Clinical characteristics of women with HIV in the RESPOND cohort: A descriptive analysis and comparison to men.

BACKGROUND: Women with HIV are globally underrepresented in clinical research. Existing studies often focus on reproductive outcomes, seldom focus on older women, and are often underpowered to assess sex/gender differences. We describe CD4, HIV viral load (VL), clinical characteristics, comorbidity burden, and use of antiretroviral therapy (ART) among women with HIV in the RESPOND study and compare them with those of the men in RESPOND. METHODS: RESPOND is a prospective, multi-cohort collaboration including over 34 000 people with HIV from across Europe and Australia. Demographic and clinical characteristics, including CD4/VL, comorbidity burden, and ART are presented at baseline, defined as the latter of 1 January 2012 or enrolment into the local cohort, stratified by age and sex/gender. We further stratify men by reported mode of HIV acquisition, men who have sex with men (MSM) and non-MSM. RESULTS: Women account for 26.0% (n = 9019) of the cohort, with a median age of 42.2 years (interquartile range [IQR] 34.7-49.1). The majority (59.3%) of women were white, followed by 30.3% Black. Most women (75.8%) had acquired HIV heterosexually and 15.9% via injecting drug use. Nearly half (44.8%) were receiving a boosted protease inhibitor, 31.4% a non-nucleoside reverse transcriptase inhibitor, and 7.8% an integrase strand transfer inhibitor. The baseline year was 2012 for 73.2% of women and >2019 for 4.2%. Median CD4 was 523 (IQR 350-722) cells/µl, and 73.6% of women had a VL <200 copies/mL. Among the ART-naïve population, women were more likely than MSM but less likely than non-MSM (p < 0.001) to have CD4 <200 cells/µL and less likely than both MSM and non-MSM (p < 0.001) to have VL ≥100 000 copies/mL. Women were also more likely to be free of comorbidity than were both MSM and non-MSM (p < 0.0001). CONCLUSION: RESPOND women are diverse in age, ethnicity/race, CD4/VL, and comorbidity burden, with important differences relative to men. This work highlights the importance of stratification by sex/gender for future research that may help improve screening and management guidelines specifically for women with HIV.

Staging of pancreatic cancer based on the number of positive lymph nodes.

BACKGROUND: The International Study Group on Pancreatic Surgery has stated that at least 12 lymph nodes should be evaluated for staging of pancreatic cancer. The aim of this population-based study was to evaluate whether the number of positive lymph nodes refines staging. METHODS: Patients who underwent pancreatectomy for stage I-II pancreatic cancer between 2004 and 2012 were identified from the Surveillance, Epidemiology, and End Results database. The predictive value of the number of positive lymph nodes for survival was assessed by generalized receiver operating characteristic (ROC) curve analysis and propensity score-adjusted Cox regression analysis. RESULTS: Some 5036 patients were included, with a median of 18 (i.q.r. 15-24) lymph nodes examined. Positive lymph nodes were found in 3555 patients (70·6 per cent). The median duration of follow-up was 15 (i.q.r. 8-28) months. ROC curve analysis revealed that two positive lymph nodes best discriminated overall survival. Patients with one or two positive lymph nodes (pN1a) and those with three or more positive lymph nodes (pN1b) had an increased risk of overall mortality compared with patients who were node-negative (pN0): hazard ratio (HR) 1·47 (95 per cent c.i. 1·33 to 1·64) and HR 2·01 (1·82 to 2·22) respectively. These findings were confirmed by propensity score-adjusted Cox regression analysis. The 5-year overall survival rates were 39·8 (95 per cent c.i. 36·5 to 43·3) per cent for patients with pN0, 21·0 (18·6 to 23·6) per cent for those with pN1a and 11·4 (9·9 to 13·3) per cent for patients with pN1b disease. CONCLUSION: The number of positive lymph nodes in the resection specimen is a prognostic factor in patients with pancreatic cancer.

Survival after resection of appendiceal carcinoma by hemicolectomy and less radical than hemicolectomy: a population-based propensity score matched analysis.

AIM: The operative treatment for non-metastatic appendiceal carcinoma is controversial despite the recommendation of right hemicolectomy (RH) by many researchers. The aim of this population-based study was to compare outcomes after RH and less radical resection than right hemicolectomy (LRH). METHOD: A total of 1144 patients who underwent resection with additional lymphadenectomy of Stages I-III appendiceal carcinoma from 2004 to 2012 were identified in the Surveillance, Epidemiology and End Results database. Overall survival (OS) and cancer-specific survival (CSS) after RH and LRH were assessed by unadjusted and risk-adjusted Cox regression analysis and by propensity score matched analysis. RESULTS: A total of 855 (74.7%) patients underwent RH and 289 (25.3%) underwent LRH. In an unadjusted analysis, survival after LRH and RH did not differ in OS [hazard ratio (HR) 0.95, 95% CI 0.71-1.26, P = 0.707] and CSS (HR 0.95, 95% CI 0.69-1.32, P = 0.762). The 5-year OS and CSS in patients who underwent RH were 71.6% (95% CI 67.8-75.6%) and 76.4% (95% CI 72.8-80.3) compared with 73.8% (95% CI 67.9-80.2) and 78.7% (95% CI 73.2-84.7) in patients with LRH, respectively. No relevant difference in survival between LRH and RH could be observed in a multivariable analysis (OS, HR 0.90, 95% CI 0.65-1.25, P = 0.493; CSS, HR 0.87, 95% CI 0.60-1.26, P = 0.420) and after propensity score adjusted analysis (OS, HR 0.87, 95% CI 0.62-1.22, P = 0.442; CSS, HR 0.97, 95% CI 0.67-1.40, P = 0.883). CONCLUSIONS: In this retrospective analysis, survival after RH for non-metastatic appendiceal carcinoma was not statistically significantly superior to LRH. Hence, LRH with lymphadenectomy might be sufficient for treatment of non-metastatic appendiceal carcinoma.

Transmission of HIV Drug Resistance and the Predicted Effect on Current First-line Regimens in Europe.

BACKGROUND: Numerous studies have shown that baseline drug resistance patterns may influence the outcome of antiretroviral therapy. Therefore, guidelines recommend drug resistance testing to guide the choice of initial regimen. In addition to optimizing individual patient management, these baseline resistance data enable transmitted drug resistance (TDR) to be surveyed for public health purposes. The SPREAD program systematically collects data to gain insight into TDR occurring in Europe since 2001. METHODS: Demographic, clinical, and virological data from 4140 antiretroviral-naive human immunodeficiency virus (HIV)-infected individuals from 26 countries who were newly diagnosed between 2008 and 2010 were analyzed. Evidence of TDR was defined using the WHO list for surveillance of drug resistance mutations. Prevalence of TDR was assessed over time by comparing the results to SPREAD data from 2002 to 2007. Baseline susceptibility to antiretroviral drugs was predicted using the Stanford HIVdb program version 7.0. RESULTS: The overall prevalence of TDR did not change significantly over time and was 8.3% (95% confidence interval, 7.2%-9.5%) in 2008-2010. The most frequent indicators of TDR were nucleoside reverse transcriptase inhibitor (NRTI) mutations (4.5%), followed by nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations (2.9%) and protease inhibitor mutations (2.0%). Baseline mutations were most predictive of reduced susceptibility to initial NNRTI-based regimens: 4.5% and 6.5% of patient isolates were predicted to have resistance to regimens containing efavirenz or rilpivirine, respectively, independent of current NRTI backbones. CONCLUSIONS: Although TDR was highest for NRTIs, the impact of baseline drug resistance patterns on susceptibility was largest for NNRTIs. The prevalence of TDR assessed by epidemiological surveys does not clearly indicate to what degree susceptibility to different drug classes is affected.

Isolated tumor cells in stage I & II colon cancer patients are associated with significantly worse disease-free and overall survival.

BACKGROUND: Lymph node (LN) involvement represents the strongest prognostic factor in colon cancer patients. The objective of this prospective study was to assess the prognostic impact of isolated tumor cells (ITC, defined as cell deposits ≤ 0.2 mm) in loco-regional LN of stage I & II colon cancer patients. METHODS: Seventy-four stage I & II colon cancer patients were prospectively enrolled in the present study. LN at high risk of harboring ITC were identified via an in vivo sentinel lymph node procedure and analyzed with multilevel sectioning, conventional H&E and immunohistochemical CK-19 staining. The impact of ITC on survival was assessed using Cox regression analyses. RESULTS: Median follow-up was 4.6 years. ITC were detected in locoregional lymph nodes of 23 patients (31.1%). The presence of ITC was associated with a significantly worse disease-free survival (hazard ratio = 4.73, p = 0.005). Similarly, ITC were associated with significantly worse overall survival (hazard ratio = 3.50, p = 0.043). CONCLUSIONS: This study provides compelling evidence that ITC in stage I & II colon cancer patients are associated with significantly worse disease-free and overall survival. Based on these data, the presence of ITC should be classified as a high risk factor in stage I & II colon cancer patients who might benefit from adjuvant chemotherapy.

Meta-analysis of the predictive value of C-reactive protein for infectious complications in abdominal surgery.

BACKGROUND: The aim of this analysis was to assess the predictive value of C-reactive protein (CRP) for the early detection of postoperative infectious complications after a variety of abdominal operations. METHODS: A meta-analysis of seven cohort studies from a single institution was performed. Laparoscopic gastric bypass and colectomies, as well as open resections of cancer of the colon, rectum, pancreas, stomach and oesophagus, were included. The predictive value of CRP was assessed by the area under the curve (AUC) of the receiver operating characteristic (ROC) curve. RESULTS: Of 1986 patients, 577 (29·1 (95 per cent c.i. 27·1 to 31·3) per cent) had at least one postoperative infectious complication. Patients undergoing laparoscopic gastric bypass (383 patients) or colectomy (285), and those having open gastric (97) or colorectal (934) resections were combined in a meta-analysis. Patients who had resection for cancer of the oesophagus (41) or pancreas (246) were analysed separately owing to heterogeneity. CRP levels 4 days after surgery had the highest diagnostic accuracy (AUC 0·76, 95 per cent c.i. 0·73 to 0·78). Sensitivity and specificity were 68·5 (60·6 to 75·5) and 71·6 (66·6 to 76·0) per cent respectively. Positive and negative predictive values were 50·4 (46·0 to 54·8) and 84·3 (80·8 to 87·3) per cent. The threshold CRP varied according to the procedure performed. CONCLUSION: The negative predictive value of serum CRP concentration on day 4 after surgery facilitates reliable exclusion of postoperative infectious complications.

Elevated preoperative CEA is associated with worse survival in stage I-III rectal cancer patients.

BACKGROUND: The objective of this investigation was to assess whether preoperative carcinoembryonic antigen (CEA) level is an independent predictor of overall survival in rectal cancer patients. METHODS: All patients (n=504) undergoing a resection for stage I-III rectal cancer at the Kantonsspital St Gallen were included into a database between 1991 and 2008. The impact of preoperative CEA level on overall survival was assessed using risk-adjusted Cox proportional hazard regression models and propensity score methods. RESULTS: In risk-adjusted Cox proportional hazard regression analyses, preoperative CEA level (hazard ratio (HR): 1.98, 95% confidence interval (CI): 1.36-2.90, P<0.001), distance from anal verge (<5 cm: HR: 1.93, 95% CI: 1.11-3.37; P=0.039), older age (HR: 1.07, 95% CI: 1.05-1.09; P<0.001), lower body mass index (HR: 0.94, 95% CI: 0.89-0.98; P=0.006), advanced tumour stage (stage II HR: 1.41, 95% CI: 0.85-2.32; stage III HR: 2.08, 95% CI: 1.31-3.31; P=0.004), R 1 resection (HR: 5.65, 95% CI: 1.59-20.1; P=0.005) and chronic kidney disease (HR: 2.28, 95% CI: 1.03-5.04; P=0.049) were all predictors for poor overall survival. CONCLUSION: This is one of the first investigations based on a large cohort of exclusively rectal cancer patients demonstrating that preoperative CEA level is a strong predictor of decreased overall survival. Preoperative CEA should be used as a prognostic factor in the preoperative assessment of rectal cancer patients.

Randomized clinical trial on the effect of coffee on postoperative ileus following elective colectomy.

BACKGROUND: Postoperative ileus is a common problem after abdominal surgery. It was postulated that coffee intake would decrease postoperative ileus after colectomy. METHODS: This was a multicentre parallel open-label randomized trial. Patients with malignant or benign disease undergoing elective open or laparoscopic colectomy were assigned randomly before surgery to receive either coffee or water after the procedure (100 ml three times daily). The primary endpoint was time to first bowel movement; secondary endpoints were time to first flatus, time to tolerance of solid food, length of hospital stay and perioperative morbidity. RESULTS: A total of 80 patients were randomized, 40 to each group. One patient in the water arm was excluded owing to a change in surgical procedure. Patient characteristics were similar in both groups. In intention-to-treat analysis, the time to the first bowel movement was significantly shorter in the coffee arm than in the water arm (mean(s.d.) 60·4(21·3) versus 74·0(21·6) h; P = 0·006). The time to tolerance of solid food (49·2(21·3) versus 55·8(30·0) h; P = 0·276) and time to first flatus (40·6(16·1) versus 46·4(20·1) h; P = 0·214) showed a similar trend, but the differences were not significant. Length of hospital stay (10·8(4·4) versus 11·3(4·5) days; P = 0·497) and morbidity (8 of 40 versus 10 of 39 patients; P = 0·550) were comparable in the two groups. CONCLUSION: Coffee consumption after colectomy was safe and was associated with a reduced time to first bowel action.

Long-term in vitro culture of hamster pancreatic ß-cells and induction of adenocarcinoma by treatment with N-nitrosobis(2-oxopropyl)amine.

OBJECTIVES: Earlier studies indicated that hamster pancreatic ductal adenocarcinoma not only derives from ductal/ductular structures but also from cells within the islet. So far unidentified cells within the islet are responsive to the carcinogenic effect of N-nitrosobis (2-oxopropyl) amine (BOP) forming poorly differentiated ductal adenocarcinoma. However, studies indicated a major role of ß-cells during carcinogenesis. To find out, if ß-cells are the primary target cells of BOP and if they are capable to form ductal adenocarcinoma after malignant transformation, we established a long-term culture of undifferentiated cells deriving from isolated ß-cells and treated them with BOP. METHODS: Langerhans' islets from pancreata of Syrian golden hamsters were isolated and dispersed into single cells by dispase digestion. Cells were labeled with a highly specific ß-cell surface antibody (K14D10) and these K14D10+ cells were extracted from the suspension by paramagnetic Dynabeads. Cells were cultured in vitro and treated with BOP. Untreated cells served as control. RESULTS: K14D10+ cells formed a monolayer and produced insulin over a period of 28 days in culture. However, with time in culture they became undifferentiated with a higher proliferation rate and after about 60 days in culture BOP treated cells showed anchorage independent growth. These cells autotransplanted s.c. formed a well-differentiated ductal adenocarcinoma. CONCLUSIONS: Pancreatic ß-cells are the primary target of BOP without necessarily being embedded in the compound of the Langerhans' islet. With time in culture, they give rise to undifferentiated cells and after malignant transformation they are able to form ductal adenocarcinoma.

Surgical site infections after simultaneous pancreas kidney and pancreas transplantation in the Swiss Transplant Cohort Study.

BACKGROUND: Among hospital-acquired infections, surgical site infections (SSIs) are frequent. SSI in the early post-transplant course poses a relevant threat to transplant recipients. AIM: To determine incidence, risk factors for SSI and its association with post-transplant outcomes and pancreas transplant (P-Tx) recipients. METHODS: Adult simultaneous kidney-pancreas transplantation (SPK-T) and P-Tx recipients with a follow-up of at least 90 days were identified in the Swiss Transplant Cohort Study (STCS) dataset. Except for the categorization of SSIs according to Centers for Disease Control and Prevention (CDC) criteria, all other data were prospectively collected. Risk factors for SSI were investigated with logistic regression. A Weibull accelerated failure-time model was applied to address the impact of SSI on length of stay, correcting for transplant-related complications and delayed graft function. FINDINGS: Of 130 transplant recipients, 108 SPK-Tx and 22 P-Tx, 18 (14%) individuals developed SSI within the first 90 days after transplantation. Deep incisional (seven, 38.9%) and organ/space infections (eight, 44.4%) predominated. In the majority of SSIs (11, 61.1%; two SSIs with simultaneous identification of fungal pathogens) bacteria were detected with Enterococcus spp. being most frequent. The median duration of hospitalization after transplantation was significantly longer in recipients with SSI (median: 26 days; interquartile range (IQR): 19-44) than in patients without SSI (median: 17 days; IQR: 12-25; P = 0.002). In multivariate analysis, SSI was significantly associated with increased length of stay and prolonged the duration of hospitalization by 36% (95% confidence interval: 4-79). CONCLUSION: SSI after SPK-Tx and P-Tx occurred at a frequency of 14%. Among pathogens, Enterococcus spp. predominated. SSI was independently associated with a longer hospitalization after transplantation.

HIV-HCV co-infected patients with low CD4+ cell nadirs are at risk for faster fibrosis progression and portal hypertension.

Patients co-infected with the human immunodeficiency virus (HIV) and the hepatitis C virus (HCV) are fraught with a rapid fibrosis progression rate and with complications of portal hypertension (PHT) We aimed to assess the influence of immune function [Centers of Disease Control and Prevention (CDC) stage] on development of PHT and disease progression in HIV-HCV co-infection. Data of 74 interferon-naïve HIV-HCV co-infected patients undergoing liver biopsy, measurement of portal pressure and of liver stiffness and routine laboratory tests (including CD4+ cell count, HIV and HCV viral load) were analysed. Time of initial exposure (risk behaviour) was used to assess fibrosis progression. Fibrosis progression, time to cirrhosis and portal pressure were correlated with HIV status (CDC stage). HIV-HCV patients had rapid progression of fibrosis [0.201 +/- 0.088 METAVIR fibrosis units/year (FU/y)] and accelerated time to cirrhosis (24 +/- 13 years), high HCV viral loads (4.83 x 10(6) IU/mL) and a mean HVPG at the upper limit of normal (5 mmHg). With moderate or severe immunodeficiency, fibrosis progression was even higher (CDC-2 = 0.177 FU/y; CDC-3 = 0.248 FU/y) compared with patients with higher CD4+ nadirs (CDC-1 = 0.120 FU/y; P = 0.0001). An indirect correlation between CD4+ cell count and rate of fibrosis progression (R = -0.6654; P < 0.001) could be demonstrated. Hepatic venous pressure gradient (HVPG) showed early elevation of portal pressure with median values of 4, 8 and 12 mmHg after 10, 15 and 20 years of HCV infection for CDC-3 patients. Patients treated with highly active anti-retroviral therapy (HAART) had similar rates of progression and portal pressure values than patients without HAART. Progression of HCV disease is accelerated in HIV-HCV co-infection, being more pronounced in patients with low CD4+ cell count. A history of a CD4+ cell nadir <200/microL is a risk factor for rapid development of cirrhosis and PHT. Thus, HCV treatment should be considered early in patients with HIV-HCV co-infection and largely preserved CD4+ cell counts.

Angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers after renal transplantation.

Renin-angiotensin system blockade retards the progression of diabetic and non-diabetic chronic kidney disease of the native kidneys. Though most patients suffer from a significant renal insufficiency (chronic kidney disease stage III) and a concomitant heart disease after renal transplantation, there is up to now no evidence supporting the use of inhibitors of the renin-angiotensin system in these patients. We wish to summarize the available evidence on the use of inhibitors of the renin-angiotensin system after renal transplantation. We specifically discuss potential beneficial as well as adverse effects of a renin-angiotensin system blockade. In addition, we review their influence on morphologic and biochemical markers as well as on renal function, graft and patient survival after renal transplantation.

Simultaneous pancreas-kidney transplantation in type 1 diabetes.

The outcome of simultaneous pancreas-kidney (SPK) transplantation in type 1 diabetes has dramatically improved in recent years because of optimized surgical techniques and new immunosuppressive drug regimens. Normoglycemia is followed by stabilization or even regression of diabetic lesions, i.e., of heart and kidneys. However, these effects are only visible after more than five yr of normoglycemia (achieved by a functioning allograft). This is also a likely explanation for the conflicting results of studies that investigated patient or kidney graft survival in SPK transplantation compared to kidney transplantation alone. Most studies had too short follow-up periods, i.e., less than five yr, to compare effectively different transplant strategies in patients with type 1 diabetes and therefore failed to discover a survival benefit in favor of simultaneously transplanted patients. Recent data now indicate that, with a longer follow-up, there is an increasing survival benefit for simultaneously transplanted patients compared to patients who received a single kidney transplant. This is paralleled by the comparison of simultaneously transplanted patients to patients who received a single kidney transplant from a living donor. A survival benefit for the combined procedure was here visible after 10 yr of follow-up. We give a short overview on SPK transplantation, with a focus on the effects of this procedure on diabetic complications as well as patient and kidney graft survival.

A single center experience of combined liver kidney transplantation.

With advancements in the operative techniques, patient survival following liver transplantation (LTx) has increased substantially. This has led to the acceleration of pre-existing kidney disease because of immunosuppressive nephrotoxicity making additional kidney transplantation (KTx) inevitable. On the other hand, in a growing number of patients on the waiting list to receive liver, long waiting time has resulted in adverse effect of decompensated liver on the kidney function. During the last two decades, the transplant community has considered combined liver kidney transplantation (CLKTx) to overcome this problem. The aim of our study is to present an overview of our experience as well as a review of the literature in CLKTx and to discuss the controversy in this regard. All performed CLKTx (n = 22) at our institution as well as all available reported case series focusing on CLKTx are extracted. The references of the manuscripts were cross-checked to implement further articles into the review. The analyzed parameters include demographic data, indication for LTx and KTx, duration on the waiting list, Model for End-Stage Liver Disease (MELD) score, Child-Turcotte-Pugh (CTP) score, immunosuppressive regimen, post-transplant complications, graft and patient survival, and cause of death. From 1988 to 2009, a total of 22 CLKTx were performed at our institution. The median age of the patients at the time of CLKTx was 44.8 (range: 4.5-58.3 yr). The indications for LTx were liver cirrhosis, hyperoxaluria type 1, polycystic liver disease, primary or secondary sclerosing cholangitis, malignant hepatic epithelioid hemangioendothelioma, cystinosis, and congenital biliary fibrosis. The KTx indications were end-stage renal disease of various causes, hyperoxaluria type 1, polycystic kidney disease, and cystinosis. The mean follow-up duration for CLKTx patients were 4.6 +/- 3.5 yr (range: 0.5-12 yr). Overall, the most important encountered complications were sepsis (n = 8), liver failure leading to retransplantation (n = 4), liver rejection (n = 3), and kidney rejection (n = 1). The overall patient survival rate was 80%. Review of the literature showed that from 1984 to 2008, 3536 CLKTx cases were reported. The main indications for CLKTx were oxalosis of both organs, liver cirrhosis and chronic renal failure, polycystic liver and kidney disease, and liver cirrhosis along with hepatorenal syndrome (HRS). The most common encountered complications following CLKTx were infection, bleeding, biliary complications, retransplantation of the liver, acute hepatic artery thrombosis, and retransplantation of the kidney. From the available data regarding the need for post-operative dialysis (n = 673), a total of 175 recipients (26%) required hemodialysis. During the follow-up period, 154 episodes of liver rejection (4.3%) and 113 episodes of kidney rejection (3.2%) occurred. The cumulative 1, 2, 3, and 5 yr survival of both organs were 78.2%, 74.4%, 62.4%, and 60.9%, respectively. Additionally, the cumulative 1, 2, 3, and 5 yr patient survival were 84.9%, 52.8%, 45.4%, and 42.6%, respectively. The total number of reported deaths was 181 of 2808 cases (6.4%), from them the cause of death in 99 (55%) cases was sepsis. It can be concluded that there is still no definitive evidence of better graft and patient survival in CLKTx recipients when compared with LTx alone because of the complexity of the exact definition of irreversible kidney function in LTx candidates. Additionally, CLKTx is better to be performed earlier than isolated LTx and KTx leading to the avoidance of deterioration of clinical status, high rate of graft loss, and mortality. Shorter graft ischemia time and more effective immunosuppressive regimens can reduce the incidence of graft malfunctioning in CLKTx patients. Providing a model to reliably determine the need for CLKTx seems necessary. Such a model can be shaped based upon new and precise markers of renal function, and modification of MELD system.

In vivo accuracy assessment of a needle-based navigation system for CT-guided radiofrequency ablation of the liver.

Computed tomography (CT)-guided percutaneous radiofrequency ablation (RFA) has become a commonly used procedure in the treatment of liver tumors. One of the main challenges related to the method is the exact placement of the instrument within the lesion. To address this issue, a system was developed for computer-assisted needle placement which uses a set of fiducial needles to compensate for organ motion in real time. The purpose of this study was to assess the accuracy of the system in vivo. Two medical experts with experience in CT-guided interventions and two nonexperts used the navigation system to perform 32 needle insertions into contrasted agar nodules injected into the livers of two ventilated swine. Skin-to-target path planning and real-time needle guidance were based on preinterventional 1 mm CT data slices. The lesions were hit in 97% of all trials with a mean user error of 2.4 +/- 2.1 mm, a mean target registration error (TRE) of 2.1 +/- 1.1 mm, and a mean overall targeting error of 3.7 +/- 2.3 mm. The nonexperts achieved significantly better results than the experts with an overall error of 2.8 +/- 1.4 mm (n=16) compared to 4.5 +/- 2.7 mm (n=16). The mean time for performing four needle insertions based on one preinterventional planning CT was 57 +/- 19 min with a mean setup time of 27 min, which includes the steps fiducial insertion (24 +/- 15 min), planning CT acquisition (1 +/- 0 min), and registration (2 +/- 1 min). The mean time for path planning and targeting was 5 +/- 4 and 2 +/- 1 min, respectively. Apart from the fiducial insertion step, experts and nonexperts performed comparably fast. It is concluded that the system allows for accurate needle placement into hepatic tumors based on one planning CT and could thus enable considerable improvement to the clinical treatment standard for RFA procedures and other CT-guided interventions in the liver. To support clinical application of the method, optimization of individual system modules to reduce intervention time is proposed.

The human homologue of the RNA polymerase II-associated factor 1 (hPaf1), localized on the 19q13 amplicon, is associated with tumorigenesis.

The 19q13 amplicon in pancreatic cancer cells contains a novel pancreatic differentiation 2 (PD2) gene (accession number AJ401156), which was identified by differential screening analysis. PD2 is the human homologue of the RNA polymerase II-associated factor 1 (hPaf1). In yeast, Paf1 is part of the transcription machinery, acting as a docking protein in between the complexes Rad6-Bre1, COMPASS-Dot1p, and the phosphorylated carboxyl terminal domain of the RNA polymerase II. As such, Paf1 is directly involved in transcription elongation via histone H2B ubiquitination and histone H3 methylation. The PD2 sequence is highly conserved from Drosophila to humans with up to 98% identity between rodent and human, suggesting the functional importance of PD2/hPaf1 to maintain cellular homeostasis. PD2 is a modular protein composed of RNA recognition motif, DEAD-boxes, an aspartic/serine (DS)-domain, a regulator of the chromosome condensation domain and myc-type helix-loop-helix domains. Our results further showed that PD2 is a nuclear 80 kDa protein, which interacts with RNA polymerase II. In addition, we have demonstrated that the overexpression of PD2 in the NIH 3T3 cells result in enhanced growth rates in vitro and tumor formation in vivo. Altogether, this paper presents strong evidence that the overexpression of PD2/hPaf1 is involved in cancer development.

Creation and establishment of a respiratory liver motion simulator for liver interventions.

Image-guided surgery and navigation have resulted from convergent developments in radiology, teletransmission, and computer science and are well-established procedures in the surgical routine in orthopedic, neurosurgery, and head-and-neck surgery. In abdominal surgery, however, these tools have gained little attraction so far. The inability to transfer the methodology from orthopedic or neurosurgery is mainly a result of intraoperative organ movement and shifting. To practice and establish navigated interventions in the liver, a custom-designed respiratory liver motion simulator was built which models the human torso and is easy to recreate. To simulate breathing motion, an explanted porcine or human liver is mounted to the diaphragm model of the simulator, and a lung ventilator causes a periodic movement of the liver along the craniocaudal axis. Additionally, the liver can be connected to a circulating pump device which simulates hepatic perfusion and provides real surgical options to establish navigated interventions and simulate management of possible complications. Respiratory motion caused by the simulator was evaluated with an optical tracking system and it was shown that in vitro movement and deformation of a liver mounted to the device are similar to the liver movements in human or porcine bodies. Based on the tests, it is concluded that the novel respiratory liver motion simulator is suitable for in vitro evaluation of navigated systems and interventional and surgical procedures.

Improved survival after retrieval of 12 or more regional lymph nodes in appendiceal cancer.

BACKGROUND: To evaluate the role of regional lymph node (RLN) retrieval on stage migration, overall (OS), and cancer-specific survival (CSS) in appendiceal cancer. METHODS: Between 2004 and 2012, 1046 patients with primary stage I-III carcinoma of the appendix were identified in the Surveillance, Epidemiology and End Results database. The impact of the number of RLN removed on OS and CSS was assessed using joinpoint regression, Cox regression, and propensity score methods. RESULTS: The rate of node-positive cancer increased with the number of retrieved RLN from 10.5% in patients with one RLN removed to 30.6% in patients with 10 RLNs removed. This leveling off at 10 RLN was confirmed by joinpoint regression analysis (p = 0.023). Despite the finding that retrieval of 10 RLN should be sufficient for appendiceal cancer, for the survival analysis the somewhat higher cutoff of 12 RLN was applied, since this cutoff is recommended by the guidelines for colorectal cancer. Retrieval of 12 or more RLN was beneficial compared to less than 12 RLN retrieved for OS (HR = 0.60, p < 0.001) and CSS (HR = 0.67, p = 0.020) in multivariable analysis, as well as in propensity score matched analysis (OS: HR = 0.58, p = 0.001, CSS: HR = 0.61, p = 0.005). CONCLUSION: The rate of node-positive cancer increased with the number of retrieved RLN up to about 10 RLN (95%CI: 3.6-16.3, p = 0.023). Over 10 retrieved RLN, the node-positive cancer rate no longer increased. This correlates with the recommended number of 12 RLN to be retrieved in colorectal cancer, but differs from the guideline for neuroendocrine tumors.

Specific immune recognition of pancreatic carcinoma by patient-derived CD4 and CD8 T cells and its improvement by interferon-gamma.

Pancreatic carcinoma is a very aggressive disease and little is known about its immunobiology. We here describe the presence in pancreatic cancer patients of spontaneously induced functional CD4 and CD8 memory/effector T cells reactive to autologous tumor cells or to the pancreatic cancer associated antigen, MUC-1. Such specific cells were present in the bone marrow or peripheral blood of most of the 23 tested patients. Low dose stimulation of primary cultures of pancreatic cancer cells with 500 IU/ml IFN-gamma for 72 h enhanced HLA-I expression and induced the de novo expression of HLA-II molecules. This led to a much better immune recognition by autologous HLA-I restricted and purified CD8 T cells and allowed tumor cell recognition by HLA-II restricted purified CD4 T-helper cells. Thus, interferon-gamma appears to be a useful adjuvant cytokine to enhance the immunogenicity of a patients' tumor cells and their recognition by tumor reactive immune cells.

German-Austrian recommendations for HIV-therapy in pregnancy and in HIV-exposed newborn - update 2005.

In Germany during the last years about 200-250 HIV infected pregnant women delivered a baby each year, a number that is currently increasing. To determine the HIV-status early in pregnancy voluntary HIV-testing of all pregnant women is recommended in Germany and Austria as part of prenatal care. In those cases, where HIV infection was known during pregnancy, since 1995 the rate of vertical transmission of HIV was reduced to 1-2%. - This low transmission rate has been achieved by the combination of anti-retroviral therapy of pregnant women, caesarean section scheduled before onset of labour, anti-retroviral post exposition prophylaxis in the newborn and refraining from breast-feeding by the HIV infected mother. To keep pace with new results in research, approval of new anti-retroviral drugs and changes in the general treatment recommendations for HIV infected adults, in 1998, 2001 and 2003 an interdisciplinary consensus meeting was held. Gynaecologists, infectious disease specialists, paediatricians, pharmacologists, virologists and members of the German AIDS Hilfe (NGO) were participating in this conference to update the prevention strategies. A third update became necessary in 2005. The updating process was started in January 2005 and was terminated in September 2005. The guidelines provide new recommendations on the indication and the starting point for therapy in pregnancies without complications, drugs and drug combinations to be used preferably in these pregnancies and updated information on adverse effects of anti-retroviral drugs. Also the procedures for different scenarios and risk constellations in pregnancy have been specified again. With these current guidelines in Germany and Austria the low rate of vertical HIV-transmission should be further maintained.