First-line venetoclax combinations versus chemoimmunotherapy in fit patients with chronic lymphocytic leukaemia (GAIA/CLL13): 4-year follow-up from a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: In the primary analysis report of the GAIA/CLL13 trial, we found that venetoclax-obinutuzumab and venetoclax-obinutuzumab-ibrutinib improved undetectable measurable residual disease (MRD) rates and progression-free survival compared with chemoimmunotherapy in patients with previously untreated chronic lymphocytic leukaemia. However, to our knowledge, no data on direct comparisons of different venetoclax-based combinations are available. METHODS: GAIA/CLL13 is an open-label, randomised, phase 3 study conducted at 159 sites in ten countries in Europe and the Middle East. Eligible patients were aged 18 years or older, with a life expectancy of at least 6 months, an Eastern Cooperative Oncology group performance status of 0-2, a cumulative illness rating scale score of 6 or lower or a single score of 4 or lower, and no TP53 aberrations. Patients were randomly assigned (1:1:1:1), with a computer-generated list stratified by age, Binet stage, and regional study group, to either chemoimmunotherapy, venetoclax-rituximab, venetoclax-obinutuzumab, or venetoclax-obinutuzumab-ibrutinib. All treatments were administered in 28-day cycles. Patients in the chemoimmunotherapy group received six cycles of treatment, with patients older than 65 years receiving intravenous bendamustine (90 mg/m2, days 1-2), whereas patients aged 65 years or younger received intravenous fludarabine (25 mg/m2, days 1-3) and intravenous cyclophosphamide (250 mg/m2, days 1-3). Intravenous rituximab (375 mg/m2, day 1 of cycle 1; 500 mg/m2, day 1 of cycles 2-6) was added to chemotherapy. In the experimental groups, patients received daily venetoclax (400 mg orally) for ten cycles after a 5-week ramp-up phase starting on day 22 of cycle 1. In the venetoclax-rituximab group, intravenous rituximab (375 mg/m2, day 1 of cycle 1; 500 mg/m2, day 1 of cycles 2-6) was added. In the obinutuzumab-containing groups, obinutuzumab was added (cycle 1: 100 mg on day 1, 900 mg on day 2, and 1000 mg on days 8 and 15; cycles 2-6: 1000 mg on day 1). In the venetoclax-obinutuzumab-ibrutinib group, daily ibrutinib (420 mg orally, from day 1 of cycle 1) was added until undetectable MRD was reached in two consecutive measurements (3 months apart) or until cycle 36. The planned treatment duration was six cycles in the chemoimmunotherapy group, 12 cycles in the venetoclax-rituximab and the venetoclax-obinutuzumab group and between 12 and 36 cycles in the venetoclax-obinutuzumab-ibrutinib group. Coprimary endpoints were the undetectable MRD rate in peripheral blood at month 15 for the comparison of venetoclax-obinutuzumab versus standard chemoimmunotherapy and investigator-assessed progression-free survival for the comparison of venetoclax-obinutuzumab-ibrutinib versus standard chemoimmunotherapy, both analysed in the intention-to-treat population (ie, all patients randomly assigned to treatment) with a split α of 0·025 for each coprimary endpoint. Both coprimary endpoints have been reported elsewhere. Here we report a post-hoc exploratory analysis of updated progression-free survival results after a 4-year follow-up of our study population. Safety analyses included all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT02950051, recruitment is complete, and all patients are off study treatment. FINDINGS: Between Dec 13, 2016, and Oct 13, 2019, 1080 patients were screened and 926 were randomly assigned to treatment (chemoimmunotherapy group n=229; venetoclax-rituximab group n=237; venetoclax-obinutuzumab group n=229; and venetoclax-obinutuzumab-ibrutinib group n=231); mean age 60·8 years (SD 10·2), 259 (28%) of 926 patients were female, and 667 (72%) were male (data on race and ethnicity are not reported). At data cutoff for this exploratory follow-up analysis (Jan 31, 2023; median follow-up 50·7 months [IQR 44·6-57·9]), patients in the venetoclax-obinutuzumab group had significantly longer progression-free survival than those in the chemoimmunotherapy group (hazard ratio [HR] 0·47 [97·5% CI 0·32-0·69], p<0·0001) and the venetoclax-rituximab group (0·57 [0·38-0·84], p=0·0011). The venetoclax-obinutuzumab-ibrutinib group also had a significantly longer progression-free survival than the chemoimmunotherapy group (0·30 [0·19-0·47]; p<0·0001) and the venetoclax-rituximab group (0·38 [0·24-0·59]; p<0·0001). There was no difference in progression-free survival between the venetoclax-obinutuzumab-ibrutinib and venetoclax-obinutuzumab groups (0·63 [0·39-1·02]; p=0·031), and the proportional hazards assumption was not met for the comparison between the venetoclax-rituximab group versus the chemoimmunotherapy group (log-rank p=0·10). The estimated 4-year progression-free survival rate was 85·5% (97·5% CI 79·9-91·1; 37 [16%] events) in the venetoclax-obinutuzumab-ibrutinib group, 81·8% (75·8-87·8; 55 [24%] events) in the venetoclax-obinutuzumab group, 70·1% (63·0-77·3; 84 [35%] events) in the venetoclax-rituximab group, and 62·0% (54·4-69·7; 90 [39%] events) in the chemoimmunotherapy group. The most common grade 3 or worse treatment-related adverse event was neutropenia (114 [53%] of 216 patients in the chemoimmunotherapy group, 109 [46%] of 237 in the venetoclax-rituximab group, 127 [56%] of 228 in the venetoclax-obinutuzumab group, and 112 [48%] of 231 in the venetoclax-obinutuzumab-ibrutinib group). Deaths determined to be associated with study treatment by the investigator occurred in three (1%) patients in the chemoimmunotherapy group (n=1 due to each of sepsis, metastatic squamous cell carcinoma, and Richter's syndrome), none in the venetoclax-rituximab and venetoclax-obinutuzumab groups, and four (2%) in the venetoclax-obinutuzumab-ibrutinib group (n=1 due to each of acute myeloid leukaemia, fungal encephalitis, small-cell lung cancer, and toxic leukoencephalopathy). INTERPRETATION: With more than 4 years of follow-up, venetoclax-obinutuzumab and venetoclax-obinutuzumab-ibrutinib significantly extended progression-free survival compared with both chemoimmunotherapy and venetoclax-rituximab in previously untreated, fit patients with chronic lymphocytic leukaemia, thereby supporting their use and further evaluation in this patient group, while still considering the higher toxicities observed with the triple combination. FUNDING: AbbVie, Janssen, and F Hoffmann-La Roche.

Survival after secondary liver resection in metastatic colorectal cancer: Comparing data of three prospective randomized European trials (LICC, CELIM, FIRE-3).

Metastatic colorectal cancer (mCRC) patients with liver-limited disease (LLD) have a chance of long-term survival and potential cure after hepatic metastasectomy. However, the appropriate postoperative treatment strategy is still controversial. The CELIM and FIRE-3 studies demonstrated that secondary hepatic resection significantly improved overall survival (OS). The objective of this analysis was to compare these favorable outcome data with recent results from the LICC trial investigating the antigen-specific cancer vaccine tecemotide (L-BLP25) as adjuvant therapy in mCRC patients with LLD after R0/R1 resection. Data from mCRC patients with LLD and secondary hepatic resection from each study were analyzed for efficacy outcomes based on patient characteristics, treatment and surveillance after surgery. In LICC, 40/121 (33%) patients, in CELIM 36/111 (32%) and in FIRE-3-LLD 29/133 (22%) patients were secondarily resected, respectively. Of those, 31 (77.5%) patients in LICC and all patients in CELIM were R0 resected. Median disease-free survival after resection was 8.9 months in LICC, 9.9 months in CELIM. Median OS in secondarily resected patients was 66.1 months in LICC, 53.9 months in CELIM and 56.2 months in FIRE-3-LLD. Median age was about 5 years less in LICC compared to CELIM and FIRE-3. Secondarily resected patients of LICC, CELIM and FIRE-3 showed an impressive median survival with a tendency for improved survival for patients in the LICC trial. A younger patient cohort but also more selective surgery, improved resection techniques, deep responses and a close surveillance program after surgery in the LICC trial may have had a positive impact on survival.

Dual targeting of MCL1 and NOXA as effective strategy for treatment of mantle cell lymphoma.

Imbalances in the composition of BCL2 family proteins contribute to tumourigenesis and therapy resistance of mantle cell lymphoma (MCL), making these proteins attractive therapy targets. We studied the efficiency of dual targeting the NOXA/MCL1 axis by combining fatty acid synthase inhibitors (NOXA stabilization) with the CDK inhibitor Dinaciclib (MCL1 reduction). This combination synergistically induced apoptosis in cell lines and primary MCL cells and led to almost complete inhibition of tumour progression in a mouse model. Apoptosis was NOXA-dependent and correlated with the NOXA/MCL1 ratio, highlighting the importance of the NOXA/MCL1 balance for effective cell death induction in MCL.

Incidence and predictors of permanent pacemaker implantation following transcatheter aortic valve implantation: analysis from the German transcatheter aortic valve interventions registry.

OBJECTIVES: To determine predictors of permanent pacemaker (PPM) implantation up to 30 days after transcatheter aortic valve implantation (TAVI) in a prospective multicenter registry. BACKGROUND: Conduction disorders requiring PPM implantation are one of the most common complications seen after TAVI. Knowledge about possible predictors may help to decrease the rate of PPM implantations. METHODS: In total, 1347 consecutive patients who underwent TAVI in 22 centers were prospectively enrolled in the German transcatheter aortic valve interventions registry. Both Medtronic CoreValve™ and Edwards Sapien™ valves were implanted. Patients with preprocedurally implanted PPM or implantable cardioverter defibrillator were excluded from the analysis (n = 199). Regression analysis of baseline and procedure characteristics of the remaining 1,147 patients was performed. RESULTS: Procedural success was achieved in 97.4% of the cases. The rate for PPM after TAVI was 33.7%. The absence of prior valve surgery, the use of Medtronic CoreValve™ prosthesis and the presence of a porcelain aorta were identified as independent predictors for PPM after TAVI. Mortality at 30 days did not differ between patients with or without PPM necessity (6.0% vs. 8.1%, respectively; HR 0.72; CI (0.45-1.16); P = 0.17). CONCLUSIONS: PPM is a common postprocedure requirement after TAVI. The absence of prior valve surgery, the implantation of Medtronic CoreValve™ prosthesis, and the presence of a porcelain aorta were independently associated with PPM after TAVI.

LICC: L-BLP25 in patients with colorectal carcinoma after curative resection of hepatic metastases: a randomized, placebo-controlled, multicenter, multinational, double-blinded phase II trial.

BACKGROUND: 15-20% of all patients initially diagnosed with colorectal cancer develop metastatic disease and surgical resection remains the only potentially curative treatment available. Current 5-year survival following R0-resection of liver metastases is 28-39%, but recurrence eventually occurs in up to 70%. To date, adjuvant chemotherapy has not improved clinical outcomes significantly. The primary objective of the ongoing LICC trial (L-BLP25 In Colorectal Cancer) is to determine whether L-BLP25, an active cancer immunotherapy, extends recurrence-free survival (RFS) time over placebo in colorectal cancer patients following R0/R1 resection of hepatic metastases. L-BLP25 targets MUC1 glycoprotein, which is highly expressed in hepatic metastases from colorectal cancer. In a phase IIB trial, L-BLP25 has shown acceptable tolerability and a trend towards longer survival in patients with stage IIIB locoregional NSCLC. METHODS/DESIGN: This is a multinational, phase II, multicenter, randomized, double-blind, placebo-controlled trial with a sample size of 159 patients from 20 centers in 3 countries. Patients with stage IV colorectal adenocarcinoma limited to liver metastases are included. Following curative-intent complete resection of the primary tumor and of all synchronous/metachronous metastases, eligible patients are randomized 2:1 to receive either L-BLP25 or placebo. Those allocated to L-BLP25 receive a single dose of 300 mg/m2 cyclophosphamide (CP) 3 days before first L-BLP25 dose, then primary treatment with s.c. L-BLP25 930 µg once weekly for 8 weeks, followed by s.c. L-BLP25 930 µg maintenance doses at 6-week (years 1&2) and 12-week (year 3) intervals unless recurrence occurs. In the control arm, CP is replaced by saline solution and L-BLP25 by placebo. Primary endpoint is the comparison of recurrence-free survival (RFS) time between groups. Secondary endpoints are overall survival (OS) time, safety, tolerability, RFS/OS in MUC-1 positive cancers. Exploratory immune response analyses are planned. The primary endpoint will be assessed in Q3 2016. Follow-up will end Q3 2017. Interim analyses are not planned. DISCUSSION: The design and implementation of such a vaccination study in colorectal cancer is feasible. The study will provide recurrence-free and overall survival rates of groups in an unbiased fashion. TRIAL REGISTRATION: EudraCT Number 2011-000218-20.

Cerebral and myocardial blood flow responses to hypercapnia and hypoxia in humans.

In humans, cerebrovascular responses to alterations in arterial Pco(2) and Po(2) are well documented. However, few studies have investigated human coronary vascular responses to alterations in blood gases. This study investigated the extent to which the cerebral and coronary vasculatures differ in their responses to euoxic hypercapnia and isocapnic hypoxia in healthy volunteers. Participants (n = 15) were tested at rest on two occasions. On the first visit, middle cerebral artery blood velocity (V(P)) was assessed using transcranial Doppler ultrasound. On the second visit, coronary sinus blood flow (CSBF) was measured using cardiac MRI. For comparison with V(P), CSBF was normalized to the rate pressure product [an index of myocardial oxygen consumption; normalized (n)CSBF]. Both testing sessions began with 5 min of euoxic [end-tidal Po(2) (Pet(O(2))) = 88 Torr] isocapnia [end-tidal Pco(2) (Pet(CO(2))) = +1 Torr above resting values]. Pet(O(2)) was next held at 88 Torr, and Pet(CO(2)) was increased to 40 and 45 Torr in 5-min increments. Participants were then returned to euoxic isocapnia for 5 min, after which Pet(O(2)) was decreased from 88 to 60, 52 and 45 Torr in 5-min decrements. Changes in V(P) and nCSBF were normalized to isocapnic euoxic conditions and indexed against Pet(CO(2)) and arterial oxyhemoglobin saturation. The V(P) gain for euoxic hypercapnia (%/Torr) was significantly higher than nCSBF (P = 0.030). Conversely, the V(P) gain for isocapnic hypoxia (%/%desaturation) was not different from nCSBF (P = 0.518). These findings demonstrate, compared with coronary circulation, that the cerebral circulation is more sensitive to hypercapnia but similarly sensitive to hypoxia.

Coronary vasospasm: is it a myth?

This review addresses some myths about coronary vasospasm as the cause of angina pectoris. Coronary artery vasospasm is a common phenomenon, which is clinically encountered by busy cardiologists almost on a daily basis. It is the cause of resting angina in many patients without significant coronary artery disease, but also in patients with atherosclerotic coronary artery disease but no subtotal lesion. Although coronary artery vasospasm can be suspected clinically, proof cannot usually be obtained by non-invasive means but is easily available during cardiac catheterization. Patients with vasospastic angina are repeatedly exposed to this invasive procedure as most cardiologists suspect a coronary lesion requiring intervention as the cause of the patient's resting angina. Adding an intracoronary acetylcholine test to the catheterization procedure may establish the correct diagnosis and enable treatment with calcium antagonists and nitrates. Epicardial vasospasm may be observed during the test in patients with and without angiographically visible lesions in the coronary arteries. Almost 50% of all pathological tests, however, do not show epicardial vasospasm but reproduction of symptoms and electrocardiogram signs of ischemia indicating spasm of the microvessels.

Oxygenation-sensitive CMR for assessing vasodilator-induced changes of myocardial oxygenation.

BACKGROUND: As myocardial oxygenation may serve as a marker for ischemia and microvascular dysfunction, it could be clinically useful to have a non-invasive measure of changes in myocardial oxygenation. However, the impact of induced blood flow changes on oxygenation is not well understood. We used oxygenation-sensitive CMR to assess the relations between myocardial oxygenation and coronary sinus blood oxygen saturation (SvO2) and coronary blood flow in a dog model in which hyperemia was induced by intracoronary administration of vasodilators. RESULTS: During administration of acetylcholine and adenosine, CMR signal intensity correlated linearly with simultaneously measured SvO2 (r2 = 0.74, P < 0.001). Both SvO2 and CMR signal intensity were exponentially related to coronary blood flow, with SvO2 approaching 87%. CONCLUSIONS: Myocardial oxygenation as assessed with oxygenation-sensitive CMR imaging is linearly related to SvO2 and is exponentially related to vasodilator-induced increases of blood flow. Oxygenation-sensitive CMR may be useful to assess ischemia and microvascular function in patients. Its clinical utility should be evaluated.

Adjuvant MUC vaccination with tecemotide after resection of colorectal liver metastases: a randomized, double-blind, placebo-controlled, multicenter AIO phase II trial (LICC).

Resection of colorectal liver metastases (CRLM) is a potential curative treatment for patients with metastatic colorectal cancer (mCRC) with liver-limited disease (LLD). Although long-term survival improved considerably within the last decades, high recurrence rates of 50-75% after resection remain a major challenge.Tecemotide (L-BLP25) is an antigen-specific cancer vaccine inducing immunity against mucin-1 (MUC1). The LICC trial aimed to improve survival in patients with mCRC after R0/R1 resection of CRLM. LICC was a binational, randomized, double-blind, placebo-controlled, multicenter phase 2 study including patients with R0/R1 resected CRLM without evidence of metastatic disease outside the liver. Co-primary endpoints were recurrence-free survival (RFS) and 3-year overall survival (OS) rate, secondary endpoints were RFS and OS in subgroups with different MUC1 expression and safety. In total, 121 patients were 2:1 randomized between Oct 2011 and Dec 2014to receive tecemotide (N=79) or placebo (N=42). Baseline characteristics were well balanced. Median RFS was 6.1 months (95% CI 4.5-8.9) and 11.4 months (95% CI 3.7-21.2) (P = .1754), 3-year OS rate 69.1% and 79.1%, median OS 62.8 months and not reached in the tecemotide vs. placebo arm (P = .2141), respectively. Cox regression models revealed no dependence of RFS or OS on MUC1 expression. The most common tecemotide-related grade 3/4 adverse events were diarrhea, injection site reaction, intestinal perforation, peritonitis and tinnitus (1.3% each). The LICC trial failed to meet its primary endpoints of significantly improving RFS and OS with tecemotide. However, both arms showed unexpectedly long OS. MUC1 expression was not associated with outcome.EudraCT No: 2011-000218-20Clinical Trial Information: NCT01462513Financial Support: Merck KGaA, Darmstadt, Germany. Abbreviations: AE: adverse event; CP: cyclophosphamide; CRC: colorectal cancer; CT: computed tomography; ECOG: Eastern Cooperative Oncology Group; FU: follow-up; HR: hazard ratio; IHC: immunohistochemical staining; ITT: intention-to-treat; DSMB: Data Safety Monitoring Board; LLD: liver-limited disease; mCRC: metastatic colorectal cancer; MPLA: monophosphoryl lipid; AMRI: magnetic resonance imaging; MUC1: mucin 1; NA: not applicable; NCI-CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events; NS: normal saline; NSCLC: non-small-cell lung carcinoma; OS: overall surviva; lPP: per protocol; RAS: Rat sarcoma; RFS: recurrence-free survival; TEAE: treatment-emergent adverse event; UICC: Union for International Cancer Control; US: ultrasound; vs.: versus.

An analysis of the role of follicular lymphoma-associated fibroblasts to promote tumor cell viability following drug-induced apoptosis.

Treatment response of follicular lymphomas (FL) is highly variable. We, therefore, investigated the role of FL cancer-associated fibroblasts (CAFs) on tumor cell viability, in particular in response to treatment with cytotoxic drugs. Stromal cells outgrown from FL patients were characterized and pure CAF populations were co-cultivated with FL cells. To analyze fibroblast-mediated effects, cells in co-culture were treated with ABT-737 and Bortezomib. The adherent cell population was positive for all fibroblastic markers tested and showed increased mRNA-expression of the activation marker FAP. No effect on FL cell viability was noted when co-cultivating them with CAFs. However, stromal cells protected tumor cells from apoptosis in response to cytotoxic treatment. This might be explained by mRNA-induction of ABCC1 and ABCG2 and up-regulation of BCL2L1 in FL cells. Our finding of protective mechanisms mediated by CAFs is of pivotal impact for further studies of cytotoxic agents in FL.

[How to do: Bone marrow biopsy]. / Die Knochenmarkpunktion.

Bone marrow examination plays an important role in the diagnosis of hematological and oncological diseases. Confirmation of a leukemia, clarification of cytopenias and risk stratification of a disease are possible indications for a bone marrow puncture.Here we describe, step by step, the workflow, possible pitfalls and complications of this procedere.

Diffuse large B-cell lymphomas of immunoblastic type are a major reservoir for MYC-IGH translocations.

The immunoblastic variant of diffuse large B-cell lymphoma (IB-DLBCL) has recently been recognized as an aggressive lymphoma type with inferior prognosis as compared with other DLBCL variants. At the same time, the presence of MYC rearrangements in DLBCL has been shown to indicate shorter survival in R-CHOP-treated patients. In this study, we investigated the occurrence of MYC gene rearrangements in IB-DLBCL versus non-IB-DLBCL in a large series. Using fluorescence in situ hybridization with an MYC break-apart and MYC-IGH fusion probe, we found that 13/39 evaluable IB-DLBCLs (33%) harbor translocations involving MYC, in contrast with only 5/68 (7%) in the non-IB-DLBCL group (P<0.01). The immunoglobulin heavy chain gene (IGH) was the translocation partner in all rearrangements (100%) involving MYC in IB-DLBCL, which is in contrast to what has been reported for DLBCL in the literature (50% to 70%). Moreover, MYC rearrangements occurred as the sole translocation in the majority of cases (77%), whereas across all DLBCLs the majority of MYC-rearranged cases carry additional rearrangements of either BCL2 and/or BCL6 genes (between 58% and 83% of cases). Finally, MYC-rearranged IB-DLBCLs were CD10 positive in 62% (8/13), whereas this was an uncommon feature in MYC germline IB-DLBCLs (15%). In conclusion, IB-DLBCLs are genetically characterized by frequent MYC-IGH translocations that often occur without additional BCL2 and/or BCL6 translocations. The activation of MYC, therefore, may be an important pathogenetic feature in IB-DLBCL.

Imaging of congenital coronary anomalies with multislice computed tomography.

OBJECTIVE: To describe a single-center experience of using retrospectively gated multislice computed tomographic (MSCT) coronary angiography for imaging congenital coronary anomalies. PATIENTS AND METHODS: We retrospectively reviewed the clinical information and imaging studies for 9 patients diagnosed as having congenital coronary anomalies on invasive, selective coronary angiography between February 2001 and October 2003 at the Mayo Clinic in Jacksonville, Fla. Two experienced observers classified by consensus the origin and proximal course of the abnormal coronary arteries as seen on MSCT. RESULTS: In 1 patient, MSCT showed a normal but extremely anterior origin of the right coronary artery from the right aortic sinus of Valsalva. In the other 8 patients, the origin and course of 4 anomalous right coronary arteries, 2 anomalous left circumflex coronary arteries, and 2 single coronary arteries were recognized easily on MSCT. CONCLUSION: Similar to electron beam computed tomography and magnetic resonance imaging, widely available MSCT can characterize the proximal course of congenitally abnormal coronary arteries and thus aid in clinical decision making for patients with such anomalies.

Contained aortic annulus rupture with persisting false aneurysm after transfemoral transcatheter aortic valve implantation.

With older age and increasing comorbidities, conventional operative procedures for severe symptomatic aortic stenosis are associated with a high surgical risk. To date, transfemoral transcatheter aortic valve implantation (TF-TAVI) represents an accepted alternative method of intervention with a cardiovascular and all-cause mortality similar to operative replacement at early and long-term follow-up in this high risk population (Thomas et al., Circulation 124:425­433, 2011). Despite growing experience of the operators and improvement of the devices procedural and perioperative complications still occur (Panchal et al., Am J Cardiol, 2013). Aortic annulus rupture as well as the rupture of the membranous ventricular septum has been reported (Aminian et al., Catheter Cardiovasc Interv 81:E72­E75, 2013). We present the unusual case of an 80-year-old female who developed a false aneurysm following a contained aortic annulus rupture during a TF-TAVI procedure.

Dynamics of coexisting HCMV-UL97 and UL54 drug-resistance associated mutations in patients after haematopoietic cell transplantation.

BACKGROUND: Resistance to antiviral drugs can be a severe problem in transplant recipients. Mutations in the HCMV phosphotransferase-gene (UL97) and the polymerase-gene (UL54) are responsible for resistance against ganciclovir (GCV), cidofovir (CDV) and foscarnet (PFA). Most frequently mutations in the UL97-gene are associated with resistance to GCV. Resistance against PFA and CDV is associated to mutations in the UL54-gene. There are only few reports about multidrug-resistance with mutations in both genes in patients after allogeneic haematopoietic cell transplantation (HCT). OBJECTIVES: To asses retrospectively the role of UL97/UL54-mutations for clinical deterioration. STUDY DESIGN: We present here three patients after HCT developing multidrug-resistance with coexisting UL97 and UL54-mutations. Genotypical resistance screening was done with restriction-fragment-length-polymorphism (RFLP), sequencing of UL97/UL54, and LightCycler real-time PCR. Phenotyipcal testing was performed by a cell-associated plaque-reduction-assay. Plasma viral-load (VL) was determined longitudinally using Roche Cobas-Amplicor-System (Roche Diagnostics). In one case VL was also correlated to different ratios of coexisting UL97-wildtype and mutant variants. RESULTS: All three patients developed multidrug resistant HCMV-infections with one or more UL97 and UL54-mutation detected by RFLP, sequencing and LightCycler-analysis. Two out of three patients showed biphasic VL kinetics with manifestation of UL97 drug-resistance prior/or at peak VL. UL54-mutations emerged also in all three patients either at increasing VL levels of ≥10(5)copies/ml or at peak VL. CONCLUSIONS: The development of coexisting HCMV UL97 and UL54-mutations conferring drug-resistance after HCT is not strictly associated with fatal outcome in one of our three patients. Manifestation of drug resistant combined UL97/UL54-mutations occurred prior to a second VL peak under (V)GCV/PFA co-treatment.

CMR gives clue to "ragged red fibers" in the heart in a patient with mitochondrial myopathy.

Mitochondrial myopathy may manifest either as isolated myopathy or as a neuromuscular multisystemic disease and is caused by genetic defects in the mitochondrial genome resulting in respiratory chain disorders. MELAS, which is characterised by mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes due to gene mutations in the mitochondrial DNA (adenine-to-guanine transition at nucleotide pair 3243, m.3243A>G), constitutes such a mitochondrial multisystemic disease. Although hypertrophied or dilated cardiomyopathy is quite common in MELAS, there have been no cardiovascular magnetic resonance (CMR)-based studies in these patients so far. This case report represents the first case in which comprehensive CMR and endomyocardial biopsy (EMB) data were obtained in the same patient with mitochondrial myopathy. Late gadolinium enhancement (LGE) imaging demonstrated a unique pattern of myocardial damage and histological work-up revealed the presence of "ragged red fibers" (conglomerates of mitochondria) in the heart tissue verifying the diagnosis of a mitochondrial cardiomyopathy as part of the underlying mitochondrial disease MELAS.

Caucasian patients suffering from coronary vasospastic angina have an intact peripheral endothelium-dependent vasoreactivity.

We sought to evaluate whether Caucasian patients suffering from vasospastic angina have a decreased brachial artery flow-mediated dilation (FMD) like their Japanese counterparts and whether certain serum factors known to be associated with impaired vasomotility or endothelial dysfunction are abnormal. In this prospectively conducted study, 33 subjects presenting with resting angina were identified to suffer from coronary vasospastic angina (coronary spasm group). A control group of 19 subjects with matched cardiovascular risk profiles was defined out of patients admitted to our hospital for evaluation of atypical chest pain. Intracoronary acetylcholine(ACh)-testing for vasospasm was performed in all patients after coronary artery disease (CAD) had been ruled out. Brachial artery FMD was measured using high-resolution ultrasound. There was no significant difference in brachial artery FMD between the coronary spasm and the control group (7.05+/-2.24% vs. 7.12+/-2.50%; p=0.93). The endothelium-independent vasodilator response of the brachial artery to sublingual nitroglycerin did not differ either between the two groups (21.88+/-6.13% vs. 21.48+/-7.38%; p=0.84). Simple and multiple linear regression analysis revealed that only baseline brachial artery diameter was a significant determinant of FMD (p<0.0001). No relationship could be detected between impaired coronary vasomotility and peripheral endothelium-dependent or independent vasodilation in Caucasian patients suffering from coronary vasospastic angina illustrating a further clue for racial differences in the pathophysiology of vasospastic angina.

Significance of late gadolinium enhancement in cardiovascular magnetic resonance imaging (CMR).

Cardiovascular magnetic resonance imaging (CMR) permits optimal differentiation between normal and diseased myocardium with the use of gadoliniumbased contrast agents and special magnetic resonance pulse sequences. Imaging is performed 10-20 min after contrast agent application to produce so-called late gadolinium enhancement (LGE) images which depict diseased myocardium with excellent reproducibility. Areas showing LGE correspond to zones of myocyte necrosis or myocardial fibrosis as shown by comparison with histopathology. Typical patterns of hyperenhancement exist in ischemic heart disease but also in dilated cardiomyopathy, hypertrophic cardiomyopathy and other inflammatory or infiltrative myocardial disease and are described in this article. LGE-CMR is helpful to distinguish advanced ischemic heart disease from nonischemic dilated cardiomyopathy. In ischemic heart disease LGE can also predict the functional recovery after revascularization procedures by directly showing the remaining viable myocardium. LGE may also become useful to predict malignant arrhythmias in patients with ischemic heart disease or nonischemic cardiomyopathy. This may lead in future to an increased role of LGE-CMR as a prognostic tool.