The REMAR (Rhein-Main-Registry) real-world study: prospective evaluation of the 21-gene breast recurrence score® assay in addition to Ki-67 for adjuvant treatment decisions in early-stage breast cancer.

PURPOSE: Ki-67 is recommended by international/national guidelines for risk stratification in early breast cancer (EBC), particularly for defining "intermediate risk," despite inter-laboratory/inter-observer variability and cutoff uncertainty. We investigated Ki-67 (> 10%- < 40%, determined locally) as a prognostic marker for intermediate/high risk in EBC, pN0-1 patients. METHODS: This prospective, non-interventional, real-world study included females ≥ 18 years, with pN0/pN1mi/pN1, HR+ , HER2-negative EBC, and locally determined Ki-67 ranging 10%-40%. The primary outcome was changes in treatment recommendations after disclosing the Oncotype DX Breast Recurrence Score®(RS) assay result. RESULTS: The analysis included 567 patients (median age, 57 [range, 29-83] years; 70%/1%/29%/ with pN0/pN1mi/pN1 disease; 81% and 19% with RS results 0-25 and 26-100, respectively). The correlations between local and central Ki-67, local Ki-67, and the RS, and central Ki-67 and the RS results were weak (r = 0.35, r = 0.3, and r = 0.46, respectively), and discrepancies were noted in both directions (e.g., local Ki-67 was lower or higher than central Ki-67). After disclosing the RS, treatment recommendations changed for 190 patients (34%). Changes were observed in pN0 and pN1mi/pN1 patients and in patients with centrally determined Ki-67 ≤ 10% and > 10%. Treatment changes were aligned with RS results (adding chemotherapy for patients with higher RS results, omitting it for lower RS results), and their net result was 8% reduction in adjuvant chemotherapy use (from 32% pre-RS results to 24% post-RS results). CONCLUSION: The Oncotype DX® assay is a tool for individualizing treatments that adds to classic treatment decision factors. The RS result and Ki-67 are not interchangeable, and Ki-67, as well as nodal status, should not be used as gatekeepers for testing eligibility, to avoid under and overtreatment.

Early initiation of MARS® dialysis in Amanita phalloides-induced acute liver injury prevents liver transplantation.

 Amanita phalloides is the most relevant mushroom intoxication leading to acute liver failure. The two principal groups of toxins, the amatoxins and the phallotoxins, are small oligopeptides highly resistant to chemical and physical influences. The amatoxins inhibit eukaryotic RNA polymerase II causing transcription arrest affecting mainly metabolically highly active cells like hepatocytes and renal cells. The clinically most characteristic symptom is a 6-40 h lag phase before onset of gastrointestinal symptoms and the rapid progression of acute liver failure leading to multi-organ failure and death within a week if left untreated. Extracorporeal albumin dialysis (ECAD) was reported to improve patient's outcome or facilitate bridging to transplantation. In our tertiary center, out of nine intoxicated individuals from five non-related families six patients presented with acute liver injury; all of them were treated with ECAD using the MARS® system. Four of them were listed on admission for high urgency liver transplantation. In addition to standard medical treatment for Amanita intoxication we initiated ECAD once patients were admitted to our center. Overall 16 dialysis sessions were performed. All patients survived with full native liver recovery without the need for transplantation. ECAD was well tolerated; no severe adverse events were reported during treatment. Coagulopathy resolved within days in all patients, and acute kidney injury in all but one individual. In conclusion, ECAD is highly effective in treating intoxication with Amanita phalloides. Based on these experiences we suggest early initiation and repeated sessions depending on response to ECAD with the chance of avoiding liver transplantation.

Ring drape do not protect against surgical site infections in colorectal surgery: a randomised controlled study.

INTRODUCTION: Surgical site infections (SSIs) remain a major problem in colorectal surgery. METHOD: In this prospective, randomised study, we compared two kinds of wound protection, namely, "plastic ring drape" versus "standard cloth towels". One hundred one patients were randomised to the control group (wet cloth towels) and 98 to the study cohort (ring drape). SSIs were classified according to Centers for Disease Control and Prevention recommendations. DISCUSSION: In the control group, 30 patients had an SSI, whereas 20 did so in the study group. This difference was not significant (p = 0.131). CONCLUSION: Plastic ring drape for wound protection does not guard against SSIs in colorectal surgery.

Subcutaneous Redon drains do not reduce the incidence of surgical site infections after laparotomy. A randomized controlled trial on 200 patients.

PURPOSE: Surgical site infections (SSI) cause excess morbidity and mortality in modern surgery. Several different approaches to reduce the incidence of SSI have been investigated with variable results. METHOD: This is to our knowledge the first systematic randomized evaluation in patients undergoing laparotomy in visceral surgery to clarify whether widely used subcutaneous drains (Redon) affect wound infection as the primary outcome measure. RESULTS: In 200 patients, we were unable to show a statistically significant impact on the postoperative healing process in patients with the full variety of abdominal surgical interventions. Overall, we observed surgical site infection in 9.5% of all patients (n = 19), of these n = 9 (47.4%) were in the control group without a drain, and 10 (52.6%) were in the experimental group with a Redon drain (not significant). CONCLUSION: As this study could not demonstrate a reduction of SSI by the use of Redon drains, there is no indication for prophylactic subcutaneous suction drains after laparotomy.

Regeneration of older patients after oncologic surgery. A temporal trajectory of geriatric assessment and quality of life parameters.

AIMS: The effectiveness of surgery depends on it being carried out safely, which allows patients to return to independent lives. Because gastrointestinal cancers are a major cause of morbidity and mortality in older people, we examined the dynamics of recuperation after elective, curative surgery. As disease parameters alone may not suffice to address geriatric patients' issues after onco-surgical interventions, Comprehensive Geriatric and QOL Assessments (CGA/QOL) were performed at four time points to gain information on clinical, functional, and cognitive aspects. METHODS: CGA/QOL including standard geriatric instruments, socio-demographic, clinical data, and the EORTCQLQ-C30 questionnaire were applied pre-operatively (T1), at discharge (T2), after three (T3), and after six months (T4). RESULTS: 200 patients gave their informed consent, 70 patients declined. At T1 n = 195, at T2 n = 155, at T3 n = 130, and at T4 n = 124 patients were actually assessed. Patients experienced a significant decline in most functional capabilities and increased symptoms at T2. While most parameters re-approached baseline results by T4, sophisticated abilities (instrumental ADL, IADL) remained impaired. Fatigue was the most prominent symptom that persisted in many at T4. Risk for malnutrition as well as BMI significantly decreased during regeneration. Global QOL correlated with parameters of independence (ADL, IADL) and low symptom burden. Role and social functions' correlation with global QOL increased from T1 to T4. CONCLUSIONS: Longitudinal assessments before and after oncologic surgery highlight changes even after six months in QOL and independence that may be ameliorated by focused supportive care. Trial registry number: DRKS: 00000425.

Effects of creatine supplementation on nutritional status, muscle function and quality of life in patients with colorectal cancer--a double blind randomised controlled trial.

BACKGROUND & AIM: Nutritional status frequently deteriorates during chemotherapy in cancer. This is associated with a poor outcome. Since creatine supplementation has shown promising results in various diseases, we investigated the effects of creatine on nutritional status in patients with colorectal cancer undergoing chemotherapy. METHODS: Thirty patients with colorectal cancer undergoing chemotherapy were randomised to receive either creatine (n=16) or placebo (n=15) for 8 weeks. Body composition was determined with bioelectrical impedance analysis; muscle function by hand grip, hip flexion and knee extension strength and quality of life (QoL) was assessed by the QLQ30 questionnaire. RESULTS: Neither muscle function, body cell mass (BCM) nor QoL improved, but phase angle, a marker of BCM and cell integrity, increased significantly in the intervention patients (5.3+/-0.3 degrees to 5.4+/-0.2 degrees , P=0.030). Evaluating patients with different chemotherapy regimens, however, only intervention patients undergoing less aggressive chemotherapy were shown to benefit, increasing phase angle (5.11+/-0.22 degrees to 5.51+/-0.30 degrees , P=0.043) as well as BCM (27.22+/-2.85 to 29.60+/-3.54kg, P=0.043). CONCLUSION: Creatine failed to improve muscle mass or function and QoL in colorectal cancer patients but improved bioimpedance parameters that are predictive of poor outcome. Creatine might therefore be useful in patients with milder chemotherapy in order to maintain or increase BCM whereas patients undergoing aggressive chemotherapy however are not likely to benefit.

Cytokine expression in colon carcinoma.

BACKGROUND: Cytokines reflect the activity of the immune system. We analyzed the local expression of characteristic cytokines indicating the level of activity of unspecific inflammatory cells, Th1-cells and Th2-cells in colon cancer. MATERIALS AND METHODS: In 25 tumor/ mucosa pairs, IL-1alpha, IL-2, IL-4, IL-5, IL-15, TNF-alpha and IFN-gamma were measured by real-time PCR. RESULTS: There was a significant increase in IL-1alpha, IL-4, IL-5 and TNF-alpha and a significant decrease in IL-2 in tumor tissue compared to normal mucosa. DISCUSSION: The cytokine profile in colon cancer indicates a strong unspecific inflammatory reaction in the tumor tissue represented by high levels of IL-1 and TNF-alpha. The comparatively low level of IL-2 suggests suppression of a specific immunological reaction, namely Th1-cells. It can be hypothesized that this is a result and/or cause of local immune escape mechanisms. Furthermore, there is an activation of TH2 cells in the carcinomas.

Antisense CD11b integrin inhibits the development of a differentiated monocyte/macrophage phenotype in human leukemia cells.

Macrophage-like development of myeloid leukemia cells which can be induced by agents such as phorbol esters (TPA) is accompanied by integrin expression and cell adhesion. Thus, in differentiating myeloid leukemia cells CD11b is predominantly expressed which can associate with CD18 to form the functional heterodimeric integrin Mac-1. To elucidate the role of cell adhesion during macrophage-like differentiation, we transfected human U937 myeloid leukemia cells with a vector containing the CD11b gene in antisense orientation. Expression of the CD11b antisense gene in stably transfected U937 cells (as-CD11b cells) resulted in an attenuated response to TPA. As-CD11b cells demonstrated poor adhesion to solid substrate upon TPA treatment in contrast to U937 control cells. Constitutive expression of c-myc in as-CD11b transfectants was higher than in control cells and failed to be repressed by TPA treatment. Moreover, unlike control cells, antisense transfectants failed to induce expression of early response genes such as c-jun and the redox factor ref-1 upon TPA stimulation. Consequently, the induction of monocytic differentiation markers such as the activity of alpha-naphthyl acetate esterase, the capacity to reduce nitroblue tetrazolium and the expression of the vimentin gene was much lower in antisense transfectants than in control U937 cells. According to the failure to undergo a monocytic differentiation program, TPA treatment of as-CD11b cells resulted in a progressively increasing amount of apoptotic cells whereas the differentiated population of U937 control cells remained alive. Taken together, these data suggest that the integrin-mediated (particularly CD11b-mediated) adhesion of myeloid leukemia cells in the course of induced monocytic differentiation is crucial for cell attachment, development of a monocytic phenotype and subsequent survival.

The 3alpha-hydroxy-steroid-dehydrogenase-mRNA and -protein are more prevalent in pericentral than in periportal hepatocytes.

BACKGROUND: Under physiological conditions, de-novo synthesis and metabolism of bile acids are confined mainly to the pericentral zone of the liver acinus. In the rat, 3alpha-hydroxy-steroid-dehydrogenase (3alpha-HSD) is the major bile acid-binding protein. At the same time, this protein is involved in the de-novo synthesis and metabolism of bile acids. Because bile acid processing is greater in the pericentral than in the periportal region, we investigated whether 3alpha-HSD is more prevalent in the pericentral than in the periportal area. DESIGN: We determined the 3alpha-HSD-protein and its mRNA in periportal and pericentral rat cells. METHOD: Rat hepatocytes from the periportal or pericentral areas were isolated using the digitonin perfusion technique. For Northern blotting, a labelled 1.3-kb cDNA insert corresponding to the mRNA sequence of 3alpha-HSD was used. For Western blotting, a polyclonal rabbit antiserum against human 3alpha-HSD was used. Blots were quantified by densitometry using phosphoimaging. RESULTS: The amounts of the 3alpha-HSD-protein and its mRNA were significantly greater in the pericentral than in the periportal cells. CONCLUSIONS: The greater occurrence of 3alpha-HSD in pericentral than in periportal hepatocytes is in line with the concept that bile acid synthesis and metabolism take place predominantly in pericentral cells.

The obesity paradox in surgical intensive care patients with peritonitis.

PURPOSE: Although obesity is usually regarded as a risk factor in surgical patients, various observations have revealed a better outcome in the obese. This finding is called the obesity paradox. To which group of patients the paradox applies and even whether it exists at all are matters of controversial discussion. MATERIALS AND METHODS: We retrospectively analyzed 253 consecutive patients with surgical peritonitis and sepsis who needed intensive care for more than 2 days postoperative. Patients were assigned to groups according to body mass index (BMI), and groups were compared with respect to outcome parameters. RESULTS: In the 4 BMI groups--less than 21, 21 to 25, 26 to 30, and more than 30 kg/m(2)--mortality rate at 28 days was 73%, 50%, 42%, and 31%, respectively. The relative risk of death at 28 days in the BMI greater than 30 kg/m(2) group compared to the normal weight group (BMI, 21-25.9 kg/m(2)) was 0.66 (95% confidence interval, 0.28-0.94). However, mortality rate at 5 years was 90%, 70%, 69%, and 75%, respectively. Patients in the lowest BMI range were less likely to be discharged home. Intensive care unit and hospital length of stay was longest in the group of highest BMI, and that group had the best mean survival (386 days for BMI >30 kg/m(2) vs 113 days for BMI <21 kg/m(2)). CONCLUSIONS: The "obesity paradox" may exist in patients with surgical peritonitis. Short-term but not long-term outcomes were improved in the obese. Concerns about obesity as a special risk factor in patients with peritonitis are not warranted according to our findings.

Improved long-term survival after esophagectomy for esophageal cancer: influence of epidemiologic shift and neoadjuvant therapy.

BACKGROUND: The study was done to determine long-term outcomes of surgically treated esophageal cancer and to identify trends in epidemiology, oncological therapy, and oncological prognosis over the last two decades. METHODS: Overall survival in 304 patients undergoing esophagectomy was analyzed. Fifty-three percent had squamous cell carcinoma and 46 % had adenocarcinoma (AC). A total of 161 patients received neoadjuvant chemoradiation, 38 received neoadjuvant chemotherapy, and 105 were treated with surgery alone. RESULTS: Median survival (MS) increased significantly from 18.0 months (1988-1994) to 26.6 months (1995-2001) and to 59.3 months (2002-2011; p < 0.001). The proportion of AC (22 vs 35 vs 65 %; p < 0.001) and the proportion of patients treated with neoadjuvant therapy (neoT; 15.9 vs 85.3 vs 77.8 %; p < 0.001) increased during the treatment period. After neoT, a beneficial outcome with a MS of 45.6 vs. 20.4 months (p = 0.003) was found. Lymph node ratio [LNR; relative risk (RR), 5.4; p < 0.001], response to neoT (RR, 1.6; p < 0.004), and histological subtype (RR, 1.7; p < 0.003) were identified as independent parameters of survival. CONCLUSION: Since 1988, the outcome of surgically resected esophageal cancer strongly improved. Besides tumorbiological factors like histological type and LNR, the outcome is also affected by the increasing use of neoT towards favorable survival rates.

Living-donor kidney transplantation: the Freiburg experience.

BACKGROUND AND AIM: The objective of this study was to determine outcome after living-donor kidney transplantation in a single-center institution in Germany. MATERIALS AND METHODS: From 1976 to May 2005, a total of 298 living-donor kidney transplants were performed at the University of Freiburg. Most recipients (78.8%) were placed on cyclosporine, mycophenolate mofetil, and corticosteroids maintenance immunosuppression. Cox proportional hazard model was applied to analyze predictors for patient and graft survival. Mean follow-up was 5.3 years. RESULTS: According to Kaplan-Meier calculation, 1-, 5-, and 10-year patient survival was 98.6, 92.7, and 86.8%, respectively. Kidney function rate was 95.5, 82.8, and 67.9%, respectively. A 5-year graft function rate continued to increase from 79.5% in patients transplanted before 1996 to 83.6% in patients transplanted thereafter. In a Cox regression model recipient age above 50 years, duration of dialysis above 2 years and preexisting type 1 diabetes mellitus were associated with a decreased patient survival. Graft survival was mostly influenced by the type of immunosuppression and preexisting hypertension of the recipient. CONCLUSIONS: Our results demonstrate that living-donor kidney transplantation is a highly effective therapy for patients with end stage renal failure. Updates in immunosuppression, recipient selection, and operative technique may have contributed to the improved graft survival over the past three decades.

Nonoperative treatment of 15 benign esophageal perforations with self-expandable covered metal stents.

BACKGROUND: Spontaneous or iatrogenic esophageal perforations after endoscopic procedures are potentially life-threatening events with a considerable mortality rate. The aim of this study was to demonstrate that a nonoperative endoscopic treatment with self-expanding metal stents may have a lower morbidity and mortality rate compared with surgical treatment. METHODS: A nonrandomized observational study was conducted with 15 consecutive patients between January 1997 and June 2004. Benign spontaneous and iatrogenic esophageal perforations after endoscopic procedures were treated with self-expandable metal stents. RESULTS: Seven patients (group 1) underwent stent insertion with an average time delay of 45 minutes. In 8 patients (group 2), the median delay was 123 hours. All patients in group 1 had an uneventful recovery and left hospital 5 days (range, 3 to 9) after stent insertion. One patient in group 2 (1 of 8) died of pneumonia after 6 days. In any other cases, perforations healed successfully after stent placement, but the clinical course was generally complicated with sepsis and multiple organ failure. The average hospital stay was 44 days (range, 15 to 70). CONCLUSIONS: Immediate insertion of a self-expandable metal stent enables an excellent outcome with minimal mortality and morbidity without the need for operation. Even in cases of old esophageal perforations, sealing with self-expandable metal stents is still a good option although the clinical course is much less impressive than in early treated perforations.

Prediction of axillary lymph node status of breast cancer patients by tumorbiological factors of the primary tumor.

BACKGROUND AND PURPOSE: The increasing use of systemic adjuvant therapy even in lymph node-negative breast cancer patients and breast cancer screening programs detecting smaller tumors with less probability of metastatic lymph nodes questions the need for routine axillary lymph node dissection. Since morbidity of breast cancer surgery is predominantly related to axillary lymph node dissection, predictive models for lymph node involvement may provide a way to avoid lymph node surgery and its side effects in subgroups of patients. PATIENTS AND METHODS: Using a multivariate logistic regression model, tumorbiological parameters such as expression of estrogen and progesterone receptors, Ki-67, p53, cathepsin D, HER2, S-phase fraction, and ploidy were analyzed regarding their ability to predict axillary lymph node involvement in 655 breast cancer patients. RESULTS: The model correctly predicted axillary lymph node metastases in 58% of the patients by including expression of progesterone receptor, HER2, and Ki-67. In a subgroup of 200 patients predicted to be at extremely high or extremely low risk for axillary lymph node metastases, the accuracy of the prediction was 70%. CONCLUSION: With a model just based on tumorbiological parameters obtained in the primary tumor it is possible to predict axillary lymph node status. By including additional parameters it appears to be feasible to further improve the model in order to avoid axillary lymph node surgery in low-risk women.

Repetitive short-term bile duct obstruction and relief causes reproducible and reversible bile acid regurgitation.

BACKGROUND: Long-term bile duct obstruction causes sinusoidal regurgitation of bile acids, a shift in bile acid metabolism, and alterations of liver histology. In this study we investigated the regurgitation of bile acids during short-term bile duct obstruction and its reversibility and reproducibility. In addition, the biotransformation of taurodeoxycholate and its appearance in bile and perfusate effluent were studied as well as liver histology. METHODS: Rat livers (n = 5) were perfused in vitro with 32 nmol/min/g liver taurodeoxycholate over 85 min with the bile duct being intermittently closed for 30 and 20 min, respectively. RESULTS: Within the first 5 min after bile duct obstruction bile acids started to regurgitate to the perfusate effluent amounting to approximately 15% of hepatic uptake until the end of the perfusion period. After relief of obstruction, bile flow and biliary bile acid excretion showed an overshoot phenomenon and were almost doubled compared to preobstruction. In contrast, sinusoidal bile acid regurgitation declined. The same phenomenon was observed during the second closure/opening cycle of the bile duct. Regurgitated bile acids consisted of significantly more taurodeoxycholate metabolites (approximately 70%) than did biliary bile acids (approximately 30%). Histology of liver parenchyma was preserved. CONCLUSIONS: During repetitive short-term bile duct obstruction bile acid regurgitation is reversible and reproducible. The absence of altered mechanical barriers suggests that specific pathways are involved in the regurgitation process of bile acids.

A butterfly's chemical key to various ant forts: intersection-odour or aggregate-odour multi-host mimicry?

Deception is a crucial yet incompletely understood strategy of social parasites. In central Europe, the Mountain Alcon Blue, Maculinea rebeli, a highly endangered butterfly, parasitises several Myrmica ant species. Caterpillars gain access to host nests probably by faking the ants' odour. We analysed gas chromatography-mass spectrometry data of body surface hydrocarbons of pre-adoption and hibernated larvae of Maculinea rebeli and of their host species Myrmica sabuleti and M. schencki. Data were ordinated by different methods, based on similarities in the relative quantities of compounds between chromatograms. The two Myrmica species exhibit species-specific profiles. The Maculinea rebeli pre-adoption larva has a complex profile that simultaneously contains species-specific substances of the two investigated host species. This evidence leads to the interpretation that, in central Europe, Maculinea rebeli is predisposed for multi-host use by the chemical signature of its pre-adoption larva. The Maculinea rebeli larva clearly does not rely on an "intersection-odour" of compounds common to all host ant species, but synthesises an "aggregate-odour" containing specific compounds of each of the investigated hosts. We term this previously unknown chemical strategy "aggregate-odour multi-host mimicry".