Systemic therapy in metastatic renal cell carcinoma (mRCC): an evidence-based recommendation of the German interdisciplinary RCC guidelines group.

PURPOSE: The treatment landscape in metastatic renal cell carcinoma (mRCC) has evolved dramatically in recent years. Within the German guideline committee for RCC we evaluated current medical treatments and gave recommendations. METHODS: A systematic review of published evidence for medical treatment of mRCC was performed (July 2016-August 2019) to cover the duration from last guideline update in 2016. Evidence was graded according to SIGN ( http://www.sign.ac.uk/pdf/sign50.pdf ). Recommendations were made on the basis of a nominal group work with consensus approach and included patient advocates and shareholder of the German RCC treatment landscape. Each recommendation was graded according to its strength as strong recommendation (A) or recommendation (B). Expert statements were given, where appropriate. RESULTS: Strong first-line recommendations (IA) exist for axitinib + pembrolizumab (all risk categories) and ipilimumab + nivolumab (intermediate or poor risk only). Axitinib + avelumab is a recommended first-line treatment across patients with any risk category (IB). In patients who are not candidates for immune check point inhibitor (ICI) combinations, targeted agents should be offered as an alternative treatment. Subsequent treatment after ICI-based combinations remain ill-defined and no standard of care can be formulated. CONCLUSION: ICI-based combinations are the first-line standard of care and should be considered accordingly. There is an unmet medical need for pivotal studies that define novel standards in patients with failure of ICI-based combinations.

Phosphodiesterase 10A: a novel target for selective inhibition of colon tumor cell growth and ß-catenin-dependent TCF transcriptional activity.

The cyclic nucleotide phosphodiesterase 10A (PDE10) has been mostly studied as a therapeutic target for certain psychiatric and neurological conditions, although a potential role in tumorigenesis has not been reported. Here we show that PDE10 is elevated in human colon tumor cell lines compared with normal colonocytes, as well as in colon tumors from human clinical specimens and intestinal tumors from Apc(Min/+) mice compared with normal intestinal mucosa, respectively. An isozyme and tumor-selective role of PDE10 were evident by the ability of small-molecule inhibitors and small interfering RNA knockdown to suppress colon tumor cell growth with reduced sensitivity of normal colonocytes. Stable knockdown of PDE10 by short hairpin RNA also inhibits colony formation and increases doubling time of colon tumor cells. PDE10 inhibition selectively activates cGMP/cGMP-dependent protein kinase signaling to suppress ß-catenin levels and T-cell factor (TCF) transcriptional activity in colon tumor cells. Conversely, ectopic expression of PDE10 in normal and precancerous colonocytes increases proliferation and activates TCF transcriptional activity. These observations suggest a novel role of PDE10 in colon tumorigenesis and that inhibitors may be useful for the treatment or prevention of colorectal cancer.

The on-line charge breeding program at TRIUMF's Ion Trap For Atomic and Nuclear Science for precision mass measurements.

TRIUMF's Ion Trap for Atomic and Nuclear science (TITAN) constitutes the only high precision mass measurement setup coupled to a rare isotope facility capable of increasing the charge state of short-lived nuclides prior to the actual mass determination in a Penning trap. Recent developments around TITAN's charge breeder, the electron beam ion trap, form the basis for several successful experiments on radioactive isotopes with half-lives as low as 65 ms and in charge states as high as 22+.

[Interdisciplinary management of a large Legionella outbreak in Germany]. / Interdisziplinäres Management eines länderübergreifenden Legionellenausbruchs.

Between December 2009 and the end of January 2010, the largest hitherto known outbreak of Legionella in Germany took place in the cities of Ulm and Neu-Ulm. Of a total of 64 patients involved, 60 patients had to be hospitalized, and 5 patients died from the infection. This event was caused by a wet cooling tower of a large air conditioning system in the city center of Ulm. The search for the source of the Legionella emission was extremely difficult, since these plants are neither notifiable nor subject to authorization in Germany. We report about the search for the source and the measures to control the outbreak. We also discuss communication and coordination during these investigations. Regulatory measures as proposed by the World Health Organization (WHO) and the European Network for Legionellosis (EWGLI) and already implemented in numerous other European countries would be desirable to prevent such outbreaks in the future.

Influence of superovulatory protocols on in vitro production of Nellore (Bos indicus) embryos.

There are indications in the literature that delaying the period between ovarian superestimulation and ovum pick up (OPU) would induce follicles to a condition of initial atresia, which could be beneficial to oocyte development. In this work, we compared three protocols for OPU and in vitro production (IVP) of embryos, in Nellore cattle. Nellore cows (n = 18) were randomly allocated in three groups: Group 1 (OPU), Group 2 [Follicle stimulating hormone (FSH) and OPU] and Group 3 (FSH deprivation and OPU). Three OPUs were performed, and the animals were switched to a different group each time (crossover), in such a way that at the end of the experiment all cows received the 3 protocols. At random stage of the oestrous cycle (D-2), all follicles ≥ 6 mm were aspirated to induce a new follicular wave 2 days afterwards (D0). In Group 1, OPU was performed on D2 and oocytes were processed to IVP. In Group 2, starting on D0, cows were superstimulated (FSH, Folltropin(®), 30 mg administered daily, i.m., during three consecutive days, total dose = 180 mg), and 6 h after the last FSH dose, they received exogenous luteinizing hormone (LH) (12.5 mg, i.m., Lutropin(®), D3). The OPU was performed 6 h after LH administration, i.e. 12 h after the last dose of FSH. Animals in Group 3 received the same treatment as those in Group 2, except that LH was administered 42 h after the last dose of FSH, and OPU occurred 6 h later. Therefore, in this group, follicles were deprived of FSH at 48 h. Both cleavage and blastocyst rates were similar (p > 0.05, anova) among oocytes from Groups 1, 2 and 3, respectively: 77.4% (144/185) and 42.70% (79/185); 75.54% (105/139) and 31.65% (44/139); 63.52% (101/159) and 33.33% (53/159). However, hatched blastocyst rate was higher (p < 0.01) in Group 1 (30.27%, 56/185) when compared with Group 2 (11.51%, 16/139) or 3 (15.72%, 25/159). It is concluded that, contrary to previous work on European breeds (Bos taurus), ovarian superstimulation associated with deprivation of FSH and OPU (Group 3) did not increase IVP of Nellore embryos (Bos indicus). On the contrary, the highest hatched blastocyst rates were observed in oocytes from non-superstimulated cows.

Associations of functional status and depressive symptoms with health-related quality of life in cancer patients.

Associations of functional status (as measured with the Karnofsky Index), depressive symptoms (as assessed with the Beck Depression Inventory), and sociodemographic characteristics with health-related quality of life (HrQoL; measured with the EORTC Quality of Life Questionnaire QLQ-C30) were assessed in 170 recently diagnosed cancer patients. A better functional status (p<0.001) and a lower level of depressive symptoms (p<0.001) were associated with better HrQoL. In addition, an interaction effect of functional status with HrQoL was found (p<0.001), indicating that stronger functional impairments were related to lower HrQoL in patients with low and average levels of depressive symptoms, but not in those with high levels of depressive symptoms. Associations of HrQoL with sociodemographic variables were not significant. It is concluded that functional decline does not additionally impair HrQoL when patients already have elevated levels of depressive symptoms.

[A questionnaire study of the relationship between gender and chronic pain]. / Geschlechtsrolle und Schmerzerleben.

INTRODUCTION: The aim of this study was to assess the relationship between gender role orientation and the prevalence of chronic pain. METHOD: The individual gender role orientation in a sample of 45 chronic pain patients (ICD 10 diagnosis, F 45.4) was compared to gender role orientation in a matched, pain-free control group. Gender role orientation was assessed by questionnaires on the self-attribution of stereotypic gender traits (GEPAQ) and on the extent of agreement with traditional feminine and masculine role norms (MRNS, FRNS). Group differences were compared by multivariate analysis. RESULTS: In accordance with the hypothesis, results confirmed that pain patients showed stronger feminine and weaker masculine role orientations than healthy controls. Pain patients additionally ascribed to themselves more 'feminine' (e.g. worried, nervous) and less 'masculine' (e.g. aggressive, cynical) traits. CONCLUSION: Sociopsychological variables of gender role orientation were related to chronic pain in the groups observed. An integrated model consisting of psychodynamic, sociological, and sociopsychological factors is proposed.

Inhibition of human immunodeficiency virus type 1 replication in vitro in acutely and persistently infected human CD4+ mononuclear cells expressing murine and humanized anti-human immunodeficiency virus type 1 Tat single-chain variable fragment intrabodies.

We have previously reported that a murine anti-Tat sFv intrabody, termed sFvtat1Ck, directed against the proline-rich N-terminal activation domain of HIV-1, is a potent inhibitor of HIV-1 replication [Mhashilkar, A. M., et al. (1995). EMBO J. 14, 1542-1551]. In this study, the protective effect of sFvtat1Ck expression on HIV-1 replication in both acutely infected and persistently infected CD4+ cells was examined. Stably transfected CD4+ SupT1 cells were resistant to HIV-1 infection at high MOI with both the laboratory isolate HxB2 and six syncytium-inducing (SI) primary isolates. Persistently infected U1 cells, which can be induced to increase HIV-1 mRNA synthesis on addition of PMA or TNF-alpha, showed decreased production of HIV-1 in the presence of sFvtat1Ck. In transduced CD4+-selected, CD8+-depleted, and total PMBCs, the sFvtat1Ck-expressing cells showed marked inhibition of HIV-1 replication. The anti-Tat sFv was subsequently humanized by substituting compatible human framework regions that were chosen from a large database of human V(H) and V(L) sequences on the basis of high overall framework matching, similar CDR length, and minimal mismatching of canonical and V(H)/V(L) contact residues. One humanized anti-Tat sFv intrabody, termed sFvhutat2, demonstrated a level of anti-HIV-1 activity that was comparable to the parental murine sFv when transduced PBMCs expressing the murine or humanized sFv intrabodies were challenged with HxB2 and two SI primary isolates. Because Tat is likely to have both direct and indirect effects in the pathogenesis of AIDS through its multiple roles in the HIV-1 life cycle and through its effects on the immune system, the strategy of genetically blocking Tat protein function with a humanized anti-Tat sFv intrabody may prove useful for the treatment of HIV-1 infection and AIDS, particularly when used as an adjuvant gene therapy together with highly active antiretroviral therapies that are currently available.

Sympathetic activation triggers systemic interleukin-10 release in immunodepression induced by brain injury.

The mechanism of immunodepression after brain injury is not yet clear. Here we demonstrate rapid systemic release of the immunoinhibitory cytokine interleukin-10, monocytic deactivation and a high incidence of infection in patients with 'sympathetic storm' due to acute accidental or iatrogenic brain trauma. In vitro studies showed that within minutes catecholamines trigger the secretion of interleukin-10 from unstimulated monocytes through a beta-adrenoreceptor-mediated, cAMP/protein kinase A-dependent pathway. We found that in a rat model of acute brain injury, the beta-receptor antagonist propranolol prevented the increase of interleukin-10 plasma levels. Rapid monocytic interleukin-10 release after sympathetic activation may represent a common pathway for immunodepression induced by stress and injury.

[Treament of morphine-induced constipation with oral naloxone]. / Aufhebung einer Morphin-induzierten Obstipation durch orales Naloxon.

INTRODUCTION: Almost all patients treated with opioids suffer from constipation. Numerous laxatives are used to overcome the problem, but none has yet been found to yield favourable results in all patients. Several studies have attempted to reverse opioid-induced constipation by the use of oral naloxone. Experiments carried out in rats showed that morphine-induced constipation is reduced by oral naloxone without impairment of antinociception [4]. However, evaluation of clinical studies reveals that there is uncertainty about the dosage regimen (the daily dose of naloxone ranged from 0.5% to about 60% that of morphine) and a lack of larger numbers of patients studied. METHODS: Fifteen patients suffering from opioid-induced constipation participated in the present study. Constipation had been present for 5 to 14 days despite the use of laxatives. According to the results obtained in the animal experiments [4], it was originally planned to administer oral naloxone at a dose ratio of 1:1 with respect to morphine on day 1 and 2; reducing it on day 3 and 4 to one-half and then to one-fourth of the initial dose on day 5 and 6. RESULTS: Twelve patients experienced a strong laxative effect with spontaneous bowel evacuation 1 to 4 h after the first intake of oral naloxone. Three patients had no laxative effects even after repeated doses. Eleven of the 15 patients reported an average loss of 10%-15% of analgesia after oral naloxone as measured by visual analogue scales. Increasing the morphine dose by about 15% restored the previous level of analgesia without reappearance of constipation. Eight of the 12 patients having a laxative effect experienced abdominal cramps, and therefore, the total dose of naloxone was reduced on day 2 to 2%-15% of that originally planned; this dose still produced a laxative effect. Four of the 15 patients had a withdrawal syndrome. A single dose of morphine equivalent to their daily morphine intake abolished the symptoms. DISCUSSION: The medical history of the 3 patients in whom naloxone failed to abolish constipation revealed neurological disturbances. Treatment of these patients included the use of neuroleptics, antiemetics, and other drugs. In this context, it should be noted that oral naloxone can be expected to abolish only opioid-induced constipation. In conclusion, it was found that the treatment of opioid-induced constipation by administration of oral naloxone produced positive results. A controlled study will show, whether the side effects can be minimized by reducing the naloxone dose.

Azure B-eosin APAAP staining: a method for simultaneous hematological and immunological cell analysis.

Azure B-eosin APAAP staining allows simultaneous analysis of peripheral blood and bone marrow cells for hematological characteristics and immunological cell marker profiles. A defined sequence of staining procedures maintains characteristic components of the Romanowsky-Giemsa stain whereas cell antigens can be detected immunologically using the alkaline phosphatase-anti-alkaline phosphatase (APAAP) detection system. Antigens are visualized by the staining product of the substrate-naphthol AS GR phosphate and variamine blue salt. The usefulness of the azure B-eosin APAAP method was demonstrated on blood and bone marrow smears of patients with various hematological disorders.

Barriers to the retention of registered and licensed practical nurses in small rural hospitals.

The availability of nursing resources is one of the most critical issues facing health care organizations in the country. The study investigated the potential factors that relate to the desire of registered nurses (RNs) and licensed practical nurses (LPNs) to continue practicing in rural hospitals of North Dakota. All RNs and LPNs who worked in North Dakota hospitals with fewer than 100 beds (490 hospitals) were mailed survey questionnaires. Approximately eight weeks later, responses were received from 291 respondents for an overall return rate of 59 percent. Correlational analyses were used to examine the subjects' responses. A moderate relationship was found among the work-related variables. Overall job satisfaction and performance constraints were the only variables to make significant contributions to the prediction of turnover intention for both RNs and LPNs. Overall job satisfaction accounted for the largest percentage of the variance (R2 = 0.42 and R2 = 0.44) for RNs and LPNs, respectively. Satisfaction with promotion was the only work-related variable to make a significant contribution to the prediction of turnover intention for RNs (R2 = 0.23). Performance constraints, role ambiguity, and shift worked were the only work-related variables contributing to the prediction of turnover for LPNs. These results are discussed in terms of their implications for the management of RNs and LPNs in rural hospitals. Clinical ladders for promotions, the identification of potential performance constraints, and supervisory training are suggested as target areas in which rural hospitals might focus attention for managing turnover in RNs and LPNs.

An exploratory study of the correlates of intent to quit among certified registered nurse anesthetists in North Dakota.

Certified registered nurse anesthetists (CRNAs) provide the majority of anesthesia services in rural hospitals. Some services provided by CRNAs are routine, while others are for emergency conditions. The effect of the current nurse shortage on the potential pool of nurse anesthetists becomes a critical concern when considering the nature of CRNA services in rural areas. This study investigated the potential factors that relate to the desire of CRNAs to continue practicing in rural hospitals of North Dakota. All CRNAs licensed in North Dakota (n = 125) were mailed survey questionnaires. Approximately five weeks later responses were received from 54 respondents for an overall return rate of 43 percent. Correlational analyses were used to examine responses of the subjects. A moderate degree of relationship was found among the work-related variables. The average interscale correlation, calculated using an r to z transformation, for the seven work-related variables was 0.47. Overall, pay and promotion satisfaction exhibited strong (r greater than 0.60) correlations with turnover intentions. Supervisory satisfaction was only moderately (r = -0.33) related to intention to quit. These results are discussed in terms of their implications for the management of CRNAs in rural hospitals. Revised salary schedules, clinical ladders for promotions, supervisory training, and the identification of potential performance constraints are suggested as areas in which rural hospitals should focus attention in an attempt to manage turnover in CRNAs.

Work-related variables and turnover intention among registered nurses.

The hospital continues to be the largest employer of nurses and the institution most strained by the nursing shortage. In an era when nurses are more frequently opting to work in alternate settings, it is particularly important for the acute care institution to know what factors influence nurse turnover. Turnover intention, as measured by Pooyan, Eberhardt, and Szigeti, addresses this critical factor.

[The effect of continuous arteriovenous hemofiltration on the pharmacokinetics of azlocillin in anuric patients]. / Der Einfluss der kontinuierlichen arteriovenösen Hämofiltration auf die Pharmakokinetik von Azlocillin bei anurischen Patienten.

The influence of continuous arteriovenous hemofiltration on the pharmacokinetics of azlocillin was examined in eight anuric intensive care patients, each of whom received a short infusion of 5.0 g azlocillin. Azlocillin concentrations in blood were measured simultaneously in the afferent and efferent loops of the amicon Dia 20 hemofilter and in the ultrafiltrate by means of an agar diffusion technique. Pharmacokinetic parameters were calculated by a computer program based on a two compartment model. We found that the elimination half-life of azlocillin ranged between 218.8 and 342.8 min, a result comparable to those of other investigators, who found similar elimination half-lives in anuric patients. During an observation period of 270 min, only 0.2-1.1% of the total dose of azlocillin was eliminated by way of the hemofilter. Apparently, continuous arteriovenous hemofiltration has no clinically relevant implications for the dosage or the dosage intervals of this antibiotic. On the other hand, azlocillin was taken up by the amicon Dia 20 hemofilter during the infusion. After the infusion was stopped the filter released azlocillin to blood and ultrafiltrate. The ratio of concentration in ultrafiltrate to plasma concentration in the afferent loop of the hemofilter was higher for about 45 min during the elimination phase than during the infusion. The volume of distribution was much larger (mean 28.5 l) than that found by other investigators. Therefore, the amicon-Dia 20 hemofilter seems to function as an additional distribution space.(ABSTRACT TRUNCATED AT 250 WORDS)

Two cases of anesthesia-free extracorporeal shock wave lithotripsy in stone-bearing pelvic kidneys.

We report 2 cases of urolithiasis in pelvic kidneys and discuss the therapy of difficult stone locations with extracorporeal shock wave lithotripsy (ESWL) alone using new techniques of positioning (prone and upright sitting position) and the modified Dornier HM3 lithotriptor for anesthesia-free ESWL.

Myocardial protection by 2-mercaptopropionylglycine during global ischemia in dogs.

The hypothesis was tested, if the addition of 2-mercaptopropionylglycine (MPG, Thiola) to a crystalloid cardioplegic solution provides superior myocardial protection as assessed by biochemical and morphological parameters. Five mongrel dogs underwent a 60-min hypothermic cardioplegic arrest (untreated group). In six dogs, MPG (1.5 mmol/l) was added to the crystalloid cardioplegic solution (treated group). Thereafter a reperfusion phase of 60 min was established. At the end of the reperfusion phase samples for mitochondrial respiration parameters and for mitochondrial energization were collected. Samples for ultrastructure and negative staining were taken at the end of ischemia, and after 15, 30 and 60 min of reperfusion. Hearts which were treated with the MPG-enriched cardioplegic solution showed a better ultrastructure (1 (1/1) vs 2 (2/2), p less than 0.001) and superior preservation of the mitochondrial ATPases (2.4 +/- 2.0 versus 8.4 +/- 2.7, p less than 0.05) as compared to the untreated group at the end of ischemia. At the end of reperfusion, mitochondrial respiration, and energization of the mitochondria was improved significantly with the addition of MPG as compared to the untreated group.

Subcapsular renal transplantation of neurogenic tumors and tumor spheroids. A comparative study of RN6 and RG2 tumor clones after syngeneic and allogeneic transplantation.

The subcapsular renal transplantation tumor model was explored to standardize the growth of rat RN6 neurinoma and RG2 glioma nitrosourea-induced clonal cell lines in syngeneic and allogeneic systems. Growth of RN6 and RG2 tumor spheroids was compared with that of solid subcutaneous tumor pieces transplanted under the renal capsule. Two morphometrical methods were applied to evaluate growth rates. Tumor specimens were examined histologically with regard to their morphology, extent of immune reactions, and development of tumor necroses. The take rate was 98%. In the syngeneic system linear progressive tumor growth was found, while in preirradiated allogeneic rats this was only the case up to 21 to 25 days post transplantation (p.t.). Strong rejection reactions in the allogeneic RN6 tumors were noted from 4 to 7 days p.t. resulting in total tumor rejection after 10 to 14 days. Both kinds of tumors, especially in the first days of growth, were characterized by strong desmoplastic reaction with rich reticulin fiber formation. However, after 10 days, in the center of RG2 subcapsular renal tumors (SRT) this kind of reaction was found only in the vicinity of tumor vessels, while RN6 SRT demonstrated reticulin fibers around tumor cells in all cases studied. The transplantation experiments revealed that the malignant RN6 and RG2 spheroids represent a suitable tool to study three-dimensional early tumor growth in both in vivo and in vitro cultures. The model of spheroid transplantation under the renal capsule is simple to handle and well reproducible. Compared with subcutaneous tumors the SRT model has advantages in early stages of tumor growth because the tumors are clearly visible grossly and can be easily submitted to adequate morphometry, indicating that this model may be suitable for experimental chemotherapy and radiotherapy studies.