Phase 1/2 and extension study of velaglucerase alfa replacement therapy in adults with type 1 Gaucher disease: 48-month experience.

Enzyme replacement therapy is the standard of care for symptomatic Gaucher disease. Velaglucerase alfa is a human beta-glucocerebrosidase produced in a well-characterized human cell line. A 9-month phase 1/2 open-label, single-center trial and ongoing extension study were conducted to evaluate safety and efficacy of velaglucerase alfa. Twelve symptomatic adult type 1 Gaucher patients (intact spleens) received velaglucerase alfa (60 U/kg per infusion) during phase 1/2. An extension study was offered to patients completing the trial; step-wise dose reduction (to 30 U/kg per infusion) was instituted. Eleven patients completed phase 1/2; 10 entered the extension; 9 patients reached 39 months of extension. No drug-related serious adverse events or withdrawals, and no antibodies were observed. Home therapy was successfully implemented during the extension. Statistically significant improvements (P < .004) were noted in mean percentage change from baseline to 9 months and baseline to 48 months for hemoglobin (+19.2%, +21.7%, respectively), platelet counts (+67.6%, +157.8%, respectively), normalized liver volume (-18.2%, -42.8%, respectively), and normalized spleen volume (-49.5%, -79.3%, respectively). These significant clinical changes and safety profile led to phase 3 trials and highlight the potential of velaglucerase alfa as alternative therapy for type 1 Gaucher disease. The extension trial is registered at http://www.clinicaltrials.gov as NCT00391625.

Gaucher disease: spectrum of sonographic findings in the liver.

OBJECTIVE: Our large tertiary clinic for patients with Gaucher disease has used sonography as the preferred modality to monitor hepatosplenomegaly in hundreds of patients for more than 18 years. With the advent of specific enzyme replacement therapy (ERT), sonographic monitoring of changes in both hepatomegaly and the echogenicity of the hepatic tissue may highlight features that are amenable to ERT. METHODS: All patients (500) seen at presentation and at annual or semiannual routine visits have undergone sonographic examinations by a single senior radiologist (I.H.-H.). RESULTS: Thirty-nine patients (7.8%) had sonographic evidence of hepatic disease (21 male and 18 female; age range, 18-90 years); 26 (66.7%) of these received ERT, and 10 (25.6%) were splenectomized. CONCLUSIONS: Liver findings are relatively rare. Among 500 patients, there was no instance of computed tomographic findings that had not been previously shown by sonography. Radiologists should be acquainted with the variable sonographic spectrum of the Gaucher liver. If hepatic lesions are small, hyperechoic, and slowly evolving, one may surmise that they are due to Gaucher cell accumulation. However, special attention should be paid to progressive deterioration and irregularities in liver texture because other metabolic processes and cancers must be ruled out.

Permanent pacemaker implantation following cardiac surgery: indications and long-term follow-up.

BACKGROUND: Conduction disturbances requiring permanent pacemaker implantation after heart surgery occur in about 1.5% of patients. Early pacemaker implantation may reduce morbidity and postoperative hospital stay. We reviewed our experience with patients undergoing surgery to try and identify predictors for pacemaker requirements and patients who will remain pacemaker dependent. METHODS: We performed a retrospective review of 4,999 patients undergoing surgery between the years 1993 and 2005. Patient age was 64 +/- 12 years, and 71% were males. Coronary bypass was performed in 4,071 (81%), aortic valve replacement in 675 (14%), and mitral valve replacement in 968 (18%) patients. RESULTS: Seventy-two patients (1.4%) required implantation of a permanent pacemaker after surgery. Indications for pacemaker implantation included complete atrioventricular block in 59, symptomatic bradycardia/slow atrial fibrillation in nine, second-degree atrioventricular block in two, and other conduction disturbances in two patients. Predictors for pacemaker requirement by multivariate analysis were left bundle branch block and aortic valve replacement (P < 0.001). Late follow-up was available in 58 patients, at 72 +/- 32 months. Thirty-seven (63%) were pacemaker dependent. Predictors for late pacemaker dependency were third-degree atrioventricular block after surgery and preoperative left bundle branch block (P < 0.001). CONCLUSIONS: Patients at high risk for pacemaker implantation after heart surgery include those with preexisting conduction disturbances, and those undergoing aortic valve replacement. Of those receiving a pacemaker, about one-third will recover at late follow-up. For patients in the high-risk group who are pacemaker dependent after surgery, we recommend implanting a permanent pacemaker at 5 days after surgery, thus enabling early mobilization and early discharge.

Radiological findings in sarcoidosis.

BACKGROUND: Sarcoidosis is a multisystemic disorder of unknown cause that primarily affects the lungs. The diagnosis is based on the clinical manifestations, radiological findings and histological examination. OBJECTIVES: To review and illustrate the typical and atypical radiological findings of sarcoidosis in the chest. METHODS: We analyzed the radiographic thoracic findings of all patients who had biopsy-proven sarcoidosis over the last 10 years. RESULTS: There were 100 consecutive patients (36 men and 64 women, age 20-84 years) with an established diagnosis of sarcoidosis. Thoracic lymphadenopathy was detected in 89 patients (89%). Lung parenchyma involvement was found in 60 patients. These changes were variable and included: ground-glass attenuation (n=39), multiple small nodules (n=44) and irregular thickening of the interlobular septa (n=16). Larger nodules (1-3 cm) were identified in 12 patients and frank consolidations were seen in 12 patients. Pleural thickening with subpleural nodules was identified in 17 patients. CONCLUSIONS: Sarcoidosis has a wide variety of radiological manifestations in the chest. Familiarity with the various radiographic findings is important for diagnosis and management.

Uniportal video-assisted thoracic surgery: the Middle East experience.

BACKGROUND: The application of uniportal video-assisted thoracic surgery (VATS) for both minor and major thoracic procedures is gaining widespread use across the globe. Believing its advantages, both in superb surgical results and less morbidity, our center has the privilege to be one of the first centers in the Middle East to introduce this surgical technique into our standard practice. This study presents our initial experience using this technique in 192 procedures and demonstrates the results of postoperative pain level in a sample of 90 patients. METHODS: In a retrospective study of prospectively collected data, 192 uniportal VATS procedures were analyzed between November 2013 and June 2016. The level of early post-operative pain (postoperative days 1-4) was analyzed in the first 90 cases between November 2013 and March 2015. Uniportal technique was used for a wide array of procedures: blebectomies, pleurectomies, wedge resections, anatomical major lung resections, mediastinal tumors, empyema drainage and decortications. RESULTS: The mean age of patients was 49.6 years, and 72 patients were females (37%). Thirty-five (18.2%) patients underwent anatomical resections with conversion to thoracotomy in three patients (8%). Six (3%) patients had air leak >4 days. The average chest drain duration was 3.25 days. The average length of stay was 4.2 days. Postoperative pain level was low in the first 4 days following the surgery and 30 days mortality was 0%. CONCLUSIONS: Uniportal VATS surgery is a safe and established technique with a minimal invasive thoracic surgery. Excellent results with minimal morbidity, short hospital stay and low postoperative pain are amongst its strong points. Thoracic surgeons experienced in thoracic surgical approaches can safely perform uniportal VATS.

Does mitral valve intervention have an impact on late survival in ischemic cardiomyopathy?

BACKGROUND: Ischemic mitral regurgitation is associated with reduced survival after coronary artery bypass surgery. OBJECTIVES: To compare long-term survival among patients undergoing coronary surgery for reduced left ventricular function and severe ischemic MR in whom the valve was repaired, replaced, or no intervention was performed. METHODS: Eighty patients with severe left ventricular dysfunction and severe MR underwent coronary bypass surgery. The mean age of the patients was 65 years (range 42-82), and 63 (79%) were male. Sixty-three (79%) were in preoperative NYHA functional class III-IV (mean NYHA 3.3), and 26 (32%) were operated on an urgent/emergent basis. Coronary artery bypass surgery was performed in all patients. The mitral valve was repaired in 38 and replaced in 14, and in 28 there was no intervention. The clinical profile was similar in the three groups, although patients undergoing repair were slightly younger. RESULTS: Operative mortality was 15% (8%, 14%, and 25% for the repair, replacement and no intervention respectively; not significant). Long-term follow up was 100% complete, for a mean of 38 months (range 2-92). Twenty-nine patients (57%) were in NYHA I-II (mean NYHA 2.3). Among the surgery survivors, late survival was improved in the repair group compared to the other groups (P < 0.05). Predictors for late mortality were non-repair of the mitral valve, residual MR, and stroke (P = 0.005). CONCLUSIONS: Patients with severe ischemic cardiomyopathy and severe MR undergoing coronary bypass surgery should have a mitral procedure at the time of surgery. Mitral valve repair offers a survival advantage as compared to replacement or no intervention on the valve. Patients with residual MR had the worst results.

Therapeutic options for refractory massive pleural effusion in systemic lupus erythematosus: a case study and review of the literature.

OBJECTIVES: Massive refractory pleural effusions are uncommon in patients with systemic lupus erythematosus. Describing such a patient, the literature was reviewed to report the various therapeutic options in such cases. METHODS: MEDLINE search using the terms "lupus" and "pleural effusion," inclusion of cases with refractory massive effusions with emphasis on treatment. RESULTS: Only 10 such cases (including the patient described here) were reported in the English literature over the past 25 years. Those 10 patients suffered symptoms related to pleural effusion for a long period of time until resolution, ranging between 2 months to 2.5 years (median 6 months). During that period of time they underwent multiple fluid aspirations. Seven different types of therapy were reported in these case descriptions. They can be divided into 2 major groups: systemic therapy (immunosuppressive therapy, plasmapheresis, and intravenous immunoglobulin) and local therapy (intrapleural steroid injections, pleurodesis with talc or tetracycline, and pleurectomy). Pleurodesis with talc seemed to be the most effective treatment modality. CONCLUSIONS: Due to the small number of reported patients, the best type of intervention is uncertain. When refractory pleural effusion is part of lupus exacerbation, the treatment of choice would be systemic, such as immunosuppressive therapy with high-dose steroids and cyclophosphamide. Intravenous immunoglobulin may also be considered. Local measures such as talc pleurodesis should be employed if systemic measures fail, or when pleural effusion is the only manifestation of lupus.

Differentiation between malignant and benign pleural effusion in patients with extra-pleural primary malignancies: assessment with positron emission tomography-computed tomography.

OBJECTIVES: We sought to define an accurate diagnostic approach for differentiating benign from malignant pleural effusion on positron emission tomography-computed tomography (PET-CT). MATERIAL AND METHODS: PET-CT studies of 31 patients with primary extrapleural malignancy and pleural effusion were reviewed retrospectively. CT parameters assessed were size and density (Hounsfield units, or HU) of the effusion and density (HU) and morphology of any solid pleural abnormality. Interpretation of PET data included review of the attenuation-corrected and nonattenuation-corrected images. RESULTS: PET-CT parameters that were found to be significant in identifying malignant pleural effusion included focal increased uptake of 18-fluorodeoxyglucose in the pleura (P<0.0001) and the presence of solid pleural abnormalities on CT (P<0.002): the sensitivity was 86% and 71%, respectively, and the specificity was 90% for each of the 2 parameters. A PET-CT pattern composed of pleural uptake and increased effusion activity on nonattenuation-corrected images was associated with sensitivity of 95%, specificity of 80%, positive predictive value of 91%, negative predictive value of 89%, and accuracy of 90%. CONCLUSIONS: On PET-CT, the presence of concomitant pleural abnormalities is the most accurate criterion in determining the malignant nature of pleural effusion.

Suction vs water seal after pulmonary resection: a randomized prospective study.

STUDY OBJECTIVE: To evaluate whether suction or water seal is superior in the management of chest tubes after pulmonary resection. DESIGN: A prospective, randomized, controlled trial. After an initial, brief period of suction, patients were randomized to water seal or - 20 cm H(2)O suction. SETTING: University hospital. PATIENTS: Sixty-eight patients who underwent wedge resection, segmentectomy, or lobectomy were included in the study. Those patients who underwent reoperative surgery or lung volume reduction surgery were excluded. RESULTS: There were 34 patients in each group. The two groups were evenly matched for age, sex, operation performed, severity of lung disease, and nutritional status. Fifteen patients in each group (44%) had an air leak at the completion of surgery. The duration of the air leak was shorter in the water seal group than in the suction group (mean +/- SEM, 1.50 +/- 0.32 days vs 3.27 +/- 0.80 days, respectively; p = 0.05). The mean times to removal of chest tubes were 3.33 +/- 0.35 days in the water seal group and 5.47 +/- 0.98 days in the suction group (p = 0.06). The length of stapled parenchyma was measured for each patient and averaged 24.9 cm for the water seal group and 18.5 cm for the suction group (p = 0.18). When corrected for the length of staple lines, the duration of air leaks and days with chest tube were dramatically lower in the water seal group (p = 0.02 and p = 0.02, respectively). CONCLUSION: Placing chest tubes on water seal after a brief period of suction after pulmonary resection shortens the duration of the air leak and likely decreases the time that the chest tubes remain in place. Adoption of this practice may result in lower morbidity and lower hospital costs.

Incidental finding of myeloproliferative disorders during sternotomy.

We report 2 cases of myeloproliferative disorders discovered incidentally at the time of routine coronary bypass surgery. Suspicion of abnormal bone marrow tissue upon performing sternotomy and subsequent sampling for frozen section made the diagnosis. The surgical plan was changed, and partial revascularization without cardiopulmonary bypass was performed.

Transcervical thymectomy for myasthenia gravis achieves results comparable to thymectomy by sternotomy.

BACKGROUND: It remains controversial whether transcervical thymectomy offers results equivalent to thymectomy by way of a median sternotomy in the treatment of myasthenia gravis. Furthermore, preoperative prognostic factors have not been clearly defined. METHODS: This study is a retrospective chart review and interview of 78 patients completing transcervical thymectomy for myasthenia gravis between 1992 and 1999. RESULTS: There were 24 men and 54 women. Mean age was 40 years (range, 13 to 78 years). Twelve patients were in Osserman class 1, 25 in class 2, 30 in class 3, and 11 in class 4 (mean, 2.5). There was no perioperative mortality and 6 (7.7%) morbidities. Mean length of stay was 1.5 days and mean follow-up, 54.6 months. The crude cumulative complete remission (asymptomatic off medications for 6 months) rate was 39.7% (n = 31). Only 8 patients (10.3%) failed to improve after transcervical thymectomy. Kaplan-Meier estimates of complete remission were 31% and 43% at 2 and 5 years, respectively. Eight patients with thymoma had a 5-year estimated complete remission rate of 75% in contrast to 43% in 38 patients with thymic hyperplasia and 36% in 32 patients with neither thymoma nor hyperplasia (p = 0.01). Twelve patients with ocular myasthenia had a 5-year estimated complete remission rate of 57%, whereas patients with mild-to-moderate (n = 55) or severe (n = 11) generalized symptoms had 5-year complete remission rates of 43% and 30%, respectively (p = 0.21). CONCLUSIONS: Overall, extended transcervical thymectomy offers results that are comparable to those published for the transsternal procedure. Patients with milder disease (including isolated ocular disease) and taking no preoperative immunosuppressive agents appear to experience higher remission rates. In contrast to previous studies, we also find that small thymomas predict better responses to thymectomy.

Ectopic pancreatic pseudocyst and cyst presenting as a cervical and mediastinal mass: case report and review of the literature.

Ectopic pancreas in the mediastinum is extremely rare. We are reporting on a case of a twenty two year old woman who presented to our clinic with a large cervical mass. The CT scan revealed a cystic lesion in the anterior mediastinum. The patient underwent surgical resection by cervical approach. A Cystic mass with pseudocysts, cysts and complete pancreatic tissue were found in pathology. There were no signs of pancreatitis or malignancy. No recurrence was observed after a follow up of four years. We reviewed the case reports describing this rare condition in the medical literature.We conclude that the possibility of ectopic pancreatic tissue should be included in the differential diagnosis of anterior mediastinal cystic mass, though as a remote possibility. Surgery is probably needed for the diagnosis and treatment. Posterior mediastinal pseudocyst is a different entity associated with acute pancreatitis. In those cases surgery is not recommended. Our third conclusion is that pancreatic tissue should be actively sought, if a structure resembling a pseudocyst is found in an unexpected location. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1849369005957671.

Predictive factors of morbidity in childhood parapneumonic effusion-associated pneumonia: a retrospective study.

STUDY OBJECTIVE: To find the clinical and laboratory criteria that best predict a prolonged fever in children with parapneumonic effusion-associated pneumonia treated conservatively. DESIGN: Retrospective, cohort study. PATIENTS: Children admitted to the Shaare Zedek Medical Center between January 1, 1997, and December 31, 2006, and who had been discharged with a diagnosis of empyema and pleurisy. MEASUREMENTS AND RESULTS: One hundred-twenty children were included, all of whom were treated with antibiotics; in 80 patients, a thoracic drain was introduced; in 23, pleural tap was performed; and in 17 patients, no special procedure was performed. In no case was video-assisted thoracic surgery performed. The mean total days of fever was 12.8 +/- 5.9 (2-29 days), and the mean length of stay at the hospital was 11.5 +/- 4.9 (3-25) days. In 44 patients (37%), a bacterial culture was positive either in blood or in pleural fluid or both. A positive blood or a positive pleural fluid culture was significantly associated with a prolonged fever as was a history of an underlying disease. Platelet counts, serum Na, serum protein, pleural lactate dehydrogenase (LDH), pleural glucose, pleural/serum LDH ratio, pleural/serum glucose ratio, and pleural fluid pH were the only factors significantly but weakly correlated with the total duration of fever or duration of fever after admission. A "fever duration" score using platelet count, pleural fluid pH, pleural/serum LDH ratio, and pleural/serum glucose ratio predicted a prolonged course of fever (>7 days) with a sensitivity of 91% (95% confidence interval: 60%-100%) and a specificity of 47% (95% confidence interval: 25%-71%). CONCLUSIONS: In children with parapneumonic effusion-associated pneumonia, a positive bacterial culture and an underlying disease are associated with prolonged fever. A low score based on platelet count, pH pleural fluid and glucose, and LDH pleural/serum ratio is associated with a prolonged fever. We speculate that children with the risk factors mentioned earlier may be the best candidates for an early aggressive approach.

Aortic valve replacement: choice between mechanical valves and bioprostheses.

BACKGROUND: The choice between a mechanical or bioprosthetic valve replacement device is not always clear, although patient age is most often the determining factor. We reviewed our experience with patients undergoing aortic valve replacement (AVR) in order to assess and compare long-term outcomes between patients receiving a mechanical valve and those receiving a bioprosthesis. METHODS: Three hundred fifty-two patients underwent AVR with or without coronary artery bypass between 1993 and 2004: 189 received a mechanical valve and 163 a bioprosthesis. Events included: late mortality, thrombo-embolic events, stroke, bleeding events, valve thrombosis, endocarditis, reoperation, and coronary catheterization. RESULTS: Patients in the bioprosthesis group were older (71 +/- 11 vs. 65 +/- 13) than in the mechanical group (p < 0.0001). There was no difference in operative mortality (6.8%) or morbidity. Follow-up (61 +/- 40 months) was available in 87%. For mechanical valves and bioprostheses, respectively: 3-, 5-, and 10-year survival was 92%, 86%, and 69% versus 90%, 86%, and 71% (p = n.s.); and event-free survival was 79%, 68%, and 41% versus 79%, 68%, and 44% (p = n.s.). Five patients (3%) in each group required re-replacement of their aortic valve (p = n.s.). Coronary artery disease requiring bypass surgery did not affect long-term survival. Age at operation and renal failure were the only predictors for late mortality. CONCLUSIONS: Survival and event-free survival are similar for patients receiving a mechanical or biological aortic valve substitute. Selection of a valve replacement device should be based on life expectancy, patient preference, ability to take anticoagulants, lifestyle, risk of bleeding, and risk of reoperation. Patient age alone should not be the determining factor.

Functional aberrant expression of CCR2 receptor on chronically activated NK cells in patients with TAP-2 deficiency.

Chemokines play a pivotal role in homeostatic and inflammatory migration of naive and activated natural killer (NK) subsets. Recent studies have shown that aberrant chemokine receptor expression on certain immune cells underlies the pathogenesis of clinical conditions in which recruitment of such cells is altered. Progressive accumulation of activated NK cells, subsequently resulting in the formation of chronic granulomatous lesions in the respiratory tract and the skin, has been described in a number of patients with transporter associated with antigen processing 2 (TAP-2) deficiency in the later stages of disease. Therefore, the goal of the present study was to elucidate whether the dysregulation of chemoattracting receptor expression on NK cells could explain abnormal navigation of these cells in TAP-2 deficiency. High-throughput proteomic comparison, followed by verification with flow cytometry, revealed that chronically activated NK cells derived from 3 newly identified patients with TAP-2 deficiency consistently expressed aberrant levels of CC chemokine receptor 2 (CCR2) chemokine receptor in vitro and in vivo. This expression pattern translated into specific responsiveness of chronically activated NK cells derived from patients with TAP-2 deficiency to multiple ligands of CCR2. Moreover, the in vivo elevated levels of interleukin-2 (IL-2) and monocyte chemoattractant protein-1 (MCP-1) detected in serum and bronchoalveolar lavage samples derived from these patients highlight the potential involvement of the CCR2 pathway in aberrant NK-cell retention at chronic inflammatory sites.

Aortic valve replacement under deep hypothermic circulatory arrest.

BACKGROUND: Aortic valve replacement (AVR) in the presence of a calcified aorta or patent grafts may preclude clamping of the ascending aorta. We employed deep hypothermic circulatory arrest in order to circumvent this problem. METHODS: Between January 1993 and December 2000, 415 patients underwent AVR in our department. Eight of these were operated using deep hypothermic circulatory arrest. There were 5 males, and mean age was 72 years (range 56-81). Indications for using circulatory arrest were reoperation with patent grafts and/or severe calcification of the ascending aorta. In six patients, cardiopulmonary bypass was achieved via femoro-femoral bypass, and in two via aortic-right atrial cannulation. Retrograde cerebral perfusion was employed in five. Mean bypass time was 155 minutes (range 122-187), and mean circulatory arrest time was 38 minutes (range 31-49). RESULTS: There was no operative mortality, and no patient suffered any neurologic sequelae. Echocardiography showed all valves to be functioning well. CONCLUSIONS: AVR under deep hypothermic circulatory arrest can be accomplished with an acceptable degree of safety. It should be considered as an alternative in patients in whom aortic clamping is prohibitive, and might otherwise be considered inoperable. The ability to connect the patient to bypass and the presence of a "window" to allow aortotomy are prerequisites for employing this method.

Does coronary endarterectomy increase the risk of coronary bypass?

BACKGROUND: With increased incidence of angioplasty and stent implantation, patients referred for coronary bypass (CABG) typically have more advanced and diffuse coronary disease. Thus, more patients may require endarterectomy in order to achieve complete revascularization. We compared our results in patients undergoing CABG with or without coronary endarterectomy. METHODS: Between 1993 and 1999, 2372 patients underwent isolated CABG in our department. A retrospective analysis was performed to compare patients requiring coronary endarterectomy of the LAD (group 1, n = 88), endarterectomy of arteries other than the LAD (group 2, n = 143), to those not requiring endarterectomy (group 3, n = 2071). Patients undergoing CABG without the use of cardiopulmonary bypass were excluded. Group 1 had a higher incidence of proximal LAD stenosis (p = 0.001) than group 3, while group 2 had a higher incidence of peripheral vascular disease (p = 0.02), preoperative MI (p = 0.03) and LV dysfunction (p = 0.001). RESULTS: Operative mortality was 10% in group 1 (p < 0.001) and 4% in group 2 (p = NS) compared to 3% in group 3. Incidence of perioperative MI was 12% in group 1 (p = 0.001) and 8% in group 2 (p = 0.001) compared to 2% in group 3. CONCLUSIONS: Patients requiring endarterectomy of the LAD are at increased risk of operative mortality. This was not true for patients requiring endarterectomy of arteries other than the LAD. In both groups there was an increased risk of perioperative myocardial infarction.