulting in severe pain, particularly dyschezia, dysmenorrhea, dyspareunia, and diminished quality of life. Advanced surgical techniques, such as laparoscopic-assisted anterior rectum resection, are recognized as safe and effective therapeutic approaches. In some cases, a laparotomy or minilaparotomy has to be performed for technical reasons. This can be avoided in some cases by transvaginal-laparoscopic low anterior rectum resection. The technique is a 4-step procedure, which can be described as follows: step 1 (vaginal) - rectovaginal examination, preparation of the rectovaginal septum, opening of the pouch of Douglas, mobilization of the endometriotic nodule and the rectum, temporary vaginal closure; step 2 (laparoscopic) - removal of additional endometriotic lesions, adhesiolysis, final mobilization of the rectum, mobilization of the rectosigmoid, endoscopic resection using an endoscopic stapler step 3 (vaginal) - transvaginal resection of the lesion, preparation of the oral anvil, closure of the vagina; and step 4 (laparoscopic) - endoscopic transanal stapler anastomosis and underwater rectoscopy, prophylaxis of adhesions, drainage. We used this procedure to treat a 46-year-old woman (gravida 2, para 2) who was admitted to our hospital for severe lower abdominal pain, constipation, dyspareunia, dyschezia, and cyclic rectal bleedings. The symptoms were caused by an endometriotic nodule accompanied by a palpable rectum stenosis. In addition, she reported a past abdominal hysterectomy with complications caused by symptomatic myomatous uterus. As a gynecologic natural orifice surgery approach, the transvaginal-laparoscopic anterior rectum resection may be an additional useful surgical technique that could be offered by surgical gynecologists to some women with deep-infiltrating endometriosis.