Specific changes in the expression of imprinted genes in prostate cancer—implications for cancer progression and epigenetic regulation

Epigenetic dysregulation comprising DNA hypermethylation and hypomethylation, enhancer of zeste homologue 2 (EZH2) overexpression and altered patterns of histone modifications is associated with the progression of prostate cancer. DNA methylation, EZH2 and histone modifications also ensure the parental-specific monoallelic expression of at least 62 imprinted genes. Although it is therefore tempting to speculate that epigenetic dysregulation may extend to imprinted genes, expression changes in cancerous prostates are only well documented for insulin-like growth factor 2 (IGF2). A literature and database survey on imprinted genes in prostate cancer suggests that the expression of most imprinted genes remains unchanged despite global disturbances in epigenetic mechanisms. Instead, selective genetic and epigenetic changes appear to lead to the inactivation of a sub-network of imprinted genes, which might function in the prostate to limit cell growth induced via the PI3K/Akt pathway, modulate androgen responses and regulate differentiation. Whereas dysregulation of IGF2 may constitute an early change in prostate carcinogenesis, inactivation of this imprinted gene network is rather associated with cancer progression.     

Near-infrared spectroscopic cerebral oxygenation reading in neonates and infants is associated with central venous oxygen saturation

BACKGROUND: The aim of the study was to elucidate easily determinable laboratory and vital parameters in clinical practice to explain variability of near-infrared spectroscopic cerebral oxygenation readings in critically ill newborns and infants using the NIRO 300 spectrometer. METHODS: Near-infrared spectroscopy (NIRS) cerebral tissue oxygenation index (cTOI) was measured on the forehead of critically ill neonates and infants with existing arterial and/or central venous access. We recorded patient characteristics and simultaneously determined sedation state, hemodynamic, respiratory and laboratory data, such as arterial blood gas analysis, electrolytes, hemoglobin and arterial lactate concentration, blood glucose and central venous oxygen saturation. Data were compared using linear, multiple and forward stepwise regression analysis (P < 0.05). RESULTS: A total of 155 neonates and infants aged from 0 to 365 days (median 12 days) were studied. cerebral tissue oxygenation index (cTOI) values ranged from 32.1 to 91.0% (60.5 +/- 11.5%). Simple linear regression analysis revealed significant associations between cTOI and arterial oxygen saturation (r = 0.254, P = 0.001), transcutaneously measured arterial oxygen saturation (r = 0.320, P < or = 0.0001), central venous oxygen saturation (r = 0.489, P < 0.0001), arteriovenous oxygen extraction (r = 0.445, P < 0.0001) and presence of a cardiac shunt (r = 0.250, P = 0.024). Multiple regression analysis and forward stepwise regression revealed two independent, significant predictors for cTOI, namely SvO2 (P < 0.0001) and presence or absence of a cardiac shunt (P = 0.003). SvO2 alone explained 23.9% of the variability of cTOI. The addition of the variable 'cardiac shunt' improved the model to 33%. CONCLUSIONS: Based on our study results cerebral tissue oxygenation readings by the NIRO 300 near-infrared spectrometer is influenced by central venous oxygen saturation, which partially explains intersubject variability of NIRS cerebral oxygenation readings.     

Hepatic Resection in the Elderly

p = 0.02) and for primary neoplasia of the liver ( p = 0.002) but not for metastatic disease to the liver. This reflects the high rate of cirrhosis in hepatocellular and cholangiocellular carcinoma (88%) and gallbladder cancer (37.5%). Both pre- and postoperative severe liver dysfunction had a significantly higher risk for postoperative mortality and morbidity, which showed an incremental risk with age. Another organ system able to predict outcome at the beginning of treatment by its moderate severe dysfunction were the lungs. Overall, only right and extended right lobectomies carried a significantly higher risk for postoperative mortality and morbidity. Postoperative complications were recorded in 43% of our patients, with infection the most frequent problem in nearly all of these patients (95%). Pneumonia was the leading complication associated patient survival. All patients who developed pneumonia as a late complication during a complicated postoperative course died postoperatively. The postoperative Goris score of the patients who died was 6.9 ± 2.9 (range 3–11), whereas the surviving patients’ score averaged 2.2 ± 1.9 (range 0–9), which was significantly different ( p = 0.0003). None of the 54 patients with a GORIS score ≤ 2 died postoperatively, whereas 5 of 6 patients with a score ≥ 9 died ( p = 0.0001). Severe liver dysfunction rather than the extent of resection influences clinical mortality. Patients > 80 years of age with a preoperative severe liver dysfunction showed a postoperative mortality of 57%, and all of these patients developed postoperative complications. Therefore resection cannot be recommended for those patients. Cirrhosis led to an unacceptable mortality of 44% after hepatic resection of ≥ 5 liver segments for primary neoplasia of the liver. Major resections cannot be recommended in the aged with gallbladder cancer because 50% of the patients died after such operations. Overall, only resection of ≥ 5 liver segments with segments I to III or less remaining were found to pose a major risk for clinical mortality and morbidity, but the cause of death was preexisting liver dysfunction and cirrhosis in all of these patients. Major resections of large neoplasia of the liver can be recommended even in the aged, but a preoperative preselection of patients with respect to liver function and pulmonary function preoperatively may help lower the postoperative morbidity and mortality, especially in patients who will undergo resection of ≥ 5 liver segments. Major hepatic resection for metastatic disease to the liver in the elderly carries no additional survival risk. Patients > 65 years of age and especially those > 80 years of age are more liable to succumb to postoperative organ failure and complications, especially infections.     

Single-portal-phase low-tube-voltage dual-energy CT for short-term follow-up of acute pancreatitis: evaluation of CT severity index,interobserver agreement and radiation dose

Objectives

To intra-individually compare single-portal-phase low-tube-voltage (100-kVp) computed tomography (CT) with 120-kVp images for short-term follow-up assessment of CT severity index (CTSI) of acute pancreatitis, interobserver agreement and radiation dose.

Methods

We retrospectively analysed 66 patients with acute pancreatitis who underwent initial dual-contrast-phase CT (unenhanced, arterial, portal phase) at admission and short-term (mean interval 11.4 days) follow-up dual-contrast-phase dual-energy CT. The 100-kVp and linearly blended images representing 120-kVp acquisition follow-up CT images were independently evaluated by three radiologists using a modified CTSI assessing pancreatic inflammation, necrosis and extrapancreatic complications. Scores were compared with paired t test and interobserver agreement was evaluated using intraclass correlation coefficients (ICC).

Results

Mean CTSI scores on unenhanced, portal- and dual-contrast-phase images were 4.9, 6.1 and 6.2 (120 kVp) and 5.0, 6.0 and 6.1 (100 kVp), respectively. Contrast-enhanced series showed a higher CTSI compared to unenhanced images (P?P?>?0.7). CTSI scores were comparable for 100-kVp and 120-kVp images (P?>?0.05). Interobserver agreement was substantial for all evaluated series and subcategories (ICC 0.67–0.93). DLP of single-portal-phase 100-kVp images was reduced by 41 % compared to 120-kVp images (363.8 versus 615.9 mGy cm).

Conclusions

Low-tube-voltage single-phase 100-kVp CT provides sufficient information for follow-up evaluation of acute pancreatitis and significantly reduces radiation exposure.

Key Points

? Single-portal-phase CT provides sufficient evaluation for follow-up of acute pancreatitis. ? Follow-up CT does not benefit from unenhanced or arterial-phase acquisition. ? CT severity index scores are equal for dual-contrast-phase 100-/120-kVp acquisition (P?>?0.05). ? 100-kVp single-portal-phase follow-up CT of acute pancreatitis significantly reduces radiation exposure.     

Neoquadruple induction with antithymocyte globulin/azathioprine/cyclosporine/prednisolone in simultaneous pancreas and kidney transplant recipients: 8.5-year results

Ten years ago therapy with antithymocyte globulin or OKT3, azathioprine, cyclosporine, and prednisolone was the most common induction treatment for simultaneous pancreas/ kidney (SPK) recipients. Although immunosuppression was started after surgery, there was a high incidence of acute rejection episodes. In 1995, we modified the application of antithymocyte globulin and prednisolone by starting prior to reperfusion. Between 1995 and 1996, 30 patients underwent a first SPK. Prior to reperfusion, antithymocyte globulin (4-6 mg/kg body weight) and 250 mg prednisolone were administered. Intraoperatively, another 250 mg prednisolone were administered as well as intravenous azathroprine 3 mg/kg. After surgery up to 10 doses of antithymocyte globulin were administered and cyclosporine trough levels targeted to 200 to 250 ng/mL. Prednisolone was reduced gradually. After a median period of 8.5 years (range: 7.8-9.5 years) patient, pancreas, and kidney graft survival were 93.3%, 70%, and 76.7%, respectively. Sixteen acute rejection episodes were diagnosed in 11 patients (36.7%), who were treated with prednisolone bolus (n = 4), prednisolone with OKT3 (n = 8), prednisolone with antithymocyte globulin (n = 1), cyclosporine to tacrolimus conversion (n = 2), or plasmapheresis (n = 1). Two recipients died after SPK due to severe infection or carcinoma with functioning grafts. Seven further pancreas grafts were lost. Five kidney losses were observed besides the two recipients who died with functioning grafts. While previous protocols yielded a rejection incidence after SPK between 50% and 80%, we observed 60% of patients with no rejection episode during an 8.5-year median follow-up.     

Rekonstruktion des medialen patellofemoralen Ligaments mit autologer Grazilissehne in patellarseitig implantatfreier Technik

Objective

Anatomic reconstruction of the medial patellofemoral ligament using autologous gracilis tendon in an implant-free technique on the patellar side to regain patellofemoral stability.

Indications

Recurrent dislocations, primary dislocation with high risk of recurrence, and dislocations with (osteo-)chondral flake fractures. As combined approach together with other procedures (trochleoplasty, tibial tubercle osteotomy). Revisions.

Contraindications

As an isolated procedure in patients with high degrees of trochlear dysplasia, chronic dislocation of the patella, and patellofemoral maltracking without instability.

Surgical technique

Harvesting of the gracilis tendon. Drilling of a V-shaped tunnel with a special aiming device in anatomic position on the medial side of the patella. Drilling of a femoral tunnel in anatomic position under fluoroscopic control. Passage of the graft, arthroscopic-guided tensioning, and femoral fixation with a biodegradable interference screw.

Postoperative management

Partial weight bearing (20 kg) for 1–2 weeks. No limitation in range of motion. No orthosis. Specific sports allowed after approximately 3 months.

Results

Perioperative complications associated specifically with the technique were observed in 1.0?% (7 of 729 cases). In a series of 72 consecutive cases from May 2010 to October 2010, the following were recorded after 4.0 ± 0.1 years: recurrent dislocations in 3.2?%, a Tegner activity score of 5.1 ± 1.8, and subjective satisfaction in 92?% (follow-up rate 87.5?%). No fracture of the patella was seen in any of our patients.

     

Operative Treatment and Soft Tissue Management of Open Distal Tibial Fractures – Pitfalls and Results

Open tibial fractures usually result from high-energy trauma. Severe soft-tissue injuries are often combined with open fractures of the distal tibia. A consecutive series of 42 patients with open extraarticular distal tibial fractures (Gustilo I–IIIc) operated on between July 2006 and February 2009 were included in the study reported here. We performed open reduction and internal fixation for the Gustilo I cases. Soft tissue was closed directly after antibiotic beads had been temporarily applied. For the Gustilo II and III cases, our treatment protocol included soft-tissue debridement of all devitalized soft tissue and bone fragments, pulsatile jet irrigation, and external stabilization. Soft tissue was temporarily closed with Epigard_ after the application of antibiotic beads. A second-look operation was scheduled after 3–5 days. Gustilo II patients needed an average of 1.1 (0–3) revisions until wound closure, compared to the average of 2.1 revisions necessary for the Gustilo III patients. It took 5.6 (0–16) days to obtain definitive wound closure in the Gustilo II patients and 9.9 (3–28) days in the Gustilo III patients. Skin grafting was sufficient for definitive softtissue closure in ten cases, local flaps in eight cases, and free musculocutaneous flaps were needed in six cases. Gustilo II patients with primary wound closure remained hospitalized for 11 days, while patients with secondary wound closure stayed in hospital for an average of 20 days. Our early results concerning infection rate, number of reoperations, and time to bony consolidation can be compared with other studies. Functional results will have to be evaluated at clinical follow-up.     

Emergency medicine techniques and the forensic autopsy

Emergency medicine measures often have to be carried out under suboptimal conditions in emergency situations and require invasive patient treatment. In the case of a fatal outcome these measures have to be evaluated at autopsy, regarding indications, correct implementation and possible complications. As well, alongside the more familiar procedures—such as endotracheal intubation, insertion of chest drains, external cardiac massage and cannulation of central and peripheral veins—there are alternative techniques being increasingly applied, that include new tools for the management of hemorrhagic shock, drug delivery and alternative airway management devices. On the one hand, all of these measures are essential for the survival and appropriate treatment of the injured and/or sick patient, but on the other hand they can damage the patient and thus contain a significant risk of both medical and forensic relevance for the patient and the physician. In the following review we provide an overview of established, new and alternative techniques for emergency airway management, administration of drugs and management of hemorrhagic shock. The aim is to facilitate the understanding and autopsy evaluation of current emergency medicine techniques.     

First demonstration of leukemia imaging with the proliferation marker 18F-fluorodeoxythymidine

Acute myeloid leukemia (AML) is a neoplasm of hematopoietic stem cells with partial or complete loss of the ability to differentiate but with preserved proliferation capacity. The aim of our study was to evaluate if the in vivo proliferation marker 3'-deoxy-3'-18F-fluorothymidine (FLT) is suitable for visualizing leukemia manifestation sites and if 18F-FLT is a surrogate marker for disease activity. METHODS: In this pilot study, 10 patients with AML underwent pretherapeutic imaging with 18F-FLT PET or 18F-FLT PET/CT. The biodistribution of 18F-FLT was assessed 60 min after intravenous injection of the radiotracer. Standardized uptake values were calculated for reference segments of bone marrow, spleen, and normal organs. 18F-FLT PET in 10 patients with benign pulmonary nodules and the absence of malignant or inflammatory disease served as controls. RESULTS: Retention of 18F-FLT was observed predominantly in bone marrow and spleen and was significantly higher in AML patients than in controls (mean 18F-FLT SUV in bone marrow, 11.5 and 6.6, P < 0.05; mean 18F-FLT SUV in spleen, 6.1 and 1.8, P < 0.05). Outside bone marrow, focal 18F-FLT uptake showed extramedullary manifestation sites of leukemia in 4 patients (meningeal disease, pericardial, abdominal, testicular, and lymph node), proven by other diagnostic procedures. CONCLUSION: This pilot study indicated that PET using 18F-FLT is able to visualize extramedullary manifestation sites of AML and reflects disease activity. Because 18F-FLT uptake in bone marrow is caused by a combination of both neoplastic and normal hematopoietic cells, the correlation of 18F-FLT uptake in bone marrow and leukemic blast infiltration did not reach statistical significance.     

Study of age dependence of epiphyseal ossification of the hand skeleton

Radiological analysis of the hand skeleton is a key pillar of forensic age diagnostics in living subjects undergoing criminal proceedings. The present study investigated whether ossification stage classification of selected epiphyses of the hand could provide added value to hand radiograph analysis. Hand radiographs from 265 male and 164 female subjects aged 10–18years old who had been X-rayed due to traumatological indications were therefore assessed. Epiphyseal ossification of selected elements of the hand skeleton (ulna, radius and third metacarpal, basal phalanx, mesophalanx and telephalanx) was graded based on the criteria of the five-stage classification system of Schmeling et al. (Int J Legal Med, 118:5–8, 2004) for clavicular epiphyseal cartilage. Stage 5 (absence of the epiphyseal scar) does not occur in the radius of men before the age of 18. Stage 5 can therefore be regarded as a potential parameter for valid determination of a minimum age of 18 years for forensic age estimation in criminal proceedings.