[Factors influencing the choice of androgen deprivation therapy for patients with hormone-sensitive prostate cancer : Results of the ProComD study]. / Einflussfaktoren bei der Wahl der Androgendeprivationstherapie für Patienten mit hormonsensitiven Prostatakarzinom : Ergebnisse der ProComD-Studie.

BACKGROUND: Androgen deprivation therapy (ADT) with a GnRH agonist or the GnRH antagonist degarelix is a central component in the treatment of prostate cancer (PCa). Little is currently known regarding the decision criteria. Knowledge of these could improve the success of treatment in the future. OBJECTIVES: To identify factors influencing the treatment decision in patients with hormone-sensitive prostate cancer receiving ADT and to determine the incidence of concomitant disease in both treatment groups. METHODS: The two-arm, prospective, non-interventional study "ProComD" was conducted from September 2014 to June 2019 at 80 study centers in Germany. After the therapy decision was made, patients with hormone-sensitive prostate cancer needing ADT were included in the study. Data were collected during routine visits. RESULTS: Data from 413 patients were evaluated (degarelix N = 268; GnRH agonists N = 145). Key factors influencing the therapy decision for both treatment options included comorbidities (42% of all patients), compliance (64%), and age (81%). The source of information consulted most frequently regarding existing comorbidities was the patient's medical history conducted by the treating urologist themselves (65% in both groups). For patients with pre-existing cardiovascular diseases, the doctor's letter (45.8% degarelix vs. 38.9% GnRH agonists) or the medical history questionnaire (38.9% degarelix vs. 20% GnRH agonists) was additionally taken into account. CONCLUSION: Comorbidities along with age and compliance are among the key factors influencing the treatment decisions made by urologists.

A large aperture row column addressed probe for in vivo 4D ultrafast doppler ultrasound imaging.

Four-dimensional (4D) Ultrafast ultrasound imaging was recently proposed to image and quantify blood flow with high sensitivity in 3D as well as anatomical, mechanical or functional information. In 4D Ultrafast imaging, coherent compounding of tilted planes waves emitted by a 2D matrix array were used to image the medium at high volume rate. 4D ultrafast imaging, however, requires a high channel count (>1000) to drive those probes. Alternative approaches have been proposed and investigated to efficiently reduce the density of elements, such as sparse or under-sampled arrays while maintaining a decent image quality and high volume rate. The row-columns configuration presents the advantage of keeping a large active surface with a low amount of elements and a simple geometry. In this study, we investigate the row and column addressed (RCA) approach with the orthogonal plane wave (OPW) compounding strategy using real hardware limitations. We designed and built a large 7 MHz 128 + 128 probe dedicated to vascular imaging and connected to a 256-channel scanner to implement the OPW imaging scheme. Using this strategy, we demonstrate that 4D ultrafast Power Doppler imaging of a large volume of [Formula: see text] up to [Formula: see text] depth, both in vitro on flow phantoms and in vivo on the carotid artery of a healthy volunteer at a volume rate of 834 Hz.

4D in vivo ultrafast ultrasound imaging using a row-column addressed matrix and coherently-compounded orthogonal plane waves.

4D ultrafast ultrasound imaging was recently shown using a 2D matrix (i.e. fully populated) connected to a 1024-channel ultrafast ultrasound scanner. In this study, we investigate the row-column addressing (RCA) matrix approach, which allows a reduction of independent channels from N × N to N + N, with a dedicated beamforming strategy for ultrafast ultrasound imaging based on the coherent compounding of orthogonal plane wave (OPW). OPW is based on coherent compounding of plane wave transmissions in one direction with receive beamforming along the orthogonal direction and its orthogonal companion sequence. Such coherent recombination of complementary orthogonal sequences leads to the virtual transmit focusing in both directions which results into a final isotropic point spread function (PSF). In this study, a 32 × 32 2D matrix array probe (1024 channels), centered at 5 MHz was considered. An RCA array, of same footprint with 32 + 32 elements (64 channels), was emulated by summing the elements either along a line or a column in software prior to beamforming. This approach allowed for the direct comparison of the 32 + 32 RCA scheme to the optimal fully sampled 32 × 32 2D matrix configuration, which served as the gold standard. This approach was first studied through PSF simulations and then validated experimentally on a phantom consisting of anechoic cysts and echogenic wires. The contrast-to-noise ratio and the lateral resolution of the RCA approach were found to be approximately equal to half (in decibel) and twice the values, respectively, obtained when using the 2D matrix approach. Results in a Doppler phantom and the human humeral artery in vivo confirmed that ultrafast Doppler imaging can be achieved with reduced performances when compared against the equivalent 2D matrix. Volumetric anatomic Doppler rendering and voxel-based pulsed Doppler quantification are presented as well. OPW compound imaging using emulated RCA matrix can achieve a power Doppler with sufficient contrast to recover the vein shape and provides an accurate Doppler spectrum.

[Wine consumption and prevention of coronary artery disease]. / Weingenuss und Prävention der koronaren Herzkrankheit.

There is a J-shaped correlation between the amount of alcohol consumed per day and overall mortality risk and an inverse correlation between the amount of alcohol consumed per day and cardiovascular mortality. The evidence is stronger for men than for women. The correlations are independent of the type of alcoholic beverage predominantly consumed. Possible mechanisms explaining the cardioprotective, antiatherosclerotic effects of moderate alcohol consumption are inhibition of platelet aggregation, increase in serum high density lipoprotein (HDL) levels and prevention of diabetes mellitus. The two latter mechanisms can also explain a delayed progression of atherosclerosis due to alcohol consumption. The beneficial effects are counteracted by detrimental effects of alcohol on the incidence of cancer diseases, liver cirrhosis, violence and accidents; therefore, alcohol consumption in general cannot be recommended for prevention of cardiovascular diseases.

FOLFOX4 versus sequential dose-dense FOLFOX7 followed by FOLFIRI in patients with resectable metastatic colorectal cancer (MIROX): a pragmatic approach to chemotherapy timing with perioperative or postoperative chemotherapy from an open-label, randomized phase III trial.

BACKGROUND: Perioperative FOLFOX4 (oxaliplatin plus 5-fluorouracil/leucovorin) chemotherapy is the current standard in patients with resectable metastases from colorectal cancer (CRC). We aimed to determine whether a sequential chemotherapy with dose-dense oxaliplatin (FOLFOX7) and irinotecan (FOLFIRI; irinotecan plus 5-fluorouracil/leucovorin) is superior to FOLFOX4. The chemotherapy timing was not imposed, and was perioperative or postoperative. PATIENTS AND METHODS: In this open-label, phase III trial, patients with resectable or resected metastases were randomly assigned either to 12 cycles of FOLFOX4 (oxaliplatin 85 mg/m(2)) or 6 cycles of FOLFOX7 (oxaliplatin 130 mg/m(2)) followed by 6 cycles of FOLFIRI (irinotecan 180 mg/m(2)). Randomization was done centrally, with stratification by chemotherapy timing, type of local treatment (surgery versus radiofrequency ablation with/without surgery), and Fong's prognostic score. The primary end point was 2-year disease-free survival (DFS). RESULTS: A total of 284 patients were randomized, 142 in each treatment group. Chemotherapy was perioperative in 168 (59.2%) patients and postoperative in 116 (40.8%) patients. Perioperative chemotherapy was preferentially proposed for synchronous metastases, whereas postoperative chemotherapy was more frequently used for metachronous metastases. Two-year DFS was 48.5% in the FOLFOX4 group and 50.0% in the FOLFOX7-FOLFIRI group. In the multivariable analysis, more than one metastasis [hazard ratio (HR) = 2.15] and synchronous metastases (HR = 1.63) were independent prognostic factors for shorter DFS. Five-year overall survival (OS) rate was 69.5% with FOLFOX4 versus 66.6% with FOLFOX7-FOLFIRI. CONCLUSIONS: FOLFOX7-FOLFIRI is not superior to FOLFOX4 in patients with resectable metastatic CRC. Five-year OS rates observed in both groups are the highest ever reported in this setting, possibly reflecting the pragmatic approach to chemotherapy timing. CLINICAL TRIALS NUMBER: NCT00268398.

FOLFOX in patients with metastatic colorectal cancer and high alkaline phosphatase level: an exploratory cohort of the GERCOR OPTIMOX1 study.

BACKGROUND: Alkaline phosphatase (ALP) is a strong prognostic factor in patients with metastatic colorectal cancer (MCRC). Patients with ALP more than three times the upper limit of normal (ULN) were excluded from our previous studies evaluating chemotherapy. An exploratory cohort of patients with ALP >3 ULN was included in the OPTIMOX1 study. PATIENTS AND METHODS: Previously untreated patients with MCRC were randomized to FOLFOX4 until progression (arm A) or FOLFOX7 for six cycles, maintenance without oxaliplatin for 12 cycles and reintroduction of FOLFOX7 (arm B). Patients were stratified according to ALP level

In-vivo measurements of coronary blood flow using 16-slice multidetector spiral computed tomography (MDCT) in a porcine model.

PURPOSE: To determine whether CTCA supplemented with CT flow measurements can be used to demonstrate and semiquantitatively evaluate poststenotic coronary blood flow in a porcine model. MATERIALS AND METHODS: In 10 thoracotomized pigs, transit time flow meter probes were attached to the aorta and left anterior descending artery (LAD) for real-time blood flow volumetry. A vascular silicone occluder was deployed around the LAD proximal to the probe to create medium-grade (MGS) and high-grade stenoses (HGS). The blood flow was measured by CT without vessel occlusion and distal to the stenoses. Time-density curves were generated from CT data. The curves were evaluated by calculating and cross-plotting the variables "slope of the density increase", "peak density" and "slope of the post-peak density decrease" from the LAD and aortic CT data. RESULTS: The flow in the LAD dropped to 41 % +/- 9 % (mean +/- SD) for MGS and 12 % +/- 6 % for HGS of the baseline. Coronary time-density curves plateaued proportional to luminal narrowing. Unimpaired flow could be differentiated statistically significant from poststenotic flow adjacent to MGS and HGS (p < 0.000 and p < 0.002, respectively). Flow adjacent to MGS and HGS was successfully differentiated for "slope of the density increase" and "slope of the post-peak density decrease" (p < 0.003 and p < 0.030, respectively). CONCLUSION: CT measurements allow semiquantitative evaluation of poststenotic coronary blood flow.

[Severe myocardial infarction due to late and very late stent thrombosis after coronary artery stenting with drug-eluting stents]. / Schwere Myokardinfarkte aufgrund von späten und sehr späten Stentthrombosen nach Implantation medikamentenbeschichteter Koronarstents.

HISTORY AND ADMISSION FINDINGS: Two men, 59 and 65 years old, both with coronary heart disease, were admitted to hospital with acute ST-segment elevation myocardial infarction. They both had undergone coronary artery stenting with drug-eluting stents 9 months and 3 years before, respectively. After stent implantation combined antiplatelet therapy with acetylsalicylic acid and clopidogrel had been administered for 6 and 18 months, respectively. Clopidogrel had been stopped 10 weeks ago in patient 1 and 18 months ago in patient 2. INVESTIGATIONS AND DIAGNOSIS: Cardiac catheterization revealed in both cases the diagnosis of stent thrombosis in the drug-eluting stent. TREATMENT AND COURSE: After successful intervention, both patients were relieved of their symptoms. The total creatinkinase reached a maximum of 4150 U/l and 3185 U/l, respectively, representing severe myocardial infarction in both cases. CONCLUSION: Myocardial infarction is common in patients with a history of coronary artery disease. Especially after coronary artery stenting with drug-eluting stents, severe myocardial infarction due to stent thrombosis may occur late after stent implantation and be independent of changes in antiplatelet therapy. These patients and physicians should therefore be fully aware of this risk and of the crucial importance of antiplatelet therapy after coronary artery stenting.

Phase II study of an optimized 5-fluorouracil-oxaliplatin strategy (OPTIMOX2) with celecoxib in metastatic colorectal cancer: a GERCOR study.

BACKGROUND: Oxaliplatin stop and go in combination with leucovorin and 5-fluorouracil has been successfully used in a previous study (OPTIMOX1) in metastatic colorectal cancer (MCR). Celecoxib is an anti-cyclooxygenase-2 drug with anti-neoplastic properties. In the present study, celecoxib was evaluated in combination with FOLFOX7 regimen and as a single agent in maintenance therapy. PATIENTS AND METHODS: This phase II study examined for previously untreated MCR patients the stop-and-go procedure [six cycles of folinic acid, 5FU and oxaliplatin (FOLFOX7) followed by chemotherapy-free intervals (CFIs) and reintroduction at progression] with continuous administration of celecoxib (800 mg/day). RESULTS: Forty-four patients were included, 42 eligible: performance status (%) 0/1/2=45/40/15, median age 60 (31-76) years. Response rate (RR) was 43% (95% CI 28%-58%). Median progression-free survival (PFS) was 6 months; median overall survival was 15.8 months. Grade 3/4 toxicity criteria were neurotoxicity 9.5%, thrombocytopenia 21.4%, neutropenia 7.1%, diarrhea 7.1%, nausea 4.8% and vomiting 2.4%. Median CFI 1 (n=27) duration was 3.9 months (range 2-39 months). CONCLUSION: With an acceptable safety profile, celecoxib combined with FOLFOX7 achieved RR and PFS in the lower range of that obtained with FOLFOX7 alone. These results indicate the lack of synergy between FOLFOX7 and celecoxib. PFS of 6 months appears lower than PFS obtained in OPTIMOX1 study with simplified LV5FU2 in maintenance therapy.

A phase II study of FOLFIRI-3 (double infusion of irinotecan combined with LV5FU) after FOLFOX in advanced colorectal cancer patients.

In advanced colorectal cancer previously treated with oxaliplatin, efficacy of irinotecan-based chemotherapy is poor and the best regimen is not defined. We designed FOLFIRI-3 and conducted a phase II study to establish its efficacy and safety in advanced colorectal cancer patients previously treated with FOLFOX. FOLFIRI-3 consisted of irinotecan 100 mg m-2 as a 60-min infusion on day 1, running concurrently with leucovorin 200 mg m-2 as a 2-h infusion on day 1, followed by 46-h continuous infusion of 5-fluorouracil (5FU) 2000 mg m-2, and irinotecan 100 mg m-2 repeated on day 3, at the end of the 5FU infusion, every 2 weeks. Sixty-five patients entered the study. The intent-to-treat objective response rate was 23% (95% CI 13-33%). Disease was stable in 37% of patients, progressed in 26% and was not assessable in 14%. From the start of FOLFIRI-3, median progression-free survival was 4.7 months and median survival 10.5 months. Main toxicities (% of patients) were grade 3-4 diarrhoea 23% and grade 4 neutropenia 11%. FOLFIRI-3 is a promising regimen achieving high response rate and progression-free survival in patients previously treated with FOLFOX with a moderate toxicity.

[Adherence to guidelines in CHF therapy in Germany]. / Leitliniengerechte Herzinsuffizienzbehandlung in Deutschland -- Ergebnisse der MAHLER-Studie.

BACKGROUND AND OBJECTIVE: The MAHLER survey examined the impact of the European guidelines for the treatment of chronic heart failure (CHF). Especially, the trial addressed the question whether adherence to treatment guidelines leads to a reduction in the rate of CHF and cardiovascular (CV) hospitalization. The present sub-study presents the Germany specific data of the MAHLER study and compares the results with the results in other European countries. PATIENTS AND METHOD: The gobal adherence index (GAI) shows the proportion of correctly prescribed heart failure medications per patient. Class adherence indicators for angiotensin-converting enzyme (AC)-inhibitors, beta-blockers, spironolactone, diuretics and cardiac glycosides and general adherence indicators (GAI3 adherence to first three classes of heart failure medications, GAI5 adherence to five classes) were constructed. In the German sub-study, 251 patient were included, who were seen by 21 cardiologists in private practice (mean age 68,6 + 10,4 years; 173 man, 78 woman; 158 NYHA II; 91 NYHA III, 2 NYHA IV). RESULTS: Mean adherence to CHF therapy guidelines was 63 % for GAI3, 62 % for GAI5. Compared to the other MAHLER-study countries, Germany was on place two and three concerning GAI3 and GAI5, respectively. Strong adherence to treatment guidelines in Germany led to a reduction of CHF and CV hospitalization rate by 40 % (p < 0.033). Thus, the German data confirm the results of the international study indicating that a good GAI3 performance is an independent predictor of time to hospitalization. Hitherto, the relative risk for hospitalization was higher for CHF patients in Germany than for patients in all other European countries. CONCLUSIONS: In Germany like in other European countries, guideline adherence for CHF therapy leads to a reduction in hospitalization rate.

[Which cardiac patients may be allowed to travel by air?]. / Patient mit Herzproblemen will fliegen. Geben Sie ihm Starterlaubnis?

During airline flights, cardiological patients in particular are put at stress by the decrease in pressure in the passenger cabin and the associated decrease in oxygen partial pressure in the blood. Possible risks are, in particular, rhythm disorders, myocardial ischemic states or an excessive increase in pulmonary artery pressure. Flight travel may be permitted at the earliest two weeks after a myocardial infarction or coronary event. It should be forbidden in patients with decompensated cardiac failure, instable angina pectoris, severe pulmonary arterial or arterial hypertension, uncontrolled arrhythmias and surgery on the heart within a period of 2 weeks prior to the intended flight.

Gemcitabine combined with oxaliplatin in advanced pancreatic adenocarcinoma: final results of a GERCOR multicenter phase II study.

PURPOSE: Based on preclinical in vitro synergy data, this study evaluated the activity and toxicity of a gemcitabine/oxaliplatin combination in patients with metastatic and locally advanced pancreatic adenocarcinoma. PATIENTS AND METHODS: Previously untreated metastatic and locally advanced unresectable pancreatic adenocarcinoma patients were enrolled onto this multicenter phase II study. Patients received gemcitabine 1,000 mg/m(2) as a 10-mg/m(2)/min infusion on day 1 and oxaliplatin 100 mg/m(2) as a 2-hour infusion on day 2 every 2 weeks. Patients with metastatic disease were treated until evidence of progressive disease, whereas patients with locally advanced disease received six cycles in the absence of progression, followed when appropriate by concomitant radiochemotherapy. RESULTS: Among 64 eligible patients included in eight centers, 30 had locally advanced and 34 had metastatic disease. Response rate for the 62 patients with measurable disease was 30.6% (95% confidence interval, 19.7% to 42.3%), 31.0% for locally advanced and 30.3% for metastatic patients. Among 58 assessable patients, 40% had clinical benefit. Median progression-free survival and median overall survival (OS) were 5.3 and 9.2 months, respectively, with 36% of patients alive at 1 year. Median OS for patients with metastatic disease and locally advanced disease were 8.7 and 11.5 months, respectively. With 574 treatment cycles (median per patient, nine; range, zero to 27), grade 3/4 toxicity per patient was 11% for neutropenia and thrombocytopenia, 14% for nausea or vomiting, 6.2% for diarrhea, and 11% for peripheral neuropathy, with no toxic deaths. CONCLUSION: Palliative effects, response rate, and survival observed with this well-tolerated gemcitabine/oxaliplatin combination deserve additional evaluation. A comparative study of combination therapy versus gemcitabine alone is ongoing.

Affect regulation in borderline personality disorder: experimental findings from psychophysiology and functional neuroimaging.

BACKGROUND: Intense and rapidly changing mood states are a major feature of borderline personality disorder (BPD), which is thought to arise from affective vulnerability. OBJECTIVE: There have been only a few studies investigating affective processing in BPD, and particularly neither psychophysiological nor neurofunctional correlates of abnormal emotional processing have been identified so far. METHODS: Studies are reported using psychophysiological or functional neuroimaging methodology. RESULTS: The psychophysiological study did not indicate a general emotional hyperresponsiveness in BPD. Low autonomic arousal seemed to reflect dissociative states in borderline subjects experiencing intense emotions. In the functional magnetic resonance imaging study enhanced amygdala activation was found in BPD, and it is suggested to reflect the intense and slowly subsiding emotions commonly observed in response to even low-level stressors. CONCLUSIONS: Implications for psychotherapy are discussed.

Differential regulation of mitogen-activated protein kinases in the failing human heart in response to mechanical unloading.

Background- Mechanical unloading of the heart with a left ventricular assist device (LVAD) leads to favorable changes in the biology of the failing cardiac myocyte. To determine a potential mechanism for these improvements, we examined the regulation of mitogen-activated protein kinases (MAPKs) in the failing heart in the presence and absence of LVAD support. Methods and Results- We examined the degree of activation (ie, phosphorylation) of p44/42 extracellularly regulated kinase, p38 kinase, and c-Jun N-terminal kinase (JNK1/2), and the corresponding activity levels of these MAPKs in myocardial samples obtained from 11 patients with LVAD support and in 11 patients without LVAD support. MAPK activity was also examined in an additional 6 patients from whom paired samples were obtained before and after LVAD support. The activity of p44/42 and JNK1/2 were reduced significantly, whereas p38 activity levels were significantly increased after LVAD support. We examined functional parameters that are linked to MAPK activation, namely cardiac myocyte hypertrophy and apoptosis. Both cardiac myocyte cell size and the incidence of cardiac myocyte apoptosis were significantly reduced after LVAD support. Conclusions- Mechanical unloading of the failing heart leads to differential regulation of MAPKs. These changes in MAPK activity are associated with changes in myocyte hypertrophy and viability, suggesting a potential mechanistic basis for some of the observed salutary changes after LVAD support.

Emotion in criminal offenders with psychopathy and borderline personality disorder.

BACKGROUND: Criminal offenders with a diagnosis of psychopathy or borderline personality disorder (BPD) share an impulsive nature but tend to differ in their style of emotional response. This study aims to use multiple psychophysiologic measures to compare emotional responses to unpleasant and pleasant stimuli. METHODS: Twenty-five psychopaths as defined by the Hare Psychopathy Checklist and 18 subjects with BPD from 2 high-security forensic treatment facilities were included in the study along with 24 control subjects. Electrodermal response was used as an indicator of emotional arousal, modulation of the startle reflex as a measure of valence, and electromyographic activity of the corrugator muscle as an index of emotional expression. RESULTS: Compared with controls, psychopaths were characterized by decreased electrodermal responsiveness, less facial expression, and the absence of affective startle modulation. A higher percentage of psychopaths showed no startle reflex. Subjects with BPD showed a response pattern very similar to that of controls, ie, they showed comparable autonomic arousal, and their startle responses were strongest to unpleasant slides and weakest to pleasant slides. However, corrugator electromyographic activity in subjects with BPD demonstrated little facial modulation when they viewed either pleasant or unpleasant slides. CONCLUSIONS: The results support the theory that psychopaths are characterized by a pronounced lack of fear in response to aversive events. Furthermore, the results suggest a general deficit in processing affective information, regardless of whether stimuli are negative or positive. Emotional hyporesponsiveness was specific to psychopaths, since results for offenders with BPD indicate a widely adequate processing of emotional stimuli.

Hepatic arterial infusion of cisplatin diluted in hypotonic 25 g/l glucose solution administered in balloon-occluded hepatic artery: experimental rationale and clinical pilot study.

Reduced osmolarity in incubation medium was previously shown to increase in vitro cellular accumulation and cytotoxicity of cisplatin on cancer cells. We confirmed in the present work that cisplatin diluted in an hypotonic 25 g/l glucose solution (124 mOsm) was dramatically more cytotoxic in vitro than cisplatin diluted in normotonic 9 g/l NaCl (300 mOsm) on the human HT29 colon and MCF7 breast cancer cells. We conducted then a pilot clinical study on the administration of cisplatin diluted in hypotonic 25 g/l glucose solution given through the balloon-occluded hepatic artery for the treatment of liver metastases from colon or breast cancer tumors. Nine patients (5 men, 4 women; mean age 58, range: 44-71) with confirmed isolated, unresectable metastases from colorectal (7) or breast (2) tumors were included in this study and a total of 23 cycles were administered (2.55 per patient; range 1-5) with an average dose of 50 mg cisplatin (range: 12.5-100). Hepatic artery dissection due to balloon injury with partial or complete arterial obstruction were encountered in 2 patients. Pain in the liver and epigastric area was the main symptom which was constant and intense during the IAH cisplatin injection. Fever > 38 degrees C was observed in 15/23 cycles and increase of creatinine in 1/23 cycles. Transient increase of hepatic transaminases without change in prothrombin time was registered in all patients. However one patient who received the highest dose of 100 mg cisplatin developed a persistent but reversible clinical jaundice and a transient increase in prothrombin time. One patient achieved a partial response (12 weeks), 7 had stable disease (mean duration: 6 weeks) and one had a progressive disease. Hepatic arterial infusion of cisplatin diluted in hypotonic 25 g/l glucose solution and administered through the balloon-occluded hepatic artery is a feasible approach. Total dose of cisplatin in hypotonic glucose solution will not exceed 80 mg by cure in a further phase II study.

Activation of the cardiac interleukin-6 system in advanced heart failure.

OBJECTIVES: The study objective was to assess the cardiac expression of interleukin-6 (IL6) and its receptor (IL6R) in advanced heart failure. BACKGROUND: While IL6 plasma levels are elevated and associated with an impaired prognosis in advanced heart failure, little is known about the intracardiac expression of the IL6 system. METHODS: Heart tissue was obtained from 20 patients (n=10, idiopathic dilated cardiomyopathy, age 44+/-15 years; n=10, ischemic cardiomyopathy, age 55+/-8 years) at the time of transplantation. Left and right ventricular tissue was subjected to in situ hybridization, Northern blot analysis, and RT-PCR. Signals were quantified by densitometric scanning and corrected for G3PDH-mRNA levels. Right ventricular biopsy specimens (n=11) of patients with arrhythmias and normal cardiac function served as controls. In addition, data were correlated with cardiac catheterization and echocardiography data obtained at transplant evaluation. RESULTS: Ventricular IL6 and IL6R transcripts were detected in all explant specimens examined. Expression of both mRNA species was higher than in controls (P=0.001). Left ventricular IL6 mRNA levels correlated positively with heart rate (r=0.77; P=0.009), pulmonary capillary wedge pressure (r=0.53; P=0.03), right atrial pressure (r=0.77; P=0.003), and inversely with left ventricular ejection fraction (r=-0.61; P=0.03). Right ventricular IL6 mRNA levels correlated inversely with cardiac index (r=-0.48; P=0.05). IL6R expression did not correlate with hemodynamic data. CONCLUSIONS: In advanced heart failure, cardiac IL6/IL6R mRNA expression is increased and may play a role in the pathophysiology of advanced heart failure.

Phase II trial of bimonthly leucovorin, 5-fluorouracil and gemcitabine for advanced pancreatic adenocarcinoma (FOLFUGEM).

BACKGROUND: Gemcitabine alone or 5-fluorouracil (5-FU) according to several schedules are used for palliation of metastatic and locally advanced (LA) pancreatic adenocarcinoma. This study was designed to test the efficacy of the leucovorin 5-FU and gemcitabine combination. PATIENTS AND METHODS: This phase II trial combined a simplified bimonthly LV5FU2 with gemcitabine: leucovorin 400 mg/m2 in a two-hour infusion, followed by 5-fluorouracil 400 mg/m2 bolus and 2 or 3 g/m2 continuous infusion over 46 hours; gemcitabine 1 g/m2 was infused over 30 min on day 3 after 5-FU. Treatment was repeated every two weeks. Gemcitabine dose could be increased (250 mg/m2 every two cycles up to 1500 mg/m2) in the absence of NCI-CTC toxicity > 2. RESULTS: Among the 62 patients included in this study, 22 had LA and 40 had metastatic disease. Objective response rate for the 54 patients with measurable disease was 25.9% (95% confidence interval (CI): 14%-37.8%) and 22.6% (95% CI: 12%-33.2%) in the intent-to-treat population: the clinical benefit rate for the 59 assessable patients was 49.2%. Median progression-free survival and median overall survival were 4.8 and 9 months, respectively, with 32.3% of patients alive at 1 year. The most frequent toxicity (grade 3-4) was neutropenia (56.5%) usually asymptomatic (1.1% febrile neutropenia), but requiring decreases of 5-FU and gemcitabine doses. Unexpected complete alopecia occurred in 97% of patients. CONCLUSIONS: Palliative effects, response rate and survival observed in this multicenter study seem to be superior to those obtained with gemcitabine or 5-FU alone, despite a limiting hematological toxicity.