Zoledronic acid combined with adjuvant endocrine therapy of tamoxifen versus anastrozol plus ovarian function suppression in premenopausal early breast cancer: final analysis of the Austrian Breast and Colorectal Cancer Study Group Trial 12.

BACKGROUND: Zoledronic acid (ZOL) plus adjuvant endocrine therapy significantly improved disease-free survival (DFS) at 48- and 62-month follow-up in the ABCSG-12 trial. We present efficacy results of a final additional analysis after 94.4 months. PATIENTS AND METHODS: Patients were premenopausal women who had undergone primary surgery for stage I/II estrogen-receptor-positive and/or progesterone-receptor-positive breast cancer with <10 positive lymph nodes, and were scheduled for standard goserelin therapy. All 1803 patients received goserelin (3.6 mg every 28 days) and were randomized to tamoxifen (20 mg/days) or anastrozole (1 mg/days), both with or without ZOL (4 mg every 6 months) for 3 years. The primary end point was DFS; recurrence-free survival and overall survival (OS) were secondary end points. RESULTS: After 94.4-month median follow-up (range, 0-114 months), relative risks of disease progression [hazard ratio (HR) = 0.77; 95% confidence interval (CI) 0.60-0.99; P = 0.042] and of death (HR = 0.66; 95% CI 0.43-1.02; P = 0.064) are still reduced by ZOL although no longer significant at the predefined significance level. Overall, 251 DFS events and 86 deaths were reported. Absolute risk reductions with ZOL were 3.4% for DFS and 2.2% for OS. There was no DFS difference between tamoxifen alone versus anastrozole alone, but there was a pronounced higher risk of death for anastrozole-treated patients (HR = 1.63; 95% CI 1.05-1.45; P = 0.030). Treatments were generally well tolerated, with no reports of renal failure or osteonecrosis of the jaw. CONCLUSION: These final results from ABCSG 12 suggest that twice-yearly ZOL enhances the efficacy of adjuvant endocrine treatment, and this benefit is maintained long-term. CLINICALTRIALSGOV: NCT00295646 (http://www.clinicaltrials.gov/ct2/results?term=00295646).

Validation of the prognostic relevance of plasma C-reactive protein levels in soft-tissue sarcoma patients.

BACKGROUND: The concept of the involvement of systemic inflammation in cancer progression and metastases has gained attraction within the past decade. C-reactive protein (CRP), a non-specific blood-based marker of the systemic inflammatory response, has been associated with decreased survival in several cancer types. The aim of the present study was to validate the prognostic value of pre-operative plasma CRP levels on clinical outcome in a large cohort of soft-tissue sarcoma (STS) patients. METHODS: Three hundred and four STS patients, operated between 1998 and 2010, were retrospectively evaluated. CRP levels and the impact on cancer-specific survival (CSS), disease-free survival (DFS) and overall survival (OS) were assessed using Kaplan-Meier curves and univariate as well as multivariate Cox proportional models. Additionally, we developed a nomogram by supplementing the plasma CRP level to the well-established Kattan nomogram and evaluated the improvement of predictive accuracy of this novel nomogram by applying calibration and Harrell's concordance index (c-index). RESULTS: An elevated plasma CRP level was significantly associated with established prognostic factors, including age, tumour grade, size and depth (P<0.05). In multivariate analysis, increased CRP levels were significantly associated with a poor outcome for CSS (HR=2.05; 95% CI=1.13-3.74; P=0.019) and DFS (HR=1.88; 95% CI=1.07-3.34; P=0.029). The estimated c-index was 0.74 using the original Kattan nomogram and 0.77 when the plasma CRP level was added. CONCLUSION: An elevated pre-operative CRP level represents an independent prognostic factor that predicts poor prognosis and improves the predictive ability of the Kattan nomogram in STS patients. Our data suggest to further prospectively validate its potential utility for individual risk stratification and clinical management of STS patients.

Efficacy of tamoxifen ± aminoglutethimide in normal weight and overweight postmenopausal patients with hormone receptor-positive breast cancer: an analysis of 1509 patients of the ABCSG-06 trial.

BACKGROUND: There exists evidence that body mass index (BMI) impacts on the efficacy of aromatase inhibitors in patients with breast cancer. The relationship between BMI and the efficacy of tamoxifen is conflicting. We investigated the impact of BMI on the efficacy of single tamoxifen and tamoxifen plus an aromatase inhibitor in the well-defined prospective study population of the ABCSG-06 trial. METHODS: ABCSG-06 investigated the efficacy of tamoxifen vs tamoxifen plus aminoglutethimide in postmenopausal women with hormone receptor-positive breast cancer. Taking BMI at baseline, patients were classified as normal weight (BMI=18.5-24.9 kg m(-)(2)), overweight (BMI=25-29.9 kg m(-)(2)), and obese (30 kg m(-)(2)) according to WHO criteria. RESULTS: Overweight+obese patients had an increased risk for distant recurrences (hazard ratio (HR): 1.51; Cox P=0·018) and a worse overall survival (OS; HR: 1·49; Cox P=0·052) compared with normal weight patients. Analysing patients treated with single tamoxifen only, no difference between overweight+obese patients and normal weight patients regarding distant recurrence-free survival (HR: 1.35; Cox P=0·24) and OS (HR: 0.99; Cox P=0·97) could be observed. In contrast, in the group of patients treated with the combination of tamoxifen plus aminoglutethimide, overweight+obese patients had an increased risk for distant recurrences (1.67; Cox P=0·03) and a worse OS (1.47; Cox P=0·11) compared with normal weight patients. CONCLUSION: BMI impacts on the efficacy of aromatase inhibitor-based treatment but not single tamoxifen.

Absence of indigenous specific West Nile virus antibodies in Tyrolean blood donors.

In the last several years, West Nile virus (WNV) was proven to be present especially in the neighboring countries of Austria, such as Italy, Hungary, and the Czech Republic, as well as in eastern parts of Austria, where it was detected in migratory and domestic birds. In summer 2010, infections with WNV were reported from Romania and northern Greece with about 150 diseased and increasingly fatal cases. We tested the sera of 1,607 blood donors from North Tyrol (Austria) and South Tyrol (Italy) for antibodies against WNV by using IgG enzyme-linked immunosorbent assay (ELISA). Initial results of the ELISA tests showed seroprevalence rates of 46.2% in North Tyrol and 0.5% in South Tyrol, which turned out to be false-positive cross-reactions with antibodies against tick-borne encephalitis virus (TBEV) by adjacent neutralization assays. These results indicate that seropositivity against WNV requires confirmation by neutralization assays, as cross-reactivity with TBEV is frequent and because, currently, WNV is not endemic in the study area.

[Water birthing: retrospective review of 2625 water births. Contamination of birth pool water and risk of microbial cross-infection]. / Partorire in acqua: esperienza dopo 2.625 parti in acqua. Contaminazione dell'acqua nella vasca da parto e rischio di infezione con diversi microrganismi.

UNLABELLED: The aim of this study was to document the practice of 2625 water births at Vipiteno over the period 1997-2009 and compare outcome and safety with normal vaginal delivery. The microbial load of the birth pool water was analyzed, and neonatal infection rates after water birth and after land delivery were compared. Methods. The variables analyzed in the 1152 primiparae were: length of labor; incidence of episiotomies and tears; arterial cord blood pH and base excess values; percentage of pH<7.10 and base excess values >/=12 mmol/L. In all 2625 water births, the variables were: analgesic requirements; shoulder dystocia/ neonatal complications; and deliveries after a previous caesarean section. Bacterial cultures of water samples obtained from the bath after filling (sample A) and after delivery (sample B) were analyzed in 300 cases. The pediatricians recorded signs of suspected neonatal infection after water birth and after conventional vaginal delivery. RESULTS: There was a marked reduction in labor duration in the primiparae who birthed in water; the episiotomy rate was 0.46%. Owing to the pain relieving effect of the warm birth pool water, pain relievers (opiates) were required in only 12.9% of water births. Arterial cord blood pH and base excess values were comparable in both groups. Shoulder dystocia/neonatal complications were managed in 4 water births; 105 women with a previous caesarean section had a water birth. In sample A, the isolated micro-organisms were Legionella spp. and Pseudomonas aeruginosa; in sample B, there was elevated colonization of birth pool water by total coliform bacilli and Escherichia coli. Despite microbial contamination of birth pool water during delivery, antibiotic prophylaxis, as indicated by clinical and laboratory suspicion of infection, was administered to only 0.98% of babies after water birth versus 1.64% of those after land delivery. CONCLUSIONS: Results suggest clear medical advantages of water birthing: significantly shorter labor duration among the primiparae; a net reduction in episiotomy rates; and a marked drop in requests for pain relievers. During expulsion of the fetus at delivery, fecal matter is released into the birth pool water, contaminating it with micro-organisms. Despite this, water birthing was found to be safe for the neonate and did not carry a higher risk of neonatal infection when compared with conventional vaginal delivery.

Foreign rectal body - Systematic review and meta-analysis.

BACKGROUND: Self-inserted foreign rectal bodies are an infrequent occurrence, however they present a serious dilemma to the surgeon, due to the variety of objects, and the difficulty of extraction. The purpose of this study is to give a comprehensive review of the literature regarding the epidemiology, diagnostic tools and therapeutic approaches of foreign rectal body insertion. METHODS: A comprehensive systematic literature review on Pubmed/ Medline and Google for 'foreign bodies' was performed on January 14th 2018. A meta-analysis was carried out to evaluate the epidemiology, diagnostics and therapeutic techniques. 1,551 abstracts were identified, of which 54 articles were included. RESULTS: The motivation of foreign rectal body insertion is mostly sexual stimulation. Patients are typically young and predominantly male, with a male to female ratio of 6:1. Sexual devices (35.7%, n=108) and glass objects (17.5%, n=53) are the most commonly self-inserted rectal foreign bodies. Patient history should be taken sensitively after diagnostic evaluation and identification of the object. Removal was performed under general anesthesia in 45.2% (n=95) and sedation in 29.0% (n=61). The total complication rate was described to be 30.4%. CONCLUSIONS: Diagnostics must be performed with caution in order to rule out perforation and establish a treatment algorithm. Manual transanal extraction under sedation or general anesthesia may be performed in conjunction with cautious abdominal compression. Because of the variety of objects, i.e. in form and material, each case must be treated individually. Sometimes creativity and surgeon imagination may be required, although different algorithms have been established.

Ventral recumbency is crucial for fast and safe orotracheal intubation in laboratory swine.

The aim of this study was to find the fastest, easiest and safest method of achieving orotracheal intubation for general anaesthesia in laboratory pigs. Twenty-one Yorkshire x Landrace crossbreed male castrated pigs (32.9 +/- 4.8 kg) were investigated. Dorsal and ventral recumbency are the alternatives most frequently described for animal positioning during intubation procedures. Based on standardized induction of general anaesthesia using pentobarbital and remifentanil, the dorsoventral and ventrodorsal positions were compared with regard to the time needed, changes in oxygenation and circulatory response. Positioning was found to be crucial for fast orotracheal intubation. The time required for safe intubation is significantly shorter with the ventrodorsal position (17.3 s) in comparison with the dorsoventral position (58.4 s; P < 0.001). Hypoxia did not occur in either group. A significant drop in systolic blood pressure was observed in both groups. Diastolic and mean arterial pressures were not influenced by intubation. A significant increase in heart rate was observed in pigs intubated in ventral recumbency, but not after intubation in the dorsal position. Preoxygenation before intubation is vitally important for preventing hypoxia. With regard to clinical practice, the haemodynamic changes observed in this investigation do not appear to be relevant, as the mean arterial pressure was not altered and heart rates only increased moderately. It may be concluded that the ventrodorsal position can be recommended for orotracheal intubation in pigs as the first choice for providing a smooth and fast airway.

[Giving birth in the water: experience after 1,825 water deliveries. Retrospective descriptive comparison of water birth and traditional delivery methods]. / Gebären im Wasser: Erfahrung nach 1825 Wassergeburten. Retrospektiv deskriptive Vergleichsanalyse zwischen Wassergeburten und traditionellen Geburtsmodalitäten.

OBJECTIVE: We reviewed 1,825 water births at a single institution over a 9-year period. METHODS: We compared 830 primipara deliveries in water with 424 primipara deliveries in the traditional bed and 136 on the delivery stool. We also evaluated the duration of labour, arterial cord blood pH and base excess in the primiparae, and perineal trauma, shoulder dystocia and deliveries after preceding caesarean section as well as rates of neonatal infection in all the 1,825 water births. RESULTS: The duration of the first stage of labour was significantly shorter with water births than with the other delivery positions. The episiotomy rate for all water births was found to be much lower compared to deliveries carried out in the bed or on the birthing stool. The rate of perineal tears was similar. There were no differences in the duration of the second stage, arterial cord blood pH and base excess. No woman using the water birth method required analgesics. There were 3 shoulder dystocias with water births. Sixty-eight women delivered in water after a preceding caesarean section. CONCLUSION: Water births appears to be associated with a significantly shorter first stage of labour, a lower episiotomy rate and reduced analgesic requirements when compared with other delivery positions. If women are selected appropriately, water birth appears to be safe for both the mother and neonate.

[Water contamination and infection rate after water births]. / Die Kontamination des Wassers und die Infektionsrate bei der Wassergeburt.

OBJECTIVE: This study aimed at examining the water of the birthing tub for pathogenic germs and at comparing the infection rates of the children born conventionally. METHOD: In a prospective study, the germs found in the water of 300 water births were determined . The tub water was sampled twice: sample A was taken after filling the tub with tap water, sample B after the water delivery. In addition, the paediatrician documented any signs of infection of the neonates during their hospital stay. RESULTS: The A samples contained Legionella in 29%, Pseudomonas aeruginosa in 22%, enterococci in 18%, colibacilli in 32% and Escherichia coli in 8%. After fitting a filter system, no Legionella was detected any more. P. aeruginosa was found in only 3% of the samples. In the B samples, we found an increased contamination by colibacilli in 81%. A marked burden with E. coli was detected in 58% of the samples. Due to a clinically an biochemically suspected beginning infection, 1.15% of the water-born children (14 out of 1,215) were given antibiotics. In contrast, 2.30% of the conventionally born neonates (19 out of 817) were treated with antibiotics. CONCLUSION: It is evident that during the bearing-down phase faeces are discharged into the birthing tube and that the water is contaminated mainly by E. coli and colibacilli, but also slightly by Staphylococcus aureus. The contamination of the tap water by Legionella and Pseudomonas could clearly be reduced by installation of a filter system into the supply hose of the birthing tub. Neonatal infections were not more frequent after water births than after conventional deliveries.

Review of 1600 water births. Does water birth increase the risk of neonatal infection?

OBJECTIVES: We reviewed 1600 water births at a single institution over an 8-year period. METHODS: We compared 737 primiparae deliveries in water with 407 primiparae deliveries in bed, and 142 primiparae on the delivery stool. We also evaluated the duration of labor, perineal trauma, arterial cord blood pH, postpartum maternal hemoglobin levels, and rates of neonatal infection. In 250 water deliveries we performed bacterial cultures of water samples obtained from the bath after filling and after delivery. RESULTS: The duration of the first stage of labor was significantly shorter with a water birth than with a land delivery (380 vs. 468 minutes, P<0.01). The episiotomy rate in all water births was lower with a water birth than with a delivery in bed or a delivery on the birthing stool (0.38%, 23%, and 8.4%, respectively). The rate of perineal tears was similar (23%, respectively). There were no differences in the duration of the second stage (34 vs. 37 minutes), arterial cord blood pH, or postpartum maternal hemoglobin levels. No woman using the water birth method required analgesics. The rate of neonatal infection was also not increased with a water birth (1.22% vs. 2.64%, respectively). CONCLUSION: Water birth appears to be associated with a significantly shorter first stage of labor, lower episiotomy rate and reduced analgesic requirements when compared with other delivery positions. If women are selected appropriately and hygiene rules are respected, water birth appears to be safe for both the mother and neonate.

Effects of selective iNOS inhibition on gut and liver O2-exchange and energy metabolism during hyperdynamic porcine endotoxemia.

We have previously demonstrated that non-selective nitric oxide synthase (NOS) inhibition did not reverse the LPS-induced deterioration of hepato-splanchnic energy status in porcine endotoxic shock. Therefore, this study investigated the effect of selective inducible NOS (iNOS) inhibition using 1400 W on intestinal and liver perfusion, O2 kinetics, and energy metabolism during hyperdynamic porcine endotoxemia. Intravenous E. Coli LPS was continuously infused over 24 h concomitant with fluid resuscitation. After 12 h of endotoxemia, continuous intravenous infusion of 1400 W was started until the end of the experiment and was titrated to maintain mean blood pressure (MAP) at baseline levels. Twelve, 18, and 24 h after starting LPS, we measured hepatic arterial and portal venous blood flow, ileal mucosal-arterial PCO2 gap, portal as well as hepatic venous lactate/pyruvate ratios, and endogenous glucose production rate. Expired NO and plasma nitrate levels were assessed as a measure of NO production. 1400 W decreased LPS-induced increase in expired NO and allowed for the maintenance of MAP without modification of cardiac output. Despite unchanged regional macrocirculation, 1400 W prevented the progressive rise of ileal mucosal-arterial PCO2 gap, significantly improved the LPS-induced impairment of hepato-splanchnic redox state, and blunted the decline in liver lactate clearance. Increased glucose production rate was not influenced. Thus, the selective iNOS inhibition with 1400 W prevented circulatory failure and largely attenuated otherwise progressive LPS-induced deterioration of intestinal and hepatocellular energy metabolism.

Effects of combined selective iNOS inhibition and peroxynitrite blockade during endotoxemia in pigs.

We investigated the effect of mercaptoethylguanidine (MEG, 3 mg kg(-1)h(-1)), a combined selective inducible nitric oxide synthase (iNOS) inhibitor, a peroxynitrite and oxygen free radical scavenger with cyclooxygenase-inhibitor properties on intestinal and hepatic perfusion, O2 exchange, and metabolism during long-term hyperdynamic porcine endotoxemia. MEG was started 12 h after onset of endotoxemia. At baseline and after 12, 18, and 24 h of endotoxemia, hepatic arterial and portal venous blood flow, ileal mucosal-arterial PCO2 gap, portal and hepatic venous lactate/pyruvate ratio, free glutathione (GSH), and 8-isoprostanes were measured. Expired NO and plasma nitrate levels were assessed as well. MEG blunted the endotoxin-induced increase in expired NO and prevented the progressive fall in blood pressure without affecting cardiac output. It attenuated both systemic and regional venous acidosis without influencing the impairment of hepatosplanchnic metabolism nor counteracting the increase in GSH levels. In our model MEG failed to beneficially affect variables of oxidative stress.

Lung recruitment maneuver in patients with cerebral injury: effects on intracranial pressure and cerebral metabolism.

OBJECTIVE: To investigate the effects of a lung recruitment maneuver on intracranial pressure (ICP) and cerebral metabolism in patients with acute cerebral injury and respiratory failure. DESIGN: Prospective investigation. SETTING: Ten-bed intensive care unit of a university hospital. PATIENTS: Eleven patients with acute traumatic or non-traumatic cerebral lesions, who were on mechanical ventilation with acute lung injury. INTERVENTIONS: Hemodynamics, ICP, cerebral perfusion pressure (CPP), jugular venous oxygen saturation (SJO(2)), and arterial minus jugular venous lactate content difference (AJDL) were measured before, during and after a volume recruitment maneuver (VRM), which included a 30-s progressive increase in peak pressure up to 60 cmH(2)O and a sustained pressure at the same level for the next 30 s. RESULTS: At the end of VRM, ICP was elevated (16+/-5 mmHg vs 13+/-5 mmHg before VRM, P<0.05) and mean arterial pressure was reduced (75+/-10 vs 86+/-9 mmHg, P<0.01), which resulted in a decrease of CPP (60+/-10 vs 72+/-8 mmHg, P<0.01). SJO(2) deteriorated at the end of the procedure (59+/-7 vs 69+/-6%, P<0.05), AJDL was not altered. In the following period all parameters returned to normal values. An improvement in arterial oxygenation was observed at the end, but not in the period after the maneuver. CONCLUSIONS: Our VRM reduced cerebral hemodynamics and metabolism. We conclude that our VRM with high peak pressure effects only a marginal improvement in oxygenation but causes deterioration of cerebral hemodynamics. We therefore cannot recommend this technique for the ventilatory management of brain-injured patients.

Effects of nicotinamide, an inhibitor of PARS activity, on gut and liver O2 exchange and energy metabolism during hyperdynamic porcine endotoxemia.

OBJECTIVE: To investigate the effects of nicotinamide (NIC), an inhibitor of poly(ADP-ribose) synthetase (PARS), on intestinal and liver perfusion, O2 kinetics, and energy metabolism over 24 h of hyperdynamic porcine endotoxemia. DESIGN: Prospective, randomized, controlled experimental study with repeated measures. SETTING: Animal laboratory in a university hospital. SUBJECTS: Sixteen pigs, divided into two groups: nine endotoxemic animals without therapy (CON); seven animals treated with NIC. INTERVENTIONS: Pigs were anesthetized, mechanically ventilated, and instrumented. Intravenous E. Coli LPS was continuously infused over 24 h concomitant with fluid resuscitation. After 12 h of endotoxemia continuous i.v. infusion of NIC (10 mg/kg per hour) was administered until the end of the experiment. MEASUREMENTS AND RESULTS: All animals developed hyperdynamic circulation with sustained increase in cardiac output and progressive fall in mean arterial pressure. NIC maintained blood pressure without affecting CO. Hepato-splanchnic macrocirculation was not modified by the treatment. Nevertheless, although NIC attenuated the progressive rise of ileal mucosal-arterial PCO2 gap, it failed to improve portal venous L/P ratio, a marker of the overall energy state of the portal venous drained viscera. Similarly, neither the increased hepatic venous L/P ratio nor the simultaneous drop in hepatic lactate uptake were influenced by NIC. CONCLUSIONS: Although NIC maintained hemodynamic stabilization during long-term endotoxemia, it was unable to improve LPS-induced deterioration of the hepato-splanchnic energy metabolism. More potent and selective PARS inhibitors are needed to elucidate the role of a PARS-dependent pathway in a clinically relevant models of sepsis.

Effect of combining nicotinamide as a PARS-inhibitor with selective iNOS blockade during porcine endotoxemia.

OBJECTIVE: To investigate the effects of combined selective inducible nitric oxide synthase (iNOS) inhibition using 1400 W with nicotinamide (NAD) as a PARS-inhibitor on hepato-splanchnic hemodynamics, O(2) kinetics, and energy metabolism during hyperdynamic porcine endotoxemia. DESIGN: Prospective, randomized, controlled, interventional experiment. SETTING: Animal research laboratory. SUBJECTS: Seventeen domestic pigs. INTERVENTIONS: After 12 h of continuous i.v. endotoxin (LPS) infusion 17 pigs received either no drug (CON, n=9) or 1400 W, titrated to maintain mean arterial pressure (MAP) at pre-endotoxin level, plus 10 mg.kg.h NAD ( n=8;). Measurements were obtained before, 12 h, 18 h, and 24 h after starting LPS infusion. MEASUREMENTS AND RESULTS: In addition to systemic and pulmonary hemodynamics and gas exchange, we measured hepatic arterial and portal venous blood flow, liver and portal venous drained viscera O(2) exchange, ileal mucosal-arterial PCO(2) gap, and portal as well as hepatic venous lactate/pyruvate ratios. Expired NO and plasma nitrate levels were assessed as a parameter of NO production. Without affecting cardiac output, therapy maintained MAP and blunted the LPS-induced rise in expired NO levels, attenuated the progressive fall in liver lactate clearance, and blunted the impairment of hepato-splanchnic redox state. The rise of ileal mucosal-arterial PCO(2) gap was not influenced. CONCLUSIONS: Combining selective iNOS inhibition with NAD as a PARS blocker may prevent circulatory failure and attenuate the detrimental consequences of LPS in intestinal and hepatocellular energy metabolism. Given the potential hepatotoxicity of high-dose NAD treatment, more potent PARS blockers with higher selectivity might further enhance the benefit of this therapeutic approach.

Increased ileal-mucosal-arterial PCO2 gap is associated with impaired villus microcirculation in endotoxic pigs.

OBJECTIVE: To investigate whether an increased ileal-mucosal-arterial PCO2 gap (delta PCO2) during hyperdynamic porcine endotoxemia is associated with impaired villus microcirculation. DESIGN: Prospective, randomized, controlled, experimental study. SETTING: Animal research laboratory. ANIMALS: Twenty-two domestic pigs. INTERVENTIONS: After baseline measurements, anesthetized and ventilated pigs received continuous i.v. endotoxin (ETX, n = 12) for 24 h or placebo (SHAM, n = 10). MEASUREMENTS AND RESULTS: Before, as well as 12 and 24 h after, the start of endotoxin or saline portal venous blood flow (QPV, ultrasound flow probe) and lactate/pyruvate ratios (L/P), the ileal-mucosal-arterial delta PCO2 (fiberoptic sensor) and bowel-wall capillary hemoglobin O2 saturation (%Hb-O2-cap, remission spectrophotometry) were assessed together with intravital video records of the ileal-mucosal microcirculation (number of perfused/heterogeneously perfused/unperfused villi) using orthogonal polarization spectral imaging (CYTOSCAN A/R) via an ileostomy. At 12 and 24 h endotoxin infusion, about half of the evaluated villi were heterogeneously or unperfused which was paralleled by a progressive significant increase of the ileal-mucosal-arterial delta PCO2 and portal venous L/P ratios, whereas QPV as well as both the mean %Hb-O2-cap and the %Hb-O2-cap frequency distributions remained unchanged. By contrast, in the SHAM-group, mucosal microcirculation was well-preserved, and none of the other parameters were influenced. CONCLUSIONS: We conclude that an increased ileal-mucosal-arterial delta PCO2 during porcine endotoxemia is related to impaired villus microcirculation. A putative contribution of disturbed cellular oxygen utilization resulting from "cytopathic hypoxia" may also assume importance.

Weekly 5-fluorouracil and high-dose folinic acid in combination with epidoxorubicin as first-line therapy in advanced breast cancer: a phase II study.

A total of 25 patients with advanced breast cancer were treated weekly with i.v. 5-fluorouracil at 350 mg/m2, folinic acid at 500 mg/m2, and epidoxorubicin at 35 mg/m2 as first-line chemotherapy for a maximum of 18 cycles. In all, 24 patients were evaluable for response. Overall, 1 patient achieved a complete response and 11 patients showed a partial response, for an objective response rate of 50%; the median duration of response was 18.3+ months and median survival amounted to 18.8+ months. Side effects were generally mild, with grade II leukopenia occurring in 10 patients and grade III leukopenia, in 1 patient. Other toxicity included nausea and vomiting (82%), diarrhea (48%), stomatitis (48%), and alopecia (92%), all of which were mainly restricted to WHO grades I and II. Our results suggest that leucovorin modulation of 5-fluorouracil can safely be incorporated into combination chemotherapy with epidoxorubicin on the investigated schedule. The observed response rate appears comparable with that obtained with other first-line regimens.

A phase I/II study of 4'-O-tetrahydropyranyl-doxorubicin, 5-fluorouracil, and high-dose leucovorin as first-line therapy in advanced breast cancer patients.

A total of 50 patients were treated weekly with 5-fluorouracil (FU), leucovorin (LV), and 4'-O-tetrahydropyranyl-doxorubicin (THP) as first-line chemotherapy for advanced breast cancer (ABC). In phase I the doses of LV (500 mg/m2, day 1) and FU (350 mg/m2, day 1) were held constant, while the dose of THP (day 1) was escalated, from the initial dose of 10 mg/m2 up to the maximum tolerated dose (MTD). Twenty-eight patients entered phase I, and MTD for THP was defined as 35 mg/m2 in this combination. Dose-limiting toxicities were myelosuppression and hepatotoxicity. In phase II, another 22 patients were treated with THP at a dose level of 30 mg/m2. Including 4 patients already treated at this dose in the first part, 25 patients were evaluable for response: 1 patient obtained a complete response (CR) and 13 showed a partial response (PR), giving an objective response rate of 56%. The median duration of response was 9.1+ months and median survival, 15.5+ months. Side effects were generally mild, with ECOG grade I and II leukopenia in 51% of all cycles and grade III in 3% of the courses. Other toxicity included nausea and vomiting (54% and 8%, respectively) and alopecia (24%), all restricted to ECOG grade I and II. Our results suggest that weekly THP/LV-FU represents an active regimen for first-line treatment of ABC with relative low toxicity.

[Breast cancer in the man: a report of 30 patients]. / Das Mammakarzinom des Mannes: Ein Bericht über 30 Patienten.

A retrospective review of male patients suffering from breast cancer seen over an 18-year period was carried out at the Department of Clinical Oncology of the University Hospital of Graz. Thirty evaluable cases were analysed. Eight patients had Stage I, 11 had Stage II, 8 had Stage III, and 3 had Stage IV disease. Local control was achieved in the majority, 29/30 (97%), by either surgery alone or combined surgery and radiation therapy. Local recurrence developed in 2 (7%) patients. Further 7 (23%) patients developed distant metastases and were treated in accordance with policies developed for the appropriate stage of the disease in females, with hormonal manipulation for hormone receptor-positive and -unknown patients and chemotherapy for hormone receptor-negative patients. The corrected five-year survival (Kaplan-Meier) is 83% for the entire group, 100% for patients with Stage I disease, 86% in Stage II, and 67% in Stage III and IV disease, respectively. This corresponds well with the results in recently published series. Stage of disease at initial presentation was a significant factor determining survival in our investigation. Our own data as well as recent data from literature suggest that with respect to TNM Stages in mammary carcinoma, there is no prognostic difference between men and women. To what extent improved local control by adequate local therapy or systemic adjuvant treatment modalities may improve overall survival remains to be discussed.

The Austrian experience with trabectedin in non-selected patients with metastatic soft tissue sarcoma (STS).

PURPOSE: The purpose of this retrospective analysis was to assess efficacy and tolerability of trabectedin in soft tissue sarcoma (STS) in the routine clinical setting. PATIENTS AND METHODS: Efficacy and safety data of trabectedin were retrospectively evaluated in patients with advanced STS who had started treatment with trabectedin at six institutions in Austria between January 2008 and May 2012. RESULTS: Data of 101 adult patients were included in the present analysis. Patients had a median age of 56 years; 59 and 41% received trabectedin as ≤2nd and ≥3rd chemotherapy line for advanced disease, respectively. Median progression-free survival (PFS) and overall survival (OS) were 3.9 and 11.6 months. Median PFS and OS were different in patients who received trabectedin as ≤2nd- or ≥3rd-line treatment: median PFS was 3.9 versus 3.6 months and OS was 15.2 versus 24.8 months, respectively. The extent and severity of trabectedin-induced toxicity were low and manageable. CONCLUSIONS: The activity and tolerability of trabectedin in the routine clinical setting is comparable to outcomes reported in phase II trials already published. Regardless of whether trabectedin was given earlier or later in the course of disease, outcomes did not differ in the cohort of analysed patients.