Adherence of Heart Transplant Recipients to Prescribed Medication and Recommended Lifestyle Habits.

INTRODUCTION: Nonadherence may cause severe health problems in heart transplant (HTx) recipients. RESEARCH QUESTIONS: The present study aimed to investigate adherence to prescribed medication and recommended lifestyle habits in post-HTx patients and to assess associations between adherence, quality of life (QOL), and psychological well-being. DESIGN: A questionnaire package was sent to all HTx patients from our clinic (n = 858) to answer questions anonymously on medication adherence, dietary recommendations (avoidance of raw animal products and ice cream), pet keeping (risk of zoonosis), anxiety and depression, QOL, and posttraumatic stress disorders. RESULTS: Of the contacted patients, 524 (61%) responded and 505 fulfilled the inclusion criteria (age ≥18 years and ability to understand German). Of the study participants, 72.4% reported taking their medications very correctly, 72.2% stated consuming alcohol less often than once a week, 58.3% performed physical exercise at least once a week, one-third reported eating nonrecommended foods, 22.1% stated pet keeping, and 4.3% reported smoking. Adherence to prescribed medication was positively associated with age ( P < .001) and mental QOL ( P = .015) but was unrelated to eating nonrecommended foods ( P > .05). Depressiveness correlated inversely with physical QOL ( r = -0.232; P < .01) and mental QOL ( r = -0.411; P < .01). Stress disorders and minor stressful events were reported by 7.8% and 46.6%, respectively. Stress disorders correlated inversely with mental QOL ( r = -0.282; P < .01) and physical QOL ( r = -0.422; P < .01). DISCUSSION: Many HTx patients adhere to prescribed medications and health advice. Nevertheless, nonadherence is a problem, especially in younger HTx patients, indicating the need for a nonadherence crisis intervention program for long-term HTx patients.

Synthesis, chemical behavior, structure elucidation and iNOS inhibitory activity of 1-substituted 3-methylsulfanyl-5,6,7,8-tetrahydro-1H-[1,2,4]triazolo[1,2-a]pyridazines.

Novel slim and shapely sp3-rich nitrogen containing heterocyclic ring systems are sought-after platforms for the expansion of molecular diversity in lead discovery. The present work describes the synthesis and characterization of a series of derivatives of hitherto unknown 3-methylsulfanyl-5,6,7,8-tetrahydro-1H-[1,2,4]triazolo[1,2-a]pyridazines 2. This approach was guided by a computational study, aiming at an optimization of previously reported [1,2,4]triazolo[1,2-a]pyridazine-1-thiones 1 known to inhibit the inducible nitric oxide synthase (iNOS). The title compounds are accessible by methylation of compounds 1 under mild conditions. The products were biologically evaluated by the same cell-based assay as applied for previous products of type 1 using RINm5F cells, which were stimulated to produce NO on the influence of proinflammatory cytokines IL-1ß and IFN-γ. Compounds 2 did not display the anticipated improved iNOS inhibitory activity in the selected assay but contribute to SAR in the field. In addition, an unprecedented formation of side-products 3 via oxidation has been investigated. The novel scaffolds represent attractive starting points for the construction of diverse molecules which differ considerably from known compounds based on flat and lipophilic aromatic scaffolds.

Aspects of fish conservation in the upper Patos Lagoon basin.

The Patos Lagoon basin is a large (201 626 km(2) ) and complex drainage system in southern Brazil. The lagoon is 250 km long and 60 km wide, covering an area of 10 360 km(2) . The exchange of water with the Atlantic Ocean occurs through a 0·8 km wide and 15 m deep inlet, fixed by 4 km long jetties, at the southernmost part of the Patos Lagoon. The estuarine area is restricted to its southern portion (10%), although the upper limit of saline waters migrates seasonally and year to year, influenced by the wind regime and river discharge. The known number of recorded limnetic fish species is 200, but this number is expected to increase. A higher endemism is observed in fish species occurring in upper tributaries. The basin suffers from the direct impact of almost 7 million inhabitants, concentrated in small to large cities, most with untreated domestic effluents. There are at least 16 non-native species recorded in natural habitats of the Patos Lagoon basin, about half of these being from other South American river basins. Concerning the fishery, although sport and commercial fisheries are widespread throughout the Patos Lagoon basin, the lagoon itself and the estuarine area are the main fishing areas. Landing statistics are not available on a regular basis or for the whole basin. The fishery in the northern Patos Lagoon captures 31 different species, nine of which are responsible for most of the commercial catches, but only three species are actually sustaining the artisanal fishery: the viola Loricariichthys anus: 455 kg per 10 000 m(2) gillnet per day, the mullet Mugil liza: 123 kg per 10 000 m(2) gillnet per day and the marine catfish Genidens barbus: 50 kg per 10 000 m(2) gillnet per day. A decline of the fish stocks can be attributed to inadequate fishery surveillance, which leads to overfishing and mortality of juveniles, or to decreasing water quality because of urban and industrial activities and power production. Global climatic changes also represent a major threat to the Patos system by changing the frequency of El Niño-La Niña-Southern Oscillation (ENSO).

[Heart and combined heart-lung transplantation. Indications, chances and risks]. / Herz- und Herz-Lungen-Transplantation. Indikationen, Chancen, Risiken.

Orthotopic heart transplantation (HTX) is nowadays the worldwide accepted gold standard for the treatment of terminal heart failure. The main indications for HTX are non-ischemic dilatative (54%) and ischemic (37%) heart failure. In the acute phase after HTX the survival rate is approximately 90%. Good short and long-term results with survival rates ranging from 81% after 1 year to more than 50% after 11 years demonstrate that there is currently no real treatment alternative to HTX for treatment of end-stage heart failure. In the case of irreversible pulmonary hypertension in combination with end-stage heart failure or complex congenital heart syndromes, a combined heart and lung transplantation (HLTX) is necessary. Compared with HTX the short-term survival of HLTX is reduced, mostly for technical reasons. Improved long-term results after HTX and HLTX are a result of highly specialized transplantation units and effective immunosuppression. However, a major problem is the shortage of organ donors in Germany and the resulting long waiting times for patients with frequently occurring blood groups of up to 10 months for transplantation. The consequence of the latter is the ever increasing number of implanted cardiac assist devices in patients not only as a bridge to transplant but also as destination therapy.

Synthesis and structure elucidation of 2,3,5,6,7,8-hexahydro-1 H-[1,2,4]triazolo[1,2-a]pyridazine-1-thione, 3,3-disubstituted and 2-substituted derivatives and evaluation of their inhibitory activity against inducible nitric oxide synthase.

The 3-monosubstituted 2,3,5,6,7,8-hexahydro-1 H-[1,2,4]triazolo[1,2-a]pyridazine-1-thiones 3 (R1, R3 = H) were recently reported to possess inhibitory activity against inducible nitric oxide synthase in a cell based assay (Schulz et al. 2013). The 3,3-disubstituted 2,3,5,6,7,8-hexahydro-1H-[1,2,4]triazolo[1,2-a]pyridazine-1-thiones 3 and 4 (R2,R3 ≠ H) were synthesized by cyclocondensation of the hexahydropyridazine-1-carbothioamides 1 with ketones. In order to access the 3,3-unsubstituted 2,3,5,6,7,8-hexahydro-1H-[1,2,4]triazolo[1,2-a]pyridazine-1-thiones, the unsubstituted parent system of these compounds, several synthetic routes were studied. By these methods the desired heterocyclic system 2a as well as new a-anellated and N-substutited hexahydropyridazines were obtained. The biological evaluation of the title compounds confirmed the previously made finding that an aromatic moiety in position 3 of the substance is important for an inducible nitric oxide synthase (iNOS) inhibitory activity.

[Pulmonary capillary blood volume and membrane components of pulmonary diffusion capacity in patients with chronic obstructive bronchitis (COPD)]. / Pulmonales kapilläres Blutvolumen und Membrankomponente der pulmonalen Diffusionskapazität bei Patienten mit chronisch obstruktiver Bronchitis (COPD).

Reduced pulmonary diffusion capacity is a hallmark of COPD, although the relative contribution of the subcomponents of pulmonary diffusion--membranous component (Dm) and capillary volume (Vc)--is unknown. These components can be measured with the method of NO single-breath diffusion (DLNO). In a prospective study, pulmonary function tests including spirometry, body plethysmography and single-breath measurements of diffusion capacity with CO and NO were performed in 183 patients with COPD of varying severity. There was a severity-dependent decrease in DLCO. Furthermore, Dm as well as Vc was positively correlated with the severity of COPD measured by FEV1. In all stages of COPD, reduction of Vc was more pronounced than constriction of Dm. In patients with most severe COPD, the preponderance of the reduction of Vc was significantly more marked than in milder stages.We conclude that Dm as well as Vc contributes to the reduction of DLCO in COPD, with a predominance of Vc at all stages of COPD. This confirms the idea that the loss of pulmonary capillaries in COPD is functionally relevant.

Far from urban areas: plastic uptake in fish populations of subtropical headwater streams.

This study investigated the occurrence of plastic particles in the digestive tracts of fish from headwater streams in a human-thinly populated region of the subtropical Sinos River basin in southern Brazil. In total, 258 individuals from 17 species were collected using electric fishing. Thirty-eight percent (38%) of the specimens contained plastic particles. All of them were fibers, with a maximum count of 43 per individual. Plastic fibers were the fourth most abundant food category. Results showed that the uptake of these plastic particles was proportional to the number of ingested food items. Fiber counts in the guts correlated with the uptake of Trichoptera, which are invertebrates using plastic particles to construct their protective cases. No significant difference in plastic uptake was detected between benthic and water column fish. No evidence of bioaccumulation of plastic particles was found in the intestines. The distance from urban areas was not related to the number of ingested plastic particles, concluding that plastics are ubiquitous and available to biota, even in remote locations. The most probable source of these particles is residences close to the streams which discharge the sewage of washing machines without any treatment.

Bosentan effects on hemodynamics and clinical outcome in heart failure patients with pulmonary hypertension awaiting cardiac transplantation.

BACKGROUND: In heart failure (HF) patients, pulmonary hypertension (PH) is associated with a poor prognosis. We assessed whether low dose treatment with the dual endothelin-1 receptor antagonist bosentan is associated with improved hemodynamics and clinical outcome in these patients. METHODS: We performed a retrospective data analysis in 82 end-stage heart failure patients on the waiting list for cardiac transplantation since January 2006. All patients had pulmonary arterial pressure >35 mmHg, pulmonary vascular resistance >240 dyn × s × cm-5, and/or a transpulmonary gradient (TPG) >15 mmHg. Fifty-four patients received a median dose of 125 mg bid bosentan (BOS group), and 28 patients received standard medical treatment (CON group). Data were assessed until June 2009. RESULTS: Hemodynamic parameters improved significantly in the BOS group but remained unchanged in the CON group. The percentage of patients who fell below the thresholds of PAP, PVR, and TPG for cardiac transplantation increased significantly by 20.3%, 34.5%, and 20.8%, respectively (p = 0.007-0.013) in the BOS group, but did not change significantly in the CON group. One-year survival on the waiting list was approximately 20% higher in the BOS group than in the CON group (p = 0.020). Bosentan treatment remained an independent predictor of reduced mortality risk on the waiting list after propensity score adjustment (relative risk = 0.107; 95% CI: 0.013-0.869; p = 0.036). CONCLUSION: Treatment with the endothelin-1 antagonist bosentan is associated with improvements in hemodynamics and clinical outcome in end-stage heart failure patients with PH. If these results can be confirmed by randomized controlled trials, bosentan may represent a treatment option in these patients.

Interleukin-10 promotes NK cell killing of autologous macrophages by stimulating expression of NKG2D ligands.

Under inflammatory conditions, the pleiotropic cytokine interleukin-10 (IL-10) is released in many tissues. It mediates anti-inflammatory effects in particular by inhibiting the release of T helper type 1 (Th1) cytokines. In contrast, we show here that NK cell cytotoxicity against autologous macrophages is elevated if both cell types are cultured with IL-10. The expression of most activatory NK receptors is increased after culture in the presence of IL-10. On the other hand, macrophages cultured in the presence of IL-10 show elevated expression of the NKG2D ligands major histocompatibility complex (MHC) class 1-like molecules (MIC) - A and - B, as well as UL-16 binding proteins (ULBP) - ULBP-1, ULBP-2 and ULBP-3. By masking the interaction of NK cells with macrophages through interruption of the NKG2D receptor with its ligands, we could reverse the IL-10-induced lysis of macrophages. Our data therefore reveal that IL-10 may exert a novel immunomodulatory role by stimulating NKG2D ligand expression on macrophages, thereby rendering them susceptible to NK cell elimination. This suggests that NK cells would delete macrophages and potentially other immature antigen-presenting cells (APC) or their precursors under inflammatory conditions as a feedback mechanism to shut off uncontrolled immune responses.

Clinical significance of lymphoid hyperplasia of the lower gastrointestinal tract.

Lymphoid hyperplasia of the intestine has been associated with multiple diseases and symptoms. This study was undertaken to analyze the number and topographical distribution of the lymphoid follicles. A total of 302 adult consecutive patients were enrolled when they underwent elective colonoscopy. Standardized pictures from terminal ileum and colon were taken using video colonoscopes. In each picture, the number, size, and mucosal elevation of lymphoid follicles were analyzed in relation to histological and immunological findings and medical history. Lymphoid hyperplasia was found to be most extensive in the terminal ileum and cecum. Patients with untreated gastrointestinally mediated allergy (GMA) showed the highest number of lymphoid follicles per visible field in the terminal ileum ( P < 0.001) and cecum ( P = 0.003) vs. the control group. Patients with infectious colitis also showed a high number of lymphoid follicles per endoscopic visible field in the transverse colon ( P = 0.020). The presence of lymphoid hyperplasia is a frequent finding during colonoscopy. It may indicate an enhanced immunological mucosal response to antigenic stimulation such as GMA or infection.

Caspofungin for post solid organ transplant invasive fungal disease: results of a retrospective observational study.

OBJECTIVE: This study was designed to determine clinical outcomes with caspofungin in patients with proven or probable invasive fungal infection (IFI) after a solid organ transplant (SOT) procedure. METHODS: In this retrospective observational study, data were collected for a single episode of IFI in patients with an SOT between January 2004 and June 2007. Response was determined by the investigator as favorable (complete or partial) or unfavorable (stable disease or failure) at the end of caspofungin therapy (EOCT). The primary effectiveness population was the proportion of patients who received >or=5 doses of caspofungin (modified all-patients-treated population). Safety was assessed for patients who received >or=1 dose of caspofungin. RESULTS: A total 81 of patients from 13 sites in China, Germany, Italy, and the United Kingdom were enrolled, including 49 (60%) liver, 22 (27%) heart, 5 (6%) lung, 2 (2%) kidney, 2 (2%) liver and kidney, and 1 (1%) pancreas and kidney recipients. Candidiasis was diagnosed in 64/81 patients (79%) and aspergillosis in 22/81 patients (27%). Most patients received caspofungin monotherapy (75%). Caspofungin was given as first-line therapy to 59 (73%) patients. The overall favorable response at EOCT was 87% (58/67; 95% confidence interval [CI]: 76%, 94%), with favorable responses in 88% (43/49; 95% CI: 75%, 95%) of patients receiving caspofungin monotherapy and 83% (15/18; 95% CI: 59%, 96%) of patients receiving combination therapy with caspofungin (modified all-patients-treated population). Response by type of SOT was as follows: liver 87% (39/45), heart 93% (14/15), kidney 100% (5/5), and lung 50% (2/4). An overall survival rate (all-patients-treated) of 69% (56/81; 95% CI: 59%, 79%) was observed at 7 days post EOCT. No serious drug-related adverse events were reported. CONCLUSION: In this study, caspofungin was effective and well tolerated in the treatment of IFIs involving SOT recipients.

[Caspofungin after solid organ transplantation in Germany: observational study on treatment of invasive fungal infections]. / Caspofungin nach Transplantation solider Organe in Deutschland: Beobachtungsstudie zur Behandlung invasiver Pilzinfektion.

BACKGROUND: This study was a pre-planned country-specific secondary analysis of results in Germany from a multinational multicenter observational study to retrospectively evaluate clinical outcomes with caspofungin in patients with probable and proven invasive fungal infection following solid organ transplantation (SOT). METHODS: Data were retrospectively collected on a single episode of invasive fungal infection (IFI) in patients who had a SOT between January 2004 and June 2007. Effectiveness was reported as the proportion of patients who received at least five doses of caspofungin with a favorable (complete or partial) response. Safety was assessed for patients who received at least one dose of caspofungin. Descriptive statistics were employed for all evaluations. RESULTS: A total of 41 SOT patients (27 male, 14 female; median age 56 years, median APACHE II score at start of caspofungin therapy 23) were enrolled from 5 sites in Germany. Organs transplanted were mainly heart (51%) and liver (46%). Prevalent risk factors for IFI at baseline were use of central venous catheter (37 out of 41 patients, 90%), steroid use (37 out of 41 patients, 90%), recent stay in intensive care (36 out of 41 patients, 88%),and duration of SOT procedure >5 hours (21 out of 41 patients, 51%). Candidiasis was diagnosed in 34 patients (83%) and aspergillosis in 10 patients (24%). The lungs were the most common site of IFI (21 out of 41, 51%). Caspofungin as monotherapy was received by 28 patients (68%); 6 patients (15%) received caspofungin as salvage therapy for IFI, in most cases because they were refractory to prior antifungal drugs. Immunosuppressants were administered with caspofungin in 39 out of 41 patients (95%). In subjects with at least 5 doses of caspofungin (modified intention to treat population) the favorable response rate at the end of caspofungin therapy was 88% overall, 29 out of 33 patients; 95% confidence interval (95%-CI) 72-97%), 86% (19 out of 22 patients) with monotherapy and 91% (10 out of 11 patients) with combination therapy. No (serious) adverse events or drug interactions related to treatment with caspofungin were reported. The overall survival rate was 79% (26 out of 33 patients; 95%-CI 61-91%) at 7 days after completion of caspofungin treatment. CONCLUSION: Caspofungin was found to be an effective treatment of probable and proven invasive fungal infections in patients following SOT in Germany.

Wideband antireflection coatings by combining interference multilayers with structured top layers.

The residual reflectance obtained for a broad wavelength range depends mainly on the refractive index of the last layer. Using interference layer stacks composed of naturally available low- and high-index materials, the residual reflection for a broad range cannot be adjusted below a certain limit. However, nanostructured (gradient) and porous layers are effective media with a refractive index lower than that of natural materials. Results demonstrate that an interference layer stack combined with a structured layer as the last layer yields better antireflection properties owing to the low effective index of the structure.

Association between cortical metabolite levels and clinical manifestations of migrainous aura: an MR-spectroscopy study.

Previous studies suggest an abnormal cerebral cortical energy metabolism in migraineurs. If causally related to the pathophysiology of migraine, these abnormalities might show a dose-response relationship with the duration and severity of aura symptoms. While such a trend has been suggested in phosphorus spectroscopy (31P-MRS) studies, it has not been considered in proton spectroscopy (1H-MRS) studies and it has not been studied in cerebral white matter. We aimed to determine whether for any of the metabolites measured by 31P-MRS or 1H-MRS there was a dose-response relationship with aura duration and severity, and whether such an association was also present in cerebral white matter. We studied patients with migraine with aura and healthy controls with 31P-MRS and with 1H-MRS. We measured metabolite ratios in grey and in white matter and in the patients, we related metabolite levels to the clinical characteristics and duration of the aura. In patients, the phosphocreatine/phosphate (PCr/Pi) ratio decreased significantly with increasing aura duration and was significantly lower in patients with hemiplegic migraine than in patients with non-motor aura. Overall the metabolite ratios did not differ significantly between patients and controls, but compared with controls the PCr/Pi ratio in patients with hemiplegic migraine and in patients with persistent aura >7 days was significantly lower. These changes were only present in grey matter. Results for 1H-MRS did not differ significantly between patients and controls, and they showed no association with duration or severity of symptoms. In this study, metabolite ratios differed significantly between patients with different aura phenotypes and with increasing aura duration. In addition, only in some patient subgroups were metabolite ratios significantly different from controls. These findings support the concept that migraine with aura is a heterogeneous disorder with distinct pathophysiological subtypes. They further suggest that rather than determining the susceptibility to developing a migraine attack, changes in cortical energy metabolism may determine the clinical manifestations of the migrainous aura once an attack has started.

Antireflection of transparent polymers by advanced plasma etching procedures.

Self-organized nanostructures that provide antireflection properties grow on PMMA caused by plasma ion etching. A new procedure uses a thin initial layer prior to the etching step. Different types of antireflective structures can now be produced in a shorter time and with fewer limitations on the type of polymer that can be used. The durability of the structured surfaces can be improved by the deposition of additional thin films.

Evolution of the diffusion-weighted signal and the apparent diffusion coefficient in the late phase after minor stroke: a follow-up study.

INTRODUCTION: Diffusion-weighted imaging (DWI) is mainly used in acute stroke, and signal evolution in the acute phase has been studied extensively. However, patients with a minor stroke frequently present late. Recent studies suggest that DWI may be helpful at this stage, but only very few published data exist on the evolution of the DW-signal in the weeks and months after a stroke. We performed a follow-up study of DWI in the late stages after a minor stroke. METHODS: 28 patients who presented 48 hours to 14 days after a minor stroke underwent serial MRI at baseline, 4 weeks, 8 weeks, 12 weeks, 6 months and>or=9 months after their event. Signal intensity within the lesion was determined on T2-weighted images, DW-images and the Apparent Diffusion Coefficient (ADC) map at each time-point, and ratios were calculated with contralateral normal values (T2r, DWIr, ADCr). RESULTS: T2r was increased in all patients from the beginning, and showed no clear temporal evolution. ADCr normalized within 8 weeks in 83% of patients, but still continued to increase for up to 6 months after the event. The DW-signal decreased over time, but was still elevated in 6 patients after>or=6 months. The evolution of ADCr and DWIr showed statistically highly significant inter-individual variation (p<0.0001), which was not accounted for by age, sex, infarct size or infarct location. CONCLUSION: The ADC and the DW-signal may continue to evolve for several months after a minor ischaemic stroke. Signal evolution is highly variable between individuals. Further studies are required to determine which factors influence the evolution of the ADC and the DW-signal.

Economic evaluation of everolimus and mycophenolate mofetil versus azathioprine in de novo heart transplantation.

UNLABELLED: Both the proliferation signal inhibitor everolimus (1.5 mg/day) and mycophenolate mofetil (MMF) (3 g/day) have shown superior efficacy versus azathioprine in de novo heart transplantation. The cost-effectiveness of everolimus and MMF versus azathioprine was assessed to 6 months posttransplantation. METHODS: The evaluation was performed from the German health insurance payer perspective. The composite efficacy endpoint in the everolimus trial was death, graft loss/retransplantation, biopsy-proven acute rejection (BPAR) grade>or=3A, rejection with hemodynamic compromise, and loss to follow-up. The composite endpoint in the MMF trial included only death, retransplantation, and BPAR with hemodynamic compromise. To mimic the everolimus endpoint, an estimated number of patients with BPAR>or=3A was added to the MMF trial results, using two mapping scenarios. RESULTS: The incremental 6-month cost versus azathioprine was euro2535 for everolimus and euro3007 for MMF. The absolute reduction in efficacy failure versus azathioprine was 10.4% for everolimus and 9.8% and 10.1% for MMF, respectively, using scenarios 1 and 2. The incremental cost per efficacy failure avoided (ie, the incremental cost versus azathioprine divided by the reduction in efficacy failure) was euro24,457 for everolimus, and euro30,628 and euro29,912 for MMF in scenarios 1 and 2. CONCLUSION: This analysis, based on findings from two clinical trials, suggested that everolimus was more cost-effective than MMF versus azathioprine in the first 6 months after heart transplantation. Data from a head-to-head trial are required to confirm these results.

Cardiac surgery after heart transplantation: coronary artery bypass grafting and heart valve replacement.

INTRODUCTION: Due to increasing need for and a shortage of donor organs, therapeutic procedures such as heart valve replacement for valve insufficiency and coronary artery bypass grafting (CABG) for graft vasculopathy (GVP) must be performed to improve allograft function to avoid retransplantation. METHODS: We performed a retrospective analysis of patients who underwent surgical procedures after orthotopic heart transplantation. Since 1989, we have performed more than 1400 heart transplantation procedures. Valve replacement was necessary in 8 patients and CABG was necessary in 3 patients. Five patients received valve prostheses (3 bioprostheses and 2 mechanical valves) at the tricuspid position. Three patients received a Hancock bioprosthesis at the mitral position. One of the 3 received the valve 3 years after heart transplantation while suffering from mitral regurgitation grade IV, and another patient received the valve 1 year following heart transplantation while suffering from mitral insufficiency grade III due to infective endocarditis. Three patients underwent coronary artery revascularization, 2 patients underwent the procedure 1 and 7 years after heart transplantation because of GVP, 1 patient underwent the procedure simultaneously with heart transplantation because of donor coronary artery disease. One patient received concomitant CABG with heart transplantation because of 75% left anterior descending stenoses in the donor organ, and one patient received CABG 1 year after heart transplantation because of rapidly progressive GVP in the left anterior descending artery. The third patient had 3-vessel disease with 95% left stem and 75% ramus circumflex, ramus marginalis, and ramus diagonalis. RESULTS: Two patients who underwent CABG and 4 patients who underwent valve replacement are still alive and maintain good clinical performance. One patient with a graft at the mitral position died 9 years after heart transplantation and 6 years after mitral valve replacement. Two patients with a graft at the tricuspid position died 17 and 4 years after heart transplantation (6 and 3 years after valve replacement, respectively). One patient with a bioprostheses at the tricuspid position had to be retransplanted 2 years following valve replacement while suffering from a paravalvular leakage grade III. CONCLUSION: Cardiac surgical procedures can be safely performed after heart transplantation. To improve graft and patient survival, such procedures must be carefully performed after heart transplantation to avoid retransplantation. The shortage of donor organs will and must lead to an increase in the number of conventional procedures performed to improve allograft function in transplanted hearts.

Communicative reprogramming non-curative hepatocellular carcinoma with low-dose metronomic chemotherapy, COX-2 inhibitor and PPAR-gamma agonist: a phase II trial.

Systemic therapy for advanced hepatocellular carcinoma (HCC) is still challenging. A biomodulatory therapy approach targeting the communicative infrastructure of HCC, including metronomic low-dose chemotherapy with capecitabine, pioglitazone and rofecoxib, has been evaluated in patients with non-curative HCC. Altogether 38 patients were evaluable in this one-arm, multicenter phase II trial. The primary endpoint, median progression-free survival was 2.7 months (95% CI: 1.6-3.79) for all evaluable patients and 8.4 months (95% CI: 0-18.13) for patients ≥ 6 weeks on protocol. Median overall survival (OS) was 6.7 months (95% CI: 4.08-9.31) and 9.4 months (95% CI: 4.82-13.97), respectively. Most common adverse events were edemas grade 3, which were commonly related to the advanced stage, with 66% of the patients suffering from liver cirrhosis. Exploratory data analyses showed significant impact of ECOG performance status grade 0 versus 1 and CLIP score 0/1 versus > 1 on OS, 9.8 months (95% CI: 4.24-15.35) versus 2.7 months (95% CI: 1.03-4.36; P = 0.002), and 9.8 months (95% CI: 3.23-16.37) versus 4.4 months (95% CI: 3.14-5.66; P = 0.009), respectively. Preceding tumor surgery had significant beneficial impact on survival, as well as maximal tumor diameter of < 5 cm. The correlation of C-reactive protein decrease with significantly improved OS underlines the close link between inflammation and tumor control. Biomodulatory therapy in advanced HCC may be a low toxic, efficacious treatment and principally demonstrates that such approaches should be followed further for treatment of advanced HCC.