Adult patients with sporadic polycystic kidney disease: the importance of screening for mutations in the PKD1 and PKD2 genes

Background

ADPKD is one of the most common inherited disorders, with high risk for end-stage renal disease. Numerous patients, however, have no relatives in whom this disorder is known and are unsure whether they may transmit the disease to their offsprings. The aim of this study was to evaluate whether germline mutation analysis adds substantial information to clinical symptoms for diagnosis of ADPKD in these patients.

Methods

Clinical data included renal function and presence of liver or pancreas cysts, heart valve insufficiency, intracranial aneurysms, colonic diverticles, and abdominal hernias. Family history was evaluated regarding ADPKD. Germline mutation screening of the PKD1 and PKD2 genes was performed for intragenic mutations and for large deletions.

Results

A total of 324 adult patients with ADPKD including 30 patients without a family history of ADPKD (sporadic cases) were included. PKD1 mutations were found in 24/30 and PKD2 mutations in 6 patients. Liver cysts were present in 14 patients and intracranial aneurysms in 2 patients. Fourteen patients (45%) had no extrarenal involvement. Compared to the 294 patients with familial ADPKD, the clinical characteristics and the age at the start of dialysis were similar in those with sporadic ADPKD.

Conclusion

The clinical characteristics of patients with sporadic and familial ADPKD are similar, but sporadic ADPKD is often overlooked because of the absence of a family history. Molecular genetic screening for germline mutations in both PKD1 and PKD2 genes is essential for the definitive diagnosis of ADPKD.     

Flow diversion treatment: intra-aneurismal blood flow velocity and WSS reduction are parameters to predict aneurysm thrombosis

Background

To evaluate the haemodynamic changes induced by flow diversion treatment in cerebral aneurysms, resulting in thrombosis or persisting aneurysm patency over time.

Method

Eight patients with aneurysms at the para-ophthalmic segment of the internal carotid artery were treated by flow diversion only. The clinical follow-up ranged between 6?days and 12?months. Computational fluid dynamics (CFD) analysis of pre- and post-treatment conditions was performed in all cases. True geometric models of the flow diverter were created and placed over the neck of the aneurysms by using a virtual stent-deployment technique, and the device was simulated as a true physical barrier. Pre- and post-treatment haemodynamics were compared, including mean and maximal velocities, wall-shear stress (WSS) and intra-aneurysmal flow patterns. The CFD study results were then correlated to angiographic follow-up studies.

Results

Mean intra-aneurysmal flow velocities and WSS were significantly reduced in all aneurysms. Changes in flow patterns were recorded in only one case. Seven of eight aneurysms showed complete occlusion during the follow-up. One aneurysm remaining patent after 1?year showed no change in flow patterns. One aneurysm rupturing 5?days after treatment showed also no change in flow pattern, and no change in the maximal inflow velocity.

Conclusions

Relative flow velocity and WSS reduction in and of itself may result in aneurysm thrombosis in the majority of cases. Flow reductions under aneurysm–specific thresholds may, however, be the reason why some aneurysms remain completely or partially patent after flow diversion.     

Perioperative assessment of left ventricular function by pressure-volume loops using the conductance catheter method

Interpretation of perioperative measurements of cardiac function during cardiac surgery is complicated by changes in loading conditions induced by anesthesia, cardiopulmonary bypass (CPB), and the surgical procedure itself. Quantification of left ventricular (LV) function by pressure-volume relations as obtained by the conductance catheter would be advantageous because load-independent indices can be determined. Accordingly, we evaluated methodological aspects of the conductance-catheter technique and documented LV function before and after CPB in eight patients undergoing coronary artery bypass grafting. LV pressure-volume loops by transesophageal echocardiography-guided transaortic application of the conductance catheter were obtained at steady-state and during preload reduction by temporary occlusion of the inferior cava. All patients remained hemodynamically stable, and no complications occurred. Complete data were acquired within 15 min before and after CPB. Cardiac output (5.2 +/- 1.3 L/min to 6.0 +/- 1.4 L/min) and LV ejection fraction (46% +/- 17% to 48% +/- 19%) did not change, but end-diastolic pressure increased significantly after CPB (8 +/- 2 mm Hg to 16 +/- 7 mm Hg; P < 0.05). Load-independent systolic indices remained constant (end-systolic elastance: 1.31 +/- 1.20 mm Hg/mL to 1.13 +/- 0.59 mm Hg/mL). Diastolic function changed significantly after CPB, as the relaxation time constant decreased from 64 +/- 6 ms to 52 +/- 5 ms (P < 0.05) and the chamber stiffness constant increased from 0.016 +/- 0.014/mL to 0.038 +/- 0.016/mL (P < 0.05). We conclude that the conductance catheter method provides detailed data on perioperative myocardial function and may be useful for evaluating the effects of new surgical and anesthetic procedures. IMPLICATIONS: Pressure-volume loops provide on-line quantification of intrinsic systolic and diastolic myocardial function in a load-independent fashion. This study shows the feasibility of perioperative pressure-volume analysis by use of the conductance-catheter method. This method provides detailed data about the immediate effects of surgery and may be used to evaluate complex cardiac procedures.     

Similar outcome after colonic pouch and side-to-end anastomosis in low anterior resection for rectal cancer: a prospective randomized trial

OBJECTIVES: To compare a colonic J-pouch or a side-to-end anastomosis after low-anterior resection for rectal cancer with regard to functional and surgical outcome. SUMMARY BACKGROUND DATA: A complication after restorative rectal surgery with a straight anastomosis is low-anterior resection syndrome with a postoperatively deteriorated anorectal function. The colonic J-reservoir is sometimes used with the purpose of reducing these symptoms. An alternative method is to use a simple side-to-end anastomosis. METHODS: One-hundred patients with rectal cancer undergoing total mesorectal excision and colo-anal anastomosis were randomized to receive either a colonic pouch or a side-to-end anastomosis using the descending colon. Surgical results and complications were recorded. Patients were followed with a functional evaluation at 6 and 12 months postoperatively. RESULTS: Fifty patients were randomized to each group. Patient characteristics in both groups were very similar regarding age, gender, tumor level, and Dukes' stages. A large proportion of the patients received short-term preoperative radiotherapy (78%). There was no significant difference in surgical outcome between the 2 techniques with respect to anastomotic height (4 cm), perioperative blood loss (500 ml), hospital stay (11 days), postoperative complications, reoperations or pelvic sepsis rates. Comparing functional results in the 2 study groups, only the ability to evacuate the bowel in <15 minutes at 6 months reached a significant difference in favor of the pouch procedure. CONCLUSIONS: The data from this study show that either a colonic J-pouch or a side-to-end anastomosis performed on the descending colon in low-anterior resection with total mesorectal excision are methods that can be used with similar expected functional and surgical results.     

Computer-aided detection of pulmonary embolism: Influence on radiologists’ detection performance with respect to vessel segments

The purpose was to assess the sensitivity of a CAD software prototype for the detection of pulmonary embolism in MDCT chest examinations with regard to vessel level and to assess the influence on radiologists' detection performance. Forty-three patients with suspected PE were included in this retrospective study. MDCT chest examinations with a standard PE protocol were acquired at a 16-slice MDCT. All patient data were read by three radiologists (R1, R2, R3), and all thrombi were marked. A CAD prototype software was applied to all datasets, and each finding of the software was analyzed with regard to vessel level. The standard of reference was assessed in a consensus read. Sensitivity for the radiologists and CAD software was assessed. Thirty-three patients were positive for PE, with a total of 215 thrombi. The mean overall sensitivity for the CAD software alone was 83% (specificity, 80%). Radiologist sensitivity was 77% = R3, 82% = R2, and R1 = 87%. With the aid of the CAD software, sensitivities increased to 98% (R1), 93% (R2), and 92% (R3) (p<0.0001). CAD performance at the lobar level was 87%, at the segmental 90% and at the subsegmental 77%. With the use of CAD for PE, the detection performance of radiologists can be improved.     

Cardiac metabolism measured noninvasively by hyperpolarized 13C MRI.

Pyruvate is included in the energy production of the heart muscle and is metabolized into lactate, alanine, and CO(2) in equilibrium with HCO(3) (-). The aim of this study was to evaluate the feasibility of using (13)C hyperpolarization enhanced MRI to monitor pyruvate metabolism in the heart during an ischemic episode. The left circumflex artery of pigs (4 months, male, 29-34 kg) was occluded for 15 or 45 min followed by 2 hr of reperfusion. Pigs were examined by (13)C chemical shift imaging following intravenous injection of 1-(13)C pyruvate. (13)C chemical shift MR imaging was used in order to visualize the local concentrations of the metabolites. After a 15-min occlusion (no infarct) the bicarbonate signal level in the affected area was reduced (25-44%) compared with the normal myocardium. Alanine signal level was normal. After a 45-min occlusion (infarction) the bicarbonate signal was almost absent (0.2-11%) and the alanine signal was reduced (27-51%). Due to image-folding artifacts the data obtained for lactate were inconclusive. These studies demonstrate that cardiac metabolic imaging with hyperpolarized 1-(13)C-pyruvate is feasible. The changes in concentrations of the metabolites within a minute after injection can be detected and metabolic maps constructed.     

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.     

Boerhaave’s syndrome: Primary repair vs. esophageal resection—Case reports and meta-analysis of the literature

Boerhaave’s syndrome is a life-threatening disease with a high mortality. With regard to the heterogeneity of treatment strategies, no comparative studies exist and recommendations remain controversial. Seventeen cases of Boerhaave’s syndrome operated on between 1989 and 2000 at our hospital were reviewed retrospectively to compare the time period between perforation and diagnosis, and the morbidity and mortality among the different treatment options. In addition, we conducted a meta-analysis of the literature including all series containing five or more patients and compared the findings with our own data. Our patients with a perforation history of less than 12 hours showed significantly fewer signs of sepsis compared to patients with a history of more than 12 hours. In a comparison of patients with primary repair vs. patients treated with esophageal resection or an exclusion operation, no differences were found. In the literature, patients with a long period of perforation (more than 24 hours) were treated more often with an esophageal resection than patients with primary repair. In cases of Boerhaave’s syndrome, primary suturing of the esophageal perforation should be reserved only for those patients presenting within 12 hours after perforation. In all other cases, depending on the extent of the tissue damage, a two-stage esophageal resection with cervical esophagostomy and gastrostomy is recommended as the safest treatment.     

CDKN2A germline mutations in familial pancreatic cancer

OBJECTIVE: To evaluate the prevalence of mutations in the CDKN2A gene encoding p16 and p14 in familial pancreatic cancer (FPC). SUMMARY BACKGROUND DATA: The genetic basis of FPC is still widely unknown. Recently, it has been shown that germline mutations in the p16 tumor suppressor gene can predispose to pancreatic cancer. The presence of p14 germline mutations has yet not been determined in this setting. METHODS: Eighteen families with at least two first-degree relatives with histologically confirmed pancreatic cancer and five families with at least one patient with pancreatic cancer and another first-degree relative with malignant melanoma of the German National Case Collection for Familial Pancreatic Cancer were analyzed for CDKN2A germline mutations including p16 and p14 by direct DNA sequencing. All participating family members were genetically counseled and evaluated by a three-generation pedigree. RESULTS: None of 18 FPC families without malignant melanoma revealed p16 mutations, compared to 2 of 5 families with pancreatic cancer and melanoma. Truncating p16 germline mutations Q50X and E119X were identified in the affected patients of pancreatic cancer plus melanoma families. None of the 23 families revealed p14 germline mutations. CONCLUSIONS: CDKN2A germline mutations are rare in FPC families. However, these data provide further evidence for a pancreatic cancer-melanoma syndrome associated with CDKN2A germline mutations affecting p16. Thus, all members of families with combined occurrence of pancreatic cancer and melanoma should be counseled and offered screening for p16 mutations to identify high-risk family members who should be enrolled in a clinical screening program.