SETD2 loss-of-function promotes renal cancer branched evolution through replication stress and impaired DNA repair.

Defining mechanisms that generate intratumour heterogeneity and branched evolution may inspire novel therapeutic approaches to limit tumour diversity and adaptation. SETD2 (Su(var), Enhancer of zeste, Trithorax-domain containing 2) trimethylates histone-3 lysine-36 (H3K36me3) at sites of active transcription and is mutated in diverse tumour types, including clear cell renal carcinomas (ccRCCs). Distinct SETD2 mutations have been identified in spatially separated regions in ccRCC, indicative of intratumour heterogeneity. In this study, we have addressed the consequences of SETD2 loss-of-function through an integrated bioinformatics and functional genomics approach. We find that bi-allelic SETD2 aberrations are not associated with microsatellite instability in ccRCC. SETD2 depletion in ccRCC cells revealed aberrant and reduced nucleosome compaction and chromatin association of the key replication proteins minichromosome maintenance complex component (MCM7) and DNA polymerase δ hindering replication fork progression, and failure to load lens epithelium-derived growth factor and the Rad51 homologous recombination repair factor at DNA breaks. Consistent with these data, we observe chromosomal breakpoint locations are biased away from H3K36me3 sites in SETD2 wild-type ccRCCs relative to tumours with bi-allelic SETD2 aberrations and that H3K36me3-negative ccRCCs display elevated DNA damage in vivo. These data suggest a role for SETD2 in maintaining genome integrity through nucleosome stabilization, suppression of replication stress and the coordination of DNA repair.

Two-year safety and effectiveness of the platinum chromium everolimus-eluting stent for the treatment of small vessels and longer lesions.

OBJECTIVES: To report 1- and 2-year clinical outcomes of patients receiving platinum chromium everolimus-eluting stents (PtCr-EES) in the prospective, single-arm PLATINUM small vessel (SV) and long lesion (LL) studies. BACKGROUND: Small vessel diameter and long lesion length are independently associated with increased risk of adverse cardiac events after drug-eluting stent implantation. METHODS: The PLATINUM SV study enrolled 94 patients with coronary artery lesions in vessels ≥2.25 mm to <2.50 mm in diameter and ≤28 mm in length. The PLATINUM LL study enrolled 102 patients with lesions >24 to ≤34 mm long in vessels ≥2.50 to ≤4.25 mm in diameter. The primary endpoint for both studies was target lesion failure (TLF) at 1 year compared to a prespecified performance goal based on outcomes with the TAXUS Express paclitaxel-eluting stent in small vessels and long lesions. RESULTS: One-year TLF rates with the PtCr-EES were significantly (P < 0.001) lower than the predetermined performance goals: 2.4% versus 21.1% in the SV cohort and 3.2% versus 19.4% in the LL cohort. Cumulative rates of TLF to 2 years were 4.7% in the SV cohort and 8.8% in the LL cohort. No myocardial infarction or ARC definite/probable stent thromboses occurred in either cohort through 2-year follow-up. CONCLUSIONS: The clinical efficacy and safety outcomes observed in these small vessel and long lesion cohorts support the use of the PtCr-EES in the treatment of small diameter vessels and long lesions.

Hypotension during surgery for femoral neck fracture in elderly patients: effect of anaesthetic techniques. A retrospective study.

BACKGROUND: The aim of this retrospective study was to compare the incidence of hypotension between different anaesthetic techniques, including general anaesthesia (GA), spinal anaesthesia single injection (SA), continuous spinal anaesthesia with 2.5 mg bolus injections as needed (CSA 2.5) or 5 mg bolus injections as needed (CSA 5) in elderly patients (>75 yrs old) undergoing surgery for femoral neck fractures. METHODS: Demographic, surgical and hemodynamic data from 333 patients over a four year period within a single hospital were recorded and examined. RESULTS: Forty-two patients underwent GA, 109 underwent SA, 61 underwent CSA 5, and 121 underwent CSA 2.5. Patients receiving GA, SA or CSA 5 had a higher incidence of hypotension (83%, 68%, and 34%, respectively) than patients who underwent CSA 2.5 (4%; P<0.05). The CSA 2.5 group required less colloid infusion (490+/-50 mL) than the GA and SA groups (810+/-330 and 645+/-230 mL, respectively). The CSA 2.5 group also required less crystalloid infusion volume (760+/-371 mL) than the GA group (1140+/-770 mL). Ephedrine infusion was higher in the GA and SA groups (30+/-10 and 26+/-9 mg, respectively) than the CSA 2.5 (15+/-8 mg; P<0.05). CONCLUSION: This study demonstrated that CSA 2.5 causes fewer episodes of hypotension than other anaesthetic techniques for surgical repair of hip fracture in elderly patients.

A novel, low-profile filter-wire (Interceptor) embolic protection device during saphenous vein graft stenting.

A novel, low-profile filter embolic protection device was deployed in 26 patients who underwent stent deployment for saphenous vein graft stenoses in a multicenter trial. Major adverse cardiovascular events were observed in only 2 patients (7.7%) and angiographic flow grades were improved.

Uso del estimulador vagal, en la epilepsia refractaria: una alternativa terapéutica / Vagus nerve stimulation in the management of intractable epilepsy

La utilización del estimulador vagal constituye una alternativa válida de tratamiento paliativo en aquellas epilepsias refractarias que no pueden ser tratadas mediante técnicas quirúrgicas a cielo abierto (lobectomias, lesionectomías, desconexiones). Se describen fundamentos del procedimiento, indicaciones del mismo, técnica quirúrgica y experiencia de los autores.

Uso del estimulador vagal, en la epilepsia refractaria: una alternativa terapéutica / Vagus nerve stimulation in the management of intractable epilepsy

La utilización del estimulador vagal constituye una alternativa válida de tratamiento paliativo en aquellas epilepsias refractarias que no pueden ser tratadas mediante técnicas quirúrgicas a cielo abierto (lobectomias, lesionectomías, desconexiones). Se describen fundamentos del procedimiento, indicaciones del mismo, técnica quirúrgica y experiencia de los autores. (AU)

Adverse events associated with balloon rupture during percutaneous coronary intervention.

BACKGROUND: Balloon rupture is a potential complication of coronary angioplasty. The literature is inconsistent regarding associated adverse consequences. The experience of St Paul's Hospital, University of British Columbia, Vancouver, British Columbia, with balloon rupture is reviewed. PATIENTS AND METHODS: All patients who underwent percutaneous coronary intervention complicated by balloon rupture at St Paul's Hospital from April 1992 to March 1996 were identified from the hospital's database (Seattle Systems, Seattle, Washington). Procedural logs, database records, clinical charts and all cineangiograms were reviewed in detail. RESULTS: A total of 2984 patients had percutaneous coronary revascularization and 110 patients experienced balloon rupture. These occurred in 101 (92%) native coronary arteries and 9 (8%) occurred in saphenous vein grafts. Stents were deployed in 44 (40%) patients; 34 of the stents used were half Johnson & Johnson PS153 stents (Johnson & Johnson Interventinal Systems, Peterborough, Ontario). An event-free postangioplasty course during the index hospitalization was observed in 102 patients (93%); eight patients (7%) had one or more important adverse events postprocedure. These included three deaths (one following a dissection and out-of-catheterization laboratory occlusion, a second following an abrupt occlusion of another target artery and emergency bypass surgery, and another with cardiogenic shock postmyocardial infarction and an unaltered course following angioplasty); one urgent bypass surgery after a left main dissection; and two nonfatal myocardial infarctions (one patient had tamponade and one patient experienced congestive heart failure). Four of the eight events were directly related to the procedure. The rate of death and emergency bypass surgery with balloon rupture did not differ from that of patients without balloon rupture in the authors' centre (1.8% versus 1.4%, not significant). CONCLUSIONS: The majority of patients did not experience any adverse clinical outcomes and demonstrated good angiographic results after balloon rupture. The data did not detect an excess of major adverse events beyond that expected in a diverse general angioplasty population.

Pullback atherectomy with the Arrow-Fischell atherectomy device.

The Arrow-Fischell pullback atherectomy catheter is designed to circumferentially debulk and retrieve coronary atheroma. We performed pullback atherectomy before balloon angioplasty or stenting in 41 patients. The device crossed the target lesion in 38 (93%) and obtained tissue in 36 (88%). All procedures were completed successfully and without myocardial infarction, emergency cardiac surgery, or death. Complications included major spasm in 8 patients, postprocedural abrupt closure in 1, and otherwise uncomplicated arterial perforation in 2. Pullback atherectomy can be performed relatively safely, but is more difficult than balloon angioplasty, obtains less tissue than directional atherectomy, and is associated with significant limitations.

Early and late assessment of the Micro Stent PL coronary stent for restenosis and suboptimal balloon angioplasty.

This prospective study represents the initial assessment of the Micro Stent PL (Arterial Vascular Engineering, Inc.) coronary stent. From one to three radiopaque stainless steel stents, each measuring 4 mm long, were premounted onto specially designed balloon catheters. A total of 123 stents were implanted in 41 patients without procedural failure or complications. Stent dislodgment proved a concern, with 7 of 123 stents (5.7%) moving > 3 mm from the site of placement and late downstream migration occurring in an additional patient. Subacute stent thrombosis occurred in two patients (5%). Six-month angiographic follow-up was available in 37 of 41 patients (90%). Minimal lumen diameter at baseline was 0.93 +/- 0.51 mm, increasing to 2.74 +/- 0.49 mm after stenting, and falling to 1.66 +/- 0.89 mm at 6 months; this represents a late loss of 60% of the initial gain. Restenosis, based on a binary definition of > 50% diameter stenosis, was documented in 18 patients (49%). Advantages of the Micro Stent PL include its radiopacity and marked ease of distal delivery. The potential for stent dislodgment has implications for future stent designs. The role of the Micro Stent PL in managing restenosis is unclear, but it appears useful in the management of dissection and threatened closure after balloon angioplasty.

Usefulness of coronary stenting for cardiogenic shock.

Coronary stenting was performed in 15 selected patients with cardiogenic shock, with favorable clinical and angiographic outcomes. This experience suggests that coronary stenting may play an important adjunctive role in the management of cardiogenic shock and may improve outcome beyond that achieved with balloon angioplasty alone.

Stenting for treatment of coronary vasospasm.

Following an acute anterior myocardial infarction, a 56-yr-old female underwent two balloon angioplasty procedures for a recurrent proximal left anterior descending artery stenosis. She had recurrent angina pectoris. Angiography showed a noncritical restenosis with marked provocable superimposed vasospasm. Despite repeat balloon dilatation and stenting of the lesion, she developed recurrent symptoms. One month later, angiography showed progressive fixed disease and reversible spasm proximal and distal to, but not involving, the stented arterial segment. She underwent single-vessel coronary artery bypass grafting, and is asymptomatic at 6-mo follow-up.

Anterior segment findings in AIDS patients with cytomegalovirus retinitis.

BACKGROUND: Anterior segment findings in AIDS patients presenting with cytomegalovirus (CMV) retinitis have not been specifically addressed in the American literature. METHODS: Our study evaluated 21 AIDS patients with CMV retinitis. RESULTS: Nineteen (90%) of these patients exhibited corneal endothelial deposits concurrent with CMV retinitis. The endothelial deposits were microscopic, opaque, linear flecks arranged in a reticular-like fashion. Of 42 eyes evaluated, 32 (76%) demonstrated active CMV retinitis. Corneal endothelial deposits were noted in 26 (81%) of the 32 eyes with retinitis. These corneal endothelial deposits were absent in the eyes which did not have CMV retinitis. CONCLUSION: Meticulous examination of the retina of an HIV-positive or AIDS patient who presents with reticularly arranged, linear, flecked corneal endothelial deposits should be performed to ensure that the diagnosis of CMV retinitis can be ruled out.

Increased numbers of mast cells in pterygia.

PURPOSE/METHODS: We examined the mast cells in 12 pterygium specimens of patients who underwent primary excisions and the conjunctival specimens of ten normal age-matched control subjects. RESULTS/CONCLUSION: The mean mast cell count per cubic millimeter was twice as high in the pterygium specimens as in the control specimens. Mast cell proliferation and activation may contribute to the pathogenesis of pterygium formation.

Multiple myeloma presenting with bilateral exudative macular detachments.

Bilateral exudative macular detachments were present on a 64-year-old diabetic Caucasian male who presented with bilateral blurring of vision. Besides the exudative macular detachments there was no diabetic retinopathy or congestive retinopathy, and a previous fluorescein angiogram revealed no focal leakage. Laboratory investigation, bone marrow biopsy, and a bone survey revealed the diagnosis of multiple myeloma.

Paracentric inversion of chromosome 3 (q21q26) in a patient with chronic myelomonocytic leukemia and a normal platelet count.

Clonal chromosomal abnormalities occur in about one-third of patients with chronic myelomonocytic leukemia (CMMoL) and are usually those found in other myelodysplastic syndromes. Abnormalities of chromosome 3, which have been associated with abnormal thrombopoiesis, are relatively uncommon. A patient with CMMoL with inv(3)(q21q26) and normal thrombopoiesis is presented, and the cytogenetics of CMMoL are reviewed. The possible significance of chromosome 3 in thrombopoiesis is discussed.